TW202542157A - Polycyclic derivative inhibitor, preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to a polycyclic derivative inhibitor, preparation method therefor and use thereof. In particular, the present invention relates to the compound represented by general formula (I’), a preparation method therefor, a pharmaceutical composition containing the compound, and a use thereof as a kinase inhibitor for the treatment of autoimmune diseases, wherein the substituents in the formula (I’) are the same as those in the description in definition.

Description

Polycyclic derivative inhibitors, their preparation methods and applications

This invention belongs to the field of drug synthesis, specifically relating to a polycyclic derivative inhibitor, its preparation method, and its application.

KIT (CD117), encoded by the c-Kit proto-oncogene, is a Type III receptor tyrosine kinase. Structurally, it mainly includes an extracellular domain similar to that of five immunoglobulins, a transmembrane domain, and an intracellular kinase domain. KIT is expressed at high levels in immune cells, hematopoietic stem cells, germ cells, and melanocytes. When SCF binds to KIT on the cell surface, it activates KIT phosphorylation, promoting the activation of downstream signaling pathways, including MAPK, JAK-STAT, and PI3K, thereby promoting their proliferation, survival, and function. Furthermore, while other immune cells may lose KIT during differentiation, mast cell differentiation, survival, and activation all depend on KIT expression. Inhibiting the KIT pathway may simultaneously inhibit mast cell degranulation and proliferation.

Genetic models in mice, in vitro or in vitro human mast cells, human skin tissue, and human clinical experiments have demonstrated that mast cells play a key role in inflammation and urticaria. Targeting mast cells has become one of the important treatment methods for this type of disease. KIT inhibitors hold promise for treating urticaria patients who do not respond well to existing therapies.

Currently available clinical drug introductions:

Celldex's wild-type KIT monoclonal antibody CDX-0159 (Barzolvolimab) is in Phase II clinical trials for urticaria. Preliminary clinical results indicate that CDX-159 has good efficacy and tolerability in urticaria patients, with minimal hematologic side effects and reversible reproductive side effects. Other indications, including eosinophilic esophagitis and pruritus nodosa, have entered Phase I clinical trials. Third Harmonic's KIT inhibitor THB001 entered Phase 1b of urticaria treatment but was terminated in December 2022 due to hepatotoxicity. The next-generation inhibitor, THB335, is expected to enter the IND phase and initiate clinical trials in the first half of 2024.

Other small molecule inhibitors of KIT include BLU-808 introduced by Blueprint Medicines and MOD-B developed by PeptiDream/Modulus, both of which are in the early preclinical stage.

Currently published patent applications for KIT inhibitors include: WO2013033070 A1, WO2013033167 A1, WO2013033116 A1, etc.

KIT inhibitors have promising applications in the pharmaceutical industry. Firstly, they offer a safer and more effective treatment for recurrent, refractory urticaria patients who respond poorly to existing therapies. Secondly, KIT inhibitors inhibit SCF-KIT binding, blocking multiple downstream signaling pathways and thus exhausting mast cells, theoretically expanding their application to other mast cell-related indications. Thirdly, as small-molecule inhibitors, KIT inhibitors offer advantages over large-molecule drugs such as oral administration and better patient compliance.

The purpose of this invention is to provide a compound of formula (I') or a pharmaceutically acceptable salt thereof: Wherein: R f is selected from substituted or unsubstituted C6 - C14 aryl, substituted or unsubstituted 5-14 heteroaryl, substituted or unsubstituted 4-14 heterocyclic, substituted or unsubstituted C3 - C14 cycloalkyl, , The substitution mentioned therein refers to substitution by 1-4 R r groups; the ring C is selected from 5-10 membered heterocyclic groups, C <sub>5 -C 10  cycloalkyl groups, C <sub>6 -C 10  aryl groups, or 5-10 membered heterocyclic groups; the ring D is selected from 5-10 membered heterocyclic groups, C<sub> 5 -C 10  cycloalkyl groups, C<sub> 6 -C 10  aryl groups, or 5-10 membered heterocyclic groups; the ring E is selected from phenyl, 5-6 membered heterocyclic groups, 5-10 membered heterocyclic groups, or C<sub> 5 -C 10  cycloalkyl groups; R c , Rd , and Re are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, substituted or unsubstituted C <sub>1 -C 6  alkyl groups, substituted or unsubstituted C 2 -C alkyl groups. 6- Alkenyl, substituted or unsubstituted C2 - C6 alkoxy, substituted or unsubstituted C1 - C6 halogenated alkyl, substituted or unsubstituted C1 - C6 halogenated alkoxy, substituted or unsubstituted C1 -C6 deuterated alkyl, substituted or unsubstituted C1 -C6 deuterated alkoxy, substituted or unsubstituted C1 - C6 hydroxyl, substituted or unsubstituted C3 - C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl , substituted or unsubstituted 5-10 membered heteroaryl, C1 - C6 alkylene- R11 , -( CH2 ) pOR11 , ( CH2 ) pNR11R12 , ( CH2 ) ( CH2 ) pCOOR13 , ( CH2 ) pCOOR11 , ( CH2 ) pCONR11R12 , ( CH2 ) pNR11COOR13 , (CH2) pNR11COOR12 , (CH2)pSOR13, (CH2)pSONR11R12, (CH2)pSO2R13 or (CH2 ) pSO2NR11R12 ; wherein , the substitution refers to substitution by 1-4 R111 ; R11 , R12 and R13 are each independently selected from hydrogen, COOC1 - C6 alkyl , SO2C1 - C6 alkyl , substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 -C6 alkyl. 6- alkenyl, substituted or unsubstituted C2 - C6 ynyl, substituted or unsubstituted C1 - C6 alkoxy, substituted or unsubstituted C1 - C6 halogenated alkyl, substituted or unsubstituted C1 - C6 halogenated alkoxy, substituted or unsubstituted C1 - C6 deuterated alkyl, substituted or unsubstituted C1 - C6 deuterated alkoxy, substituted or unsubstituted C1 -C6 hydroxyl, substituted or unsubstituted C3 - C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl; wherein, the substitution refers to substitution by 1-4 R1111 ; R111 and R 1111 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1 -C6 alkyl, C2 - C6 alkenyl, C2- C6 alkynyl, C1-C6 alkoxy , C3 -C10 cycloalkyl, 4-10 heterocyclic, C6- C10 aryl, 5-10 heteroaryl, C1 -C6 halogenated alkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1 -C6 hydroxyl, C2 -C6 halogenated alkenyl, C2- C6 halogenated alkynyl, C1 - C6 halogenated alkoxy, C3-C6 halogenated alkoxy, C3-C6 halogenated alkyl, C2 - C6 halogenated alkenyl, C2 - C6 halogenated alkoxy, C3 -C6 halogenated alkyl, C2- C6 halogenated alkenyl, C3- C6 halogenated alkyl, C2 -C6 halogenated alkoxy, C3 -C6 halogenated alkyl, C2 ...2-C6 halogenated alkyl, C2- C6 halogenated alkyl, C2-C6 halogenated alkyl, C2 - C6 halogenated alkyl, C2- C6 halogen 10- membered halogenated cycloalkyl, 4-10-membered halogenated heterocyclic, C6 - C10 halogenated aryl, or 5-10-membered halogenated heteroaryl; R r is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2 - C6 alkoxy, substituted or unsubstituted C1-C6 halogenated alkyl , substituted or unsubstituted C1 - C6 halogenated alkoxy, substituted or unsubstituted C1 -C6 deuterated alkyl, substituted or unsubstituted C1 - C6 deuterated alkoxy, substituted or unsubstituted C1 - C 6 -Hydroalkyl, substituted or unsubstituted C3 - C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, C1 - C6 alkylene- R21 , ( CH2 ) q OR21 , ( CH2 ) q NR21 R22 , ( CH2 ) q COR23, ( CH2 ) q COOR21 , ( CH2 ) q CONR21 R22 , ( CH2 ) q NR21 COR23 , ( CH2 ) q NR21 COOR22 , ( CH2 ) q SOR23 , ( CH2 ) q SONR21 R22 ( CH₂ ) qSO₂R₁ , ( CH₂ ) qSO₂NR₁R₂ ; wherein the substitution refers to substitution by 1-4 R⁻¹fff ; R₁ , R₂ , and R₂₃ are each independently selected from: hydrogen, COOC₁ - C₆ alkyl, SO₂C₁ - C₆ alkyl, substituted or unsubstituted C₁ - C₆ alkyl, substituted or unsubstituted C₂ - C₆ alkenyl, substituted or unsubstituted C₁ - C₆ alkoxy, substituted or unsubstituted C₁ - C₆ halogenated alkyl, substituted or unsubstituted C₁ -C₆ halogenated alkoxy, substituted or unsubstituted C₁ - C₆ deuterated alkyl, substituted or unsubstituted C₁ - C₆ deuterated alkoxy ... 6 -Hydroalkyl, substituted or unsubstituted C3 - C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein the substitution refers to substitution by 1-4 R ffff ; R fff and R ffff are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1 - C6 alkyl, C2 -C6 alkenyl, C2 - C6 alkynyl, C1 - C6 alkoxy, C3 - C10 cycloalkyl, 4-10 membered heterocyclic, C6 - C10 aryl, 5-10 membered heteroaryl, C1 - C6 halogenated alkyl, C1 -C 6- Deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyalkyl, C2-C6 halogenated alkenyl, C2 - C6 halogenated alkynyl, C1 - C6 halogenated alkoxy, C3 - C10 halogenated cycloalkyl, 4-10-membered halogenated heterocyclic, C6 - C10 halogenated aryl , or 5-10-membered halogenated heteroaryl; ring A is selected from C6 - C10 aryl, 5-10-membered heteroaryl, 4-10-membered heterocyclic, C3 - C10 cycloalkyl, phenyl-5-6-membered heterocyclic, phenyl- C5 -C 6 -cycloalkyl, 5-6-membered heteroaryl and 5-6-membered heterocyclic, 5-6-membered heteroaryl and C5 - C6 cycloalkyl; Ra is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, NHC1 - C6 alkyl, N( C1 - C6 alkyl) 2 , substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2 - C6 alkoxy, substituted or unsubstituted C1 - C6 halogenated alkyl, substituted or unsubstituted C1 - C6 halogenated alkoxy, substituted or unsubstituted C1 - C6 deuterated alkyl, substituted or unsubstituted C1 - C6 cycloalkyl. 6 -Deuterated alkoxy, substituted or unsubstituted C1 - C6 hydroxyl, substituted or unsubstituted C3 - C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl, wherein the substitution refers to substitution by 1-4 groups selected from the following groups: hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, oxo, thio, NH2, NHC1-C6 alkyl, N( C1 - C6 alkyl) 2 , C1 - C6 alkyl, C1 -C6 alkoxy, C1-C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C1 -C6 deuterated alkyl, C1 - C6 alkyl, C1 -C6 alkyl, C1 -C6 alkyl -C6 alkoxy, C1 - C6 halogenated alkyl, C1 -C6 alkyl ... 6- Deuterated alkoxy or C1 - C6 hydroxyl; L1 is selected from the following: ( CH2 ) m1 , C2 - C4 alkenyl, C2- C4 alkyneyl, ( CH2 )m2-O-( CH2 )m3, (CH2) m2 -S-( CH2 )m3, ( CH2 ) m2 -NRh-(CH2) m3 , ( CH2 ) m2 -CO-(CH2)m3, ( CH2 ) m2 - COO- ( CH2 ) m3 , ( CH2 ) m2 -CONRh-( CH2 ) m3 , ( CH2 )m2-NRhCOO-(CH2) m3 , ( CH2 ) m2 -RlNCONRh-(CH2)m3, ( CH2 ) m2 - RlNCONRh- ( CH2 ) m3 , ( CH2 ) m2 - RlNCONRh- (CH2)m3, ( CH2 )m2-RlNCONRh-(CH2) m3 , ( CH2 ) m2 - RlNCONRh- (CH2) m3 , ( CH2 ) m2 -C6- H2O ... (CH2) m2 - SO2- ( CH2 ) m3 , ( CH2 ) m2 - SO2NRh- ( CH2 ) m3 , (CH2) m2 - RlNSO2NRh- ( CH2 ) m3 , ( CH2 ) m2 - SO- ( CH2 ) m3 , ( CH2 ) m2 - SONRh- ( CH2 ) m3 , (CH2)m2 - RlNSONRh- ( CH2 ) m3 or ( CH2 ) m2 - RlNC (= NH ) NRh- ( CH2 ) m3 ; ring B is selected from C6 - C10 aryl, 5-10 heteroaryl, 4-10 heterocyclic, C3 - C10 cycloalkyl, phenyl -5-6 heterocyclic, phenyl- C5 -C 6 cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocyclic or 5-6 membered heteroaryl and C 5 -C 6 cycloalkyl; R b are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 ynyl, substituted or unsubstituted C 1 -C 6 halogenated alkyl, substituted or unsubstituted C 1 -C 6 halogenated alkoxy, substituted or unsubstituted C 1 -C 6 deuterated alkyl, substituted or unsubstituted C 1 -C 6 deuterated alkoxy, substituted or unsubstituted C 1 -C 6 hydroxyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 10 -cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, ( CH2 ) k OR B-1 , ( CH2 ) k NR B-1 RB -2 , ( CH2 ) k COR B-3 , =NHOR B-1 , =CR B-1 RB -2 , ( CH2 ) k C(=NH)OR B-1 , ( CH2 ) k CONR B-1 RB -2 , ( CH2 ) k NR B-1 COR B-3 , ( CH2 ) k COOR B-3 , ( CH2 ) k NR B-1 COOR B-3 , ( CH2 ) k C(=NH)NR B-1 RB -2 , ( CH2 ) k NR B-1 C(=NH) RB-3 , ( CH2 ) kSORB -1 , ( CH2 ) kSONRB -1RB -2 , ( CH2 ) kNRB - 1SORB-3, (CH2)kSO2RB- 1 , ( CH2 ) kSO2NRB - 1RB- 2 or ( CH2 ) kNRB - 1SO2RB -3 ; wherein the substitution refers to substitution by 1-4 Rbb ; Rbb is selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, oxo, thio, C1-C6 alkyl, C1 - C6 alkoxy, C2 -C6 alkenyl, C2- C6 alkynyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 deuterated alkoxy, C1-C6 deuterated alkyl ... 6- Hydroalkyl, C3 - C10 Cycloalkyl, 4-10 Membered Heterocyclic, C6 - C10 Aryl, 5-10 Membered Heterocyclic, C1 - C6 Halogenated Alkyl, C1 - C6 Halogenated Alkoxy, C3 - C10 Halogenated Cycloalkyl, 4-10 Membered Halogenated Heterocyclic, C6 - C10 Halogenated Aryl, 5-10 Membered Halogenated Heterocyclic, ( CH2 ) j OR b-1 , ( CH2 ) j NR b-1 R b-2 , ( CH2 ) j COR b-3 , =NHOR b-1 , =CR b-1 R b-2 , ( CH2 ) j C(=NH)OR b-1 , ( CH2 ) j CONR b-1 R b-2 、(CH 2 ) j NR b-1 COR b-3 、(CH 2 ) j NR b-1 COOR b-3 、(CH 2 ) j COOR b-3 、(CH 2 ) j C(=NH)NR b-1 R b-2 、(CH 2 ) j NR b-1 C(=NH)R b-3 、(CH 2 ) j SOR b-1 、(CH 2 ) j SONR b-1 R b-2 、(CH 2 ) j NR b-1 SOR b-3 、(CH 2 ) j SO 2 R b-1 、(CH 2 ) j SO 2 NR b-1 R b-2 or (CH 2 ) j NR b-1 SO 2 R b-3 、 wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6- alkynyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyalkyl, C3 - C10 cycloalkyl, 4-10 membered heterocyclic, C6 - C10 aryl, 5-10 membered heteroaryl may be further substituted by 1-4 R bbb ; R bbb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, hydroxyl, oxo, thio, C1 - C6 alkyl, C1 - C6 alkyl, C1 - C6 alkoxy, C2 - C6 alkenyl, C2-C6 alkynyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyalkyl, C3 - C 10- membered cycloalkyl, 4-10-membered heterocyclic, C6 - C10 aryl, 5-10-membered heterocyclic, C1 - C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C3 - C10 halogenated cycloalkyl, 4-10-membered heterocyclic, C6 - C10 halogenated aryl, or 5-10-membered heterocyclic; RB -1 , RB -2 , RB -3 , Rb -1 , Rb -2 , and Rb -3 are each independently selected from H, COOC, C1 - C6 alkyl, SO2 , C1 - C6 alkyl, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2- C6 alkenyl. 6- alkynyl, substituted or unsubstituted C1 - C6 halogenated alkyl, substituted or unsubstituted C1 - C6 halogenated alkoxy, substituted or unsubstituted C1 - C6 deuterated alkyl, substituted or unsubstituted C1 - C6 deuterated alkoxy, substituted or unsubstituted C1 -C6 hydroxyl, substituted or unsubstituted C3 - C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10 membered heterocyclic, C1 - C6 halogenated alkyl, C3 - C10 halogenated cycloalkyl, 4-10 membered halogenated heterocyclic, C6 -C 10 -Halogenated aryl, 5-10-membered halogenated heteroaryl; wherein the substitution refers to substitution by 1-4 R bbbb ; R bbbb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, hydroxyl, oxo, thio, C1 - C6 alkyl, C1 - C6 alkyl, C1 - C6 alkoxy, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C10 cycloalkyl, 4-10-membered heterocycloyl, C6 - C10 aryl, 5-10-membered heteroaryl, C1 - C6 halogenated alkyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyl, C3 -C 10- membered halogenated cycloalkyl, 4-10-membered halogenated heterocyclic, C6 - C10 halogenated aryl, or 5-10-membered halogenated heteroaryl; the H in the above CH2 may be optionally substituted with a substituent selected from the following group: hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, oxo, thio , NH2, NHC1 - C6 alkyl, N( C1 - C6 alkyl) 2 , C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C2 - C6 alkenyl, C2 - C6 alkynyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 -C 6 -Hydroalkyl; Rh and Rl are each independently selected from hydrogen, deuterium, halogen, C1 -C6 alkyl, C2 - C6 alkenyl, C2- C6 alkoxy, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclic, C6 - C10 aryl, 5-10 membered heteroaryl, C1 - C6 halogenated alkyl, C2-C6 halogenated alkenyl, C2 - C6 halogenated alkynyl, C1-C6 halogenated alkoxy, C3- C10 hydroxyalkyl, 4-10 membered heterocyclic, C6 - C10 aryl, 5-10 membered heteroaryl, C1 - C6 halogenated alkyl, C2 - C6 halogenated alkenyl, C2 - C6 halogenated alkoxy, C3-C10 hydroxyalkyl, C2 ... 10- membered halogenated cycloalkyl, 4-10-membered halogenated heterocyclic, C6 - C10 halogenated aryl or 5-10-membered halogenated heteroaryl; m1, m2 and m3 are each independently selected from 0, 1, 2, 3, 4, 5, 6; x is selected from 0, 1, 2, 3, 4, 5, 6; y is selected from 0, 1, 2, 3, 4, 5, 6; p, q, j, k, z, e and f are each independently selected from 0, 1, 2, 3, 4, 5, 6.

In some embodiments of the present invention, when ring A is phenyl, _Rf is either unsubstituted or non-substituted. .

In certain embodiments of the present invention, _Rf is selected from substituted or unsubstituted _C6 - _C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-12 membered heterocyclic, or substituted or unsubstituted _C3 - _C12 cycloalkyl. Preferably, _Rf is selected from substituted or unsubstituted _C6 - _C10 aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 8-10 membered heteroaryl, substituted or unsubstituted 5-12 membered heterocyclic, or substituted or unsubstituted _C3 - _C12 cycloalkyl. Preferably, _Rf is selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 9-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heterocyclic, or substituted or unsubstituted C5 _-C12 cycloalkyl. -C ₁₀ cycloalkyl, more preferably, _Rf is selected from substituted or unsubstituted 9-10 membered heteroaryl containing 1, 2, 3, 4, 5 or 6 N atoms, wherein the substitution means substitution by 1-4 _Rr , and _Rr is defined as above.

In certain embodiments of the present invention, R _{_r} is selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 halogenated alkyl, _C1 - _C6 halogenated alkoxy, C1-C6 deuterated alkyl, _C1 - _C6 deuterated alkoxy, _C1 - _C6 hydroxyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, _5-6 membered heteroaryl, C1- _C6 alkylene-R₂₁, (CH_₂)OR_₂₁, (CH_₂)NR_²¹R_²², (CH _₂)COR ^₂₃ , (CH _₂)COOR_²¹, (CH_₂)CONR₂₁ R_²¹ ²² , ( _CH2 ) ^NR21COR23 , (CH2) ^NR21COOR22 , ( _CH2 ) ^SOR23 , ( _CH2 ) ^SONR21R22 , ( _CH2 ) ^SO2R21 , ( _{CH2 ) SO2NR21R22} , ^OR21 , ^NR21R22 _, ^{COR23 , COOR21 , CONR21R22, NR21COR23, NR21COOR22, SOR23 , SONR21R22 , SO2R21 , SO2NR21R22} _{, wherein the C1} ^{- C6} _{alkyl ,} ^{C1 - C6} alkoxy _, ^{C1 - C6} _halogenated ^alkyl _, ^C1 -C ₆ halogenated alkoxy, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ deuterated alkoxy, C ₁ -C ₆ hydroxyl, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, optionally further replaced by deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkoxy, C _{3 -} C ₆ cycloalkyl, _4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ deuterated alkoxy, C ₁ -C One or more of the following: ₆ -hydroxyl, _C2 - _C6 halogenated alkenyl, _C2 - _C6 halogenated alkynyl, _C1 - _C6 halogenated alkoxy, _C3 - _C6 halogenated cycloalkyl, 4-6-membered halogenated heterocyclic, halogenated phenyl, or 5-6-halogenated heteroaryl.

In certain embodiments of the present invention, R _{_r} is selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 halogenated alkyl, _C1 - _C6 halogenated alkoxy, C1-C6 deuterated alkyl, _C1 - _C6 deuterated alkoxy, _C1 - _C6 hydroxyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, _5-6 membered heteroaryl, C1- _C6 alkylene-R₂₁, (CH_₂)OR_₂₁, (CH_₂)NR_²¹R_²², (CH _₂)COR ^₂₃ , (CH _₂)COOR_²¹, (CH_₂)CONR₂₁ R_²¹ ²² , ( _CH2 )NR ²¹ COR ²³ , ( _CH2 )NR ²¹ COOR ²² , ( _CH2 )SOR ²³ , ( _CH2 )SONR ²¹ R ²² , ( _CH2 )SO ₂ R ²¹ , ( _CH2 )SO _2NR ²¹ R ²² ; wherein, the _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 halogenated alkyl, _C1 - _C6 halogenated alkoxy, _C1 -C6 deuterated alkyl, _C1 - _C6 deuterated alkoxy, _{C1 -C6 hydroxyl} , _C3 -C ₆ -cycloalkyl, 4-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl can optionally be further replaced by deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, _C1 -C6 alkyl, C2- _C6 alkenyl, _C2 - _C6 alkoxy, C3-C6 cycloalkyl, 4-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl, C1-C6 halogenated alkyl, _C1 - _C6 deuterated alkyl, _C1 - _C6 deuterated alkoxy, C1- _{C6 hydroxyalkyl, C2-C6} halogenated alkenyl, C2- _C6 halogenated alkynyl, _C1 - _C6 halogenated alkoxy, C3-C6 cycloalkyl, 4-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl, _C1 -C6 halogenated alkyl, _C1 - _C6 halogenated alkoxy, C3-C6 cycloalkyl, _4-6- membered heterocyclic, phenyl, _5-6- membered heteroaryl, _C1 -C6 halogenated alkyl, C2- _C6 halogenated alkenyl, C2-C6 halogenated alkoxy, C3 _-C6 cycloalkyl, 4-6-membered heterocyclic, _{4-6 -} membered heterocyclic, _4-6 -membered heterocyclic, _5-6- membered heteroaryl, _5-6 -membered heterocyclic ... One or more of the following substitutions: _6- halogenated cycloalkyl, 4-6-membered halogenated heterocyclic, halogenated phenyl, or 5-6-halogenated heteroaryl.

In certain embodiments of the present invention, R _{_r} is selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, _C1 - _C3 alkyl, _C1 - _C3 alkoxy, _C1 - _C3 halogenated alkyl, _C1 - _C3 halogenated alkoxy, C1-C3 deuterated alkyl, _C1 - _C3 deuterated alkoxy, _C1 - _C3 hydroxyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, _5-6 membered heteroaryl, C1- _C3 alkylene-R₂₁, (CH_₂)OR_₂₁, (CH_₂)NR_²¹R_²², (CH _₂)COR ^₂₃ , (CH _₂)COOR_²¹, (CH_₂)CONR₂₁ R_²¹ ²² , ( _CH2 )NR ²¹ COR ²³ , ( _CH2 )NR ²¹ COOR ²² , ( _CH2 )SOR ²³ , ( _CH2 )SONR ²¹ R ²² , ( _CH2 )SO ₂ R ²¹ , ( _CH2 )SO _2NR ²¹ R ²² ; wherein, the _C1 - _C3 alkyl, _C1 - _C3 alkoxy, _C1 - _C3 halogenated alkyl, _C1 - _C3 halogenated alkoxy, _C1 -C3 deuterated alkyl, _C1 - _C3 deuterated alkoxy, _{C1 -C3 hydroxyl} , _C3 -C _{The 6-} cycloalkyl, 4-6-membered heterocycloyl, phenyl, and 5-6-membered heteroaryl groups may optionally be further substituted by one or more of deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 halogenated alkyl, _C1 - _C6 deuterated alkyl, _C1 - _C6 deuterated alkoxy, _C1 - _C6 hydroxyl, and _C1 - _C6 halogenated alkoxy.

In some embodiments of this invention, Rf is Wherein: ring C is selected from phenyl, naphthyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl; or ring D is selected from 5-6 membered heterocyclic or C5-C6 cycloalkyl; preferably, ring C is selected from phenyl, naphthyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, indolyl, pyrrolopyridinyl, imidazoolopyridinyl, imidazoolopyrimidinyl, triazolopyrimidinyl, triazolopyridinyl; preferably, ring D is a 5-6 membered heterocyclic group containing 1, 2 or 3 N atoms; Further optimization , , , , , , , The preferred location is , , , Wherein, Rc1 , Rc2 , and Rc3 are defined as Rc , and Rd1 , Rd2 , and Rd3 are defined as Rd ; preferably, Rc1 , Rc2 , and Rc3 are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2 - C6 alkoxy, substituted or unsubstituted C1 - C6 halogenated alkyl, substituted or unsubstituted C1 - C6 halogenated alkoxy, substituted or unsubstituted C1 - C6 deuterated alkyl, substituted or unsubstituted C1 - C6 deuter ... 6 -hydroxyl, substituted or unsubstituted C3 - C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, C1 - C6 alkylene- Rc11 , ORc11 , NRc11 Rc12 , CORc13 , CONRc11 Rc12 , NRc11 CORc13, NRc11 COORc12 , SORc13 , SONRc11 Rc12 , SO2 Rc13 , SO2 NRc11 Rc12 ; wherein , the substitution mentioned in Rc1 , Rc2 and Rc3 refers to substitution by 1-4 Rcc ; Rc11 , Rc12 and R c13 is independently selected from hydrogen, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2 - C6 alkynyl, substituted or unsubstituted C1 - C6 alkoxy, substituted or unsubstituted C1 - C6 halogenated alkyl, substituted or unsubstituted C1 - C6 halogenated alkoxy, substituted or unsubstituted C1 - C6 deuterated alkyl, substituted or unsubstituted C1 - C6 deuterated alkoxy, substituted or unsubstituted C1 - C6 hydroxyl, substituted or unsubstituted C3 - C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein, Rc11 , Rc12 and R In C13, substitution refers to substitution by 1-4 R ccc groups; R d1 , R d2 , and R d3  are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, substituted or unsubstituted C  1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkoxy, substituted or unsubstituted C 1 -C 6  halogenated alkyl, substituted or unsubstituted C 1 -C 6  halogenated alkoxy, substituted or unsubstituted C 1 -C 6  deuterated alkyl, substituted or unsubstituted C 1 -C 6  deuterated alkoxy, substituted or unsubstituted C 1 -C 6  hydroxyl, substituted or unsubstituted C 3 -C6 10 -cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, C1 - C6 alkylene- Rd11 , ORd11 , NRd11 Rd12 , CORd13 , CONRd11 Rd12 , NRd11 CORd13 , NRd11 COORd12, SORd13 , SONRd11 Rd12 , SO2 Rd13 , SO2 NRd11 Rd12 ; wherein, the substitution mentioned in Rd1 , Rd2 , and Rd3 refers to substitution by 1-4 Rdd , R Each of the following groups (dd) is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkoxy, C1- C6 deuterated alkyl, C1 -C6 deuterated alkoxy, C1 -C6 hydroxyl, C3 - C10 cycloalkyl, 4-10 heterocyclic, C6- C10 aryl, 5-10 heteroaryl, C1 -C6 halogenated alkyl, C2-C6 halogenated alkenyl, C2 -C6 halogenated alkynyl, C1-C6 halogenated alkoxy, C3 - C10 cycloalkyl, 4-10 heterocyclic, C6-C10 aryl, 5-10 heteroaryl, C1 - C6 halogenated alkyl, C2-C6 halogenated alkenyl, C2 - C6 halogenated alkoxy, C3-C10 cycloalkyl, C2- C6 halogenated alkenyl, C2 -C6 halogenated alkenyl, C3- C10 cycloalkyl, C2 ... 10- membered halogenated cycloalkyl, 4-10-membered halogenated heterocyclic, C6 - C10 halogenated aryl, or 5-10-membered halogenated heteroaryl; Rd11 , Rd12 , and Rd13 are each independently selected from hydrogen, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2 - C6 alkoxy, substituted or unsubstituted C1 - C6 halogenated alkyl, substituted or unsubstituted C1 -C6 halogenated alkoxy, substituted or unsubstituted C1- C6 deuterated alkyl, substituted or unsubstituted C1 - C6 deuterated alkoxy, substituted or unsubstituted C1 - C6 hydroxyl, substituted or unsubstituted C3 -C 10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein, substitution in R d11 , R d12 and R d13 refers to substitution by 1-4 R ddd ; R cc , R ccc , R dd and R ddd are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkoxy, C 1 -C 6 deuterated alkyl, C 1 - C 6 deuterated alkoxy, C 1 -C 6 hydroxyl, C 3 -C 10- membered cycloalkyl, 4-10-membered heterocyclic, C6 - C10 aryl, 5-10-membered heteroaryl, C1 - C6 halogenated alkyl, C2 - C6 halogenated alkenyl, C2 - C6 halogenated alkynyl, C1 - C6 halogenated alkoxy, C3 - C10 halogenated cycloalkyl, 4-10-membered halogenated heterocyclic, C6 - C10 halogenated aryl, or 5-10-membered halogenated heteroaryl; preferably, Rc1 is selected from C1 - C6 alkylene- Rc11 , ORc11 , NRc11Rc12 ; more preferably, Rc1 is selected from amino, NHCH3 , N( CH3 ) 2 , , , , , Rc2 and Rc3 are each independently selected from hydrogen, deuterium, and C1 - C6 alkyl, preferably hydrogen, methyl, and ethyl; preferably, Rd1 is selected from hydrogen, C1 - C6 alkyl, and C3 - C6 cycloalkyl, more preferably, Rd1 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl; Rd2 and Rd3 are each independently selected from hydrogen and C1 - C6 alkyl, preferably hydrogen, methyl, and ethyl.

In some embodiments of this invention, _Rf is Wherein: ring C is selected from a 5-6 membered heterocyclic group or a C5-C6 cycloalkyl group; or ring D is selected from phenyl, naphthyl, 5-6 membered heteroaryl, or 9-10 membered heteroaryl; preferably, ring D is selected from pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, indolyl, pyrrolopyridinyl, imidazoolopyridinyl, imidazoolopyrimidinyl, triazolopyrimidinyl, or triazolopyridinyl.

In some embodiments of the present invention, the compound has the structure shown in formula (I'-A) or (I'-B). Wherein, cyclo(Cy) is selected from phenyl, 5-6-membered heteroaryl, 5-6-membered heterocycloyl or C5-C6 cycloalkyl; wherein the phenyl, 5-6-membered heteroaryl, 5-6-membered heterocycloyl or C5-C6 cycloalkyl is further substituted by 1-4 R r ; X 2  is selected from N or CR 2 r; X 4  is selected from N or CR 4 r ; X 7 is selected from N or CR 7 r;X 8  is selected from N or C; R 2 r , R 4 r and R 7  r are defined as Rr; preferably, R 2  r , R 4  r and R 7  r are each independently selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 halogenated alkyl, C 1 - C6 halogenated alkoxy, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyl, C3- C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C1 - C6 alkylene- R21 , ( CH2 ) OR21 , (CH2) NR21R22 , ( CH2 ) COR23 , (CH2) COOR21 , ( CH2 ) CONR21R22, (CH2)NR21COR23 , ( CH2 ) NR21COOR22 , ( CH2 ) SOR23 , ( CH2 ) SONR21R22 , ( CH2 ) SO 2 R 21 , (CH 2 )SO 2 NR 21 R 22 , OR 21 , NR 21 R 22 , COR 23 , COOR 21 , CONR 21 R 22 , NR 21 COR 23 , NR 21 COOR 22 , SOR 23 , SONR 21 R 22 , SO 2 R 21 , SO 2 NR 21 R 22 ; wherein, the C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C1 - C6 deuterated alkyl, C1- C6 deuterated alkoxy, C1 - C6 hydroxyl, C3 -C 6 -cycloalkyl, 4-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl can optionally be further replaced by deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1 -C6 alkyl, C2- C6 alkenyl, C2 - C6 alkoxy, C3-C6 cycloalkyl, 4-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl, C1-C6 halogenated alkyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1- C6 hydroxyalkyl, C2-C6 halogenated alkenyl, C2- C6 halogenated alkynyl, C1 - C6 halogenated alkoxy, C3-C6 cycloalkyl, 4-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl, C1 -C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C3-C6 cycloalkyl, 4-6- membered heterocyclic, phenyl, 5-6- membered heteroaryl, C1 -C6 halogenated alkyl, C2- C6 halogenated alkenyl, C2-C6 halogenated alkoxy, C3 -C6 cycloalkyl, 4-6-membered heterocyclic, 4-6 - membered heterocyclic, 4-6 -membered heterocyclic, 5-6- membered heteroaryl, 5-6 -membered heterocyclic ... One or more of the following substitutions: 6- halogenated cycloalkyl, 4-6-membered halogenated heterocyclic, halogenated phenyl, or 5-6-halogenated heteroaryl.

In some embodiments of the present invention, the compound has the structure shown in formula (I'') or formula (I'''). in, and Each is independently a substituted or unsubstituted 8-9 membered heteroaryl group; Ar is selected from 5-6 membered heteroaryl groups, wherein the heteroaryl group is optionally further substituted by 1-4 _Rr groups; ^X2 is selected from N or ^CR2r ; ^X4 is selected from N or _{CR4r ;} ^X7 is selected from N or ^CR7r _; ^X8 is selected from N or ^C ; _{R2r, R4r and R7r are defined as Rr; preferably, R2r ,} ^{R4r and R7r} _are ^{each independently} _selected from hydrogen, _deuterium , halogen, amino, cyano, nitro, hydroxyl, ^C1 - _C6 alkyl, ^C1 - _C6 alkoxy, C1- ^C6 halogenated alkyl, _C1 - _C6 halogenated alkoxy, C1-C6 deuterated alkyl, C1-C6 alkyl, C1- _C6 alkyl, _C1 -C6 alkyl, _C1 - _C6 alkyl, C1-C6 alkyl, _C1 - _{C6 alkyl, C1-C6} alkyl, _C1 - _C6 alkyl, C1 _- C6 alkyl _6- Deuterated alkoxy, _C1 - _C6 hydroxyl, C3- _C6 cycloalkyl, _4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, _C1 - _C6 alkylene- ^R21 , ⁽ _CH2 ) ^OR21 , ( _CH2 ) ^NR21R22 , (CH2) ^COR23 , ( _CH2 ) ^COOR21 , (CH2) ^CONR21R22 , ( _CH2 ) ^NR21COR23 , ( _CH2 ⁾ _NR21COOR22 , ⁽ _CH2 ) ^SOR23 , ( _{CH2 )} ^{SONR21R22 , (} _CH2 ^{) SO2R21 , (} _{CH2 ) SO2NR21R22} ; wherein, the _C1 - _C6 alkyl, _C1 - _C6 alkoxy, C1-C6 halogenated alkyl, _C1 - _C6 halogenated alkoxy, C1-C6 deuterated alkyl, _C1 - _C6 deuterated alkoxy, _C1 - _C6 hydroxyl, C3- _C6 cycloalkyl, _4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl may optionally be further replaced by deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, _{C1 -} C6 alkyl, _C2 -C6 alkenyl, C2- _C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C1-C6 alkyl, _C2 -C6 alkyne, _C1 -C6 alkoxy, _C3 - _C6 cycloalkyl, 4-6 _membered heterocyclic, phenyl, C1-C6 alkyl, C3- _C6 cycloalkyl, C4- _C6 membered heterocyclic, phenyl, C3-C6 membered heteroaryl, _C1 -C6 alkyl, C3-C6 cycloalkyl, _C4 - _C6 membered heterocyclic, phenyl, C3-C6 membered heteroaryl, C1-C6 alkyl, C3-C6 alkyl, C3 _- C6 membered heterocyclic ... One or more of the following _{: 6-} halogenated alkyl, _C1 - _C6 deuterated alkyl, _C1 - _C6 deuterated alkoxy, _C1 - _C6 hydroxyalkyl, _C2 - _C6 halogenated alkenyl, _C2 - _C6 halogenated alkynyl, _C1 - _C6 halogenated alkoxy, _C3 - _C6 halogenated cycloalkyl, 4-6-membered halogenated heterocyclic, halogenated phenyl, or 5-6-halogenated heteroaryl.

In certain embodiments of the present invention, ^R2r , ^R4r _, and _R7r are each independently selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, _C1 ^- _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 halogenated alkyl, _C1 - _C6 halogenated alkoxy, _C1 - _C6 deuterated alkyl, _C1 - _C6 deuterated alkoxy, _{C1 -C6 hydroxyl} , C3- _C6 cycloalkyl, _4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, _C1 - _C6 alkylene ^{- R21} , ( _CH2 ) ^OR21 , ( _CH2 ) ^NR21R22 , ( _CH2 ) ^COR23 , ( _CH2 )COOR ²¹ , ( _CH2 )CONR ²¹ R ²² , ( _CH2 )NR ²¹ COR ²³ , ( _CH2 )NR ²¹ COOR ²² , ( _CH2 )SOR ²³ , (CH2)SONR ²¹ R ²² , ( _CH2 )SO ₂ R ²¹ , ( _{CH2 )} SO ₂ NR ²¹ R ²² , OR ²¹ , NR ²¹ R ²² , COR ²³ , COOR ²¹ , CONR ²¹ R ²² , NR ²¹ COR ²³ , NR ²¹ COOR ²² , SOR ²³ , SONR ²¹ R ²² , SO ₂ R ²¹ , SO ₂ NR ²¹ R ²² ; wherein, the _C1 - _C6 alkyl, _C1 -C _6- alkoxy, _C1 - _C6 halogenated alkyl, _C1 - _C6 halogenated alkoxy, _C1 - _C6 deuterated alkyl, _C1 - _C6 deuterated alkoxy, _C1 - _C6 hydroxyl, _C3 -C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, _5-6 membered heteroaryl, optionally further replaced by deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkoxy, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, _5-6 membered heteroaryl, _{C1 - C6} halogenated alkyl, _C1 - _C6 deuterated alkyl, C One or more of the following: ₁ - _C6 deuterated alkoxy, _C1 - _C6 hydroxyl, _C2 - _C6 halogenated alkenyl, _C2 - _C6 halogenated alkynyl, _C1 - _C6 halogenated alkoxy, _C3 - _C6 halogenated cycloalkyl, 4-6 membered halogenated heterocyclic, halogenated phenyl, or 5-6 halogenated heteroaryl.

In some embodiments of this invention, _Rf is .

In some embodiments of the present invention, the compound has the structure shown in formula (I'-1), formula (I''-1), or formula (I'''-1). in, For substituted or unsubstituted 9-membered heteroaryl groups; and Each is an ₈ -membered heteroaryl group _, substituted or _{unsubstituted} ; ^X1 is selected from N or ^CR1r _; ^X2 is selected from N or ^CR2r ; ^X3 is selected from N or ^CR3r ; ^X4 is selected from N or ^CR4r ; ^X5 is selected from _N or ^CR5r _; ^X6 is selected from N or ^CR6r _; ^X7 is selected from N or ^CR7r ; ^X8 is selected from N or C; ^Y1 is selected from N, O, S or ^CR8r _; ^Y2 is selected from _N , O, S or ^CR9r _; ^Y3 is selected _from N _, ^O , _S ^{or CR10r} _; ^R1r , ^R2r , _R3r , _R4r , ^{R5r , R6r} , _R7r , ^{R8r , R9r} and _R10r are _defined as _{Rr .}

In certain embodiments of the _present invention _, ^R1r , _R2r , ^R3r , ^R4r , _R5r , ^R6r , ^R7r , ^R8r , ^R9r _, ^and _R10r are each independently selected from hydrogen, deuterium, _halogen , _amino , ^cyano , _nitro , ^hydroxyl , _C1 - _C6 alkyl, C1- _C6 alkoxy, _C1 - _C6 halogenated alkyl, _C1 - _C6 halogenated alkoxy, _C1 - _C6 deuterated alkyl, _C1 - _C6 deuterated alkoxy, _C1 - _C6 hydroxyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, _5-6 membered heteroaryl, _{C1 - C6} alkylene- ^R21 , ( _CH2 )OR ²¹ , ( _CH2 )NR ²¹ R ²² , ( _CH2 )COR ²³ , ( _CH2 )COOR ²¹ , ( _CH2 )CONR ²¹ R ²² , ( _CH2 )NR ²¹ COR ²³ , ( _CH2 )NR ²¹ COOR ²² , ( _CH2 )SOR ²³ , ( _CH2 )SONR ²¹ R ²² , ( _CH2 )SO ₂ R ²¹ , ( _CH2 )SO _2NR ²¹ R ²² ; wherein, the _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 halogenated alkyl, _C1 - _C6 halogenated alkoxy, _C1 - _C6 deuterated alkyl, _C1 - _C6 deuterated alkoxy, _C1 -C _6- Hydroalkyl, _C3 -C6 cycloalkyl, _4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, optionally further replaced by deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, _C1 -C6 alkyl, C2- _C6 alkenyl, _C2 -C6 alkoxy, C3- _C6 cycloalkyl, _4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, _C1 -C6 halogenated alkyl, _C1 - _C6 deuterated alkyl, _C1 - _C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C2-C6 halogenated alkenyl, _C2 - _C6 halogenated alkynyl ... alkenyl, _C2 - _C6 halogenated alkenyl, C2-C6 halogenated alkenyl, _C2 - _C6 halogenated alkenyl, _C2 - _C6 halogenated alkenyl, C2-C6 halogenated alkenyl, _C2 - _C6 halogenated alkenyl, _C2 - _C6 halogenated alkenyl, _C2 -C One or more of the following substitutions: _6- halogenated alkoxy, _C3 - _C6- halogenated cycloalkyl, 4-6-membered halogenated heterocyclic, halogenated phenyl, or 5-6-halogenated heteroaryl.

In certain embodiments of this invention, and It is a 5-membered heterocyclic aromatic ring.

In some embodiments of the present invention, ring A is phenyl, 5-6-membered heteroaryl, 5-10-membered heterocycloyl, or _C5 - _C10 cycloalkyl. Preferably, ring A is phenyl or 5-6-membered heteroaryl, and preferably phenyl, pyridyl, pyridine, pyridyl, pyridinyl, pyridone, thiophene, furanyl, thiazolyl, or imidazolyl.

In some embodiments of the present invention, the compound has the structure shown in formula (I'-2), formula (I'-3), or formula (I'-A'-1): ^Ra1 , ^Ra2 , ^Ra3 , ^Ra4 , ^Ra5 and ^Ra6 are defined as ^Ra ; preferably, ^Ra1 , Ra2, ^Ra3 , ^Ra4 , ^Ra5 and ^Ra6 are each independently selected from hydrogen, deuterium, halogen, amino, ^cyano , hydroxyl, _C1 - _C3 alkyl, _C1 - _C3 halogenated alkyl, _C1 - _C3 deuterated alkyl, _C1 - _C3 alkoxy, _C1 - _C3 halogenated alkoxy, _C1 - _C3 deuterated alkoxy.

In certain embodiments of the present invention, cyclic B is a 5-6 member heteroaryl group; preferably, cyclic B is acezolyl, pyrazolyl, triazolyl, thiazolyl, thiadiazolyl, or acezolyl; preferably, cyclic B is... , , , , , , or The preferred location is Ring B. or .

In some embodiments of the present invention, the compound has the structure shown in formula (I'-4), formula (I'-5), formula (I'-A-1), or formula (I'-A-2). Rb ^' is defined the same as ^Rb , and Rb ^' is preferably selected from hydrogen, deuterium, halogen, _C1 - _C3 alkyl, _C1 - _C3 halogenated alkyl, _C1 - _C3 deuterated alkyl, _C1 - _C3 alkoxy, _C1 - _C3 halogenated alkoxy, and _C1 - _C3 deuterated alkoxy.

In some embodiments of the present invention, the compound has the structure shown in formula (I'-6)-(I'-9), formula (I'-A-3), or formula (I'-A-4). .

In some embodiments of this invention, _Rf is selected from... Or a thiazolyl group, wherein Cy1 is a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the thiazolyl group, the 5-6 membered heteroaryl group, or the 5-6 membered heterocyclic group is optionally further substituted by 1-4 R_{_r}groups; preferably R_{_f} is selected from the substituted or unsubstituted group of the next group. , , , , , , , , , , , Preferred R _f is selected from substituted or unsubstituted subgroups. , , , , , , , , , , Preferred R _f is selected from substituted or unsubstituted subgroups. , or The substitution mentioned therein refers to being replaced by 1-4 R _r .

In some embodiments of this invention, _Rf is selected from... , or .

In some embodiments of the present invention, the compound has the structure shown in formula (I'-10), formula (I'-11), formula (I'-10'), formula (I'-11'), (I''-10), or formula (I''-11). .

In some embodiments of the present invention, the compound has the structure shown in formula (I'-12), formula (I'-13), formula (I'-12'), formula (I'-13'), (I''-12), formula (I''-13), formula (I'-A'-6), or formula (I'-A'-7). .

In some embodiments of the present invention, the compound has the structure shown in formula (I'-14) or formula (I'-15). .

In some embodiments of the present invention, the compound has the structure shown in formula (I'-16), formula (I'-17), formula (I'-16'), or formula (I'-17'). .

In certain embodiments of the present invention, _Rf is selected from -Ar3- _L2 - _Rp , wherein Ar3 is selected from substituted or unsubstituted 5-10-membered heteroaryl groups, wherein the substitution refers to substitution by 1-3 groups selected from the following group: hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, substituted or unsubstituted _C1 - _C6 alkyl, substituted or unsubstituted _C2 - _C6 alkenyl, substituted or unsubstituted _C2 - _C6 alkynyl, substituted or unsubstituted _C1 - _C6 alkoxy, substituted or unsubstituted _{C1 - C6} halogenated alkyl, substituted or unsubstituted _C1 - _C6 halogenated alkoxy, substituted or unsubstituted _C1 - _C6 deuterated alkyl, substituted or unsubstituted _C1 -C6 _deuter ... ₆ -Hydroalkyl, substituted or unsubstituted _C3 - _C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted _C6 - _C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein the substitution refers to substitution by 1-4 _Rfff ; _L2 is selected from hydroxyl, _C1 - _C6 alkylene, O, _NRp1 , CO, COO, _CONRp2 , _NRp3 , COO, _{SO, SONRp4, SO2, SO2NRp5; Rp1, Rp2, Rp3, Rp4 and Rp5 are each independently selected from hydrogen , C1 - C6} alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkoxy, _C1 - _C6 halogenated alkyl, _{C1 - C 6-} Haloxyalkoxy, _C1 - _C6 deuterated alkyl, _C1 - _C6 deuterated alkoxy, _C1 - _C6 hydroxyalkyl; _Rp is selected from hydrogen, COOC ₁ - _C6 alkyl, _{SO2 C1} - _C6 alkyl, substituted or unsubstituted _C1 - _C6 alkyl, substituted or unsubstituted _C2 - _C6 alkenyl, substituted or unsubstituted _C2 - _C6 ynyl, substituted or unsubstituted _C1 - _C6 alkoxy, substituted or unsubstituted _C1 - _C6 haloxyalkoxy, substituted or unsubstituted _C1 - _C6 haloxyalkoxy, substituted or unsubstituted _C1 - _C6 deuterated alkyl, substituted or unsubstituted _C1 - _C6 deuterated alkoxy, substituted or unsubstituted _C1 - _C6 hydroxyalkyl, substituted or unsubstituted _C3 -C ₁₀ -cycloalkyl, substituted or unsubstituted 4-10-membered heterocyclic, substituted or unsubstituted _C6 - _C10 aryl, substituted or unsubstituted 5-10-membered heteroaryl; wherein the substitution refers to substitution by 1-4 R _ffff .

In some embodiments of this invention, _Rf is or _Rf is preferred. or _Rf is the preferred choice or ^X2 is selected from O, S, N, NR ¹¹ _r or CR ² _r ; preferably, ^X2 is selected from N or CR ² _r ; ^X3 is selected from N or CR ³ _r ; ^X4 is selected from O, S, N, NR ¹¹ _r or CR ⁴ _r ; preferably, ^X4 is selected from N or CR ⁴ _r ; ^X5 is selected from N or CR ⁵ _r ; ^X6 is selected from N or CR ⁶ _r ; ^X7 is selected from N or CR ⁷ _r ; ^X8 is selected from N or C; ^Y1 is selected from N, O, S or CR ⁸ _r ; ^Y2 is selected from N, O, S or CR ⁹ _r ; ^Y3 is selected from N, O, S or CR ¹⁰ _r ; ^R1 _r , ^R2 _r , ^R3 _r , ^R4 _r , ^R5 _r , ^R6 _r , ^R7 _r , ^R8 _r , ^R9 The definitions of _r , ^R10 _r and ^R11 _r are the same as R _r .

In certain embodiments of the present invention, the cycloCy is selected from phenyl, 5-6-membered heteroaryl, 5-6-membered heterocycloyl or C5-C6 cycloalkyl; wherein the phenyl, 5-6-membered heteroaryl, 5-6-membered heterocycloyl or C5-C6 cycloalkyl is optionally further substituted with 1-4 R _r .

In certain embodiments of this invention, and Each is independently a substituted or unsubstituted 8-9 member heteroaryl. In certain embodiments of the invention, and Each is an 8-membered heteroaryl group, either substituted or unsubstituted. In some embodiments of the invention, _Rf is selected from... Cy1 is a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group or the 5-6 membered heterocyclic group is optionally further substituted by 1-4 R_{_r}groups; preferably, R_{_f} is selected from the substituted or unsubstituted group: , The substitution mentioned therein refers to being replaced by 1-4 R _r ; R _fff , R _ffff and R _r are defined as described above.

In certain embodiments of the present invention, ring B is selected from the following group of substituted or unsubstituted groups: _C6 - _C10 aryl, 5-10-membered heteroaryl, 4-10-membered heterocyclol, _C3 - _C10 cycloalkyl, phenyl-5-6-membered heterocyclol, phenyl- _C5 - _C6 cycloalkyl, 5-6-membered heteroaryl-5-6-membered heterocyclol, or 5-6-membered heteroaryl- _C5 - _C6 cycloalkyl; wherein, substitution refers to being substituted by 1-4 R groups. ^b' substitution; preferably, ring B is a substituted or unsubstituted 5-6-membered heteroaryl group or a substituted or unsubstituted 5-6-membered heteroaryl group with a 5-6-membered heterocyclic group, preferably, ring B is a substituted or unsubstituted 5-6-membered heteroaryl group, a substituted or unsubstituted 5-membered heteroaryl group with a 5-membered heterocyclic group, a substituted or unsubstituted 5-membered heteroaryl group with a 6-membered heterocyclic group, a substituted or unsubstituted 6-membered heteroaryl group with a 5-membered heterocyclic group, or a substituted or unsubstituted 6-membered heteroaryl group with a 6-membered heterocyclic group; preferably, ring B is a substituted or Unsubstituted lower group: azolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, isothiazolyl, azidizolyl, isoazolyl, tetrazolyl, pyrroleyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyridyl, pyridoneyl, dazolyl, triazolyl; more preferably, ring B is a substituted or unsubstituted lower group: azolyl, isoazolyl, pyrazolyl, triazolyl, thiazolyl, thiadiazolyl, azidizolyl; wherein, the substitution refers to being formed by 1-4 R groups. ^b' substitution; wherein each of R ^b' is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, hydroxyl, oxo, thio, _C1 -C6 alkyl, C1- _C6 alkyl, _C1 - _C6 alkoxy, _C2 - _C6 alkenyl, _C2 -C6 alkynyl, C1- _C6 deuterated alkyl, _C1 - _C6 deuterated alkoxy, _C1 - _C6 hydroxyl, _C3 - _C10 cycloalkyl, 4-10 heterocyclic, C6-C10 aryl, _5-10 heteroaryl, _C1 -C6 halogenated alkyl, _C1 - _C6 halogenated alkoxy, _C3 -C10 cycloalkyl, _4-10 heterocyclic, C6-C10 aryl, 5-10 heteroaryl, _C1 - _C6 halogenated alkyl, _C1 -C6 halogenated alkoxy, C3- _C10 cycloalkyl, _C2 ... _10- membered halogenated cycloalkyl, 4-10-membered halogenated heterocyclic, _C6 - _C10 halogenated aryl, or 5-10-membered halogenated heteroaryl; preferably, ring B is selected from... Preferred locations are selected from , , , Cy3 is a 5-membered heteroaryl group; Cy2 is a 5-6-membered heterocyclic group; y'' is 0, 1, or 2; y''' is 0, 1, 2, or 3; ^Rb'-6 , Rb' ^-7 , and Rb' ^-8 are defined as Rb ^' ; preferably, ^Rb'-6 , Rb' ^-7 , and Rb' ^-8 are each independently selected from H, deuterium, halogen, amino, cyano, nitro, hydroxyl, _C1 - _C6 alkyl, _C1 - _C6 halogenated alkyl, _C1 - _C6 alkoxy, and _C1 - _C6 halogenated alkoxy.

In certain embodiments of the present invention, Rb ^' is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, hydroxyl, oxo, thio, _{C1-C6 alkyl, C1} - _C6 alkyl, _C1 - _C6 alkoxy, _C2 -C6 alkenyl, C2- _C6 alkynyl, _C1 - _C6 deuterated alkyl, _C1 - _C6 deuterated alkoxy, _C1 - _C6 hydroxyl, C3- _C10 cycloalkyl, 4-10 heterocyclic, C6- _C10 aryl, 5-10 heteroaryl, _C1 - _C6 halogenated alkyl, _C1 -C6 halogenated alkoxy, C3- _C10 cycloalkyl, 4-10 heterocyclic, _C6 - _C10 aryl, 5-10 heteroaryl, _C1 - _{C6 halogenated alkyl, C1-C6} halogenated alkoxy, _C3 - _C10 cycloalkyl, _C2 ... _10- halogenated cycloalkyl, 4-10-membered halogenated heterocyclic, _C6 - _C10- halogenated aryl or 5-10-membered halogenated heteroaryl.

In certain embodiments of this invention, for or Wherein, cyclic G is selected from _C3 - _C8 cycloalkyl or 4-8 membered heterocyclic groups, f1 is 1, 2, 3 or 4; y' is 0, 1, 2 or 3; Rb ^' and _Rbb are defined as described above, and further preferably... Selected from , Wherein, Ar1 is a 5-membered heteroaryl group; Ar2 is a 6-membered heteroaryl group; _Z2 is selected from C or N; _Z3 is selected from O, S, N, NR ^b'-4 , CR ^b'-2 ; _Z4 is selected from O, S, N, NR ^b'-4 , CR ^b'-3 ; _Z5 is selected from C or N; _Z6 is selected from O, S, N, NR ^b'-4 , CR ^b'-1 ; _W1 is selected from CR ^b'-1 or N; _W2 is selected from CR ^b'-2 or N; _W3 is selected from CR ^b'-3 or N; _W4 is selected from CR ^b'-5 or N; preferably, Selected from , , , , , , , , , , , ; wherein Rb' ^-1 , Rb' ^-2 , Rb' ^-3 , Rb' ^-4 and Rb' ^-5 are defined as ^Rb' ; preferably, ^Rb'-1 , Rb' ^-2 , Rb'- ³ and Rb' ^-5 are selected from H, deuterium, halogen, amino, cyano, nitro, hydroxyl, _C1 - _C6 alkyl, _C1 - _C6 halogenated alkyl, _C1 - _C6 alkoxy, _C1 - _C6 halogenated alkoxy; ^Rb'-4 is selected from H, _C1 - _C6 alkyl, _C1 - _C6 halogenated alkyl.

In certain embodiments of the present invention, ^Rb is independently selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, oxo, thio, substituted or unsubstituted _C1 - _C6 alkyl, substituted or unsubstituted _C2 - _C6 alkenyl, substituted or unsubstituted _C2 - _C6 ynyl, substituted or unsubstituted _C1 - _C6 halogenated alkyl, substituted or unsubstituted _C1 - _C6 halogenated alkoxy, substituted or unsubstituted _C1 - _C6 deuterated alkyl, substituted or unsubstituted _C1 - _C6 deuterated alkoxy, substituted or unsubstituted _C1 -C6 hydroxyl, substituted or unsubstituted _{C1 -C6 alkoxy} , substituted or unsubstituted _C3 - _C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C ₆ -C ₁₀ aryl, substituted or unsubstituted 5-10 heteroaryl, (CH ₂ ) _k OR _B-1 , (CH ₂ ) _k NR _B-1 RB _-2 , (CH ₂ ) _k COR _B-3 , (CH ₂ ) _k COOR _B-3 , (CH ₂ ) _k OCOR _B-3 , =NHOR _B-1 , =CR _B-1 RB _-2 , (CH ₂ ) _k C(=NH)OR _B-1 , (CH ₂ ) _k CONR _B-1 RB _-2 , (CH ₂ ) _k NR _B-1 COR _B-3 , (CH ₂ ) _k NR _B-1 COOR _B-3 , (CH ₂ ) _k C(=NH)NR _B-1 RB _-2 , (CH ₂ ) _k NR _B-1 C(=NH)RB _-3 , (CH ₂ ) _k SOR _B-1 , ( _CH2 ) _{kSONR B-} 1RB _-2 , ( _CH2 ) _{kNR B-} 1SOR _B-3 , ( _CH2 ) _kSO2RB - ₁ , ( _CH2 ) _{kSO2NR B -} 1RB _-2 , or ( _CH2 ) _{kNR B- 1SO2RB -3} ; _wherein the substitution refers to substitution by 1-4 _Rbb ; _Rbb is selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, oxo, thio, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C2 - _C6 alkenyl, C2- _C6 alkynyl, _C1 - _{C6 deuterated alkyl, C1 - C6 deuterated} alkoxy, _C1 - _C6 hydroxyl, _C3 -C _10- membered cycloalkyl, 4-10-membered heterocyclic, _C6 - _C10 aryl, 5-10-membered heterocyclic, _C1 - _C6 halogenated alkyl, _C1 - _C6 halogenated alkoxy, _C3 - _C10 halogenated cycloalkyl, 4-10-membered halogenated heterocyclic, _C6 - _C10 halogenated aryl, 5-10-membered halogenated heterocyclic, ( _CH2 ) _j OR _b-1 , ( _CH2 ) _j NR _b-1 R _b-2 , ( _CH2 ) _j COR _b-3 , ( _CH2 ) _j COOR _b-3 , ( _CH2 ) _j OCOR _b-3 , =NHOR _b -1, =CR _b-1 R _b-2 , ( _CH2 ) _j C(=NH)OR _b-1 ( _CH2 ) _j CONR _b-1 R _b-2 , ( _CH2 ) _j NR _b-1 COR _b-3 , ( _CH2 ) _j NR _b-1 COOR _b-3 , ( _CH2 ) _j C(=NH)NR _b-1 R _b-2 , ( _CH2 ) _j NR _b-1 C(=NH)R _b-3 , ( _CH2 ) _j SOR _b-1 , ( _CH2 ) _j SONR _b-1 R _b-2 , ( _CH2 ) _j NR _b-1 SOR _b-3 , ( _CH2 ) _{j SO2} R _b-1 , ( _CH2 ) _{j SO2} NR _b-1 R _b-2 or ( _CH2 ) _j NR _{b-1 SO2} R _b-3 , wherein the _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C2 - _C6 alkenyl, _C2 -C ₆ alkynyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ deuterated alkoxy, C ₁ -C ₆ hydroxyl, C ₃ -C ₁₀ cycloalkyl, 4-10 heterocyclic, C ₆ -C ₁₀ aryl, and 5-10 heteroaryl may be further substituted with 1-4 R _bbb . In certain embodiments of the present invention, R_^b is independently selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, oxo, thio, substituted or unsubstituted C _₁-C_₆ alkyl, substituted or unsubstituted C _₂-C_₆ alkenyl, substituted or unsubstituted C_₂-C_₆ alkynyl, substituted or unsubstituted C _₁-C_₆ halogenyl, substituted or unsubstituted C_₁-C_₆ alkoxy, substituted or unsubstituted C_₁-C_₆ deuteryl, substituted or unsubstituted C_₁-C_₆ deuteryloxy, substituted or unsubstituted C_₁-C_₆ hydroxyl, substituted or unsubstituted C_₁-C _₆ alkoxy, substituted or unsubstituted C_₃-C_₈ cycloalkyl, substituted or unsubstituted 4-8 membered heterocyclic groups, substituted or unsubstituted C_₆ -C ₁₀ aryl, substituted or unsubstituted 5-10 heteroaryl, OR _B-1 , NR _B-1 RB _-2 , COR _B-3 , COOR _B-3 , OCOR _B-3 , =NHOR _B-1 , CONR _B-1 RB _-2 , NR _B-1 COR _B-3 , NR _B-1 COOR _B-3 , C(=NH)NR _B-1 RB _-2 , =CR _B-1 RB _-2 , NR _B-1 C(=NH)RB _-3 , SOR _B-1 , SONR _B-1 RB _-2 , NR _B-1 SOR _B-3 , SO ₂ RB _-1 , SO ₂ NR _B-1 RB _-2 or NR _B-1 SO ₂ RB _-3 ; wherein, the substitution mentioned in ^Rb refers to substitution by 1-4 R _bb , where R _bb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C2 -C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 deuterated alkyl, _C1 - _C6 deuterated alkoxy, _C1 - _C6 hydroxyl, C3 _{-C8 cycloalkyl} , _4-8 membered heterocyclic, phenyl, 5-6 membered heteroaryl, _C1 - _C6 halogenated alkyl, _C1 - _C6 halogenated alkoxy, _C3 - _C8 halogenated cycloalkyl, 4-8 membered heterocyclic, halogenated phenyl, 5-6 membered heteroaryl, OR _b-1 , NR _b-1 , R _b-2 COR _b-1 , COOR _b-1 , OCOR _b-1 , CONR _b-1 R _b-2 , NR _b-1 COR _b-1 , =NHOR _b-1 , NR _b-1 COOR _b-3 , C(=NH)NR _b-1 R _b-2 , NR _b-1 C(=NH)R _b-3 , =CR _b-1 R _b-2 , SOR _b-1 , SONR _b-1 R _b-2 , NR _b-1 SOR _b-3 , SO ₂ R _b-1 , SO ₂ NR _b-1 R _b-2 or NR _b-1 SO ₂ R _b-3 , preferably, R ^b is independently selected from substituted or unsubstituted _C1 - _C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted _C2 - _C6 alkynyl, substituted or unsubstituted _C1 - _C6 alkyl, or substituted or unsubstituted _C1 -C6 alkyl. _6- halogenated alkyl, substituted or unsubstituted _C1 - _C6- halogenated alkoxy, substituted or unsubstituted _C1 - _C6- deuterated alkyl, substituted or unsubstituted _C1 - _C6- deuterated alkoxy, substituted or unsubstituted _C1 - _C6- hydroxyalkyl, substituted or unsubstituted _C1 - _C6- alkoxy, substituted or unsubstituted C3- _{C8 -} cycloalkyl, substituted or unsubstituted 4-8-membered heterocyclic, substituted or unsubstituted _C6 - _C10 aryl, substituted or unsubstituted 5-10-membered heteroaryl, OR _B-1 , NR _B-1 RB _-2 , COR _B-3 , =NHOR _B-1 , CONR _B-1 RB _-2 , NR _B-1 COR _B-3 , COOR _B- 3, NR _B-1 COOR _B-3 , C(=NH)NR _B-1 RB _-2 = CR _B-1 RB _-2 , NR _B-1 C(=NH)RB _-3 , SOR _B-1 , SONR _B-1 RB _-2 , NR _B-1 SOR _{B-3 ,} SO ₂ RB-1, SO ₂ NR _B-1 RB _-2 or NR _B-1 SO ₂ RB _-3 ; wherein, the substitution mentioned in ^Rb refers to substitution by 1-4 R _bb , wherein R _bb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, _thio , _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 deuterated alkyl, C1- _C6 deuterated alkoxy, _C1 - _C6 hydroxyl, _C3 -C _8- membered cycloalkyl, 4-8-membered heterocyclic, phenyl, 5-6-membered heteroaryl, _C1 - _C6 halogenated alkyl, _C1 - _C6 halogenated alkoxy, _C3 - _C8 halogenated cycloalkyl, 4-8-membered halogenated heterocyclic, halogenated phenyl, 5-6-membered halogenated heteroaryl, OR _b-1 , NR _b-1 R _b-2 , COR _b-1 , CONR _b-1 R _b-2 , NR _b-1 COR _b-1 , =NHOR _b-1 , COOR _b-3 , NR _b-1 COOR _b-3 , C(=NH)NR _b-1 R _b-2 , NR _b-1 C(=NH)R _b-3 , =CR _b-1 R _b-2 , SOR _b-1 , SONR _b-1 R _b-2 , NR _b-1 SOR _b-3 , SO ₂ R _b-1 , SO ₂ NR _b-1 R _b-2 , or NR _b-1 SO ₂ R _b-3 , wherein the _{C1 - C6} alkyl, _C1 - _C6 alkoxy, C2-C6 alkenyl, _{C1 - C6} deuterated alkyl, _C1 - _C6 deuterated alkoxy, _C1 - _C6 hydroxyl, _C2 - _C6 alkynyl, _C3 - _C8 cycloalkyl, 4-8 membered heterocyclic, phenyl, and 5-6 membered heteroaryl can be further substituted by 1-4 R _bbb , _and R _bbb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C2 - _C6 alkenyl, _C2 -C ₆ alkynyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ deuterated alkoxy, C ₁ -C ₆ hydroxyalkyl, C ₃ -C ₈ cycloalkyl, 4-8 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C ₁ -C ₆ halogenated alkyl, C ₁ -C ₆ halogenated alkoxy, C ₃ -C ₈ halogenated cycloalkyl, 4-8 membered heterocyclic, halogenated phenyl, 5-6 membered heteroaryl; wherein, RB _-1 , RB _-2 , RB _-3 , Rb _-1 , _Rb-2 and Rb _-3 are each independently selected from hydrogen, COOC ₁ -C ₆ alkyl, SO ₂ C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C _6- alkyl, substituted or unsubstituted _C2 - _C6 alkenyl, substituted or unsubstituted _C2 - _C6 ynynyl, substituted or unsubstituted _C1 - _C6 halogenated alkyl, substituted or unsubstituted _C1 - _C6 halogenated alkoxy, substituted or unsubstituted _C1 - _C6 deuterated alkyl, substituted or unsubstituted _C1 - _C6 deuterated alkoxy, substituted or unsubstituted _C1 - _C6 hydroxyalkyl, substituted or unsubstituted C3- _C8 cycloalkyl, substituted or unsubstituted _4-8 membered heterocyclic, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, _C1 - _C6 halogenated alkyl, _C3 -C _8- membered halogenated cycloalkyl, 4-8-membered halogenated heterocyclic, halogenated phenyl, 5-6-membered halogenated heteroaryl; wherein, the substitution in _RB-1 , _RB-2 , RB _-3 , Rb _-1 , Rb _-2 , and Rb _-3 refers to substitution by 1-4 R _bbbb , wherein R _bbbb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, hydroxyl, oxo, thio, _{C1 - C6} alkyl, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C2 - _C6 alkenyl, _C2 - _{C6 alkynyl, C1-C6 deuterated} alkyl, _C1 - _C6 deuterated alkoxy, _C1 - _C6 hydroxyl, _C3 -C ₈ -cycloalkyl, 4-8-membered heterocyclic, phenyl, 5-6-membered heteroaryl, _C1 - _C6 halogenated alkyl, _C1 - _C6 halogenated alkoxy, _C3 - _C8 halogenated cycloalkyl, 4-8-membered halogenated heterocyclic, halogenated phenyl, 5-6-membered halogenated heteroaryl.

In certain embodiments of this invention, R ^{and b} are each independently... _C1 - _C3 alkylene _OC1 - _C3 alkyl, _C1 - _C3 alkylene _OC1 - _C3 halogenated alkyl, wherein cycloG is selected from _C3 - _C6 cycloalkyl or 4-6 heterocyclic groups, and f1 is 1, 2, 3 or 4.

In certain embodiments of the present invention, R_^b is independently selected from C <sub>₁ -C_₃ alkylene OC<sub> ₁ -C_₃ alkyl, C<sub> _{1 -} C_₃ alkylene OC<sub> _{1 -} C_₃ halogenated alkyl, C<sub> ₃ -C_₆ cycloalkyl, C<sub> ₃ -C_₆ halogenated cycloalkyl, C<sub> ₁ -C_₃ alkylene C<sub> ₃ -C_₆ cycloalkyl, C<sub> ₁ -C_₃ alkyl <sub>4-6-membered heterocyclic, C_1-C₃ alkylene C<sub> ₃ -C₆ halogenated cycloalkyl, C<sub> ₁ -C _₃ alkylene 4-6-membered heterocyclic, C<sub>1-C_₃ alkoxy-substituted C <sub>₃ -C₆ cycloalkyl, C<sub> ₁ -C_₃ halogenated C<sub> ₃ -C _₆ cycloalkyl, C<sub> ₁ -C_₃ alkyl COO-substituted C _{₃ -C} ₆ -Cycloalkyl, _C1 - _C3 alkyl OCO-substituted _C3 -C6 cycloalkyl, _{C1 - C3} alkyl CONH-substituted _C3 - _C6 cycloalkyl, _C1 - _C3 alkyl NHCO-substituted C3- _C6 cycloalkyl, _C1 - _C3 alkyl NHCOO-substituted _{C3 - C6} cycloalkyl, 4-6 membered heterocyclic, 4-6 membered halogenated heterocyclic, _C1 - _C3 alkoxy-substituted 4-6 membered heterocyclic, _C1 - _C3 halogenated alkoxy-substituted 4-6 membered heterocyclic, _C1 - _C3 alkyl COO-substituted 4-6 membered heterocyclic, _C1 - _C3 alkyl OCO-substituted 4-6 membered heterocyclic, _C1 -C 4-6 membered heterocyclic groups substituted with ₃ -alkylCONH, 4-6 membered heterocyclic groups substituted with _C1 - _C3 alkylNHCO, or 4-6 membered heterocyclic groups substituted with _C1 - _C3 alkylNHCOO.

In some embodiments of this invention, _Rf is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

In some embodiments of this invention, _Rf is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Preferred location, R _f selected from , , , , , , , , , , , , , , , , , , , , , ; Preferred R _f selected from , , , , , , , , , , , , , , , In some embodiments of this invention, _Rf is selected from... , , , , , , , , , , , , , , , In some embodiments of this invention, _Rf is selected from... , , , , , , .

In certain embodiments of this invention, for or Further preferred locations for or The definitions of ^Ra1 , ^Ra2 , ^Ra3 and ^Ra4 are as described above.

In some embodiments of the present invention, ^Ra1 is selected from halogens, _C1 - _C3 alkyl groups, _C1 - _C3 halogenated alkyl groups, and preferably methyl groups.

In some embodiments of the present invention, ^Ra2 is selected from hydrogen or halogens (such as fluorine, chlorine or bromine), with hydrogen and fluorine being preferred.

In some embodiments of the present invention, ^Ra3 is selected from hydrogen or halogens (such as fluorine, chlorine or bromine), with hydrogen and fluorine being preferred.

In some embodiments of the present invention, ^Ra4 is selected from hydrogen.

In certain embodiments of this invention, for The definitions of ^Ra5 and ^Ra6 are as described above.

In some embodiments of the present invention, ring A is... , , , , , , , , , , , Preferred location A is , , , Preferred location A is , , .

In some embodiments of this invention, ring A is , , .

In certain embodiments of the present invention, ^Ra is independently selected from hydrogen, deuterium, halogen, _C1 - _C3 alkyl, _C1 - _C3 halogenated alkyl, _C1 - _C3 deuterated alkyl, _C1 - _C3 alkoxy, _C1 - _C3 halogenated alkoxy, and _C1 - _C3 deuterated alkoxy. Preferably, ^Ra is independently selected from hydrogen, deuterium, halogen, and _C1 - _C3 alkyl.

In certain embodiments of the present invention, ^Rb is independently selected from _C1 - _C3 alkyl, _C1 - _C3 halogenated alkyl, _C2 - _C4 alkenyl, _C2 - _C4 halogenated alkenyl, _C2 - _C4 alkynyl, _C2 - _C4 halogenated alkynyl, _COC1 - _C3 alkyl, CH=NOH, CH= _NOC1 - _C3 alkyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; The preferred choices R and ^b are each selected independently. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , R ^b is the preferred choice .

In some embodiments of the present invention, cyclic B is selected from substituted or unsubstituted subgroups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Wherein, the substitution refers to being replaced by 1, 2 or 3 R ^b' .

In certain embodiments of the present invention, Rb ^' is selected from hydrogen, deuterium, halogen, amino, _cyano , hydroxyl, C1- _C3 alkyl, _C1 - _C3 halogenated alkyl, _C1 - _C3 deuterated alkyl, _C1 - _C3 alkoxy, _C1 - _C3 halogenated alkoxy, and _C1 - _C3 deuterated alkoxy.

In some embodiments of the present invention, cyclo(G) is selected from _C3 - _C6 cycloalkyl or 4-6 heterocyclic groups, preferably. , , , , , , , , , , , , , , , , .

In certain embodiments of the present invention, R _bb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, _C1 - _C3 alkyl, _C1 - _C3 halogenated alkyl, _C1 -C3 alkoxy, _C1 - _C3 halogenated alkoxy, _C1 - _C3 alkyl COO, C1- _C3 alkyl OCO, _{C1 - C3 alkyl} CONH, _C1 - _C3 alkyl NHCO, C1-C3 alkyl NHCOO, _C1 - _C3 halogenated alkyl COO, _C1 - _C3 halogenated alkyl OCO, _C1 - _C3 halogenated alkyl CONH, _C1 - _C3 halogenated alkyl NHCO, _{and C1-C3 halogenated alkyl NHCOO} .

In some embodiments of the present invention, _L2 is selected from NH or NHCOO.

In certain embodiments of the present invention, Ar3 is selected from a substituted or unsubstituted 5-6 member heteroaryl group, preferably from the following subgroups: thiazolyl, thiadiazolyl, thiophene, furanyl, pyrazolyl, imidazolyl, acezolyl, pyridinyl, pyridine, pyracloyl, pyridyl, pyridinyl, pyrimidinyl; more preferably from the following subgroups: , The substitution mentioned therein refers to substitution by one or more of the following: hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, _C1 - _C2 alkyl, _C2 - _C4 alkenyl, _C2 - _C4 alkynyl, _{C1 - C3} alkoxy, _C1 - _C3 halogenated alkyl, _C1 - _C3 halogenated alkoxy, _C1 - _C3 deuterated alkyl, C1- _C3 deuterated alkoxy, _C1 - _C3 hydroxyl, _C3 -C6 cycloalkyl, _4-6 membered heterocyclic, _C6 - _C10 aryl, and 5-6 membered heteroaryl.

In certain embodiments of the present invention, Ar and Cy1 are each independently selected from the following group, either substituted or unsubstituted: azolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, azidiazolyl, isoazolyl, tetrazolyl, pyrroleyl, thiophene, furanyl, pyridinyl, pyrimidinyl, pyridinoneyl, pyridyl, triazolyl; wherein the substitution refers to being substituted with hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1-C2 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1- _C3 halogenated alkyl, _C1 -C3 halogenated alkoxy, _C1 - _C2 alkyl, _C2 - _C4 alkyne, _C1 - _C3 alkoxy, _C1 -C3 halogenated alkyl, C1- _C3 halogenated alkoxy, _C1 - _C3 alkyl, _C1- C3 ... One or more of the following: _3- deuterated alkyl, _C1 - _C3 deuterated alkoxy, _C1 - _C3 hydroxyalkyl, _C3 - _C6 cycloalkyl, 4-6-membered heterocyclic, _C6 - _C10 aryl, and 5-6-membered heteroaryl.

In certain embodiments of the present invention, _Rp is selected from _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkoxy, C1-C6 halogenated alkyl, _C1 - _C6 halogenated alkoxy, _C1 - _C6 deuterated alkyl, _C1 - _C6 deuterated alkoxy, _C1 -C6 hydroxyalkyl, _C3 - _C6 cycloalkyl, _4-6 membered heterocyclic, C6- _C10 aryl, and 5-6 membered heteroaryl; wherein, the _C1 -C6 alkyl, _C2 - _C6 alkenyl, C2-C6 alkoxy, _C1 -C6 halogenated alkyl, C1- _C6 halogenated alkoxy, _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclic, C6- _C10 aryl, and _5-6 membered heteroaryl are selected from _C1- C6 alkyl, C2- _C6 alkenyl, _C2 - _C6 alkoxy, _C1 - _C6 halogenated alkyl, _C1 -C10 ... _6- Deuteryl, _C1 - _C6 -Deuterylalkoxy, _C1 - _C6 -Hydroalkyl, C3- _C6 - _C6 -cycloalkyl, 4-6-membered heterocyclic, _C6 - _C10 aryl, 5-6-membered heteroaryl are optionally further substituted by one or more of hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, _C1 - _C3 alkyl, _C1 -C3 _- halogenyl, _C1 - _C3 alkoxy, and _C1 - _C3- halogenylalkoxy; preferably, _Rp is selected from methyl, ethyl, propyl, cyclopropyl, , , , , .

In some embodiments of the present invention, _L1 is selected from the key, NH, O, CO, CONH, and _L1 is the preferred key.

In some embodiments of the present invention, ^X1 is N. In some embodiments of the present invention, ^X2 is N.

In some embodiments of the present invention, ^X5 is N. In some embodiments of the present invention, ^X7 is N.

In some embodiments of the present invention, ^X2 and ^X7 are N. In some embodiments of the present invention, ^X1 , ^X2 , and ^X7 are N. In some embodiments of the present invention, ^X2 , ^X5 , and ^X7 are _N. In some embodiments of the present invention, ^X3 is ^CR3r . In some embodiments of the present invention, ^X4 is _CR4r . In some embodiments of the present invention, ^X6 _is ^CR6r . In some embodiments of the present invention, ^Y1 is selected from S or O. In some embodiments ^of the present invention, ^Y2 is selected _from ^CR9r . In some embodiments of the present invention, ^Y3 is selected _from ^CR10r . In some embodiments of the present invention, ^X7 is N or C. In some embodiments of the present invention, ^X8 is N.

In certain embodiments of the present invention _, ^R1r , _R2r , ^R3r , ^R4r , _R5r , ^R6r , ^R7r , ^R8r , ^R9r _, ^and _R10r are each independently selected from hydrogen, deuterium, _halogen , ^amino , _cyano , _nitro , ^hydroxyl , _C1 - _{C3 alkyl} , C1- _C3 alkoxy, _C1 - _C3 halogenated alkyl, _C1 - _C3 halogenated alkoxy, _C1 - _C3 deuterated alkyl, _C1 - _C3 deuterated alkoxy, _C1 - _C3 hydroxyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, _5-6 membered heteroaryl, _{C1 - C3} alkylene- ^R21 , ( _CH2 )OR ²¹ , ( _CH2 )NR ²¹ R ²² , ( _CH2 )COR ²³ , ( _CH2 )COOR ²¹ , ( _CH2 )CONR ²¹ R ²² , ( _CH2 )NR ²¹ COR ²³ , ( _CH2 )NR ²¹ COOR ²² , ( _CH2 )SOR ²³ , ( _CH2 )SONR ²¹ R ²² , ( _CH2 )SO ₂ R ²¹ , ( _CH2 )SO _2NR ²¹ R ²² ; wherein, the _C1 - _C3 alkyl, _C1 - _C3 alkoxy, _C1 - _C3 halogenated alkyl, _C1 - _C3 halogenated alkoxy, _C1 -C3 deuterated alkyl, _C1 - _{C3 deuterated} alkoxy, _C1 -C _{The 3-} hydroxyl group, _C3 -C6 cycloalkyl group, _4-6 membered heterocyclic group, phenyl group, and 5-6 membered heteroaryl group may optionally be further substituted by one or more of the following: deuterium, halogen, amino, _cyano , hydroxyl, nitro, oxo, thio, _C1 - _C6 alkyl, _{C1 - C6} alkoxy, _C1 - _C6 halogenated alkyl, _C1 - _C6 deuterated alkyl, _C1 -C6 deuterated alkoxy, C1- _C6 hydroxyl group, and _C1 - _C6 halogenated alkoxy.

In some embodiments of the present invention, m1 is 0, 1, 2 or 3.

In some embodiments of this invention, m2 and m3 are each independently 0 or 1, preferably 0.

This invention also provides a compound as shown below. Wherein, R ^N is selected from H or an amino protecting group; wherein the amino protecting group is selected from allyloxycarbonyl, trifluoroacetyl, tributylsulfinyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, methoxycarbonyl, 9-fluorenmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthalic acid dimethyl, tributyloxycarbonyl, benzyl, or p-methoxyphenyl; ^Ra1 , ^Ra2 , ^Ra4 , _L1 , cycloB, y, and ^Rb are defined as described above.

The present invention also provides a method for preparing a compound of formula (I''-10), formula (I''-14), formula (I''-15) or formula (I'-A'-1) or a pharmaceutically acceptable salt thereof: Method 1: reacting the compounds shown in formula (INT-3) and formula (INT-2) to prepare the compound shown in formula (I''-10), Method 2: React the compounds shown in formula (INT-3) and (INT'-2) to prepare the compound shown in formula (I''-14). Method 3: React the compounds shown in formula (INT-3) and (INT''-2) to prepare the compound shown in formula (I''-15). Method 4: React the compounds shown in formula (INT-4) and (INT'''-2) to prepare the compound shown in formula (I'-A'-4). Preferably, the reactions described in methods one to four are carried out in the presence of an organic base and a catalyst, wherein the base is an amide condenser; wherein R O  is selected from OH or C<sub> 1 -C 6 alkoxy;R N  is selected from H or an amino protecting group; wherein the amino protecting group is selected from allyloxycarbonyl, trifluoroacetyl, tri-butylsulfinyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, phosphoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthalyldimethyl, tri-butyloxycarbonyl, benzyl, or p-methoxyphenyl; R 4 r , R 9 r , R 10 r , Ra, R b , Ln r. 1. The definitions of ring A, ring B, x, y, Rf , Ra1 , Ra2 , Ra4 , L1 , Rb ' and Rb are as described above.

The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of the above-mentioned compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

In some embodiments of the present invention, the compound or its pharmaceutically acceptable salt constitutes 0.1% to 95% by weight in the composition, preferably 0.5% to 85%, more preferably 1% to 60%, further preferably 10% to 50%, even more preferably 15% to 40%, even more preferably 20% to 30%, and even more preferably 20% to 25% (based on the total weight of the pharmaceutical composition).

This invention further relates to the use of the compounds described above or their pharmaceutically acceptable salts, or the pharmaceutical compositions described above, in the preparation of a medicament for the preparation of a kinase inhibitor, preferably FMS (CSF1R), PDGFRβ, PDGFRα, FLT3, c-KIT kinase inhibitors, more preferably c-KIT kinase inhibitors, and even more preferably inhibitors exhibiting good selectivity for c-KIT.

This invention further relates to the use of the said compound or its pharmaceutically acceptable salt, or a pharmaceutical composition as described above, in the preparation of a medicament for treating c-KIT kinase-related diseases.

In a preferred embodiment of the present invention, the disease is selected from: mast cell-related diseases, respiratory diseases, inflammatory diseases, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), autoimmune diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary hypertension (PAH) or primary pulmonary hypertension (PPH); preferably, the disease is selected from: asthma, allergic rhinitis, pulmonary hypertension (PAH), and pulmonary fibrosis. For conditions such as fibrosis, liver fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, chronic urticaria, spontaneous chronic urticaria, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, gastrointestinal stromal tumor, mast cell tumor, mastocytosis, allergic reaction syndrome, type I or type II diabetes, urticaria or chronic urticaria are preferred.

This invention further relates to the method of preparing the said compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of mast cell-related diseases, respiratory diseases, inflammatory conditions, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), autoimmune diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary hypertension (PAH), or primary pulmonary hypertension (PPH).

This invention also relates to a method for treating, preventing, and/or treating mast cell-related diseases, respiratory diseases, inflammatory conditions, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), autoimmune diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary hypertension (PAH), or primary pulmonary hypertension (PPH), comprising administering to a patient a therapeutically effective dose of the compound as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

The present invention also provides a method for treating disease conditions using the compounds or drug combinations of the present invention, including but not limited to conditions related to FMS (CSF1R), PDGFRβ, PDGFRα, FLT3, c-KIT kinase inhibitors, with preference for c-KIT kinase dysfunction, and exhibiting good selectivity for c-KIT.

This invention also relates to methods for treating mast cell-related diseases, respiratory diseases, inflammatory conditions, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), autoimmune diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary hypertension (PAH), or primary pulmonary hypertension (PPH) in mammals, comprising administering to the mammal a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, prodrug, solvent, hydrate, or derivative thereof.

In some implementation protocols, this approach is used to treat conditions such as asthma, eosinophilic esophagitis, allergic rhinitis, pulmonary hypertension (PAH), pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, chronic urticaria, spontaneous chronic urticaria, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, gastrointestinal stromal tumor, mast cell tumor, mastocytosis, allergic reaction syndrome, type I or type II diabetes, with urticaria or chronic urticaria being preferred.

In some implementation protocols, urticaria or chronic urticaria includes acute urticaria, chronic spontaneous urticaria (IgE-mediated/IgG-mediated type II), and chronic inducible urticaria.

To make the above and other objects, features and advantages of this invention more apparent, embodiments are described below in detail with reference to the accompanying drawings.

Unless otherwise stated, the terms used in the specification and the scope of the patent application shall have the following meanings.

Unless otherwise stated, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains, and specifically, the terms used in the specification and the scope of the patent application have the following meanings.

The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, which may optionally be substituted by one or more substituents. In a particular embodiment, an alkyl group refers to a straight-chain saturated hydrocarbon having 1 to 20 ( _C1 - _C20 ), 1 to 15 ( _C1 - _C15 ), 1 to 12 ( _C1 - _C12 ), 1 to 10 ( _C1 - _C10 ), 1 to 8 ( _C1 - _C8 ), 1 to 6 ( _C1 - _C6 ), or 1 to 3 ( _C1 - _C3 ), or a branched saturated hydrocarbon having 3 to 20 ( _C3 - _C20 ), 3 to 15 ( _C3 - _C15 ), 3 to 12 ( _C3 - _C12 ), 3 to 10 ( _C3 - _C10 ), 3 to 8 ( _C3 - _C8 ), or 3 to 6 ( _C3 - _C6 ). The straight-chain C1 _{- C6} alkyl and branched C3 _{- C6} alkyl groups used herein are also referred to as "lower alkyl groups". For example, C1 _{- C6} alkyl refers to a linear saturated monovalent hydrocarbon having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon having 3 to 6 carbon atoms. In one embodiment, the C1 _{- C6} alkyl contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tributyl, dibutyl, 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. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, wherein "alkyl" is defined as previously stated. Non-limiting examples of "alkylene" include methylene ( _-CH₂- ), ethylene (-( _CH₂ ) _₂- ), propylene (-( _CH₂ ) _₃- ), or butylene (-( _CH₂ ) _₄- ). In one embodiment, the alkylene is an alternatively substituted alkyl group as described elsewhere herein.

The term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which can be located at any position within the alkenyl group, which may be optionally substituted by one or more substituents. In a particular embodiment, the alkenyl group is a straight-chain unsaturated hydrocarbon having 2 to 20 ( _C2 - _C20 ), 2 to 15 ( _C2 - _C15 ), 2 to 12 ( _C2 - _C12 ), 2 to 10 ( _C2 - _C10 ), 2 to 8 ( _C2 - _C8 ), 2 to 6 ( _C2 - _C6 ), or 2 to 4 ( _C2 - _C4 ) carbon atoms, or a branched unsaturated hydrocarbon having 3 to 20 ( _C3 - _C20 ), 3 to 15 ( _C3 - _C15 ), 3 to 12 ( _{C3 - C12} ), 3 to 10 (C3- _C10 ), 3 to 8 ( _C3 - _C8 ), or 3 to 6 ( _C3 - _C6 ) carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both linear and branched alkenyl groups. For example, a _C2 - _C6 alkenyl group refers to a linear unsaturated hydrocarbon having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon having 3 to 6 carbon atoms. In one embodiment, the _C2 - _C6 alkenyl group contains 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms. Non-limiting examples of alkenyl groups include: , , , , or As will be understood by those skilled in the art to which this invention pertains, the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl as described elsewhere herein.

The term "alkynyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which can be located at any position within the alkynyl group, and the alkynyl group can be optionally substituted by one or more substituents. In a particular embodiment, the alkynyl group is a straight-chain unsaturated hydrocarbon having 2 to 20 ( _C2 - _C20 ), 2 to 15 ( _C2 - _C15 ), 2 to 12 ( _C2 - _C12 ), 2 to 10 ( _C2 - _C10 ), 2 to 8 ( _C2 - _C8 ), 2 to 6 ( _C2 - _C6 ), or 2 to 4 ( _C2 - _C4 ) carbon atoms, or a branched unsaturated hydrocarbon having 3 to 20 ( _C3 - _C20 ), 3 to 15 ( _C3 - _C15 ), 3 to 12 ( _{C3 - C12} ), 3 to 10 (C3- _C10 ), 3 to 8 ( _C3 - _C8 ), or 3 to 6 ( _C3 - _C6 ) carbon atoms. Unless otherwise specified, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, a _C2 - _C6 alkynyl group refers to a straight-chain unsaturated hydrocarbon having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon having 3 to 6 carbon atoms. In one embodiment, the _C2 -C6 alkynyl group contains 2 to ₆ (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkynyl groups include: , , or In one embodiment, the alkynyl group is an optionally substituted alkynyl group as described elsewhere herein.

The term "cycloalkyl" refers to a saturated or partially unsaturated aliphatic hydrocarbon monocyclic or polycyclic (two or more) cyclic group, which may optionally be substituted with one or more substituents. In a particular embodiment, the cycloalkyl ring contains 3 to 20 ( _C3 - _C20 ), 3 to 12 ( _C3 - _C12 ), 3 to 10 ( _C3 - _C10 ), 3 to 8 ( _C3 - _C8 ), or 3 to 6 ( _C3 - _C6 ); in one embodiment, the cycloalkyl ring contains 6 to 14 ( _C6 - _C14 ) or 7 to 10 ( _C7 - _C10 ); it may contain one or more double bonds, but does not have a fully conjugated π-electron system. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, or cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl groups in one embodiment. In one embodiment, the cycloalkyl group is an optionally substituted cycloalkyl group or an optionally fused cycloalkyl group with a heterocyclic, aryl, or heteroaryl group as described elsewhere herein, with non-limiting examples including indaminozyl, tetrahydronaphthyl, benzocycloheptyl, etc.

The term "spirocycloalkyl" refers to an aliphatic polycyclic group in which a single carbon atom (called a spiro atom) is shared between the rings. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spirocycloalkyl group contains 5 to 20 (C ₅ -C ₂₀ ), 6 to 14 (C ₆ -C ₁₄ ), or 7 to 10 (C ₇ -C ₁₀ ) carbon atoms (e.g., 7, 8, 9, 10). Spirocycloalkyl groups are classified as monospirocycloalkyl, dispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings; in one embodiment, they are monospirocycloalkyl and dispirocycloalkyl. In one embodiment, the spirocycloalkyl group is a quaternary/quaternary, tert- or quinary, quaternary/quinary, quaternary/six-membered, quinary/quinary, or quinary/six-membered monospirocycloalkyl group. In one embodiment, the spirocycloalkyl group is an optionally substituted spirocycloalkyl group as described elsewhere herein. Non-limiting examples of spirocycloalkyl groups include: .

The term "fused cycloalkyl" refers to a polycyclic aromatic hydrocarbon group in which each ring shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In a particular embodiment, the fused cycloalkyl group comprises 5 to 20 (C ₅ -C ₂₀ ), 6 to 14 (C ₆ -C ₁₄ ), or 7 to 10 (C ₇ -C ₁₀ ) carbon atoms (e.g., 7, 8, 9, 10). Based on the number of constituent rings, fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. In one embodiment, they are bicyclic or tricyclic, and in another embodiment, they are 3-membered/5-membered, 4-membered/5-membered, 5-membered/5-membered, or 5-membered/6-membered bicyclic alkyl groups. In one embodiment, the fused cycloalkyl group is an optionally substituted fused cycloalkyl group described elsewhere herein or an fused cycloalkyl group optionally fused with a heterocyclic, aryl, or heteroaryl group. Non-limiting examples of fused cycloalkyl groups include: , , , , , or .

The term "bridged cycloalkyl" refers to a polycyclic aromatic hydrocarbon group in which any two rings share two non-directly linked carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the bridged cycloalkyl group comprises 5 to 20 ( _C5 - _C20 ), 6 to 14 ( _C6 - _C14 ), or 7 to 10 ( _C7 - _C10 ) carbon atoms (e.g., 7, 8, 9, 10). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups, preferably bicyclic or tricyclic. In one embodiment, the bridged cycloalkyl group is an optionally substituted bridged cycloalkyl group as described elsewhere herein. Non-limiting examples of bridged cycloalkyl groups include: .

The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, wherein the nitrogen, phosphorus or sulfur atom may be oxidized, the nitrogen atom may be quaternized, the ring carbon atom may be substituted with oxygen, but excluding the -O-O- or -O-S- ring moieties, and the remaining ring atoms are carbon, which may contain one or more double bonds, but does not have a fully conjugated π-electron system. In a particular embodiment, the heterocyclic base comprises 3 to 20, 3 to 12, 3 to 10, 3 to 8, 4 to 10, 4 to 8, 3 to 6, or 4 to 6 ring atoms, of which 1 to 4 are heteroatoms, such as nitrogen, oxygen, or sulfur; in one embodiment, the heterocyclic base comprises 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10, or 7 to 11 ring atoms; in one embodiment, the heterocyclic base comprises 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) ring atoms. Non-limiting examples of monocyclic heterocyclic groups include tetrahydropyrroleyl, azirmonobutyl, oxocyclobutyl, oxocyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrroleyl, piperidinyl, piperidine, morpholinyl, thiomorpholinyl, homopiperidine, and pyranyl. Polycyclic heterocyclic groups include spirocyclic, fused heterocyclic, and bridged heterocyclic groups. In one embodiment, the heterocyclic group is optionally substituted as described elsewhere herein, or is a heterocyclic group further circumcyclicly linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which rings share a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, a spiroheterocyclic group contains 5 to 20 or 6 to 14 ring atoms; in one embodiment, it contains 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; spiroheterocyclic groups are classified as monospirocyclic, dispirocyclic, or polyspirocyclic groups based on the number of spiro atoms shared between the rings. Preferred are mono- and bi-spirocyclic heterocyclic bases; in one embodiment, the spirocyclic base is a quaternary/quaternary, quaternary/quinary, quaternary/hexanal, quinary/quinary, or quinary/hexanal mono-spirocyclic base; in another embodiment, the spirocyclic base is an alternatively substituted spirocyclic base described elsewhere herein; non-limiting examples of the spirocyclic base include: , , , , , , , , , , , , or .

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In a particular embodiment, the fused heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms, and in one embodiment comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic group according to the number of constituent rings; bicyclic or tricyclic is preferred; in one embodiment it is a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group; in one embodiment, the fused heterocyclic group is optionally substituted as described elsewhere herein, or is a fused heterocyclic group that can be fused with cycloalkyl, heterocyclic, aryl, or heteroaryl groups; non-limiting examples of fused heterocyclic groups include: , , , , , , , , , , , , , , , , , , , , , or .

The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In a particular embodiment, the bridging heterocyclic base comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; it can be classified as a bicyclic, tricyclic, tetracyclic, or multicyclic bridging heterocyclic base according to the number of constituent rings; preferably bicyclic, tricyclic, or tetracyclic; in one embodiment, it is bicyclic or tricyclic; in one embodiment, the bridging heterocyclic base is an optionally substituted bridging heterocyclic base described elsewhere herein; non-limiting examples of bridging heterocyclic bases include: , , , , , , , or .

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group containing at least one conjugated π-electron system, which may optionally be substituted by one or more substituents. In a particular embodiment, the aryl group comprises 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring, and the other rings may be saturated, partially unsaturated carbon rings, or rings containing one or more heteroatoms independently selected from O, S, and N. In one embodiment, the aryl group is selected from benzo5-10-membered heteroaryl, benzo3-10-membered cycloalkyl, or benzo3-10-membered heterocycloyl. In another embodiment, the aryl group is selected from benzo5-6-membered heteroaryl, benzo3-6 (e.g., 5-6)-membered cycloalkyl, or benzo3-6 (e.g., 5-6)-membered heterocycloyl, wherein the heterocycloyl group is a heterocycloyl group containing 1-3 nitrogen, oxygen, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, chamomileyl, anthraceneyl, phenanthryl, pyrene, biphenyl, terphenyl, dihydronaphthyl, indyl, tetrahydronaphthyl (naphthyl), etc. , , , , , , , , , , , , and .

The term "arylene" refers to a divalent aryl group formed by further substitution of one hydrogen atom of an aryl group. In this case, the arylene group can be substituted or unsubstituted, as defined above.

The term "heteroaryl" refers to a monocyclic, polycyclic or cyclic system comprising at least one aromatic ring, wherein the aromatic ring has one or more heteroatoms independently selected from O, S and N. In a particular embodiment, the heteroaryl group comprises 5 to 20, 5 to 15, or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl group comprises 5 or 6 ring atoms; in a particular embodiment, the heteroaryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the other rings may be saturated or partially unsaturated carbocyclic rings or rings containing one or more heteroatoms independently selected from O, S, and N. In one embodiment, the heteroaryl group is selected from heteroaryl-6-10 aryl, heteroaryl-3-10 cycloalkyl, or heteroaryl-3-10 heterocyclic groups; further in another embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl-6-10 aryl, 5- or 6-membered heteroaryl-3-6 cycloalkyl, or 5- or 6-membered heteroaryl-3-6 heterocyclic groups, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include: furanyl, imidazolyl, isothiazolyl, isothiazolyl, acediazolyl, acezolyl, pyrazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrololyl, thiadiazolyl, thiazolyl, thiophene, tetrazolyl, triazolyl, triazolyl, benzofuranyl, benzimidazolyl, benzoisoazolyl, benzopyranyl, benzothiadiazolyl, benzothiaphenyl, benzobenzenethio, benzothiaphenyl, benzotriazolyl, imidazopyridyl, imidazothiazolyl Indole, indolyl, inzolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolinyl, naphridyl, thiazopyridyl, phthaloyl, pteridinyl, purine, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazopyrimidinyl, thiaphenopyridyl, acridineyl, benzoindolyl, zozopyranyl, bibenzofuranyl, phenanthrololinyl, phenanthidyl, phenpyryl, phenylyl, phenthiayl, phenanthioyl, xantonyl, , , , , , , , , , , , , , , , , , .

The term "hybrid aryl" refers to a divalent heteroaryl group formed by further substitution of one hydrogen atom of a cycloalkyl group, wherein the heteroaryl group can be substituted or unsubstituted, as defined above.

The term "heteroalkyl" refers to a stable linear or branched, or cyclic, hydrocarbon, or combination thereof, consisting of a specified number of carbon atoms and one or more (one to three in one embodiment) heteroatoms selected from O, N, Si, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom may optionally be quaternarily amination-treated. In one embodiment, the heteroatoms O, N, and S may be placed at any internal position within the heteroalkyl group. In one embodiment, the heteroatom Si may be placed at any position within the heteroalkyl group (e.g., internal or terminal), including positions where the alkyl group is attached to the remainder of the molecule. Non-limiting examples include: _-CH₂ - _CH₂ -O- _CH₃ , _-CH₂ - _CH₂ -NH- _CH₃ , _-CH₂ - _CH₂ -N( _CH₃ ) _-CH₃ , _-CH₂ -S-CH₂- _CH₃ , _-CH₂ - _CH₂ -S(O) _-CH₃ , _{-CH₂ - CH₂} -S(O) _₂ - _CH₃ , -CH＝CH-O- _CH₃ , -Si( _CH₃ ) _₃ , _-CH₂ -CH＝N- _OCH₃ , and -CH＝CH-N( _CH₃ ) _-CH₃ . At most two heteroatoms can be consecutive, for example, _-CH₂ -NH-O- _CH₃ and _-CH₂ -O-Si( _CH₃ ) _₃ . In a particular embodiment, the heteroalkyl group is an optionally substituted heteroalkyl group as described elsewhere herein.

The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl or cycloalkyl is defined as previously stated. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy. In one embodiment, the alkoxy group is an optionally substituted alkoxy group as described elsewhere herein.

The term "alkyl acetyl" refers to -C(O)-alkyl, where alkyl is defined as described above.

The term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the definition of alkyl is as described above. Non-limiting examples of said halogenated alkyl groups include: trifluoromethyl, _{-CH₂CF₃ ,} or .

The term "halogenated alkoxy" refers to an alkoxy group that is substituted by one or more halogens, with the definition of alkoxy group as described above.

The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group, and the definition of alkyl is the same as described above.

The term "alkathio" refers to -S- (alkyl) and -S- (unsubstituted cycloalkyl), wherein the alkyl or cycloalkyl group is defined as previously described. Non-limiting examples of alkathio groups include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, or cyclohexylthio. In one embodiment, the alkathio group is an optionally substituted alkathio group as described elsewhere herein.

The term "halogenated alkylthio" refers to an alkylthio group that is substituted by one or more halogens, where the definition of alkylthio is as described above.

The term "alkenyl carbonyl" refers to -C(O)-(alkenyl), where alkenyl is defined as previously stated. Non-limiting examples of alkenyl carbonyl include vinyl carbonyl, propenyl carbonyl, or butenyl carbonyl. In one embodiment, the alkenyl carbonyl is an optionally substituted alkenyl carbonyl as described elsewhere herein.

The term "aminocarbonyl" refers to NH₂ _- C(O)-.

The term "alkylaminocarbonyl" refers to an aminocarbonyl group (NH ₂ -C(O)-) in which one or both of the two hydrogen atoms are replaced by an alkyl group, wherein the definition of alkyl is as described above.

The term "alkylamine" refers to an amino group in which one or both of the two hydrogen atoms are replaced by an alkyl group, with the definition of alkyl as described above.

The term "carbonyl" refers to the -C(O)-, -(CO)-, or -C(=O)- group. All designations are interchangeable in the manual.

The term "hydroxyl" refers to the -OH group.

The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

The term "amine" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "carboxyl group" refers to -C(O)OH.

The term "acetylated" refers to -C(O) _CH3 .

The term "oxo" or "lateral oxygen" refers to O.

The term "巰基" refers to -SH.

The term "hydrogen" includes protons ( ^¹H ), deuterium ( ^²H ), tritium ( ^³H ), and/or mixtures thereof. In certain embodiments, one or more hydrogen-occupied sites in a compound may be enriched with deuterium and/or tritium. Such isotope-enriched analogs can be prepared using suitable isotopically labeled starting materials available from commercial sources or by known literature procedures.

This invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that can be listed as compounds of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as ^2H , ^3H , ^13C , ^11C , ^14C , ^15N , ^18O , ^17O , ^31P , ^32P , ^35S , ^18F , and ^36Cl , respectively. Isotopically labeled compounds can be prepared using general methods, by replacing the non-isotopic reagents with readily available isotopically labeled reagents, according to the schemes disclosed in the examples.

The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloyl, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacetyl groups may be substituted or unsubstituted. In one embodiment, the substituent is selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacetyl, halogen, teryl, hydroxyl, nitro, cyano, azido, oxime, phosphate ester, oxo, thio, carboxyl, carboxylic acid ester, cycloalkyl, heterocycloyl, aryl, heteroaryl, heterocycloalkoxy, cyclothio, or heterocyclothio.

The different terms "X is chosen from A, B, or C", "X is chosen from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

Unless otherwise specified, when a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, _-CH₂O- is equivalent to _-OCH₂- , and -CONH- is equivalent to -NHCO-.

In this application, " "or" The symbol "" indicates the connection location of the group. The key extending into the ring ( This refers to a connection at any available toroidal apex, such as a group. middle, key ( It can be attached to any connectable position of the ring, and its substituents ^Rc and/or ^Rd can replace any hydrogen atom on the ring, including any hydrogen on the carbon atom and any hydrogen on the nitrogen atom.

In certain embodiments of this invention, This represents a ring system in which rings C, D, and E are fused pairwise, for example... .

"Optional" or "optional location" means that the event or environment described thereafter may but does not have to occur, and the description includes the circumstances in which the event or environment may or may not occur. For example, "optionally alkyl-substituted heterocyclic groups" means that alkyl groups may but do not have to be present, and the description includes cases where heterocyclic groups are substituted with alkyl groups and cases where heterocyclic groups are not substituted with alkyl groups.

Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

"Substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, provided that the valence state of the specific atom is normal and the substituted compound is stable in one embodiment. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on the basis of chemical feasibility. It goes without saying that substituents are only in their possible chemical positions, and those skilled in the art to which this invention pertains can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

Unless stated to the contrary, the indefinite articles “a” and “an” and the definite article “the” in this specification and the scope of the patent application include both plural and singular forms.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or their physiologically/pharmacologically acceptable salts or prodrugs, with other chemical components, such as physiologically/pharmacologically acceptable carriers and excipients. The purpose of pharmaceutical compositions is to facilitate drug delivery to organisms, enhance the absorption of the active ingredient, and thereby exert its biological activity.

"Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity.

"Stage isomers" encompass all enantiomers/non-enantiomers/stereoisomers of the present invention, as well as compounds enriched with enantiomers/non-enantiomers/stereoisomers.

"Statomeric purity" refers to a composition containing one stereoisomer of a compound but essentially none of its other stereoisomers. For example, a stereoisomer of a compound having one chiral center will essentially contain none of its corresponding enantiomers. A stereoisomer of a compound having two chiral centers will essentially contain none of its other diastereoisomers. A typical stereoisomer of a pure compound comprises, by mass, more than about 80% of one stereoisomer of the compound and less than about 20% of another stereoisomer of the compound; more than about 90% of one stereoisomer of the compound and less than about 10% of another stereoisomer of the compound; more than about 95% of one stereoisomer of the compound and less than about 5% of another stereoisomer of the compound; more than about 97% of one stereoisomer of the compound and less than about 3% of another stereoisomer of the compound; or more than about 99% of one stereoisomer of the compound and less than about 1% of another stereoisomer of the compound.

"Stereoisomeric enrichment" refers to a composition of stereoisomers of a compound comprising more than about 55%, more than about 60%, more than about 70%, or more than about 80% by mass.

"Enantiomeric pure" refers to a stereoisomeric pure composition of a compound having a single chiral center. Similarly, the term "enantiomeric enrichment" refers to a stereoisomeric enriched composition of a compound having a single chiral center.

"Optical activity" and "enantiomeric activity" refer to a molecular combination having an enantiomer excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In a particular embodiment, the compound comprises about 95% or more of the desired enantiomer or diastereomer by weight of the racemate and about 5% or less of the subpreferred enantiomer or diastereomer.

In describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the molecule relative to its chiral center. (+) and (-) are used to indicate the optical rotation of the compound, that is, the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) for optical rotation are independent of the absolute configurations R and S of the molecule.

The invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.

Implementation Examples

The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR determinations were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl monoxide (DMSO - _d6 ), deuterated methanol ( _CD3OD ), and deuterated chloroform ( _CDCl3 ), and tetramethylsilane (TMS) as the internal standard.

The determinations by liquid chromatography-mass spectrometry (LC-MS) were performed using an Agilent 1200 Infinity Series mass spectrometer. The determinations by HPLC were performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C ₁₈ 150 × 4.6 mm column).

Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silicone plates. The standard thickness for TLC is 0.15 mm to 0.20 mm, while the standard thickness for separating and purifying products is 0.4 mm to 0.5 mm. Column chromatography generally uses Yantai Huanghai silicone 200-300 mesh as the carrier.

The starting materials used in this embodiment of the invention are known and commercially available, or can be synthesized using methods known in the art.

Unless otherwise specified, all reactions of this invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is measured in degrees Celsius.

Preparation of intermediate 2-(5-cyclopropylisoazol-3-yl)-5-methylpyridin-4-amine

Step 1: Preparation of 5-methyl-4-nitro-pyridine-2-carboxaldehyde oxime 5-Methyl-4-nitro-pyridine-2-carboxaldehyde (12 g, 72.23 mmol) was dissolved in ethanol (80 mL), and 50% aqueous hydroxylamine solution (5 mL) was added. The reaction mixture was heated and stirred at 80°C for 1 h. The solvent was removed by depressurization to obtain the crude compound 5-methyl-4-nitro-pyridine-2-carboxaldehyde oxime (12.5 g, 95.5%), which was used directly in the next step. MS m/z (ESI): 182.0 [M+H] ⁺ .

Step 2: Preparation of 5-cyclopropyl-3-(5-methyl-4-nitro-2-pyridyl)isoxaazole 5-Methyl-4-nitro-pyridine-2-carboxaldehyde oxime (12.5 g, 69.00 mmol) and cyclopropylacetylene (9.12 g, 138.01 mmol) were dissolved in methanol (100 mL)/water (20 mL) under ice bath conditions. [bis(trifluoroacetoxy)iodide]benzene (44.51 g, 103.51 mmol) was added, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was diluted with ethyl acetate and washed successively with saturated sodium carbonate solution and saturated brine to separate the organic phase. The organic phase was dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (10.6 g, 62.6%). MS m/z (ESI): 246.1 [M+H] ⁺ .

Step 3: Preparation of 2-(5-cyclopropylisoazol-3-yl)-5-methylpyridine-4-amine 5-Cyclopropyl-3-(5-methyl-4-nitro-2-pyridyl)isoxaazole (8.4 g, 34.25 mmol) was dissolved in ethanol (100 mL), and zinc powder (11.20 g, 171.27 mmol) and acetic acid (10 mL) were added. The reaction solution was heated and stirred at 80°C for 6 h. The reaction solution was diluted with ethyl acetate and washed successively with saturated sodium carbonate solution and saturated brine. The organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (3.3 g, 44.8%). MS m/z (ESI): 216.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.98 (s, 1H), 7.15 (s, 1H), 6.55 (s, 1H), 6.03 (s, 2H), 2.20-2.11 (m, 1H), 2.04 (s, 3H), 1.13 - 1.02 (m, 2H), 1.00 - 0.87 (m, 2H).

Preparation of the intermediate methyl 3-(3-(4-amino-5-methylpyridin-2-yl)isoazol-5-yl)acetidine-1-carboxylic acid

Step 1: Preparation of (2-methoxy-5-methylpyridin-4-yl)aminocarbamate tributyl ester At room temperature, tributyl 2-bromo-5-methylpyridin-4-yl)aminocarbamate (600.8 mg, 2.1 mmol) was dissolved in tetrahydrofuran (8 mL), cooled to -78°C, and n-butyllithium (3.3 mL, 5.3 mmol) was added dropwise. After the addition was complete, the mixture was stirred at -78°C for 30 minutes. Nitrodimethylformamide (766.5 mg, 10.5 mmol) was added dropwise, and the mixture was stirred at -78°C for 30 minutes. The reaction mixture was added to a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude tributyl (2-methoxy-5-methylpyridin-4-yl)aminocarbamate (495.6 mg, 100%), which was used directly in the next reaction. MS m/z (ESI): 237.1 [M+H] ⁺ .

Step 2: Preparation of tributyl (2-((oxime)methyl)-5-methylpyridin-4-yl)aminocarbamate At room temperature, tributyl (2-methoxy-5-methylpyridin-4-yl)aminocarbamate (495.6 mg, 2.1 mmol) was dissolved in ethanol (8 mL), and 50% aqueous hydroxylamine solution (693.0 mg, 10.5 mmol) was added. The mixture was stirred at room temperature for 10 hours. The reaction solution was concentrated to give crude tributyl (2-((oxime)methyl)-5-methylpyridin-4-yl)aminocarbamate (527.1 mg, 100%), which was used directly in the next reaction. MS m/z (ESI): 252.1 [M+H] ⁺ .

Step 3: Preparation of 3-(3-(4-((tert-butoxycarbonyl)amino)-5-methylpyridin-2-yl)isoazol-5-yl)acetidine-1-carboxylic acid tributyl ester At room temperature, tributyl (2-((oxime)methyl)-5-methylpyridin-4-yl)aminocarboxylate (527.1 mg, 2.1 mmol) was dissolved in tetrahydrofuran/methanol/water (5 mL/5 mL/2 mL), and tributyl 3-ethynylacrylidine-1-carboxylic acid (760.2 g, 4.2 mmol) and [bis(trifluoroacetoxy)iodo]benzene (2.7 g, 6.3 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was added to a saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to give the target compound (284.1 mg, 31%). MS m/z (ESI): 431.2 [M+H] ⁺ .

Step 4: Preparation of 2-(5-(acetidin-3-yl)isoazol-3-yl)-5-methylpyridine-4-amine At room temperature, 3-(3-(4-((tri-butoxycarbonyl)amino)-5-methylpyridin-2-yl)isoazol-5-yl)acetidine-1-carboxylic acid tributyl ester (284.1 mg, 0.66 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give crude 2-(5-(acetidine-3-yl)isoazol-3-yl)-5-methylpyridin-4-amine (151.8 mg, 100%), which was used directly in the next reaction. MS m/z (ESI): 231.1 [M+H] ⁺ .

Step 5: Preparation of methyl 3-(3-(4-amino-5-methylpyridin-2-yl)isoazol-5-yl)acetidine-1-carboxylic acid At room temperature, 2-(5-(acetidin-3-yl)isoazol-3-yl)-5-methylpyridin-4-amine (151.8 mg, 0.66 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, and triethylamine (333.3 mg, 3.3 mmol) was added. Dimethyl dicarbonate (176.9 mg, 1.32 mmol) was added dropwise, and the mixture was stirred at 0°C for 1 hour. The reaction solution was added to a saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to give the target compound (169.6 mg, 89%), which was used directly in the next reaction. MS m/z (ESI): 289.1 [M+H] ⁺ .

Preparation of the intermediate methyl 3-[3-(5-amino-2-fluoro-4-methyl-phenyl)isoazol-5-yl]azacyclobutane-1-carboxylate

Step 1: Preparation of 2-fluoro-4-methyl-5-nitrobenzaldehyde oxime 2-Fluoro-4-methyl-5-nitrobenzaldehyde (5 g, 27.30 mmol) was dissolved in ethanol (50 mL), and 50% aqueous hydroxylamine solution (5 mL) was added. The reaction mixture was heated and stirred at 80°C for 1 h. The solvent was removed by depressurization to obtain the crude compound 2-fluoro-4-methyl-5-nitrobenzaldehyde oxime (5.1 g, 94.3%), which was used directly in the next step. MS m/z (ESI): 199.0 [M+H] ⁺ .

Step 2: Preparation of 3-[3-(2-fluoro-4-methyl-5-nitrophenyl)isoazol-5-yl]azacyclobutane-1-carboxylic acid tributyl ester Under ice bath conditions, 2-fluoro-4-methyl-5-nitrobenzaldehyde oxime (5.10 g, 25.74 mmol) and tributyl 3-alkynyl-1-azacyclobutanecarboxylate (5.60 g, 30.89 mmol) were dissolved in methanol (50 mL)/water (10 mL), and [bis(trifluoroacetoxy)iodide]benzene (16.60 g, 38.61 mmol) was added. The reaction mixture was stirred at room temperature for 12 h. The reaction solution was diluted with ethyl acetate and washed successively with saturated sodium carbonate solution and saturated brine to separate the organic phase. The organic phase was dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (4.89 g, 50.4%). MS m/z (ESI): 378.1 [M+H] ⁺ .

Step 3: Preparation of methyl 3-[3-(2-fluoro-4-methyl-5-nitrophenyl)isoazol-5-yl]azacyclobutane-1-carboxylate 3-[3-(2-fluoro-4-methyl-5-nitrophenyl)isoazol-5-yl]azacyclobutane-1-carboxylic acid tributyl ester (4.89 g, 12.96 mmol) was dissolved in DCM (20 mL)/4M HCl dioxane (5 mL) and stirred at room temperature for 30 min. The reaction solution was depressurized to remove the solvent, and the residue was dissolved in DCM (20 mL). Triethylamine (8.01 g, 79.11 mmol, 11.03 mL) was added, and dimethyl dicarbonate (2.55 g, 18.99 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 1 h. The reaction solution was diluted with ethyl acetate and washed successively with saturated ammonium chloride solution and saturated brine to separate the organic phase. The organic phase was dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (3.83 g, 88.2%). MS m/z (ESI): 336.1 [M+H] ⁺ .

Step 4: Preparation of methyl 3-[3-(5-amino-2-fluoro-4-methyl-phenyl)isoazol-5-yl]azacyclobutane-1-carboxylate Methyl 3-[3-(2-fluoro-4-methyl-5-nitrophenyl)isoazol-5-yl]azacyclobutane-1-carboxylate (3.83 g, 11.42 mmol) was dissolved in ethanol (80 mL), and zinc powder (3.73 g, 57.12 mmol) and acetic acid (10 mL) were added. The reaction solution was heated and stirred at 80°C for 6 h. The reaction solution was diluted with ethyl acetate and washed successively with saturated sodium carbonate solution and saturated brine solution to separate the organic phase. The organic phase was dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (2.75 g, 78.9%). MS m/z (ESI): 306.1 [M+H] ⁺ .

Preparation of the intermediate methyl 3-(5-(4-amino-5-methylpyridin-2-yl)isoazol-3-yl)acetidine-1-carboxylic acid

Step 1: Preparation of 3-((oxime)methyl)acetidine-1-carboxylic acid tributyl ester At room temperature, 3-methoxyazino-1-carboxylic acid tributyl ester (5.0 g, 27.0 mmol) was dissolved in ethanol (50 mL), and 50% aqueous hydroxylamine solution (8.9 g, 135.0 mmol) was added. The mixture was stirred at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure to obtain crude 3-((oxime)methyl)azino-1-carboxylic acid tributyl ester (5.4 g, 100%), which was used directly in the next reaction. MS m/z (ESI): 201.1 [M+H] ⁺ .

Step 2: Preparation of N-(2-bromo-5-methyl-4-pyridyl)-N-tert-butyl butyrylaminocarbamate 2-Bromo-5-methylpyridin-4-amine (10 g, 53.47 mmol) was dissolved in THF (200 mL), DMAP (1.31 g, 10.69 mmol) and triethylamine (16.23 g, 160.40 mmol, 22.37 mL) were added, and dibutyl dicarbonate (29.17 g, 133.66 mmol) was slowly added under ice bath conditions. The mixture was stirred at room temperature for 12 h. The reaction solution was diluted with ethyl acetate and washed successively with saturated sodium carbonate solution and saturated brine to separate the organic phase. The organic phase was dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (16.6 g, 80.2%). MS m/z (ESI): 387.1 [M+H] ⁺ .

Step 3: Preparation of N-tertiary butoxycarbonyl-N-[5-methyl-2-(2-trimethylsilylethynyl)-4-pyridyl]aminocarbamate tributyl ester N-(2-bromo-5-methyl-4-pyridyl)-N-tert-butoxycarbonylaminocarbamate tributyl ester (16.6 g, 42.86 mmol) and trimethylsilylacetylene (12.63 g, 128.59 mmol) were dissolved in THF (200 mL), and CuI (816.35 mg, 4.29 mmol), Pd( _PPh3 ) _2Cl2 (3.01 g, 4.29 mmol) and triethylamine (21.69 g, 214.32 mmol, 29.89 mL) were added _. The mixture was heated at 50°C and stirred for 2 h. The reaction solution was diluted with ethyl acetate and washed successively with saturated sodium carbonate solution and saturated brine to separate the organic phase. The organic phase was dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (12.8 g, 73.8%). MS m/z (ESI): 405.2 [M+H] ⁺

Step 4: Preparation of N-tertiary butoxycarbonyl-N-(2-ethynyl-5-methyl-4-pyridyl)carbamate tributyl ester Under ice bath conditions, N-tertiary butylcarbamate (12.8 g, 31.64 mmol) was dissolved in THF (200 mL), and a tetrahydrofuran solution of TBAF (1 M, 34.8 mL, 34.80 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was diluted with ethyl acetate and washed successively with saturated sodium carbonate solution and saturated brine. The organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (8.4 g, 81.1%). MS m/z (ESI): 333.2 [M+H] ⁺ .

Step 5: Preparation of 3-(5-(4-(di(tert-butoxycarbonyl)amino)-5-methylpyridin-2-yl)isoazol-3-yl)acetidine-1-carboxylic acid tributyl ester At room temperature, N-tertiary butoxycarbonyl-N-(2-ethynyl-5-methyl-4-pyridyl)aminocarboxylic acid tributyl ester (2.5 g, 7.5 mmol) was dissolved in tetrahydrofuran/methanol/water (20 mL/20 mL/8 mL), and 3-((oxime)methyl)acetidine-1-carboxylic acid tributyl ester (4.5 g, 22.5 mmol) and [bis(trifluoroacetoxy)iodo]benzene (9.7 g, 22.5 mmol) were added and stirred at room temperature for 16 hours. The reaction solution was added to a saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was separated by column chromatography to obtain the target compound (3.3 g, 83%). MS m/z (ESI): 531.3 [M+H] ⁺ .

Step 6: Preparation of 2-(3-(acetidin-3-yl)isoazol-5-yl)-5-methylpyridin-4-amine At room temperature, 1.0 g (1.9 mmol) of tributyl 3-(5-(4-(di(tert-butoxycarbonyl)amino)-5-methylpyridin-2-yl)isoazol-3-yl)acetidine-1-carboxylic acid was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated to give crude 2-(3-(acetidine-3-yl)isoazol-5-yl)-5-methylpyridin-4-amine (437.0 mg, 100%), which was used directly in the next reaction. MS m/z (ESI): 231.1 [M+H] ⁺ .

Step 7: Preparation of methyl 3-(5-(4-amino-5-methylpyridin-2-yl)isoazol-3-yl)acetidine-1-carboxylic acid At room temperature, 2-(3-(acetidin-3-yl)isoazol-5-yl)-5-methylpyridin-4-amine (437.0 mg, 1.9 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, and triethylamine (959.5 mg, 9.5 mmol) was added. Dimethyl dicarbonate (388.6 mg, 2.9 mmol) was added dropwise, and the mixture was stirred at 0°C for 1 hour. The reaction solution was then added to a saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to give the target compound (366.1 mg, 67%). MS m/z (ESI): 289.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.01 (s, 1H), 7.09 (s, 1H), 6.98 (s, 1H), 6.14 (s, 2H), 4.35-4.22 (m, 2H), 4.16 -3.94 (m, 3H), 3.35 (s, 3H), 2.06 (s, 3H).

Preparation of the intermediate 2-(3-cyclopropylisoazol-5-yl)-5-methylpyridin-4-amine

Step 1: Preparation of N-tert-butoxycarbonyl-N-[2-(3-cyclopropylisoazol-5-yl)-5-methyl-4-pyridinyl]aminocarbamate tributyl ester Under ice bath conditions, N-tert-butyl butyryloxycarbonyl-N-(2-ethynyl-5-methyl-4-pyridyl)aminocarbamate (4.1 g, 12.33 mmol) and cyclopropaneformaldehyde oxime (2.10 g, 24.67 mmol) were dissolved in MeOH (60 mL)/water (10 mL), and [bis(trifluoroacetoxy)iodide]benzene (15.91 g, 37.00 mmol) was added. The mixture was stirred at room temperature for 12 h. The reaction solution was diluted with ethyl acetate and washed successively with saturated sodium carbonate solution and saturated brine to separate the organic phase. The organic phase was dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (3.3 g, 64.39%). MS m/z (ESI): 416.2 [M+H] ⁺ .

Step 2: Preparation of 2-(3-cyclopropylisoazol-5-yl)-5-methylpyridine-4-amine N-tertiary butylcarbamate (3.3 g, 7.94 mmol) was dissolved in DCM (60 mL), and trifluoroacetic acid (9.06 g, 79.43 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was diluted with ethyl acetate and washed successively with saturated sodium carbonate solution and saturated brine solution. The organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (1.56 g, 91.25%). MS m/z (ESI): 216.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.98 (s, 1H), 7.03 (s, 1H), 6.59 (s, 1H), 6.11 (s, 2H), 2.04 (s, 3H), 2.03-1.96 (m, 1H), 1.05-0.98 (m, 2H), 0.86- 0.80 (m, 2H).

Example 1: 6-Cyclopropyl-N-(5-(5-((1R,2S)-2-fluorocyclopropyl)-1,2,4-diazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide

Step 1: Synthesis of ethyl 6-bromoimidazolo[1,2-a]pyridine-3-carboxylic acid 5-bromopyridine-2-amine (1.74 g, 10 mmol) and ethyl 2-chloro-3-carbonylpropionate (4.52 g, 30 mmol) were mixed in NMP (30 mL), acetic acid (1 mL) was added, and the reaction was carried out at room temperature for 12 hours, followed by a reaction at 140 ^° C for 1 hour. The reaction solution was cooled to room temperature, and water (100 mL) was added. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target compound (1 g, 37%). MS m/z (ESI): 270.0 [M+H] ⁺ .

Step 2: Synthesis of 6-bromoimidazolo[1,2-a]pyridine-3-carboxylic acid. Ethyl 6-bromoimidazolo[1,2-a]pyridine-3-carboxylic acid (1 g, 3.70 mmol) was dissolved in a mixture of THF (16 mL), MeOH (2 mL), and water (2 mL). Lithium hydroxide (106.3 mg, 4.44 mmol) was added, and the reaction mixture was stirred at 55 ^° C for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature, the organic solvent was concentrated, and water (20 mL) and 1N HCl aqueous solution were added to adjust the pH to 3-4. The resulting mixture was then freeze-dried to obtain the crude target compound (890 mg). MS m/z (ESI): 242.0 [M+H] ⁺ .

Step 3: Synthesis of 6-bromo-N-(5-(5-(((1R,2S)-2-fluorocyclopropyl)-1,2,4-diazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxylic acid (242 mg, 1 mmol), 5-(5-((1R,2S)-2-fluorocyclopropyl)-1,2,4-diazol-3-yl)-2-methylaniline (233.2 mg, 1 mmol), and N-methylimidazole (262.7 mg, 3.2 mmol) were mixed in acetonitrile (5 mL), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (336.7 mg, 1.2 mmol) was added. The reaction solution was stirred at 45 ^° C for 2 hours. After the reaction, the organic solvent was concentrated under reduced pressure and then separated by column chromatography to obtain the target compound (180 mg, 39%). MS m/z (ESI): 457.0 [M+H] ⁺ .

Step 4: Synthesis of 6-cyclopropyl-N-(5-(5-(((1R,2S)-2-fluorocyclopropyl)-1,2,4-diazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide. 6-bromo-N-(5-(5-(((1R,2S)-2-fluorocyclopropyl)-1,2,4-diazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (91.5 mg, 0.2 mmol) and 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-diboronylcyclopentane (50.4 mg, 0.3 mmol) were mixed in dioxane (2.5 mL) and water (0.5 mL). Potassium carbonate (55.3 mg, 0.4 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (16.2 mg, 0.02 mmol) were added to a solution containing potassium carbonate (55.3 mg, 0.4 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (16.2 mg, 0.02 mmol). After purging with nitrogen, the solution was heated to 100 ^° C and reacted for 2 hours. After the reaction was completed, the solution was cooled to room temperature, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound (42 mg, 50%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.30 (s, 1H), 9.35 (s, 1H), 9.23 (s, 1H), 8.73 (s, 1H), 8.12 (s, 1H), 7.88 (d, J = 7.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 5.45-5.25 (m, 1H), 3.18-3.09 (m, 1H), 2.44 (s, 3H), 2.36-2.30 (m, 1H), 2.09-2.04 (m, 1H), 1.71-1.62 (m, 1H), 1.35-1.28 (m, 2H), 1.05-1.01 (m, 2H);MS m/z (ESI): 419.2 [M+H] ⁺ .

The synthesis methods of Embodiments 2 to 538 are described in Embodiment 1. Implementation Examples Structure MS m/z (ESI): [M+H] ⁺ Implementation Examples Structure MS m/z (ESI): [M+H] ⁺ 2 451.2 270 440.1 3 445.2 271 457.1 4 445.2 272 458.1 5 474.2 273 442.2 6 473.2 274 441.2 7 487.2 275 456.2 8 487.2 276 341.1 9 487.2 277 358.1 10 487.2 278 359.1 11 419.2 279 343.1 12 451.2 280 342.1 13 445.2 281 357.1 14 445.2 282 439.1 15 474.2 283 456.1 16 473.2 284 457.1 17 487.2 285 441.1 18 487.2 286 440.1 19 487.2 287 455.1 20 487.2 288 433.2 twenty one 439.1 289 439.1 twenty two 471.1 290 453.1 twenty three 465.1 291 457.1 twenty four 465.1 292 450.1 25 494.1 293 456.1 26 493.1 294 470.1 27 507.1 295 474.1 28 507.1 296 450.1 29 507.1 297 456.1 30 507.1 298 470.1 31 483.1 299 474.1 32 515.1 300 468.1 33 509.1 301 474.1 34 509.1 302 488.1 35 538.1 303 492.1 36 537.0 304 334.1 37 551.1 305 340.1 38 551.1 306 354.1 39 551.1 307 358.1 40 551.1 308 351.1 41 437.1 309 357.1 42 469.2 310 371.1 43 463.2 311 375.1 44 463.2 312 351.1 45 492.2 313 357.1 46 491.1 314 371.1 47 505.2 315 375.1 48 505.2 316 369.1 49 505.2 317 375.1 50 505.2 318 389.1 51 439.1 319 393.1 52 471.1 320 432.1 53 465.1 321 438.1 54 465.1 322 452.1 55 494.1 323 456.1 56 493.1 324 449.1 57 507.1 325 455.1 58 507.1 326 469.1 59 507.1 327 473.1 60 507.1 328 449.1 61 483.1 329 455.1 62 515.1 330 469.1 63 509.1 331 473.1 64 509.1 332 467.1 65 538.1 333 473.1 66 537.0 334 487.1 67 551.1 335 491.1 68 551.1 336 449.1 69 551.1 337 467.1 70 551.1 338 450.1 71 437.1 339 467.1 72 469.2 340 350.1 73 463.2 341 368.1 74 463.2 342 351.1 75 492.2 343 368.1 76 491.1 344 448.1 77 505.2 345 466.1 78 505.2 346 449.1 79 505.2 347 466.1 80 505.2 348 501.1 81 446.2 349 483.1 82 446.2 350 402.1 83 466.1 351 384.1 84 466.1 352 500.1 85 510.1 353 482.1 86 510.1 354 455.1 87 464.2 355 473.1 88 464.2 356 469.1 89 435.2 357 487.1 90 436.2 358 455.1 91 437.2 359 473.1 92 384.1 360 469.1 93 425.1 361 487.1 94 439.1 362 439.1 95 480.1 363 456.1 96 388.1 364 439.1 97 429.1 365 457.1 98 443.1 366 453.1 99 484.1 367 470.1 100 490.2 368 453.1 101 491.2 369 471.1 102 492.2 370 450.2 103 404.1 371 466.1 104 459.1 372 433.2 105 409.1 373 433.2 106 464.2 374 467.2 107 429.1 375 450.2 108 484.1 376 432.2 109 447.1 377 446.2 110 502.1 378 463.2 111 419.2 379 463.2 112 474.2 380 450.1 113 393.1 381 446.2 114 448.2 382 463.2 115 413.1 383 463.2 116 468.1 384 449.2 117 404.1 385 467.1 118 459.1 386 467.1 119 409.1 387 470.1 120 464.2 388 486.1 121 429.1 389 453.1 122 484.1 390 487.1 123 447.1 391 470.1 124 502.1 392 452.1 125 375.1 393 466.2 126 403.1 394 483.2 127 423.1 395 483.2 128 404.1 396 470.1 129 418.2 397 466.2 130 494.2 398 483.2 131 429.1 399 483.2 132 393.1 400 469.1 133 421.1 401 487.1 134 441.1 402 487.1 135 422.1 403 473.1 136 436.1 404 499.1 137 512.1 405 491.1 138 447.1 406 517.1 139 384.1 407 473.1 140 416.1 408 490.1 141 410.1 409 499.1 142 410.0 410 516.1 143 439.1 411 495.1 144 438.1 412 512.1 145 452.1 413 495.1 146 452.1 414 513.1 147 452.1 415 495.1 148 452.1 416 512.1 149 340.1 417 495.1 150 368.1 418 513.1 151 388.1 419 495.1 152 369.1 420 512.1 153 383.1 421 495.1 154 459.1 422 513.1 155 394.1 423 495.1 156 402.1 424 512.1 157 434.1 425 495.1 158 428.1 426 513.1 159 428.1 427 495.1 160 457.1 428 512.1 161 456.1 429 495.1 162 470.1 430 513.1 163 470.1 431 467.2 164 470.1 432 484.2 165 470.1 433 467.2 166 358.1 434 485.2 167 386.1 435 432.2 168 406.1 436 375.1 169 387.1 437 449.2 170 401.1 438 392.1 171 477.1 439 419.1 172 412.1 440 436.1 173 398.1 441 362.1 174 430.1 442 379.1 175 424.1 443 433.2 176 424.1 444 450.1 177 453.1 445 376.1 178 452.1 446 393.1 179 466.1 447 433.2 180 466.1 448 450.1 181 466.1 449 376.1 182 466.1 450 393.1 183 354.1 451 452.1 184 382.1 452 395.1 185 402.1 453 469.1 186 383.1 454 412.1 187 397.1 455 439.1 188 473.1 456 456.1 189 408.1 457 382.1 190 416.1 458 399.1 191 448.1 459 453.1 192 442.1 460 470.1 193 442.1 461 396.1 194 471.1 462 413.1 195 470.1 463 453.1 196 484.1 464 470.1 197 484.1 465 396.1 198 484.1 466 413.1 199 484.1 467 450.2 200 372.1 468 467.2 201 400.1 469 393.1 202 420.1 470 410.1 203 401.1 471 389.2 204 415.1 472 406.2 205 491.1 473 389.2 206 426.1 474 406.2 207 424.1 475 375.1 208 456.1 476 392.1 209 450.1 478 409.1 210 450.1 479 426.1 211 479.1 480 409.1 212 478.1 481 426.1 213 492.1 482 395.1 214 492.1 483 412.1 215 492.1 484 425.1 216 492.1 485 437.2 217 380.1 486 438.2 218 408.1 487 439.2 219 428.1 488 402.1 220 409.1 489 457.1 221 423.1 490 461.2 222 499.1 491 529.2 223 434.1 492 490.1 224 442.1 493 490.1 225 474.1 494 380.1 226 468.1 495 453.1 227 468.1 496 477.2 228 497.1 497 470.2 229 496.1 498 484.2 230 510.1 499 473.2 231 510.1 500 501.2 232 510.1 501 501.2 233 510.1 502 526.3 234 398.1 503 528.3 235 426.1 504 511.2 236 446.1 505 470.2 237 427.1 506 523.3 238 441.1 507 525.3 239 517.1 508 495.2 240 452.1 509 497.3 241 457.1 510 509.3 242 402.1 511 513.3 243 456.1 512 512.2 244 358.1 513 567.3 245 475.1 514 457.2 246 420.1 515 473.2 247 474.1 516 555.3 248 376.1 517 476.1 249 422.1 518 487.2 250 439.1 519 473.2 251 440.1 520 466.2 252 424.2 521 508.2 253 423.2 522 460.1 254 438.2 523 480.2 255 437.2 524 541.2 256 323.2 525 462.2 257 340.1 526 414.1 258 341.1 527 512.3 259 325.1 528 444.2 260 324.1 529 503.2 261 339.1 530 510.2 262 338.2 531 472.2 263 421.1 532 472.2 264 438.1 533 493.2 265 439.1 534 487.2 266 423.1 535 455.2 267 422.1 536 488.1 268 437.1 537 529.2 269 436.2 538 529.2

The ^1H NMR data of some compounds are as follows: Implementation Case Number ^1H NMR 139 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.97 (s, 1H), 8.28 (d, J = 4.4 Hz, 1H), 8.23 (s, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.77 (dd, J = 7.8, 1.8 Hz, 1H), 7.53-7.44 (m, 2H), 5.38-5.17 (m, 1H), 3.13-2.98 (m, 1H), 2.33 (s, 3H), 2.06-1.96 (m, 1H), 1.63-1.53 (m, 1H). 143 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.98 (s, 1H), 8.30 (d, J = 4.4 Hz, 1H), 8.24 (s, 1H), 8.08 (d, J = 1.2 Hz, 1H), 7.84 (dd, J = 7.9, 1.5 Hz, 1H), 7.52-7.47 (m, 2H), 4.47-4.33 (m, 2H), 4.32-4.24 (m, 1H), 4.23-4.15 (m, 2H), 3.60 (s, 3H), 2.35 (s, 3H). 160 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.17 (s, 1H), 8.30 (d, J = 4.4 Hz, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.66 (d, J = 9.8 Hz, 1H), 7.51 (d, J = 4.4 Hz, 1H), 4.43-4.34 (m, 2H), 4.32-4.25 (m, 1H), 4.23-4.16 (m, 2H), 3.60 (s, 3H), 2.24 (s, 3H).

Example 5 Methyl 3-(3-(6-cyclopropylimidazo[1,2-a]pyridine-3-methamido)-4-methylphenyl)-1,2,4-diazol-5-yl)azacyclobutane-1-carboxylate can also be prepared by the following method.

Step 1: Preparation of ethyl 6-cyclopropylimidazo[1,2-a]pyridine-3-carboxylate Ethyl 6-bromoimidazolo[1,2-a]pyridine-3-carboxylate (270.1 mg, 1.0 mmol) and 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-diboronylcyclopentane (252 mg, 1.5 mmol) were mixed in dioxane (4 mL)/water (0.5 mL), potassium carbonate (276.4 mg, 2.0 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (81.7 mg, 0.1 mmol) were added, and the reaction mixture was heated and stirred at 100 ^° C for 2 hours. The reaction solution was diluted with ethyl acetate and washed successively with saturated sodium carbonate solution and saturated brine to separate the organic phase. The organic phase was dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (185 mg, 80%). MS m/z (ESI): 232.1 [M+H] ⁺ .

Step 2: Preparation of 6-cyclopropylimidazo[1,2-a]pyridine-3-carboxylic acid Ethyl 6-cyclopropylimidazo[1,2-a]pyridine-3-carboxylate (185 mg, 0.8 mmol) was dissolved in a mixture of THF (4 mL), MeOH (1 mL), and water (1 mL). Lithium hydroxide (28.7 mg, 1.2 mmol) was added, and the reaction mixture was stirred at 55 ^° C for 1 hour. The reaction mixture was cooled to room temperature, the organic solvent was concentrated, and water (5 mL) was added. The pH was adjusted to 3-4 with 1N HCl aqueous solution. The resulting mixture was then freeze-dried to obtain the crude target compound (162 mg). MS m/z (ESI): 204.1 [M+H] ⁺ .

Step 3: Preparation of methyl 3-(3-(6-cyclopropylimidazo[1,2-a]pyridine-3-methacrylamide)-4-methylphenyl)-1,2,4-diazol-5-yl)azacyclobutane-1-carboxylate 6-Cyclopropylimidazo[1,2-a]pyridine-3-carboxylic acid (101.6 mg, 0.5 mmol), methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-diazol-5-yl)acetidine-1-carboxylic acid (144.2 mg, 0.5 mmol) and N-methylimidazolium (131.4 mg, 1.6 mmol) were mixed in acetonitrile (3 mL), and N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (168.3 mg, 0.6 mmol) was added. The reaction mixture was stirred at 45 ^° C for 2 hours. The reaction solution was diluted with ethyl acetate, washed successively with saturated sodium carbonate solution and saturated brine, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (106.5 mg, 45%). MS m/z (ESI):474.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.24 (s, 1H), 9.29 (d, J = 1.2 Hz, 1H), 9.16 (d, J = 1.2 Hz, 1H), 8.66 (s, 1H), 8.12 (s, 1H), 7.86 (dd, J = 8.0, 1.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 4.42-4.33 (m, 2H), 4.32-4.24 (m, 1H), 4.23-4.14 (m, 2H), 3.60 (s, 3H), 2.38 (s, 3H), 2.30-2.23 (m, 1H), 0.91-0.99 (m, 4H).

Example 173 N-(5-(5-((1R,2S)-2-fluorocyclopropyl)-1,2,4-diazol-3-yl)-2-methylphenyl)-2-methylimidazo[2,1-b]thiazol-5-methylamine can also be prepared by the following method. 2-Methylimidazole[2,1-b]thiazol-5-carboxylic acid (182.2 mg, 1 mmol), 5-(5-((1R,2S)-2-fluorocyclopropyl)-1,2,4-diazol-3-yl)-2-methylaniline (233.2 mg, 1 mmol) and N-methylimidazole (262.7 mg, 3.2 mmol) were mixed in acetonitrile (5 mL), and N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (336.7 mg, 1.2 mmol) was added. The reaction mixture was stirred at 45 ^° C for 2 hours. The reaction solution was diluted with ethyl acetate, washed successively with saturated sodium carbonate solution and saturated salt water, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (151 mg, 38%). MS m/z (ESI):398.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.94 (s, 1H), 8.16 (s, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 7.79-7.73 (m, 1H), 7.47 (d, J = 8.0 Hz, 1H), 5.39-5.18 (m, 1H), 3.11-3.01 (m, 1H), 2.48 (s, 3H), 2.33 (s, 3H), 2.01-1.88 (m, 1H), 1.63-1.54 (m, 1H).

Example 177 3-(3-(4-methyl-3-(2-methylimidazo[2,1-b]thiazolyl-5-methamido)phenyl)-1,2,4-diazol-5-yl)acetidine-1-carboxylic acid methyl ester can also be prepared according to the following method. 2-Methylimidazole[2,1-b]thiazol-5-carboxylic acid (182.2 mg, 1 mmol), methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-diazol-5-yl)acetidine-1-carboxylic acid (288.3 mg, 1 mmol) and N-methylimidazole (262.7 mg, 3.2 mmol) were mixed in acetonitrile (5 mL), and N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (336.7 mg, 1.2 mmol) was added. The reaction mixture was stirred at 45 ^° C for 2 hours. The reaction solution was diluted with ethyl acetate, washed successively with saturated sodium carbonate solution and saturated salt water, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (162.9 mg, 36%). MS m/z (ESI):453.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.93 (s, 1H), 8.18-8.12 (m, 2H), 8.08 (d, J = 1.6 Hz, 1H), 7.83 (dd, J = 8.0, 1.6 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 4.41-4.32 (m, 2H), 4.30-4.23 (m, 1H), 4.22-4.15 (m, 2H), 3.60 (s, 3H), 2.48 (s, 3H), 2.34 (s, 3H).

Example 194 3-(3-(3-fluoro-4-methyl-5-(2-methylimidazo[2,1-b]thiazo-5-methamido)phenyl)-1,2,4-diazol-5-yl)acetidine-1-carboxylic acid methyl ester can also be prepared according to the following method. 2-Methylimidazole[2,1-b]thiazol-5-carboxylic acid (182.2 mg, 1 mmol), methyl 3-(3-(3-amino-5-fluoro-4-methylphenyl)-1,2,4-diazol-5-yl)acetidine-1-carboxylic acid (306.3 mg, 1 mmol) and N-methylimidazole (262.7 mg, 3.2 mmol) were mixed in acetonitrile (5 mL), and N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (336.7 mg, 1.2 mmol) was added. The reaction mixture was stirred at 45 ^° C for 2 hours. The reaction solution was diluted with ethyl acetate, washed successively with saturated sodium carbonate solution and saturated brine, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (150.6 mg, 32%). MS m/z (ESI):471.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.13 (s, 1H), 8.18 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.97 (s, 1H), 7.66 (dd, J = 9.7, 1.7 Hz, 1H), 4.42-4.33 (m, 2H), 4.32-4.24 (m, 1H), 4.23-4.15 (m, 2H), 3.60 (s, 3H), 2.48 (s, 3H), 2.23 (s, 3H).

Example 245 Methyl 3-(3-(3-fluoro-5-(2-fluoroimidozop[2,1-b]thiazol-5-methamido)-4-methylphenyl)-1,2,4-diazol-5-yl)acetidine-1-carboxylic acid can also be prepared by the following method.

Step 1: Preparation of ethyl 2-fluoroimidozop[2,1-b]thiazole-5-carboxylate 5-Fluorothiazol-2-amine (1.18 g, 10 mmol) and ethyl 2-chloro-3-carbonylpropionate (4.52 g, 30 mmol) were mixed in NMP (30 mL), and acetic acid (1 mL) was added. The reaction was carried out at room temperature for 12 hours, followed by a reaction at 130 ^° C for 1 hour. The reaction solution was diluted with ethyl acetate and washed successively with saturated sodium carbonate solution and saturated brine. The organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (749.7 mg, 35%). MS m/z (ESI): 215.0 [M+H] ⁺ .

Step 2: Preparation of 2-Fluorimidozolo[2,1-b]thiazole-5-carboxylic acid Ethyl 2-fluoroimidazolo[2,1-b]thiazol-5-carboxylate (749.7 mg, 3.5 mmol) was dissolved in a mixture of THF (8 mL), MeOH (2 mL), and water (2 mL). Lithium hydroxide (100.6 mg, 4.2 mmol) was added, and the reaction mixture was stirred at 55 ^° C for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature, the organic solvent was concentrated, and water (20 mL) was added. The pH was adjusted to 3-4 with 1N HCl aqueous solution. The resulting mixture was then freeze-dried to obtain the crude target compound (651 mg). MS m/z (ESI): 187.0 [M+H] ⁺ .

Step 3: Preparation of methyl 3-(3-(3-fluoro-5-(2-fluoroimidazo[2,1-b]thiazolyl-5-methamido)-4-methylphenyl)-1,2,4-diazol-5-yl)acetidine-1-carboxylic acid 2-Fluorimidazole[2,1-b]thiazol-5-carboxylic acid (186.2 mg, 1 mmol), methyl 3-(3-(3-amino-5-fluoro-4-methylphenyl)-1,2,4-diazol-5-yl)acetidine-1-carboxylic acid (306.3 mg, 1 mmol) and N-methylimidazole (262.7 mg, 3.2 mmol) were mixed in acetonitrile (5 mL), and N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (336.7 mg, 1.2 mmol) was added. The reaction mixture was stirred at 45 ^° C for 2 hours. The reaction solution was diluted with ethyl acetate and washed successively with saturated sodium carbonate solution and saturated salt water to separate the organic phase. The organic phase was dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (156.6 mg, 33%). MS m/z (ESI):475.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.25 (s, 1H), 8.46 (s, 1H), 8.23 (s, 1H), 7.96 (s, 1H), 7.67 (d, J = 9.6 Hz, 1H), 4.41-4.33 (m, 2H), 4.32-4.25 (m, 1H), 4.22-4.15 (m, 2H), 3.60 (s, 3H), 2.33 (s, 3H).

Example 290: Methyl 3-(3-(5-methyl-4-(2-methylimidazo[2,1-b]thiazolyl-5-methamido)pyridin-2-yl)isoazol-5-yl)acetidine-1-carboxylic acid can also be prepared by the following method. At room temperature, methyl 3-(3-(4-amino-5-methylpyridin-2-yl)isoazol-5-yl)acetidine-1-carboxylate (95.0 mg, 0.33 mmol) and 2-methylimidazo[2,1-b]thiazol-5-carboxylic acid (90.1 mg, 0.49 mmol) were mixed in nitrilodimethylformamide (4 mL), and nitrilodimethylimidazolium (81.3 mg, 0.99 mmol) and tetramethylchlorourea hexafluorophosphate (137.5 mg, 0.49 mmol) were added. The mixture was heated to 90°C and stirred for 5 hours. The reaction solution was added to a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to give the title compound (20.1 mg, 13%). MS m/z (ESI): 453.1 [M+H] ⁺ .

Example 293 3-(3-(2-fluoro-5-(imidazo[2,1-b]thiazolyl-5-methamido)-4-methylphenyl)isoazol-5-yl)acetidine-1-carboxylic acid methyl ester can also be prepared according to the following method. Methyl 3-[3-(5-amino-2-fluoro-4-methyl-phenyl)isoazol-5-yl]azacyclobutane-1-carboxylate (50 mg, 163.77 μmol) and imidazo[2,1-B]thiazol-5-carboxylate (34.4 mg, 175.51 μmol) were dissolved in tetrahydrofuran (5 mL) solution, and 1 M LiHMDS tetrahydrofuran solution (1 mmol, 1 mL) was added. The reaction mixture was heated and stirred at 60°C for 2 h. The reaction solution was diluted with ethyl acetate, washed successively with saturated ammonium chloride solution and saturated brine, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (10.1 mg, 13.5%). MS m/z (ESI): 456.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.98 (s, 1H), 8.29-8.25 (m, 1H), 8.21 (s, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.51-7.47 (m, 1H), 7.42-7.36 (d, J = 10.4 Hz, 1H), 7.01 (d, J = 2.8 Hz, 1H), 4.37-4.29 (m, 2H), 4.19-4.12 (m, 1H), 4.11-4.03 (m, 2H), 3.59 (s, 3H), 2.32 (s, 3H).

Example 373 3-(5-(4-(imidazo[1,2-a]pyridine-3-methamido)-5-methylpyridin-2-yl)isoazol-3-yl)acetidine-1-carboxylic acid methyl ester can also be prepared according to the following method. At room temperature, imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (32.9 mg, 173.43 μmol) and 3-(5-(4-amino-5-methylpyridin-2-yl)isoazol-3-yl)acetidine-1-carboxylic acid methyl ester (50 mg, 173.43 μmol) were dissolved in tetrahydrofuran (2 mL), and 1M LiHMDS tetrahydrofuran solution (0.68 mL, 0.68 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was added to saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (34.3 mg, 45.7%). MS m/z (ESI): 433.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.98 (s, 1H), 9.48-9.44 (m, 1H), 8.67 (s, 1H), 8.59 (s, 1H), 8.30 (s, 1H), 7.84-7.80 (m, 1H), 7.61-7.54 (m, 1H), 7.25-7.22 (m, 2H), 4.38-4.27 (m, 2H), 4.12-4.04 (m, 2H), 4.03-3.97 (m, 1H), 3.59 (s, 3H), 2.40 (s, 3H).

Example 490 N-(2-(5-cyclopropylisoazol-3-yl)-5-methylpyridin-4-yl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazolyl-5-methamide can also be prepared by the following method.

Step 1: Preparation of N'-(5-bromothiazo-2-yl)-N,N-dimethylformamide At room temperature, 5-bromothiazol-2-amine (5.0 g, 28.0 mmol) was dissolved in toluene (60 mL), and triethylamine (8.5 g, 84.0 mmol) was added. The mixture was stirred for 10 minutes, and N,N-dimethylformamide dimethyl acetal (16.7 g, 140.0 mmol) was added. The mixture was heated to 110°C and stirred for 2 hours. The reaction solution was then added to water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to give the target compound (6.5 g, 100%). MS m/z (ESI): 234.0 [M+H] ⁺ .

Step 2: Preparation of ethyl 2-bromoimidazolo[2,1-b]thiazole-5-carboxylate At room temperature, N'-(5-bromothiazo-2-yl)-N,N-dimethylformamidin (1.5 g, 6.4 mmol) was dissolved in ethyl bromoacetate (8 mL) and stirred at room temperature for 10 hours. Then, 1,8-diazabicyclo[5.4.0]undec-7-ene (4.9 g, 32.0 mmol) was added dropwise and stirred at room temperature for 1 hour. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to give the target compound (650.5 mg, 37%). MS m/z (ESI): 274.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.41 (s, 1H), 8.01 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H).

Step 3: Preparation of ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazolium-5-carboxylate At room temperature, ethyl 2-bromoimidazolo[2,1-b]thiazolium-5-carboxylate (650.5 g, 2.37 mmol), (1-(tri-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (807.8 mg, 3.56 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (173.2 mg, 0.237 mmol), and cesium carbonate (2.3 g, 7.11 mmol) were mixed in dioxane/water (10 mL/2 mL) and microwaved at 125°C for 2 hours. The reaction solution was added to a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to obtain the target compound (450.2 mg, 50%). MS m/z (ESI): 378.1 [M+H] ⁺ .

Step 4: Preparation of ethyl 2-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazole-5-carboxylate Ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazolium-5-carboxylate (450.2 mg, 1.2 mmol) was dissolved in dichloromethane (5 mL) at room temperature, and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give crude ethyl 2-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazolium-5-carboxylate (332.4 mg, 100%), which was used directly in the next reaction. MS m/z (ESI): 278.1 [M+H] ⁺ .

Step 5: Ethyl 2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazolium-5-carboxylate Ethyl 2-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazolium-5-carboxylate (332.4 mg, 1.2 mmol) was dissolved in methanol (6 mL) at room temperature. Formaldehyde (972.9 mg, 12.0 mmol) and 2 drops of acetic acid were added, and the mixture was stirred at room temperature for 1 hour. Sodium cyanoboronide (226.1 mg, 3.6 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then added to a saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to give the target compound (265.7 mg, 76%). MS m/z (ESI): 292.1 [M+H] ⁺ .

Step 6: Preparation of N-(2-(5-cyclopropylisoazol-3-yl)-5-methylpyridin-4-yl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazolyl-5-methamide At room temperature, ethyl 2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazolium-5-carboxylate (81.2 mg, 0.28 mmol) and 2-(5-cyclopropylisoazol-3-yl)-5-methylpyridin-4-amine (50.0 mg, 0.23 mmol) were mixed in tetrahydrofuran (4 mL), and 1M LiHMDS tetrahydrofuran solution (0.92 mL, 0.92 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction solution was added to a saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to obtain the target compound (38.6 mg, 36%). MS m/z (ESI): 461.2[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.91 (s, 1H), 8.54 (s, 1H), 8.29 (s, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 6.70 (s, 1H), 6.13-6.08 (m, 1H), 3.07-3.00 (m, 2H), 2.61-2.52 (m, 3H), 2.36 (s, 3H), 2.28 (s, 3H), 2.24-2.16 (m, 1H), 2.04-1.95 (m, 1H), 1.14-1.08 (m, 2H), 1.00-0.94 (m, 2H).

Example 494 N-(2-(3-cyclopropylisoazol-5-yl)-5-methylpyridin-4-yl)-2-methylimidazo[2,1-b]thiazol-5-methamide can also be prepared by the following method. At room temperature, 2-(3-cyclopropylisoazol-5-yl)-5-methylpyridine-4-amine (45 mg, 209.06 μmol) and ethyl 2-methylimidazo[2,1-B]thiazolium-5-carboxylate (43.96 mg, 209.06 μmol) were dissolved in tetrahydrofuran (2 mL) solution, and 1M LiHMDS tetrahydrofuran solution (1 mmol, 1 mL) was added. The reaction solution was heated and stirred at 60°C for 2 h. The reaction solution was diluted with ethyl acetate and washed successively with saturated ammonium chloride solution and saturated brine to separate the organic phase. The organic phase was dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (21.8 mg, 27.48%). MS m/z (ESI): 380.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.88 (s, 1H), 8.54 (s, 1H), 8.25 (s, 1H), 8.21 (s, 1H), 8.21-8.16 (m, 1H), 6.81 (s, 1H), 2.43 (s, 3H), 2.36 (s, 3H), 2.10-2.04 (m, 1H), 1.08-1.03 (m, 2H), 0.89-0.85 (m, 2H).

Example 500: Methyl 4-[3-[[2-(5-cyclopropylisothiazolyl-3-yl)-5-methyl-4-pyridyl]aminomethyl]pyrazolo[1,5-a]pyridin-5-yl]piperidine-1-carboxylic acid can also be prepared by the following method.

Step 1: Preparation of ethyl 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate At room temperature, ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (1.0 g, 3.7 mmol), (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (1.1 g, 4.8 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (270.5 g, 0.37 mmol), and sodium carbonate (1.2 g, 11.1 mmol) were mixed in dioxane/water (12 mL/2 mL) and stirred at 100°C for 5 hours. The reaction solution was added to a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (1.1 g, 80%). MS m/z (ESI): 372.2 [M+H] ⁺ .

Step 2: Preparation of ethyl 5-(1-tert-butoxycarbonyl-4-piperidinyl)pyrazolo[1,5-a]pyridine-3-carboxylate Ethyl 5-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (100 mg, 269.23 μmol) was dissolved in THF (5 mL)/MeOH (1 mL), and 10% Pd/C (50 mg) and 10% Pd(OH) _₂ /C (50 mg) were added. The hydrogen gas was replaced three times, and the reaction solution was heated and stirred at 60°C for 2 h. The reaction solution was filtered through diatomaceous earth to remove insoluble solids, and the solvent was removed by depressurization of the filtrate to obtain ethyl 5-(1-tert-butoxycarbonyl-4-piperidinyl)pyrazolo[1,5-a]pyridine-3-carboxylate (80 mg, 79.6%), which was used directly in the next step. MS m/z (ESI): 374.2 [M+H] ⁺ .

Step 3: Preparation of 4-[3-[[2-(5-cyclopropylisothiazolyl-3-yl)-5-methyl-4-pyridinyl]aminoformic acid]pyrazolo[1,5-a]pyridin-5-yl]piperidine-1-carboxylic acid tributyl ester Ethyl 5-(1-tert-butoxycarbonyl-4-piperidinyl)pyrazolo[1,5-a]pyridine-3-carboxylate (80 mg, 214.22 μmol) and 2-(5-cyclopropylisoazol-3-yl)-5-methylpyridine-4-amine (46.1 mg, 214.22 μmol) were dissolved in tetrahydrofuran (5 mL), and 1 M LiHMDS tetrahydrofuran solution (1 mmol, 1 mL) was added. The reaction mixture was heated and stirred at 60°C for 2 h. The reaction solution was diluted with ethyl acetate and washed successively with saturated ammonium chloride solution and saturated brine to separate the organic phase. The organic phase was dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (56 mg, 48.2%). MS m/z (ESI): 543.3 [M+H] ⁺ .

Step 4: Preparation of methyl 4-[3-[[2-(5-cyclopropylisoazol-3-yl)-5-methyl-4-pyridyl]aminoformic acid]pyrazolo[1,5-a]pyridin-5-yl]piperidine-1-carboxylate 4-[3-[[2-(5-cyclopropylisoazol-3-yl)-5-methyl-4-pyridyl]aminomethyl]pyrazolo[1,5-a]pyridin-5-yl]piperidin-1-carboxylic acid tributyl ester (56 mg, 103.20 μmol) was dissolved in DCM (5 mL)/4M HCl dioxane (5 mL) and stirred at room temperature for 30 min. The reaction solution was depressurized to remove the solvent, and the residue was dissolved in DCM (5 mL). Triethylamine (52.21 mg, 516.01 μmol, 71.97 μL) was added. Under ice bath conditions, dimethyl dicarbonate (16.61 mg, 123.84 μmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was diluted with ethyl acetate, washed successively with saturated ammonium chloride solution and saturated brine, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (28.9 mg, 55.9%). MS m/z (ESI): 501.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.62 (s, 1H), 8.82 (d, J = 7.1 Hz, 1H), 8.80 (s, 1H), 8.52 (s, 1H), 8.40 (s, 1H), 8.18 (d, J = 1.8 Hz, 1H), 7.13 (dd, J = 7.1, 1.8 Hz, 1H), 6.70 (s, 1H), 3.70 (s, 3H), 2.58-2.53 (m, 4H), 2.38 (s, 3H), 2.27 - 2.16 (m, 1H), 2.05-1.93 (m, 4H), 1.15 - 1.07 (m, 2H), 1.01- 0.96 (m, 2H).

Example 511 N-[2-(5-cyclopropylisoazol-3-yl)-5-methyl-4-pyridyl]-5-(3-oxa-9-azaspiro[5.5]undecane-9-yl)pyrazolo[1,5-a]pyridine-3-methylamine can also be prepared by the following method.

Step 1: Preparation of ethyl 5-(3-oxa-9-azaspiro[5.5]undecane-9-yl)pyrazolo[1,5-a]pyridine-3-carboxylate Ethyl 5-bromopyrazolo[1,5-A]pyridine-3-carboxylate (433 mg, 1.61 mmol), 3-oxa-9-azaspiro[5.5]undecane (250 mg, 1.61 mmol), XantPhos Pd G4 (154.99 mg, 161.04 μmol), and cesium carbonate (1.05 g, 3.22 mmol) were dissolved in a 20 mL solution of dioxane. The reaction mixture was heated and stirred at 100°C for 12 h. The reaction solution was diluted with ethyl acetate and washed successively with saturated ammonium chloride solution and saturated brine to separate the organic phase. The organic phase was dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (410 mg, 74.1%). MS m/z (ESI): 344.2 [M+H] ⁺ .

Step 2: Preparation of N-[2-(5-cyclopropylisoazol-3-yl)-5-methyl-4-pyridyl]-5-(3-oxa-9-azaspiro[5.5]undecane-9-yl)pyrazolo[1,5-a]pyridine-3-methylamine Ethyl 5-(3-oxa-9-azaspiro[5.5]undecane-9-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (50 mg, 145.59 μmol) and 2-(5-cyclopropylisoazol-3-yl)-5-methylpyridine-4-amine (31.3 mg, 145.59 μmol) were dissolved in tetrahydrofuran (5 mL), and 1 M LiHMDS tetrahydrofuran solution (1 mmol, 1 mL) was added. The reaction mixture was heated and stirred at 60°C for 2 h. The reaction solution was diluted with ethyl acetate, washed successively with saturated ammonium chloride solution and saturated brine, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (15.4 mg, 20.6%). MS m/z (ESI): 513.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.26 (s, 1H), 8.60 (s, 1H), 8.56 (d, J = 7.8 Hz, 1H), 8.48 (s, 1H), 8.45 (s, 1H), 7.36 (d, J = 2.7 Hz, 1H), 7.00 (dd, J = 7.8, 2.8 Hz, 1H), 6.68 (s, 1H), 3.58 (t, J = 5.3 Hz, 4H), 3.38 (t, J = 5.9 Hz, 4H), 2.37 (s, 3H), 2.24 - 2.17 (m, 1H), 1.62 (t, J = 5.9 Hz, 4H), 1.48 (t, J = 5.3 Hz, 4H), 1.14 - 1.07 (m, 2H), 0.99-0.94 (m, 2H).

Example 512 N-(2-(3-cyclopropylisoazol-5-yl)-5-methylpyridin-4-yl)-5-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-methylamine can also be prepared by the following method.

Step 1: Preparation of 1-(4-Borate Pinanoyl Ester-3-methyl-1H-pyrazol-1-yl)-2-methylprop-2-ol and 1-(4-Borate Pinanoyl Ester-5-methyl-1H-pyrazol-1-yl)-2-methylprop-2-ol 3-Methylpyrazole-4-borate pinanoyl ester (6.4 g, 30.76 mmol) was dissolved in DMF (100 mL), and 1,2-epoxy-2-methylpropane (4.44 g, 61.52 mmol) and potassium carbonate (12.75 g, 92.28 mmol) were added. The mixture was heated and stirred at 110°C for 12 h. The reaction mixture was added to a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give a mixture of 1-(4-borate pinacol-3-methyl-1H-pyrazol-1-yl)-2-methylprop-2-ol and 1-(4-borate pinacol-5-methyl-1H-pyrazol-1-yl)-2-methylprop-2-ol (5.63 g, 20.09 mmol, 65.33%). MS m/z (ESI): 281.2 [M+H] ⁺ .

Step 2: Preparation of ethyl 5-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate and ethyl 5-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate A mixture of 1-(4-boronanol ester-3-methyl-1H-pyrazol-1-yl)-2-methylprop-2-ol and 1-(4-boronanol ester-5-methyl-1H-pyrazol-1-yl)-2-methylprop-2-ol (5.63 g, 20.09 mmol) was dissolved in 1',4-Dioxane (100 mL)/water (20 mL), and ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (5.41 g, 20.09 mmol), Pd(dppf) _Cl2 (1.47 g, 2.01 mmol) and potassium carbonate (5.55 g, 40.19 mmol) were added. The mixture was heated and stirred at 100°C for 6 h. The reaction solution was added to a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by reverse-phase reaction to give ethyl 5-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (1.95 g, 5.70 mmol) and ethyl 5-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (2.93 g, 8.55 mmol). MS m/z (ESI): 343.2 [M+H] ⁺ .

Step 3: N-(2-(3-cyclopropylisoazol-5-yl)-5-methylpyridin-4-yl)-5-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-methylamine Ethyl 5-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (80 mg, 233.65 μmol) and 2-(3-cyclopropylisoazol-5-yl)-5-methylpyridine-4-amine (50.3 mg, 233.65 μmol) were dissolved in THF (5 mL), 1 M LiHMDS THF (1 mL), and heated and stirred at 60°C for 2 h. The reaction solution was added to a saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, and the residue was purified by reverse-phase preparation to obtain the title compound (36.8 mg, 71.93 μmol, 30.8%). MS m/z (ESI): 512.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.60 (s, 1H), 8.86 (d, J = 7.2 Hz, 1H), 8.81 (s, 1H), 8.52 (s, 1H), 8.32 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.89 (s, 1H), 7.30 (dd, J = 7.2, 2.0 Hz, 1H), 6.81 (s, 1H), 4.72 (s, 1H), 4.06 (s, 2H), 2.54 (s, 3H), 2.39 (s, 3H), 2.11-2.03 (m, 1H), 1.15 (s, 6H), 1.08-1.01 (m, 2H), 0.89-0.80 (m, 2H).

Example 514 N-(2-(5-cyclopropylisoazol-3-yl)-5-methylpyridin-4-yl)-6-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridin-3-methylamine can also be prepared by the following method.

Step 1: Preparation of ethyl 6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine-3-carboxylate At room temperature, ethyl 6-bromoimidazolo[1,2-a]pyridine-3-carboxylate (1.0 g, 3.7 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-diboronyl-2-yl)-1,2,3,6-tetrahydropyridine (1.24 g, 5.55 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (270.5 g, 0.37 mmol), and sodium carbonate (1.2 g, 11.1 mmol) were mixed in dioxane/water (15 mL/2 mL) and stirred at 100°C for 5 hours. The reaction solution was added to a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to obtain the target compound (1.0 g, 95%). MS m/z (ESI): 286.1 [M+H] ⁺ .

Step 2: Preparation of ethyl 6-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxylate At room temperature, ethyl 6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine-3-carboxylate (285 mg, 1.0 mmol) was dissolved in tetrahydrofuran/methanol (5 mL/5 mL), and palladium carbon (150 mg) and palladium hydroxide (150 mg) were added. The mixture was purged with hydrogen three times, and the temperature was raised to 60°C and stirred for 1 hour. The reaction solution was filtered, and the filtrate was concentrated to give crude ethyl 6-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxylate (215.3 mg, 75%), which was used directly in the next reaction. MS m/z (ESI): 288.2 [M+H] ⁺ .

Step 3: N-(2-(5-cyclopropylisoazol-3-yl)-5-methylpyridin-4-yl)-6-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridin-3-methylamine At room temperature, ethyl 6-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxylate (65.6 mg, 0.23 mmol) and 2-(5-cyclopropylisoazol-3-yl)-5-methylpyridine-4-amine (50.0 mg, 0.23 mmol) were mixed in tetrahydrofuran (4 mL), and 1M LiHMDS tetrahydrofuran solution (0.92 mL, 0.92 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was added to saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to obtain the target compound (59.1 mg, 56%). MS m/z (ESI): 457.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.91 (s, 1H), 9.30 (s, 1H), 8.60 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.57-7.52 (m, 1H), 6.71 (s, 1H), 2.92-2.84 (m, 2H), 2.66-2.57 (m, 1H), 2.38 (s, 3H), 2.21 (s, 3H), 2.05-1.96 (m, 3H), 1.87-1.79 (m, 2H), 1.74-1.63 (m, 2H), 1.13-1.09 (m, 2H), 1.01-0.95 (m, 2H).

Example 515 Methyl 3-(5-(4-(6-cyclopropylimidazo[1,2-a]pyridine-3-methamido)-5-methylpyridin-2-yl)isoazol-3-yl)acetidine-1-carboxylic acid can also be prepared by the following method.

Step 1: Preparation of ethyl 6-cyclopropylimidazo[1,2-a]pyridine-3-carboxylate At room temperature, ethyl 6-bromoimidazolo[1,2-a]pyridine-3-carboxylate (1.5 g, 5.6 mmol), cyclopropylboronic acid (952 mg, 11.2 mmol), potassium phosphate (4.8 g, 22.4 mmol), palladium acetate (125.4 mg, 0.56 mmol), and tricyclohexylphosphine (156.8 mg, 0.56 mmol) were mixed in toluene/water (15 mL/2 mL) and stirred at 100°C for 5 hours. The reaction mixture was added to a saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give ethyl 6-cyclopropylimidazo[1,2-a]pyridine-3-carboxylate (1.0 g, 78%). MS m/z (ESI): 231.1 [M+H] ⁺ .

Step 2: Preparation of methyl 3-(5-(4-(6-cyclopropylimidazo[1,2-a]pyridine-3-methamido)-5-methylpyridin-2-yl)isoazol-3-yl)acetidine-1-carboxylic acid ester At room temperature, 6-cyclopropylimidazo[1,2-a]pyridine-3-carboxylate (39.1 mg, 0.17 mmol) and methyl 3-(5-(4-amino-5-methylpyridin-2-yl)isoazol-3-yl)acetidine-1-carboxylate (48.9 mg, 0.17 mmol) were dissolved in tetrahydrofuran (2 mL), and 1M LiHMDS tetrahydrofuran solution (0.68 mL, 0.68 mmol) was added dropwise. The reaction was stirred at room temperature for 1 hour. The reaction solution was added to a saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to obtain the target compound (32.5 mg, 41%). MS m/z (ESI): 473.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.86 (s, 1H), 9.30 (d, J = 7.2 Hz, 1H), 8.58 (d, J = 5.0 Hz, 2H), 8.30 (s, 1H), 7.53 (s, 1H), 7.23 (s, 1H), 6.96-6.91 (m, 1H), 4.37-4.28 (m, 2H), 4.13-3.99 (m, 3H), 3.59 (s, 3H), 2.39 (s, 3H), 2.14-2.05 (m, 1H), 1.12-1.07 (m, 2H), 0.91–0.83 (m, 2H).

Example 516 N-[2-(5-cyclopropylisoazol-3-yl)-5-methyl-4-pyridyl]-5-[3-(2-fluoroethyl)-3-azaspiro[5.5]undec-9-en-9-yl]pyrazolo[1,5-a]pyridine-3-methylamine can also be prepared by the following method.

Step 1: Preparation of 9-(3-ethoxycarbonylpyrazolo[1,5-a]pyridin-5-yl)-3-azaspiro[5.5]undec-9-en-3-carboxylic acid tributyl ester 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3-azaspiro[5.5]undec-8-en-3-carboxylic acid tributyl ester (250 mg, 662.56 μmol), 5-bromopyrazolo[1,5-A]pyridine-3-carboxylic acid ethyl ester (178.3 mg, 662.56 μmol), Pd(dppf)Cl ₂ (48.5 mg, 66.26 μmol) and potassium carbonate (183.1 mg, 1.33 mmol) were dissolved in dioxane (20 mL)/water (4 mL) and heated and stirred at 100°C for 6 h. The reaction solution was diluted with ethyl acetate and washed successively with saturated ammonium chloride solution and saturated brine to separate the organic phase. The organic phase was dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was separated by column chromatography to obtain 9-(3-ethoxycarbonylpyrazolo[1,5-a]pyridin-5-yl)-3-azaspiro[5.5]undec-9-en-3-carboxylic acid tributyl ester (180 mg, 61.8%). MS m/z (ESI): 440.2 [M+H] ⁺ .

Step 2: Preparation of ethyl 5-[3-(2-fluoroethyl)-3-azaspiro[5.5]undec-9-en-9-yl]pyrazolo[1,5-a]pyridine-3-carboxylic acid 300 mg (682.52 μmol) of 9-(3-ethoxycarbonylpyrazolo[1,5-a]pyridin-5-yl)-3-azaspiro[5.5]undec-9-en-3-carboxylic acid tributyl ester was dissolved in dichloromethane (5 mL)/4M HCl dioxane (5 mL) and stirred at room temperature for 30 min. The solvent was removed by depressurization of the reaction solution, and the residue was dissolved in acetonitrile (10 mL). Potassium carbonate (282.99 mg, 2.05 mmol) and 1-fluoro-2-iodoethane (237.4 mg, 1.37 mmol) were added, and the reaction solution was stirred at 80°C for 12 h. The reaction solution was diluted with ethyl acetate and washed successively with saturated ammonium chloride solution and saturated brine to separate the organic phase. The organic phase was dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (160 mg, 60.8%). MS m/z (ESI): 386.2 [M+H] ⁺ .

Step 3: Preparation of N-[2-(5-cyclopropylisoazol-3-yl)-5-methyl-4-pyridyl]-5-[3-(2-fluoroethyl)-3-azaspiro[5.5]undec-9-en-9-yl]pyrazolo[1,5-a]pyridine-3-methylamine 5-[3-(2-fluoroethyl)-3-azaspiro[5.5]undec-9-en-9-yl]pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (80 mg, 207.54 μmol) and 2-(5-cyclopropylisoazol-3-yl)-5-methyl-pyridine-4-amine (44.7 mg, 207.54 μmol) were dissolved in tetrahydrofuran (5 mL) solution, and 1M LiHMDS tetrahydrofuran solution (1 mmol, 1 mL) was added. The reaction solution was heated and stirred at 60°C for 2 h. The reaction solution was diluted with ethyl acetate, washed successively with saturated ammonium chloride solution and saturated brine, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (8.1 mg, 7.1%). MS m/z (ESI): 555.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.52 (s, 1H), 8.74-8.60 (m, 2H), 8.44 (s, 1H), 8.33 (s, 1H), 8.07 (d, J = 1.5 Hz, 1H), 7.27 (dd, J = 7.5, 1.5 Hz, 1H), 6.62 (s, 1H), 6.43 (s, 1H), 4.51 (t, J = 4.9 Hz, 1H), 4.39 (t, J = 4.9 Hz, 1H), 2.60-2.51 (m, 2H), 2.40-2.33 (m, 4H), 2.31 (s, 3H), 2.17-2.09 (m, 2H), 2.08-2.04 (m, 2H), 1.95-1.87 (m, 1H), 1.59-1.52 (m, 2H), 1.40-1.32 (m, 4H), 1.08-0.99 (m, 2H), 0.94-0.85 (m, 2H).

Example 520 N-(2-(3-cyclopropylisoazol-5-yl)-5-methylpyridin-4-yl)-5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrazolo[1,5-a]pyridin-3-methylamine can also be prepared according to the following method.

Step 1: Preparation of ethyl 5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylate 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-borate pinacol ester (250 mg, 1.07 mmol) and 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate ethyl ester (287.4 mg, 1.07 mmol) were dissolved in 1',4-Dioxane (40 mL) / water (8 mL), and Pd(dppf)Cl ₂ (78.14 mg, 106.79 μmol) and potassium carbonate (295.18 mg, 2.14 mmol) were added. The mixture was heated at 100°C and stirred for 4 h. The reaction solution was added to a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by reverse-phase reaction to give the title compound (263 mg, 887.54 μmol, 83.1%). MS m/z (ESI): 297.1 [M+H] ⁺ .

Step 2: Preparation of N-(2-(3-cyclopropylisoazol-5-yl)-5-methylpyridin-4-yl)-5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrazolo[1,5-a]pyridin-3-methylamine Ethyl 5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (55 mg, 185.6 μmol) and 2-(3-cyclopropylisoazol-5-yl)-5-methylpyridine-4-amine (39.9 mg, 185.61 μmol) were dissolved in THF (5 mL), and 1 M LiHMDS THF (0.74 mL) was added. The mixture was heated and stirred at 60°C for 2 h. The reaction solution was added to a saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, and the residue was purified by reverse-phase preparation to obtain the title compound (28.8 mg, 61.9 μmol, 33.3%). MS m/z (ESI): 466.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.55 (s, 1H), 8.84 (dd, J = 7.2, 0.9 Hz, 1H), 8.79 (s, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 8.24 (dd, J = 2.0, 0.9 Hz, 1H), 8.11 (s, 1H), 7.36 (dd, J = 7.2, 2.0 Hz, 1H), 6.81 (s, 1H), 4.14 (t, J = 7.3 Hz, 2H), 3.17 (t, J = 7.3 Hz, 2H), 2.70-2.65 (m, 2H), 2.40 (s, 3H), 2.12-2.03 (m, 1H), 1.11-1.01 (m, 2H), 0.92-0.84 (m, 2H).

Example 521 N-(2-(3-cyclopropylisoazol-5-yl)-5-methylpyridin-4-yl)-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-methylamine can also be prepared by the following method.

Step 1: Preparation of ethyl 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-5-(trifluoromethyl)-1H-pyrazole (250 mg, 905.6 μmol) and ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (243.7 mg, 905.6 μmol) were dissolved in 1',4-Dioxane (40 mL) / water (8 mL), and Pd(dppf) _Cl₂ (662.6 mg, 905.59 μmol) and potassium carbonate (125.16 mg, 905.59 μmol) were added. The mixture was heated and stirred at 100°C for 4 h. The reaction solution was added to a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by reverse-phase reaction to give the title compound (195 mg, 576.44 μmol, 63.65%). MS m/z (ESI): 339.1 [M+H] ⁺ .

Step 2: Preparation of N-(2-(3-cyclopropylisoazol-5-yl)-5-methylpyridin-4-yl)-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-methylamine Ethyl 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (80 mg, 236.49 μmol) and 2-(3-cyclopropylisoazol-5-yl)-5-methylpyridine-4-amine (50.9 mg, 236.49 μmol) were dissolved in THF (2 mL)/1M LiHMDS THF (840.00 μL) and heated and stirred at 100°C for 4 h. The reaction solution was added to a saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, and the residue was purified by reverse-phase preparation to obtain the title compound (36.6 mg, 72.12 μmol, 30.50%). MS m/z (ESI): 508.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.64 (s, 1H), 8.88 (d, J = 7.2Hz, 1H), 8.81 (s, 1H), 8.46 (s, 1H), 8.22 (s, 1H), 8.18 (d, J = 2.0Hz, 1H), 7.90 (s, 1H), 7.09 (dd, J = 7.2, 2.0 Hz, 1H), 6.73 (s, 1H), 4.02 (s, 3H), 2.32 (s, 3H), 2.04-1.96 (m, 1H), 1.01 -0.95 (m, 2H), 0.83–0.77 (m, 2H).

Some compounds can also be prepared using the same methods described above, and their ^1H NMR data are as follows: Implementation Case Number ^1H NMR 294 ¹ H NMR (400 MHz, DMSO) δ 9.94 (s, 1H), 8.13 (s, 1H), 8.10 (s, 1H), 7.86 (d, J = 7.1 Hz, 1H), 7.39 (d, J = 11.5 Hz, 1H), 7.01 (d, J = 2.8 Hz, 1H), 4.37-4.29 (m, 2H), 4.16 (m, 1H), 4.11-4.03 (m, 2H), 3.59 (s, 3H), 2.47 (s, 3H), 2.31 (s, 3H). 489 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.99 (s, 1H), 8.28 (d, J = 4.4 Hz, 1H), 8.21 (s, 1H), 8.03 (d, J = 6.9 Hz, 1H), 7.49 (dd, J = 4.4, 1.1 Hz, 1H), 7.44 (d, J = 11.3 Hz, 1H), 4.43-4.34 (m, 2H), 4.33- 4.25 (m, 1H), 4.23-4.15 (m, 2H), 3.59 (s, 3H), 2.34 (s, 3H). 491 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.90 (s, 1H), 8.54 (s, 1H), 8.28 (s, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 6.70 (s, 1H), 6.06 (s, 1H), 2.4-2.38 (m, 4H), 2.37-2.20 (m, 5H), 2.22 (s, 3H), 2.10-2.06 (m, 2H), 2.01-1.96 (m, 1H), 1.62-1.56 (m, 2H), 1.46-1.38 (m, 4H), 1.14-1.07 (m, 2H), 1.03-0.94 (m, 2H). 492 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.19 (s, 1H), 8.19 (s, 1H), 8.16 - 8.11 (m, 2H), 7.89 (d, J = 10.4 Hz, 1H), 7.19 (d, J = 3.1 Hz, 1H), 4.38-4.27 (m, 2H), 4.14 -3.99 (m, 3H), 3.59 (s, 3H), 2.48 (s, 3H). 493 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.17 (s, 1H), 8.17 (s, 1H), 8.12-8.06 (m 2H), 7.84 (d, J = 10.4 Hz, 1H), 7.07 (d, J = 2.6 Hz, 1H), 4.40-4.28 (m, 2H), 4.24 - 4.11 (m, 1H), 4.10-4.00 (m, 2H), 3.59 (s, 3H), 2.47 (s, 3H). 495 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.88 (s, 1H), 8.58 (s, 1H), 8.28 (s, 1H), 8.26 (s, 1H), 8.19 (d, J = 1.5 Hz, 1H), 7.22 (s, 1H), 4.36-4.26 (m, 2H), 4.17-3.95 (m, 3H), 3.59 (s, 3H), 3.35 (s, 3H), 2.37 (s, 3H). 496 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.32 (s, 1H), 8.65 (t, J = 3.9 Hz, 2H), 8.48 (s, 1H), 8.46 (s, 1H), 7.41 (d, J = 2.7 Hz, 1H), 7.04 (dd, J = 7.8, 2.7 Hz, 1H), 6.68 (s, 1H), 4.70-4.43 (m, 2H), 4.09-3.99 (m, 1H), 3.93-3.62 (m, 4H), 2.95-2.83 (m, 1H), 2.72 (t, J = 11.5 Hz, 1H), 2.38 (s, 3H), 2.24-2.16(m, 1H), 1.14-1.06 (m, 2H), 1.03 - 0.94 (m, 2H). 499 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.60 (s, 1H), 8.81 - 8.76 (m, 2H), 8.52 (s, 1H), 8.42 (s, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.40 (dd, J = 7.5, 2.1 Hz, 1H), 6.70 (s, 1H), 6.66 (s, 1H), 2.42-2.36 (m, 5H), 2.30 (s, 3H), 2.25 - 2.21 (m, 2H), 1.15 - 1.05 (m, 2H), 1.01 - 0.93 (m, 3H), 0.60-0.55 (m, 2H), 0.51-0.47 (m, 2H). 501 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.59 (s, 1H), 8.82-8.78 (m, 2H), 8.52 (s, 1H), 8.33 (s, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.14 (dd, J = 7.2, 2.0 Hz, 1H), 6.81 (s, 1H), 4.21-4.07 (m, 2H), 3.62 (s, 3H), 3.01-2.81 (m, 3H), 2.39 (s, 3H), 2.12-2.02 (m, 1H), 1.91-1.83 (m, 2H), 1.66 -1.49 (m, 2H), 1.10-0.99 (m, 2H), 0.92-0.82 (m, 2H). 504 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.91 (s, 1H), 9.03 (d, J = 1.8 Hz, 1H), 8.56 (s, 1H), 8.55 (s, 1H), 8.32 (s, 1H), 7.78 (dd, J = 9.4, 1.8 Hz, 1H), 7.71 (d, J = 9.4 Hz, 1H), 7.35 (s, 1H), 6.71 (s, 1H), 2.72 (s, 2H), 2.45-2.32 (m, 7H), 2.19 (s, 3H), 2.07-1.93 (m, 1H), 1.86 -1.69 (m, 4H), 1.15 -1.06 (m, 2H), 1.03-0.94 (m, 2H). 505 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.78 (s, 1H), 8.55 (d, J = 2.2 Hz, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 7.66 (d, J = 9.5, 1H), 7.04 (dd, J = 9.5, 2.2 Hz, 1H), 6.70 (s, 1H), 3.92 (s, 4H), 3.27 (s, 4H), 2.37 (s, 3H), 2.25-2.19 (m, 1H), 2.19 (s, 3H), 1.16-1.06 (m, 2H), 1.01-0.93 (m, 2H). 508 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.60 (s, 1H), 8.78-8.74 (m, 2H), 8.52 (s, 1H), 8.42 (s, 1H), 8.14 (d, J = 2.1 Hz, 1H), 7.33 (dd, J = 7.4, 2.1 Hz, 1H), 6.70 (s, 1H), 6.50 (s, 1H), 3.08 (d, J = 6.9 Hz, 2H), 2.98 (d, J = 6.9 Hz, 2H), 2.46 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.21 (m, 1H), 2.08-1.94 (m, 2H), 1.91 (t, J = 6.2 Hz, 2H), 1.15-1.08 (m, 2H), 1.02 - 0.94 (m, 2H). 509 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.57 (s, 1H), 8.83-8.75 (m, 2H), 8.51 (s, 1H), 8.40 (s, 1H), 8.02 (s, 1H), 7.07 (dd, J = 7.3, 1.9 Hz, 1H), 6.69 (s, 1H), 3.04 (s, 2H), 2.92 (s, 2H), 2.65-2.58 (m, 1H), 2.38 (s, 3H), 2.26 (s, 3H), 2.23-2.17 (m, 1H), 2.02-1.94 (m, 2H), 1.82-1.74 (m, 2H), 1.54-1.39 (m, 4H), 1.15-1.08 (m, 2H), 1.02-0.94 (m, 2H). 510 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.61 (s, 1H), 8.78-8.74 (m, 2H), 8.52 (s, 1H), 8.40 (s, 1H), 8.03 (s, 1H), 7.41 (d, J = 7.3 Hz, 1H), 6.70 (s, 1H), 6.61-6.54 (m, 1H), 2.77 (t, J = 7.0 Hz, 2H), 2.58-2.52 (m, 2H), 2.38 (s, 3H), 2.24-2.17 (m, 6H), 1.86 (t, J = 7.0 Hz, 2H), 1.69-1.62 (m, 2H), 1.52-1.44 (m, 2H), 1.13-1.08 (m, 2H), 0.99-0.95 (m, 2H). 513 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.59 (s, 1H), 8.79 (s, 1H), 8.76 (d, J = 7.3 Hz, 1H), 8.52 (s, 1H), 8.35 (s, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.37 (dd, J = 7.3, 2.1 Hz, 1H), 6.81 (s, 1H), 6.52 (s, 1H), 3.58 (s, 3H), 3.49-3.41 (m, 4H), 2.40 (s, 3H), 2.21-2.15 (m, 2H), 2.13-2.05 (m, 2H), 2.03-1.92 (m, 1H), 1.70-1.65 (m, 2H), 1.40-1.34 (m, 4H), 1.10-1.02 (m, 2H), 0.93-0.82 (m, 2H). 517 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.23 (s, 1H), 8.29-8.25 (m, 2H), 8.09 (d, J = 7.2 Hz, 1H), 7.85 (d, J = 10.2 Hz, 1H), 7.52-7.48 (m, 1H), 7.07 (d, J = 2.6 Hz, 1H), 4.41-4.30 (m, 2H), 4.21-4.13 (m, 1H), 4.12-4.04 (m, 2H), 3.60 (s, 3H). 518 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.60 (s, 1H), 8.80-8.75 (m, 2H), 8.52 (s, 1H), 8.41 (s, 1H), 8.14 (s, 1H), 7.39-7.34 (m, 1H), 6.69 (s, 1H), 6.60-6.53 (m, 1H), 4.66 (t, J = 4.9 Hz, 1H), 4.54 (t, J = 4.9 Hz, 1H), 2.83-2.78 (m, 1H), 2.77-2.71 (m, 3H), 2.58-2.53 (m, 2H), 2.39 (s, 3H), 2.25-2.16 (m, 1H), 2.03-1.94 (m, 2H), 1.13-1.07 (m, 2H), 1.00-0.95 (m, 2H). 519 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.82 (s, 1H), 8.94 (d, J = 2.3 Hz, 1H), 8.54 (s, 1H), 8.52 (s, 1H), 8.30 (s, 1H), 7.65 (d, J = 9.8 Hz, 1H), 7.55 (dd, J = 9.8, 2.3 Hz, 1H), 6.71 (s, 1H), 4.35 (s, 1H), 3.26-3.19 (m, 2H), 3.12-3.03 (m, 2H), 2.37 (s, 3H), 2.26-2.16 (m, 1H), 1.65-1.59(m, 4H), 1.17 (s, 3H), 1.13-1.07 (m, 2H), 1.03-0.94 (m, 2H). 522 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.94 (s, 1H), 8.56 (s, 1H), 8.31 (d, J = 1.4 Hz, 2H), 8.24 (s, 1H), 7.75 (s, 1H), 6.82 (s, 1H), 3.81 (s, 3H), 2.44 (s, 3H), 2.38 (s, 3H), 2.02-1.96 (m, 1H), 1.10 -1.02 (m, 2H), 0.95-0.84 (m, 2H). 523 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.57 (s, 1H), 8.84 (d, J = 7.2 Hz, 1H), 8.80 (s, 1H), 8.52 (s, 1H), 8.32 (s, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.00 (s, 1H), 7.36 (dd, J = 7.2, 2.0 Hz, 1H), 6.81 (s, 1H), 4.14 (t, J = 6.0 Hz, 2H), 3.04 (t, J = 6.0 Hz, 2H), 2.40 (s, 3H), 2.12-2.06 (m, 1H), 2.04-1.98 (m, 2H), 1.94-1.86 (m, 2H), 1.09-1.02 (m, 2H), 0.91-0.85 (m, 2H). 524 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.58 (s, 1H), 8.79-8.75 (m, 2H), 8.51 (s, 1H), 8.40 (s, 1H), 8.02 (s, 1H), 7.04 (dd, J = 7.2, 2.0 Hz, 1H), 6.69 (s, 1H), 3.75-3.64 (m, 1H), 3.58 (s, 3H), 3.32-3.12 (m, 4H), 2.38 (s, 3H), 2.35-2.27 (m, 2H), 2.25-2.17 (m, 1H), 1.95-1.86 (m, 2H), 1.68 (t, J = 5.7 Hz, 2H), 1.48 (t, J = 5.7 Hz, 2H), 1.15-1.07 (m, 2H), 1.04-0.94 (m, 2H). 525 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.64 (s, 1H), 8.85 (d, J = 7.1 Hz, 1H), 8.81 (s, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 7.11 (dd, J = 7.1, 1.9 Hz, 1H), 6.81 (s, 1H), 4.68 (s, 2H), 4.47 (s, 1H), 3.28 (s, 2H), 2.39 (s, 3H), 2.12- 2.03 (m, 1H), 1.14 (s, 6H), 1.08-1.02 (m, 2H), 0.90-0.82 (m, 2H). 526 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.35 (s, 1H), 8.51 (s, 1H), 8.50 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 6.99 (s, 1H), 3.63-3.51 (m, 1H), 2.30 (s, 3H), 2.28-2.22 (m, 2H), 2.21-2.11 (m, 2H), 1.98-1.80 (m, 2H). 527 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.55 (s, 1H), 8.82-8.73 (m, 2H), 8.52 (s, 1H), 8.34 (s, 1H), 8.11-8.05 (m, 1H), 7.13 (dd, J = 7.2, 2.0 Hz, 1H), 6.80 (s, 1H), 3.61-3.53 (m, 4H), 2.73-2.60 (m, 1H), 2.39 (s, 3H), 2.15-2.03 (m, 1H), 1.91-1.83 (m, 2H), 1.79-1.58 (m, 6H), 1.38-1.25 (m, 4H), 1.11-1.01 (m, 2H), 0.93-0.84 (m, 2H). 528 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.58 (s, 1H), 8.81 (d, J = 7.2 Hz, 1H), 8.79 (s, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.14 (dd, J = 7.2, 2.0 Hz, 1H), 6.80 (s, 1H), 4.02-3.95 (m, 2H), 3.51-3.42 (m, 2H), 3.04-2.91 (m, 1H), 2.39 (s, 3H), 2.03-1.95 (m, 1H), 1.85-1.78 (m, 2H), 1.76-1.64 (m, 2H), 1.11-1.01 (m, 2H), 0.89-0.83 (m, 2H). 529 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.55 (s, 1H), 8.79-8.76 (m, 2H), 8.51 (s, 1H), 8.41 (s, 1H), 8.03 (d, J = 1.9 Hz, 1H), 7.02 (dd, J = 7.1, 1.9 Hz, 1H), 6.69 (s, 1H), 4.55 (t, J = 5.0 Hz, 1H), 4.43 (t, J = 5.0 Hz, 1H), 2.90-2.81 (m, 2H), 2.68-2.63(m, 2H), 2.61-2.57 (m, 1H), 2.55-2.51 (m, 4H), 2.38 (s, 3H), 2.25-2.16 (m, 1H), 2.03-1.88 (m, 2H), 1.62-1.51 (m, 2H), 1.14-1.08 (m, 2H), 1.02-0.93 (m, 2H). 530 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.58 (s, 1H), 8.78 (s, 1H), 8.75 (d, J = 7.4 Hz, 1H), 8.52 (s, 1H), 8.35 (s, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.35 (dd, J = 7.4, 2.1 Hz, 1H), 6.80 (s, 1H), 6.51 (s, 1H), 3.67-3.53 (m, 4H), 2.48-2.43 (m, 2H), 2.40 (s, 3H), 2.24-2.19 (m, 2H), 2.13-2.03 (m, 1H), 1.73-1.66 (m, 2H), 1.45-1.38 (m, 4H), 1.11-1.01 (m, 2H), 0.91-0.85 (m, 2H). 531 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.59 (s, 1H), 8.80 (d, J = 7.2 Hz, 1H), 8.78 (s, 1H), 8.51 (s, 1H), 8.41 (s, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.13 (dd, J = 7.2, 2.0 Hz, 1H), 6.70 (s, 1H), 3.75-3.70 (m, 2H), 3.20-3.10 (m, 1H), 2.38 (s, 3H), 2.24-2.17 (m, 1H), 1.81-1.73 (m, 2H), 1.60-1.46 (m, 2H), 1.28 (s, 3H), 1.21 (s, 3H), 1.14-1.08 (m, 2H), 1.04-0.95 (m, 2H). 532 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.59 (s, 1H), 8.80 (d, J = 7.2 Hz, 1H), 8.78 (s, 1H), 8.51 (s, 1H), 8.41 (s, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.13 (dd, J = 7.2, 2.0 Hz, 1H), 6.70 (s, 1H), 3.78-3.69 (m, 2H), 3.20-3.10 (m, 1H), 2.38 (s, 3H), 2.25-2.17 (m, 1H), 1.81-1.73 (m, 2H), 1.63-1.46 (m, 2H), 1.28 (s, 3H), 1.21 (s, 3H), 1.14-1.07 (m, 2H), 1.02-0.90 (m, 2H). 533 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.61 (s, 1H), 8.82 (d, J = 7.1 Hz, 1H), 8.80 (s, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 8.18 (s, 1H), 7.13 (dd, J = 7.1, 1.9 Hz, 1H), 6.70 (s, 1H), 3.70 (s, 2H), 2.59-2.53 (m, 4H), 2.38 (s, 3H), 2.25-2.17 (m, 1H), 2.04-1.92 (m, 4H), 1.15-1.06 (m, 2H), 1.01-0.93 (m, 2H). 534 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.74 (s, 1H), 8.86 (d, J = 2.3 Hz, 1H), 8.46 (s, 1H), 8.45 (s, 1H), 8.24 (s, 1H), 7.58 (d, J = 9.7 Hz, 1H), 7.48 (dd, J = 9.7, 2.3 Hz, 1H), 6.63 (s, 1H), 3.22-3.13 (m, 2H), 3.06 (s, 3H), 2.91-2.83 (m, 2H), 2.30 (s, 3H), 2.21-2.08 (m, 1H), 1.80-1.70 (m, 2H), 1.60-1.49 (m, 2H), 1.08 (s, 3H), 1.05-1.00 (m, 2H), 0.92-0.87 (m, 2H). 536 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.13 (s, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.72 (d, J = 6.0 Hz, 1H), 7.08 (d, J = 2.3 Hz, 1H), 4.38-4.28 (m, 2H), 4.23-4.12 (m, 1H), 4.11-4.03 (m, 2H), 3.59 (s, 3H), 2.47 (s, 3H), 2.24 (s, 3H). 537 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.69 (s, 1H), 8.80 (d, J = 7.2 Hz, 1H), 8.72 (s, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.15 (s, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.35 (d, J = 11.6 Hz, 1H), 7.26 (dd, J = 7.2, 2.1 Hz, 1H), 6.62 (d, J = 3.0 Hz, 1H), 4.74 (s, 1H), 3.98 (s, 2H), 2.40 (s, 3H), 2.33 (s, 3H), 2.21 (m, 1H), 1.17-1.07 (m, 8H), 1.00-0.94 (m, 2H). 538 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.70 (s, 1H), 8.82 (d, J = 7.3 Hz, 1H), 8.72 (s, 1H), 8.19 (d, J = 2.1 Hz, 1H), 7.85 (s, 1H), 7.83 (d, J = 7.1 Hz, 1H), 7.35 (d, J = 11.6 Hz, 1H), 7.25 (dd, J = 7.2, 2.1 Hz, 1H), 6.62 (d, J = 3.0 Hz, 1H), 4.70 (s, 1H), 4.05 (s, 2H), 2.42 (s, 3H), 2.32 (s, 3H), 2.25-2.15 (m, 1H), 1.14 (s, 6H), 1.12-1.07 (m, 2H), 0.99- 0.94 (m, 2H).

Biological test evaluation

The invention is further described and explained below with reference to test examples, but these examples are not intended to limit the scope of the invention.

Test Example 1: Determination of the inhibitory effect of the compound of the present invention on the activity of enzymes (KIT, FMS (CSF1R), PDGFRβ, PDGFRα, FLT3) 1. Experimental Objective: The purpose of this test example is to measure the inhibitory ability of the compound on the activity of enzymes (KIT, FMS (CSF1R), PDGFRβ, PDGFRα, FLT3). 2. Experimental Instruments and Reagents: 2.1 Instruments: Instrument Name Manufacturer Specifications and Models EnVision PerkinElmer ENVISION 2015 2.2 Reagents: Reagent materials Manufacturer Item Number KIT Carna 08-156 FMS (CSF1R) Carna 08-155 PDGFRβ Carna 08-158 PDGFRα Carna 08-157 FLT3 Carna 08-154 LANCE Ultra ULight™-poly GT Perkinelmer TRF0100-M ATP Solution Invitrogen PV3227 DMSO Sigma D2650 HEPES (1M) Gibco 15630-080 MgCl2 (1M) Invitrogen AM9530G Tween 20 Sigma P9416 EGTA Alfa Aesar J60767 DTT(1M) Sigma 43816 LANCE® Eu-W1024 Anti-phosphor tyrosine (PT66) PerkinElmer AD0068 EDTA (0.5M) Invitrogen AM9260G 10X LANCE detection buffer PerkinElmer CR97-100 384-hole plate Perkinelmer 6007299 96V type base plate (PS) Axygen WIPP02280 3. Experimental Method: Incubate 1 nM KIT and gradient-diluted compounds for 0.5 hours in 1× enzyme reaction buffer (50 mM HEPES pH 7.5, 1 mM EGTA, 10 mM MgCl2, 2 mM DTT, 0.01% Tween-20). Add 100 nM ULight-poly GT and 20 μM ATP, and react at room temperature for 0.5 hours. Add an equal volume of detection and termination mixture (1×LANCE detection buffer containing 20 mM EDTA and 4 nM LANCE® Eu-W1024 Anti-phosphor tyrosine (PT66), mix well, centrifuge, seal with a film, and react at room temperature for 1 hour. The plate was read using the TR-FRET program on an EnVision instrument, and the fluorescence values at 665nm/615nm were measured for each well. 4. Experimental Data Processing: The raw data (665nm/615nm reading ratio) was calculated using the following formula to obtain the inhibition rate: Inhibition rate % = [(Average value of positive control wells – Sample well value) / (Average value of positive control wells – Average value of negative control wells)] × 100, where positive control wells are those without the compound enzyme reaction, and negative control wells are those without the enzyme reaction. The log(inhibitor) vs. response -- Variable slope (four parameters) function in GraphPad Prism 6 was used to perform a fitting equation analysis on the compound concentration and corresponding inhibition rate, and the fitting curve was used to obtain the compound's _IC50 value. The approximate calculation equation is Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)). 5. Experimental results: Implementation Examples KIT IC ₅₀ CSF1R IC ₅₀ 5 A E 173 A D 177 A E 194 A E 290 B E 293 A E 348 B E 373 B E 490 B E 491 A E 492 A E 493 B E 494 B E 496 B E 497 B E 498 B E 500 A E 506 A E 510 A D 511 A E 514 B E 515 A E 516 A E 517 A E 518 B E 519 A D 520 B E 522 B E 523 A E 524 A E 527 A E 528 A E 530 A E 535 B E Wherein: "A" represents _IC50 ≤ 0.05 µM, "B" represents 0.05 µM ≤ _IC50 ≤ 0.5 µM, "C" represents 0.5 µM ≤ _IC50 ≤ 5 µM, "D" represents 5 µM ≤ _IC50 ≤ 25 µM, and "E" represents _IC50 ≥ 25 µM. 6. Experimental Results and Conclusions: The above data show that the compounds of the present invention have a strong inhibitory effect on KIT enzyme activity. Furthermore, the compounds of the present invention exhibit varying degrees of selectivity for FMS (CSF1R). Specifically, the compounds of the present invention show selectivity of more than 50 times for FMS (CSF1R), preferably more than 100 times, and even more than 500 times.

Test Example 2: Inhibitory effect of the compound of the invention on the cell proliferation of cell lines (Ba/F3-ETV6-cKIT, Ba/F3-ETV6-Ckit, Ba/F3-TEL-CSF1R, Ba/F3-TEL-PDGFRβ, Ba/F3-TEL-PDGFRα, and Ba/F3-TEL-FLT3). 1. Experimental objective: The purpose of this test example is to measure the inhibitory ability of the compound on the proliferation of Ba/F3-ETV6-cKIT, Ba/F3-ETV6-Ckit, Ba/F3-TEL-CSF1R, Ba/F3-TEL-PDGFRβ, Ba/F3-TEL-PDGFRα, and Ba/F3-TEL-FLT3 cells. 2. Experimental instruments and reagents: 2.1 Instruments: Instrument Name Manufacturer Specifications and Models Plate shaker QILINBEIER QB-9001 CO2 Incubator Thermo Scientific Model 3100 Series Microscope OLYMPUS CKX41SF Multifunctional microplate reader BMG LABTECH CLARIOstar® Plus Biosafety cabinet Thermo Model 1300 Series A2 refrigerator SIEMENS KK25E76TI 2.2 Reagents: Reagent materials Manufacturer Item Number RPMI1640 Hyclone SH30809.01 Fetal Bovine Serum (FBS) Gibco 10099-141 Phosphate Buffered Saline (PBS) Solarbio P1020-500 DMSO Sigma D4540-1L CellCounting-Lite 2.0 Luminescent Cell Viability Assay Vazyme DD1101-02 White 96-cell culture plate Absin abs7016 3. Experimental Methods: 3.1 Cell Culture: Cell number Cell name Growth characteristics Complete culture medium KC-3053 Ba/F3-ETV6-cKIT Suspension RPMI 1640 + 10% FBS 3.2 Cell proliferation experiment: a) All cell lines were cultured in complete medium at 37 ^° C and 5% _CO2 . b) Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was assessed using the trypan blue exclusion method to ensure it was above 90%. c) Cell density was adjusted using complete medium and then seeded into 96-well cell culture plates, 90 μL per well, for a total of 3000 cells. d) The cells in the 96-well plates were incubated at 37°C and 5% _CO2 . e) Prepare a 10-fold drug solution with a maximum working concentration of 10 µM for the positive compound, 9 concentrations, and a 3.16-fold dilution. Then transfer 10 μL of each continuously diluted compound to the corresponding wells of a 96-well cell plate, with two replicates for each drug concentration. f) Incubate the cells in the drug-treated 96-well plate at 37 °C and 5% _CO2 for 72 hours, then perform CellCounting-Lite® 2.0 analysis. g) Melt the CellCounting-Lite 2.0 Luminescent Cell Viability Assay reagent and equilibrate the cell plate to room temperature for 30 minutes. h) Add an equal volume of CellCounting-Lite 2.0 Luminescent Cell Viability Assay solution to each well. i) Vibrate on a stationary shaking table for 5 minutes to lyse the cells. j) Place the cell plate at room temperature for 20 minutes to stabilize the cryo-light signal. k) Read the cryo-light values and collect the data. 3.3 Data Analysis: GraphPad Prism 7.0 software was used to analyze the data. Nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, and the _IC50 value was calculated from it. Cell viability (%) = (Lum _{test drug} - Lum _{culture medium control} ) / (Lum _{solvent control} - Lum _{culture medium control} ) × 100%. 4. Experimental Results and Conclusions: Implementation Examples KIT IC ₅₀ (nM) PDGFRα IC ₅₀ (nM) Selection multiple 5 4.5 5738 1275 177 1.9 5913 3112 194 1.9 7059 3715 348 6.1 6741 1105 Experimental conclusions: The compounds of this invention exhibit varying degrees of selectivity for the target PDGFRα at the cellular level. Among them, the compounds of this invention show more than 1000-fold selectivity for the target PDGFRα at the cellular level.

Test Example 3: Selective inhibition of phosphorylation in stable cell lines by the compound of the invention.

I. Inhibitory Effect of the Compound of the Invention on Phosphorylation of the Stable Transgenic Cell Line HEK293-KIT 1. Experimental Objective: The purpose of this test case is to examine the inhibitory effect of the compound of the invention on phosphorylation of the stable transgenic cell line HEK293-KIT. 2. Experimental Instruments and Reagents: 2.1 Instruments: Instrument Name Manufacturer Specifications and Models Nano-splitter separation system Dispendix I-DOT Ultrasensitive multi-factor electrochemiluminescence analyzer MSD Inc. (USA) MESO QuickPlex SQ 120MM 2.2 Reagents Reagent materials Manufacturer Item Number FBS gibco A5669701 DMEM gibco 11995-065 PBS Gibco 10010-023 Recombinant Human SCF Peprotech 300-07 Trypsin-EDTA (0.05%) Gibco 25300054 Corning® 96-well transparent V-shaped bottom microplate corning 3894 9Corning® 96-well transparent flat-bottom polystyrene microplate corning 3599 PhosSTOP™ Roche 4906837001 cOmplete Tablets EDTA-free, EASYpack Roche 469312001 Cell Lysis Buffer (10X) CST 9803 QuickPlex 96-Well High Bind Plate Pack MSD L55XB-3 MSD Read Buffer T (4x) MSD R92TC-2 Anti Phospho-Tyrosine Antibody SULFO-TAG Labeled MSD R32AP-1 Purified anti-human CD117 (c-kit) Antibody BioLegend 313202 c-Kit Monoclonal Antibody (104D2) MSD R61TX-1 Tris Lysis Buffer (1X) MSD R93BA-4 3. Experimental Methods: Cell Preparation: Hek293-KIT cells were adjusted to a cell density of 15k cells/well and laid in 96-well plates, 100uL per well, and cultured overnight. Compound Preparation and Incubation: Hek293-KIT Cells: The stock solution concentration was 10mM. The maximum concentration for detection in Hek293-KIT cells was 1000nM. The stock solution was first diluted with DMSO to a 1000x (1mM) intermediate dilution solution to the set maximum concentration. Then, 31.55x intermediate dilution solutions were added sequentially for a total of 3 concentrations. Using the I DOT non-contact microdispensing system, the compound was dispensed into 96-well plates at a total volume of 100 nmol (containing 0.1% DMSO) per well, for a total of 9 doses. 100 nmol/well of DMSO was added to the Max well, and 100 nmol/well of 10 mM fluorogenic analyte was added to the Min well. The plates were incubated in a CO2 incubator for 2 hours. Cytokine stimulation: The 96-well plate was removed, and 100 ng/ml of human SCF was added, followed by stimulation for 10 minutes. Cell lysis: 10X Cell Lysis Buffer was diluted to 1X with ddH2O. The 1X buffer was chilled on ice, and before use, appropriate amounts of protease inhibitor and phosphatase inhibitor were added at a rate of 1 tablet/ml. The 96-well plate was removed, and 120 μl of cells was added to each well, followed by lysis for 15 minutes. MSD Detection: One day in advance, coat the MSD plate: Dilute the coating antibody with PBS, add 30 μL to each well for coating, and incubate overnight at 24°C. Blocking: Wash the MSD detection plate, add 300 μL of blocking buffer, and block at room temperature for 1 hour. Sample Incubation: Wash the blocked detection plate 4 times, add 300 μL to each well, remove all liquid, and add 40 μL of the lysed cell supernatant to the corresponding well, incubate at 24°C for 2 hours. Antibody Incubation: Wash the plate, add 25 μL of antibody to each well, and incubate at 24°C for 1 hour. Reading: Wash the plate, add 150 μL of 2x read buffer, and perform detection on the MSD plate. Data processing: The compound signal was converted into an inhibition rate. The nonlinear regression fitting of the compound concentration and the corresponding inhibition rate was performed using the log(inhibitor) vs. response -- Variable slope (four parameters) function in Graphpad. The fitting curve was then used to obtain the _IC50 value.

II. Inhibitory Effect of the Compound of the Invention on Phosphorylation of Transiently Transfected Cell Lines HEK293-PDGFRα and HEK293-PDGFRβ 1. Experimental Objective: The purpose of this test example is to examine the inhibitory effect of the compound of the invention on phosphorylation of stable transfected cell lines HEK293-PDGFRα and HEK293-PDGFRβ. 2. Experimental Instruments and Reagents: 2.1 Instruments: Instrument Name Manufacturer Specifications and Models Nano-splitter separation system Dispendix I-DOT Envision Perkin Elmer 2105-0020 2.2 Reagents Reagent materials Manufacturer Item Number FBS gibco A5669701 RPMI 1640 Gibco 22400-071 DMEM gibco 11995-065 Recombinant Human PDGF-AA Peprotech 100-13A Trypsin-EDTA (0.05%) Gibco 25300054 Countess® Cell Counting Chamber Slides Invitrogen C10228 Large-scale plasmid PDGFRα Genscript NA FuGENE(R) HD Transfection Reagent promega E2312 Human Phospho-M-CSF R DuoSet IC ELISA R&D DYC3268-5 Corning® 96-well transparent V-shaped bottom microplate corning 3894 Corning® 96-well transparent flat-bottom polystyrene microplate corning 3599 1.5 EP tube Corning 430791 PhosSTOP™ Roche 4906837001 cOmplete Tablets EDTA-free, EASYpack Roche 469312001 Cell Lysis Buffer (10X) CST 9803 3. Experimental Methods: Cell Preparation: Stock cells in 6-well plates and culture overnight. Mix PDGFRα plasmid with FuGENE transfection reagent, incubate at room temperature for 10 minutes, add the mixture to cells, and culture for 24 hours. Adjust Hek293-PDGFRα cells to a cell density of 15k cells/well and stock 100μL per well in 96-well plates, culture overnight. Stock cells in 6-well plates and culture overnight. Mix PDGFRβ plasmid with FuGENE transfection reagent, incubate at room temperature for 10 minutes, add the mixture to cells, and culture for 24 hours. Hek293-PDGFRβ cells were adjusted to a cell density of 15k cells/well and plated in 96-well plates, 100μL per well, and cultured overnight. Compound preparation and incubation: HEK293-PDGFRα cells: The stock solution concentration was 10mM. The highest detection concentration in HEK293-PDGFRα cells was 30000nM. The stock solution was diluted with DMSO to obtain 31.55x intermediate dilution buffers, for a total of 3 concentrations. Then, using an I DOT non-contact microdispensing system, the compound was dispensed into each well of a 96-well plate at a total volume of 300nL (containing 0.3% DMSO), for a total of 9 doses. The stock solution of the compound was first diluted with DMSO to a 1000x (2mM) intermediate dilution solution, which was then used to determine the maximum concentration. This was followed by further dilution with 31.55x intermediate dilution solutions, resulting in three concentrations. Using an I DOT non-contact microdispensing system, the compound was dispensed into 96-well plates at a total volume of 300 nL (containing 0.3% DMSO) per well, for a total of nine doses. 300 nL/well of DMSO was added to the Max and Min wells. The plates were incubated in a CO2 incubator for 2 hours. For HEK293-PDGFRβ cells: the stock solution concentration was 10 mM, and the maximum detection concentration in HEK293-PDGFRβ cells was 30000 nM. The stock solution of the compound was then diluted with DMSO with 31.55x intermediate dilution solutions, resulting in three concentrations. Using the I DOT non-contact microdispensing system, the compound was dispensed into 96-well plates at a total volume of 300 nL (containing 0.3% DMSO) per well, for a total of 9 doses. The stock solution of the compound was first diluted with DMSO to a 1000x (2 mM) intermediate dilution solution at the set maximum concentration, and then further diluted with 31.55x intermediate dilution solutions, for a total of 3 concentrations. The compound was then dispensed into 96-well plates at a total volume of 300 nL (containing 0.3% DMSO) per well using the I DOT non-contact microdispensing system, for a total of 9 doses. 300 nL/well of DMSO was added to the Max and Min wells. The plates were incubated in a CO2 incubator for 2 hours. Cytokine stimulation: Remove the 96-well plate and add cytokines PGFRAA or PDGFRBB to a final concentration of 50 ng/ml, stimulating for 10 minutes. Cell lysis: Dilute 10X Cell Lysis Buffer to 1X with _ddH₂O , chill the 1X buffer on ice, and add appropriate amounts of protease inhibitor and phosphatase inhibitor at a rate of 1 tablet/ml before use. Remove the 96-well plate and add 120 μl of cells to each well, lysing the cells for 15 minutes. ELISA detection: Dilute the coated antibody with PBS one day in advance, add 100.0 μl to each well for coating, and incubate overnight at room temperature. On the day of ELISA testing, collect the cell supernatant, thaw it at room temperature, and set aside for use. Blocking: Wash the test plate, add 300 μl of blocking solution, and block at room temperature for 1 hour. Wash the blocked test plate 4 times, adding 300 μl to each well to remove all liquid. Add 100 μl of centrifuged and diluted cell supernatant to the corresponding well and incubate at 24°C for 2 hours. Antibody incubation: Wash the plate, add 100 μl of HRP-labeled antibody to each well, and incubate at 24°C for 1.5-2 hours. Color development and termination: Wash the plate, add 100 μl of colorimetric reagent, and incubate in the dark for approximately 5-10 minutes. Add 50 μl of termination solution to terminate color development and perform detection at 450/570 nm using an Envision microscope. 4. Data processing: The inhibition rate of each concentration of the compound was calculated using OD (450-570nm). Nonlinear regression fitting of the compound concentration and the corresponding inhibition rate was performed using log(inhibitor) vs. response -- Variable slope (four parameters) in Graphpad. The fitting curve was obtained and the _IC50 value was obtained.

III. Experimental Results and Conclusions on the Selective Inhibition of Phosphorylation in Stable Cell Lines by the Compounds of this Invention 1. Experimental Results Implementation Examples KIT IC ₅₀ (nM) PDGFRα IC ₅₀ (nM) Selection multiple 1 3.5 / / 491 1.3 / / 495 9.2 10339 1124 496 1.6 / / 497 1.5 / / 498 0.8 / / 499 3.1 1920 619. 500 1.6 2067 1292 502 1.7 699 411 504 2.3 6784 2950 505 1.9 1259 663 506 0.4 348 870 507 0.9 288 320 508 0.8 423 529 509 0.3 382 127 510 1.1 1146 1042 511 0.8 / / 512 1.8 408 227 514 1.1 698 635 516 1.3 495 381 519 3.0 2154 718 520 1.5 958 639 521 0.2 403 1752 522 2.5 1004 402 523 1.7 / / 524 2.0 / / 526 1.9 / / 527 2.8 1444 516 528 2.9 1497 516 529 3.8 / / 530 1.4 1307 934 532 2.7 / / 535 3.9 1192 306 2. Experimental Conclusions: The compounds of this invention exhibit varying degrees of selectivity for the target PDGFRα at the cellular level. Among them, some compounds show selectivity for PDGFRα of more than 100-fold, preferred selectivity of more than 500-fold, and even more than 1000-fold.

Although the present invention has been disclosed above with examples, it is not intended to limit the present invention. Those skilled in the art to which the present invention pertains may make some modifications and refinements without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention shall be determined by the scope of the appended invention application.

without

without

Claims (15)

A compound of formula (I'') or a pharmaceutically acceptable salt thereof: in, The aryl group is a substituted or unsubstituted 8-9 membered heteroaryl group; Ar is selected from a 5-6 membered heteroaryl group, wherein the heteroaryl group is optionally further substituted by 1-4 Rr groups ; X2 is selected from N or CR2r ; X4 is selected from N or CR4r ; X7 is selected from N or CR7r ; R2r , R4r and R7r are defined as Rr ; Rr is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2-C6 alkoxy, substituted or unsubstituted C1 - C6 halogenated alkyl , substituted or unsubstituted C1 ... 6- Haloxyalkyl, substituted or unsubstituted C1 - C6 deuterated alkyl, substituted or unsubstituted C1 - C6 deuterated alkoxy, substituted or unsubstituted C1 - C6 hydroxyalkyl, substituted or unsubstituted C3- C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, C1 - C6 alkylene- R21 , ( CH2 ) q OR21 , ( CH2 ) q NR21 R22 , (CH2) q COR23 , ( CH2 )q COOR21 , ( CH2 ) q CONR21 R22 , ( CH2 ) q NR21 COR 23 , ( CH2 ) q NR 21 COOR 22 , ( CH2 ) q SOR 23 , ( CH2 ) q SONR 21 R 22 , ( CH2 ) q SO 2 R 21 , ( CH2 ) q SO 2 NR 21 R 22 ; wherein the substitution refers to substitution by 1-4 R fff ; R 21 , R 22 and R 23 are each independently selected from: hydrogen, COOC 1 -C 6 alkyl, SO 2 C 1 -C 6 alkyl, substituted or unsubstituted C 1 - C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkoxy, substituted or unsubstituted C 1 - C 6 halogenated alkyl, substituted or unsubstituted C 1 -C 6 halogenated alkoxy, substituted or unsubstituted C 1 -C 6 deuterated alkyl, substituted or unsubstituted C 1 -C 6 deuterated alkoxy, substituted or unsubstituted C 1 -C 6 hydroxyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein the substitution refers to substitution by 1-4 R ffff ; R fff and R ffff are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 10 -Cycloalkyl, 4-10-membered heterocyclic, C6 - C10 aryl, 5-10-membered heterocyclic, C1 - C6 halogenated alkyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C2 -C6 halogenated alkenyl, C2 - C6 halogenated alkynyl, C1 - C6 halogenated alkoxy, C3 - C10 halogenated cycloalkyl, 4-10-membered heterocyclic, C6 - C10 halogenated aryl, or 5-10-membered heterocyclic; ring A is selected from C6 - C10 aryl, 5-10 -membered heterocyclic, 4-10-membered heterocyclic, C3-C10 halogenated alkyl, C6 ... -C 10 cycloalkyl, phenyl-5-6 membered heterocyclic, phenyl-C 5 -C 6 cycloalkyl, 5-6 membered heteroaryl-5-6 membered heterocyclic, 5-6 membered heteroaryl-C 5 -C 6 cycloalkyl; Ra is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 ynyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 1 -C 6 halogenated alkyl, substituted or unsubstituted C 1 -C 6- Haloxy, substituted or unsubstituted C1 - C6 deuterated alkyl, substituted or unsubstituted C1 - C6 deuterated alkoxy, substituted or unsubstituted C1 - C6 hydroxyl, substituted or unsubstituted C3- C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl, wherein the substitution refers to substitution by 1-4 groups selected from the following groups: hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, oxo, thio, NH2 , NHC1 - C6 alkyl, N( C1 - C6 alkyl) 2 , C1 - C6 alkyl, C1 -C6 alkoxy, C1 - C6 haloxyalkyl , C 1 - C6 halogenated alkoxy, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, or C1 - C6 hydroxyalkyl; L1 is selected from the bond, ( CH2 ) m1 , C2 - C4 alkenyl, C2 - C4 alkyneyl, ( CH2 ) m2 -O-(CH2) m3 , ( CH2 ) m2 -S-( CH2 ) m3 , ( CH2 ) m2 - NRh- ( CH2 ) m3 , ( CH2 ) m2 -CO-( CH2 ) m3 , ( CH2 ) m2 -COO-( CH2 ) m3 , ( CH2 ) m2 - CONRh- ( CH2 ) m3 , ( CH2 ) m2 - NRhCOO- ( CH2 ) m3 , (CH 2 ) m2 -R l NCONR h -(CH 2 ) m3 , (CH 2 ) m2 -SO 2 -(CH 2 ) m3 , (CH 2 ) m2 -SO 2 NR h -(CH 2 ) m3 , (CH 2 ) m2 -R l NSO 2 NR h -(CH 2 ) m3 , (CH 2 ) m2 -SO-(CH 2 ) m3 , (CH 2 ) m2 -SONR h -(CH 2 ) m3 , (CH 2 ) m2 -R l NSONR h -(CH 2 ) m3 or (CH 2 ) m2 -R l NC(=NH)NR h -(CH 2 ) m3 ; Ring B is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic, C3 - C10 cycloalkyl, phenyl-5-6 membered heterocyclic, phenyl- C5 - C6 cycloalkyl, 5-6 membered heteroaryl-5-6 membered heterocyclic or 5-6 membered heteroaryl- C5 - C6 cycloalkyl; Rb is independently selected from substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C1 - C6 halogenated alkyl, substituted or unsubstituted C1 - C6 halogenated alkoxy, substituted or unsubstituted C1 - C6 deuterated alkyl, substituted or unsubstituted C1 -C6 alkyl, etc. 6 -Deuterated alkoxy, substituted or unsubstituted C1 - C6 hydroxyl, substituted or unsubstituted C1 -C6 alkoxy, substituted or unsubstituted C3 - C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, ( CH2 ) k OR B-1 , ( CH2 ) k NR B-1 RB -2 , ( CH2 ) k COR B-3 , =NHOR B-1 , =CR B-1 RB -2 , ( CH2 ) k C(=NH)OR B-1 , ( CH2 ) k CONR B-1 RB -2 , (CH2) k NR B-1 COR B-3 , ( CH2 ) k COOR B-3 , (CH 2 ) kNR B-1 COOR B-3 , (CH 2 ) k C(=NH)NR B-1 RB -2 , (CH 2 ) kNR B-1 C(=NH)RB -3 , (CH 2 ) k SOR B-1 , (CH 2 ) k SONR B-1 RB -2 , (CH 2 ) kNR B-1 SOR B-3 , (CH 2 ) k SO 2 RB -1 , (CH 2 ) k SO 2 NR B-1 RB -2 or (CH 2 ) kNR B-1 SO 2 RB -3 ; wherein the substitution refers to substitution by 1-4 R bb ; R bb is selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, oxo, thio, C1 - C6 alkyl, C1 - C6 alkoxy, C2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 deuterated alkoxy, C 1 -C 6 hydroxyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclic, C 6 -C 10 aryl, 5-10 membered heterocyclic, C 1 -C 6 halogenated alkyl, C 1 -C 6 halogenated alkoxy, C 3 -C 10 halogenated cycloalkyl, 4-10 membered heterocyclic, C 6 -C 10 halogenated aryl, 5-10 membered heterocyclic, (CH 2 ) j OR b-1 , (CH 2 ) j NR b-1 R b-2 , (CH 2 ) j COR b-3 , =NHOR b-1 , = CR b-1 R b-2 , (CH 2 ) j C(=NH)OR b-1 , (CH 2 ) j CONR b-1 R b-2 , (CH 2 ) j NR b-1 COR b-3 , (CH 2 ) j NR b-1 COOR b-3 , (CH 2 ) j COOR b-3 , (CH 2 ) j C(=NH)NR b-1 R b-2 , (CH 2 ) j NR b-1 C(=NH)R b-3 , (CH 2 ) j SOR b-1 , (CH 2 ) j SONR b-1 R b-2 , (CH 2 ) j NR b-1 SOR b-3 , (CH 2 ) j SO 2 R b-1 , (CH 2 ) j SO 2 NR b-1 R b-2 or (CH 2 ) j NR b-1 SO₂Rb -3 , wherein the C₁ - C₆ alkyl, C₁-C₆ alkoxy, C₂ - C₆ alkenyl, C₂ - C₆ ynyl, C₁ - C₆ deuterated alkyl, C₁ - C₆ deuterated alkoxy, C₁ - C₆ hydroxyl, C₃ - C₁₀ cycloalkyl, 4-10 membered heterocyclic, C₆ - C₁₀ aryl, and 5-10 membered heteroaryl may be further substituted by 1-4 Rbbb ; Rbbb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, hydroxyl, oxo, thio, C₁ - C₆ alkyl, C₁- C₆ alkyl, C₁ - C₆ alkoxy, C₂ - C₆ alkenyl, C₂ - C₁₀ ynyl, C₂- C₁₀ ynyl, C₂- C₁₀ alkyl ... 1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyl, C3- C10 cycloalkyl, 4-10 membered heterocyclic, C6- C10 aryl, 5-10 membered heterocyclic, C1 - C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C3 -C10 halogenated cycloalkyl, 4-10 membered heterocyclic, C6 - C10 halogenated aryl or 5-10 membered heterocyclic; RB -1 , RB -2 , RB- 3, Rb -1 , Rb -2 and Rb -3 are each independently selected from H, COOC 1 - C6 alkyl, SO2 C1 - C6 alkyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 halogenated alkyl, substituted or unsubstituted C 1 -C 6 halogenated alkoxy, substituted or unsubstituted C 1 -C 6 deuterated alkyl, substituted or unsubstituted C 1 -C 6 deuterated alkoxy, substituted or unsubstituted C 1 -C 6 hydroxyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, C 1 -C 6 halogenated alkyl, C 3 -C 10 halogenated cycloalkyl, 4-10 membered heterocyclic, C 6 - C10 halogenated aryl, 5-10-membered halogenated heteroaryl; wherein the substitution refers to substitution by 1-4 R bbbb ; R bbbb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, hydroxyl, oxo, thio, C1 - C6 alkyl, C1 - C6 alkyl, C1 - C6 alkoxy, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C10 cycloalkyl, 4-10-membered heterocycloyl, C6 - C10 aryl, 5-10-membered heteroaryl, C1 - C6 halogenated alkyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyl, C3 -C 10- membered halogenated cycloalkyl, 4-10-membered halogenated heterocyclic, C6 - C10 halogenated aryl, or 5-10-membered halogenated heteroaryl; the H in the above CH2 may be optionally substituted with a substituent selected from the following group: hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, oxo, thio , NH2, NHC1 - C6 alkyl, N( C1 - C6 alkyl) 2 , C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C2 - C6 alkenyl, C2 - C6 alkynyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 -C 6- Hydroalkyl; Rh and Rl are each independently selected from hydrogen, deuterium, halogen, C1 -C6 alkyl, C2 - C6 alkenyl, C2- C6 alkoxy, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclic, C6 - C10 aryl, 5-10 membered heteroaryl, C1 - C6 halogenated alkyl, C2-C6 halogenated alkenyl, C2 - C6 halogenated alkynyl, C1-C6 halogenated alkoxy, C3- C10 hydroxyalkyl, 4-10 membered heterocyclic, C6 - C10 aryl, 5-10 membered heteroaryl, C1 - C6 halogenated alkyl, C2 - C6 halogenated alkenyl, C2 - C6 halogenated alkoxy, C3-C10 hydroxyalkyl, C2 ... 10- membered halogenated cycloalkyl, 4-10-membered halogenated heterocyclic, C6 - C10 halogenated aryl or 5-10-membered halogenated heteroaryl; m1, m2 and m3 are each independently selected from 0, 1, 2, 3, 4, 5, 6; x is selected from 0, 1, 2, 3, 4, 5, 6; y is selected from 0, 1, 2, 3, 4, 5, 6; q, j and k are each independently selected from 0, 1, 2, 3, 4, 5, 6. The compound of claim 1 or its pharmaceutically acceptable salt, wherein ring A is phenyl, 5-6-membered heteroaryl, 5-10-membered heterocycloyl, or C5 - C10 cycloalkyl; preferably ring A is phenyl or 5-6-membered heteroaryl, preferably phenyl, pyridyl, pyridyl, pyridyl, pyridinyl, pyridone, thiophene, furanyl, thiazolyl, or imidazolyl. A compound of formula (I'-A'-1) or a pharmaceutically acceptable salt thereof, Wherein, Ra1 , Ra2 , and Ra4 are defined as Ra ; preferably, Ra1 , Ra2 , and Ra4 are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1 - C3 alkyl, C1 - C3 halogenated alkyl, C1 - C3 deuterated alkyl, C1 - C3 alkoxy, C1 - C3 halogenated alkoxy, and C1 - C3 deuterated alkoxy; Ra is each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, NHC1 - C6 alkyl, N (C1- C6 alkyl) 2 , substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 1 -C 6 halogenated alkyl, substituted or unsubstituted C 1 -C 6 halogenated alkoxy, substituted or unsubstituted C 1 -C 6 deuterated alkyl, substituted or unsubstituted C 1 -C 6 deuterated alkoxy, substituted or unsubstituted C 1 -C 6 hydroxyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl, wherein the substitution refers to substitution by 1-4 groups selected from the following group: hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, oxo, thio, NH₂ , NHC 1 -C 6- alkyl, N( C1 - C6alkyl ) 2 , C1 -C6alkyl, C1 -C6alkoxy , C1 - C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, or C1 - C6 hydroxyalkyl; L1 is selected from the bond, ( CH2 ) m1 , C2 - C4 alkenyl, C2 - C4 alkyneyl, ( CH2 ) m2 -O-( CH2 ) m3 , ( CH2 ) m2 -S-( CH2 ) m3 , ( CH2 ) m2 - NRh- ( CH2 ) m3 , ( CH2 ) m2 - CO- ( CH2 ) m3 , ( CH2 ) m2 -COO-(CH2) m3 ) m3 , (CH 2 ) m2 -CONR h -(CH 2 ) m3 , (CH 2 ) m2 -NR h COO-(CH 2 ) m3 , (CH 2 ) m2 -R l NCONR h -(CH 2 ) m3 , (CH 2 ) m2 -SO 2 -(CH 2 ) m3 , (CH 2 ) m2 -SO 2 NR h -(CH 2 ) m3 , (CH 2 ) m2 -R l NSO 2 NR h -(CH 2 ) m3 , (CH 2 ) m2 -SO-(CH 2 ) m3 , (CH 2 ) m2 -SONR h -(CH 2 ) m3 , (CH 2 ) m2 -R l NSONR h -(CH 2 ) m3 or (CH 2 ) m2 -R l NC(=NH)NR h -( CH2 ) m3 ; Rf is selected from substituted or unsubstituted C6 - C14 aryl, substituted or unsubstituted 5-14 heteroaryl, substituted or unsubstituted 4-14 heterocyclic, substituted or unsubstituted C3 - C14 cycloalkyl, , The substitution mentioned therein refers to substitution by 1-4 R r groups; the ring C is selected from 5-10 membered heterocyclic groups, C <sub>5 -C 10  cycloalkyl groups, C <sub>6 -C 10  aryl groups, or 5-10 membered heterocyclic groups; the ring D is selected from 5-10 membered heterocyclic groups, C<sub> 5 -C 10  cycloalkyl groups, C<sub> 6 -C 10  aryl groups, or 5-10 membered heterocyclic groups; the ring E is selected from phenyl, 5-6 membered heterocyclic groups, 5-10 membered heterocyclic groups, or C<sub> 5 -C 10  cycloalkyl groups; R c , Rd , and Re are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, substituted or unsubstituted C <sub>1 -C 6  alkyl groups, substituted or unsubstituted C 2 -C alkyl groups. 6- Alkenyl, substituted or unsubstituted C2 - C6 alkoxy, substituted or unsubstituted C1 - C6 halogenated alkyl, substituted or unsubstituted C1 - C6 halogenated alkoxy, substituted or unsubstituted C1 -C6 deuterated alkyl, substituted or unsubstituted C1 -C6 deuterated alkoxy, substituted or unsubstituted C1 - C6 hydroxyl, substituted or unsubstituted C3 - C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl , substituted or unsubstituted 5-10 membered heteroaryl, C1 - C6 alkylene- R11 , -( CH2 ) pOR11 , ( CH2 ) pNR11R12 , ( CH2 ) ( CH2 ) pCOOR13 , ( CH2 ) pCOOR11 , ( CH2 ) pCONR11R12 , ( CH2 ) pNR11COOR13 , (CH2) pNR11COOR12 , (CH2)pSOR13, (CH2)pSONR11R12, (CH2)pSO2R13 or (CH2 ) pSO2NR11R12 ; wherein , the substitution refers to substitution by 1-4 R111 ; R11 , R12 and R13 are each independently selected from hydrogen, COOC1 - C6 alkyl , SO2C1 - C6 alkyl , substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 -C6 alkyl. 6- alkenyl, substituted or unsubstituted C2 - C6 ynyl, substituted or unsubstituted C1 - C6 alkoxy, substituted or unsubstituted C1 - C6 halogenated alkyl, substituted or unsubstituted C1 - C6 halogenated alkoxy, substituted or unsubstituted C1 - C6 deuterated alkyl, substituted or unsubstituted C1 - C6 deuterated alkoxy, substituted or unsubstituted C1 -C6 hydroxyl, substituted or unsubstituted C3 - C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl; wherein, the substitution refers to substitution by 1-4 R1111 ; R111 and R 1111 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1 -C6 alkyl, C2 - C6 alkenyl, C2- C6 alkynyl, C1-C6 alkoxy , C3 -C10 cycloalkyl, 4-10 heterocyclic, C6- C10 aryl, 5-10 heteroaryl, C1 -C6 halogenated alkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1 -C6 hydroxyl, C2 -C6 halogenated alkenyl, C2- C6 halogenated alkynyl, C1 - C6 halogenated alkoxy, C3-C6 halogenated alkoxy, C3-C6 halogenated alkyl, C2 - C6 halogenated alkenyl, C2 - C6 halogenated alkoxy, C3 -C6 halogenated alkyl, C2- C6 halogenated alkenyl, C3- C6 halogenated alkyl, C2 -C6 halogenated alkoxy, C3 -C6 halogenated alkyl, C2 ...2-C6 halogenated alkyl, C2- C6 halogenated alkyl, C2-C6 halogenated alkyl, C2 - C6 halogenated alkyl, C2- C6 halogen 10- membered halogenated cycloalkyl, 4-10-membered halogenated heterocyclic, C6 - C10 halogenated aryl, or 5-10-membered halogenated heteroaryl; R r is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2 - C6 alkoxy, substituted or unsubstituted C1-C6 halogenated alkyl , substituted or unsubstituted C1 - C6 halogenated alkoxy, substituted or unsubstituted C1 -C6 deuterated alkyl, substituted or unsubstituted C1 - C6 deuterated alkoxy, substituted or unsubstituted C1 - C 6 -Hydroalkyl, substituted or unsubstituted C3 - C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, C1 - C6 alkylene- R21 , ( CH2 ) q OR21 , ( CH2 ) q NR21 R22 , ( CH2 ) q COR23, ( CH2 ) q COOR21 , ( CH2 ) q CONR21 R22 , ( CH2 ) q NR21 COR23 , ( CH2 ) q NR21 COOR22 , ( CH2 ) q SOR23 , ( CH2 ) q SONR21 R22 ( CH₂ ) qSO₂R₁ , ( CH₂ ) qSO₂NR₁R₂ ; wherein the substitution refers to substitution by 1-4 R⁻¹fff ; R₁ , R₂ , and R₂₃ are each independently selected from: hydrogen, COOC₁ - C₆ alkyl, SO₂C₁ - C₆ alkyl, substituted or unsubstituted C₁ - C₆ alkyl, substituted or unsubstituted C₂ - C₆ alkenyl, substituted or unsubstituted C₁ - C₆ alkoxy, substituted or unsubstituted C₁ - C₆ halogenated alkyl, substituted or unsubstituted C₁ -C₆ halogenated alkoxy, substituted or unsubstituted C₁ - C₆ deuterated alkyl, substituted or unsubstituted C₁ - C₆ deuterated alkoxy ... 6 -Hydroalkyl, substituted or unsubstituted C3 - C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein the substitution refers to substitution by 1-4 R ffff ; R fff and R ffff are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1 - C6 alkyl, C2 -C6 alkenyl, C2 - C6 alkynyl, C1 - C6 alkoxy, C3 - C10 cycloalkyl, 4-10 membered heterocyclic, C6 - C10 aryl, 5-10 membered heteroaryl, C1 - C6 halogenated alkyl, C1 -C 6- Deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyalkyl, C2-C6 halogenated alkenyl, C2 - C6 halogenated alkynyl, C1 - C6 halogenated alkoxy, C3 - C10 halogenated cycloalkyl, 4-10-membered halogenated heterocyclic, C6 - C10 halogenated aryl , or 5-10-membered halogenated heterocyclic; ring B is selected from C6 - C10 aryl, 5-10-membered heterocyclic, 4-10-membered heterocyclic, C3 - C10 cycloalkyl, phenyl-5-6-membered heterocyclic, phenyl- C5 -C 6 -Cycloalkyl, 5-6-membered heteroaryl and 5-6-membered heterocycloalkyl, or 5-6-membered heteroaryl and C5 - C6 cycloalkyl; Rb is independently selected from substituted or unsubstituted C1 -C6 alkyl, substituted or unsubstituted C2 -C6 alkenyl , substituted or unsubstituted C2 - C6 ynynyl, substituted or unsubstituted C1 - C6 halogenated alkyl, substituted or unsubstituted C1 - C6 halogenated alkoxy, substituted or unsubstituted C1 - C6 deuterated alkyl, substituted or unsubstituted C1 - C6 deuterated alkoxy, substituted or unsubstituted C1 -C6 hydroxyl, substituted or unsubstituted C1 -C6 alkoxy , substituted or unsubstituted C3 -C 10 -cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, ( CH2 ) k OR B-1 , ( CH2 ) k NR B-1 RB -2 , ( CH2 ) k COR B-3 , =NHOR B-1 , =CR B-1 RB -2 , ( CH2 ) k C(=NH)OR B-1 , ( CH2 ) k CONR B-1 RB -2 , ( CH2 ) k NR B-1 COR B-3 , ( CH2 ) k COOR B-3 , ( CH2 ) k NR B-1 COOR B-3 , ( CH2 ) k C(=NH)NR B-1 RB -2 , ( CH2 ) k NR B-1 C(=NH) RB-3 , ( CH2 ) kSORB -1 , ( CH2 ) kSONRB -1RB -2 , ( CH2 ) kNRB - 1SORB-3, (CH2)kSO2RB- 1 , ( CH2 ) kSO2NRB - 1RB- 2 or ( CH2 ) kNRB - 1SO2RB -3 ; wherein the substitution refers to substitution by 1-4 Rbb ; Rbb is selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, oxo, thio, C1-C6 alkyl, C1 - C6 alkoxy, C2 -C6 alkenyl, C2- C6 alkynyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 deuterated alkoxy, C1-C6 deuterated alkyl ... 6- Hydroalkyl, C3 - C10 Cycloalkyl, 4-10 Membered Heterocyclic, C6 - C10 Aryl, 5-10 Membered Heterocyclic, C1 - C6 Halogenated Alkyl, C1 - C6 Halogenated Alkoxy, C3 - C10 Halogenated Cycloalkyl, 4-10 Membered Halogenated Heterocyclic, C6 - C10 Halogenated Aryl, 5-10 Membered Halogenated Heterocyclic, ( CH2 ) j OR b-1 , ( CH2 ) j NR b-1 R b-2 , ( CH2 ) j COR b-3 , ( CH2 ) j COOR b-3 , ( CH2 ) j OCOR b-3 , =NHOR b-1 , =CR b-1 R b-2 , ( CH2 ) j C(=NH)OR b-1 , (CH 2 ) j CONR b-1 R b-2 , (CH 2 ) j NR b-1 COR b-3 , (CH 2 ) j NR b-1 COOR b-3 , (CH 2 ) j C(=NH)NR b-1 R b-2 , (CH 2 ) j NR b-1 C(=NH)R b-3 , (CH 2 ) j SOR b-1 , (CH 2 ) j SONR b-1 R b-2 , (CH 2 ) j NR b-1 SOR b-3 , (CH 2 ) j SO 2 R b-1 , (CH 2 ) j SO 2 NR b-1 R b-2 or (CH 2 ) j NR b-1 SO 2 R b-3 , wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 ynyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 deuterated alkoxy, C 1 -C 6 hydroxyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclic, C 6 -C 10 aryl, 5-10 membered heteroaryl may be further substituted by 1-4 R bbb ; R bbb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, hydroxyl, oxo, thio, C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 ynyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 deuterated alkoxy, C 1 -C 6- Hydroalkyl, C3 - C10 cycloalkyl, 4-10 membered heterocyclic, C6 - C10 aryl, 5-10 membered heterocyclic, C1 - C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C3 - C10 halogenated cycloalkyl, 4-10 membered heterocyclic, C6 - C10 halogenated aryl, or 5-10 membered heterocyclic; RB -1 , RB-2, RB -3 , Rb - 1 , Rb -2 , and Rb -3 are each independently selected from H, COOC, C1 - C6 alkyl, SO2 , C1 - C6 alkyl, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2 -C 6 alkynyl, substituted or unsubstituted C1 -C 6 halogenated alkyl, substituted or unsubstituted C1 -C 6 halogenated alkoxy, substituted or unsubstituted C1 -C 6 deuterated alkyl, substituted or unsubstituted C1 -C 6 deuterated alkoxy, substituted or unsubstituted C1 -C 6 hydroxyl, substituted or unsubstituted C3 -C 10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 -C 10 aryl, substituted or unsubstituted 5-10 membered heterocyclic, C1 -C 6 halogenated alkyl, C3 -C 10 halogenated cycloalkyl, 4-10 membered heterocyclic, C6 -C 10 -Halogenated aryl, 5-10-membered halogenated heteroaryl; wherein the substitution refers to substitution by 1-4 R bbbb ; R bbbb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, hydroxyl, oxo, thio, C1 - C6 alkyl, C1 - C6 alkyl, C1 - C6 alkoxy, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C10 cycloalkyl, 4-10-membered heterocycloyl, C6 - C10 aryl, 5-10-membered heteroaryl, C1 - C6 halogenated alkyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyl, C3 -C 10- membered halogenated cycloalkyl, 4-10-membered halogenated heterocyclic, C6 - C10 halogenated aryl, or 5-10-membered halogenated heteroaryl; the H in the above CH2 may be optionally substituted with a substituent selected from the following group: hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, oxo, thio , NH2, NHC1 - C6 alkyl, N( C1 - C6 alkyl) 2 , C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C2 - C6 alkenyl, C2 - C6 alkynyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 -C 6- Hydroalkyl; Rh and Rl are each independently selected from hydrogen, deuterium, halogen, C1 -C6 alkyl, C2 - C6 alkenyl, C2- C6 alkoxy, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclic, C6 - C10 aryl, 5-10 membered heteroaryl, C1 - C6 halogenated alkyl, C2-C6 halogenated alkenyl, C2 - C6 halogenated alkynyl, C1-C6 halogenated alkoxy, C3- C10 hydroxyalkyl, 4-10 membered heterocyclic, C6 - C10 aryl, 5-10 membered heteroaryl, C1 - C6 halogenated alkyl, C2 - C6 halogenated alkenyl, C2 - C6 halogenated alkoxy, C3-C10 hydroxyalkyl, C2 ... 10- membered halogenated cycloalkyl, 4-10-membered halogenated heterocyclic, C6 - C10 halogenated aryl or 5-10-membered halogenated heteroaryl; m1, m2 and m3 are each independently selected from 0, 1, 2, 3, 4, 5, 6; y is selected from 0, 1, 2, 3, 4, 5, 6; p, q, j, k, z, e and f are each independently selected from 0, 1, 2, 3, 4, 5, 6. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein it has the structure shown in formula (I'-A'-4). Among them, Rb ' is defined the same as Rb , and Rb ' is preferably hydrogen, deuterium, halogen, C1 - C3 alkyl, C1 - C3 halogenated alkyl, C1 - C3 deuterated alkyl, C1 - C3 alkoxy, C1 - C3 halogenated alkoxy, and C1 - C3 deuterated alkoxy. The compound or its pharmaceutically acceptable salt as described in any of claims 3-4, wherein Rf is selected from Or a thiazolyl group, wherein Cy1 is a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the thiazolyl group, the 5-6 membered heteroaryl group, or the 5-6 membered heterocyclic group is optionally further substituted by 1-4 R r groups; preferably R f  is selected from the substituted or unsubstituted group of the next group. , , , , , , , , , , , Preferred R f is selected from substituted or unsubstituted subgroups. , , , , , , , , , , Preferred R f is selected from substituted or unsubstituted subgroups. , or The substitution mentioned therein refers to substitution by 1-4 R r groups; or Rf selected from -Ar3-L 2 -R p , wherein Ar3 is selected from substituted or unsubstituted 5-10-membered heteroaryl groups, wherein the substitution refers to substitution by 1-3 groups selected from the group consisting of: hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2  -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkoxy, substituted or unsubstituted C 1 -C 6  halogenated alkyl, substituted or unsubstituted C 1 -C 6  halogenated alkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1 -C 6  deuterated alkoxy, substituted or unsubstituted C 1  1 - C6 hydroxyl, substituted or unsubstituted C3- C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein the substitution refers to substitution by 1-4 Rfff ; L2 is selected from hydroxyl, C1 - C6 alkylene, O, NRp1 , CO, COO, CONRp2, NRp3 , COO, SO, SONRp4 , SO2 , SO2 NRp5 ; Rp1 , Rp2 , Rp3 , Rp4 and Rp5 are each independently selected from hydrogen, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkoxy, C1 -C6 halogenated alkyl, C1 -C 6 halogenated alkoxy, C 1 -C 6 deuterated alkyl, C 1 -C 6 deuterated alkoxy, C 1 -C 6 hydroxyalkyl; R p selected from hydrogen, COOC 1 -C 6 alkyl, SO 2 C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 - C 6 alkenyl, substituted or unsubstituted C 2 - C 6 alkoxy, substituted or unsubstituted C 1 -C 6 halogenated alkyl, substituted or unsubstituted C 1 -C 6 halogenated alkoxy, substituted or unsubstituted C 1 -C 6 deuterated alkyl, substituted or unsubstituted C 1 -C 6 deuterated alkoxy, substituted or unsubstituted C 1 -C 6 hydroxyalkyl, substituted or unsubstituted C 3 -C 10 -cycloalkyl, substituted or unsubstituted 4-10-membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10-membered heteroaryl; wherein the substitution refers to substitution by 1-4 R ffff ; or R f  is... or Rf is preferred. or Rf is the preferred choice or X2 is selected from O, S, N, NR 11 r or CR 2 r ; preferably, X2 is selected from N or CR 2 r ; X3 is selected from N or CR 3 r ; X4 is selected from O, S, N, NR 11 r or CR 4 r ; preferably, X4 is selected from N or CR 4 r ; X5 is selected from N or CR 5 r ; X6 is selected from N or CR 6 r ; X7 is selected from N or CR 7 r ; X8 is selected from N or C; Y1 is selected from N, O, S or CR 8 r ; Y2 is selected from N, O, S or CR 9 r ; Y3 is selected from N, O, S or CR 10 r ; R1 r , R2 r , R3 r , R4 r , R5 r , R6 r , R7 r , R8 r , R9 The definitions of r , R10r , and R11r are the same as Rr ; or Rf is chosen from ... Cy1 is a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group or the 5-6 membered heterocyclic group is optionally further substituted by 1-4 R r groups; preferably, R f  is selected from the substituted or unsubstituted group: , The substitution mentioned therein refers to substitution by 1-4 Rr groups ; Rr is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2 - C6 alkoxy, substituted or unsubstituted C1 - C6 halogenated alkyl, substituted or unsubstituted C1 - C6 halogenated alkoxy, substituted or unsubstituted C1 - C6 deuterated alkyl, substituted or unsubstituted C1- C6 deuterated alkoxy, substituted or unsubstituted C1 - C6 hydroxyl, substituted or unsubstituted C3 -C6 alkoxy , and substituted or unsubstituted C4 -C6 alkoxy. 10 -cycloalkyl, substituted or unsubstituted 4-10-membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10-membered heteroaryl, C1 - C6 alkylene- R21 , ( CH2 ) q OR21 , ( CH2 ) q NR21 R22 , ( CH2 ) q COR23 , (CH2)q COOR21 , ( CH2 ) q CONR21 R22 , ( CH2 ) q NR21 COR23, (CH2)q NR21 COOR22 , ( CH2 ) q SOR23 , ( CH2 ) q SONR21 R22 , ( CH2 ) q SO2 R21 ( CH₂ ) ₂SO₂NR₂₁R₂₂ ; wherein the substitution refers to substitution by 1-4 R⁻¹fff ; R₂₁ , R₂₂ , and R₂₃ are each independently selected from: hydrogen, COOC₁ - C₆ alkyl, SO₂₁ -C₆ alkyl, substituted or unsubstituted C₁ - C₆ alkyl, substituted or unsubstituted C₂ - C₆ alkenyl, substituted or unsubstituted C₁ - C₆ alkoxy, substituted or unsubstituted C₁ - C₆ halogenated alkyl, substituted or unsubstituted C₁ - C₆ halogenated alkoxy, substituted or unsubstituted C₁ - C₆ deuterated alkyl, substituted or unsubstituted C₁-C₆ deuterated alkoxy, substituted or unsubstituted C₁ - C₆ hydroxyl, substituted or unsubstituted C₃ - C₆ alkyl, COOC₁-C₆ alkyl, SO₂₁ -C₆ alkyl, substituted or unsubstituted C₁ - C₆ alkyl, COOC₁- C₆ alkyl, SO� ... 10 -Cycloalkyl, substituted or unsubstituted 4-10-membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10-membered heteroaryl; wherein the substitution refers to substitution by 1-4 R ffff ; R ffff  and R ffff  are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C1 - C6 alkoxy, C3 - C10 cycloalkyl, 4-10-membered heterocyclic, C6 - C10 aryl, 5-10-membered heteroaryl, C1 -C6 halogenated alkyl, C1 - C6 deuterated alkyl, C1 -C 6- Deuterated alkoxy, C1 - C6 hydroxyalkyl, C2 -C6 halogenated alkenyl, C2 - C6 halogenated alkynyl, C1 - C6 halogenated alkoxy, C3 - C10 halogenated cycloalkyl, 4-10 -membered halogenated heterocyclic, C6 - C10 halogenated aryl or 5-10-membered halogenated heteroaryl. The compound or its pharmaceutically acceptable salt according to any one of claims 1-2, wherein the structure is shown in (I''-10), (I''-11), (I''-14), or (I''-15). Wherein: Rb' -1 is defined the same as Rb ' ; Rb ' is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, hydroxyl, oxo, thio, C1-C6 alkyl, C1 - C6 alkyl, C1 - C6 alkoxy, C2 -C6 alkenyl, C2- C6 alkynyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 -C6 hydroxyl, C3- C10 cycloalkyl, 4-10 heterocyclic, C6 - C10 aryl, 5-10 heteroaryl, C1 - C6 halogenated alkyl, C1 -C6 halogenated alkoxy, C3- C10 cycloalkyl, 4-10 heterocyclic, C6 - C10 aryl, 5-10 heteroaryl, C1 - C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C3-C10 cycloalkyl, C2 ... 10- membered halogenated cycloalkyl, 4-10-membered halogenated heterocyclic, C6 - C10 halogenated aryl, or 5-10-membered halogenated heteroaryl; preferably, Rb' -1 is selected from H, deuterium, halogen, amino, cyano, nitro, hydroxyl, C1 - C6 alkyl, C1 - C6 halogenated alkyl, C1 - C6 alkoxy, C1 - C6 halogenated alkoxy; R4r , R9r , and R10r are defined as Rr ; preferably, R4r , R9r , and R10r are each independently selected from hydrogen, deuterium , halogen, amino, cyano, nitro, hydroxyl, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C 6- Halogenated alkyl, C1 - C6 halogenated alkoxy, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C1 - C6 alkylene- R21 , ( CH2 ) OR21 , ( CH2 ) NR21R22 , (CH2) COR23 , ( CH2 )COOR21 , ( CH2 ) CONR21R22 , ( CH2 ) NR21COR23 , ( CH2 ) NR21COOR22 , ( CH2 ) SOR23 , ( CH2 ) SONR21R22 ( CH₂ ) SO₂R₂₁ , ( CH₂ ) SO₂NR₂₁R₂₂ ; wherein, the C₁ - C₆ alkyl, C₁ - C₆ alkoxy, C₁ - C₆ halogenated alkyl, C₁-C₆ halogenated alkoxy, C₁- C₆ deuterated alkyl, C₁ -C₆ deuterated alkoxy, C₁ - C₆ hydroxyl, C₃ -C₆ cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl can optionally be further replaced by deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C₁ - C₆ alkyl, C₂ - C₆ alkenyl, C₂ - C₆ alkoxy, C₃-C₆ alkyl, C₂-C₆ alkyne, C₁-C₆ alkoxy, C₃-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ alkyl, C� ...alkyl, C₂ - C₆ alkyl, C₃-C₆ alkyl, C₂ - C₆ alkyl, C₂-C₆ alkyl, C₃- C₆ alkyl, C₂ -C₆ alkyl, C₃-C₆ alkyl, C₂-C₆ alkyl, C₃ - C₆ alkyl, C₃ -C₆ One or more of the following: 6 -cycloalkyl, 4-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl, C1 - C6 halogenated alkyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 -C6 hydroxyalkyl , C2 - C6 halogenated alkenyl, C2- C6 halogenated alkynyl, C1 - C6 halogenated alkoxy, C3 - C6 halogenated cycloalkyl, 4-6-membered halogenated heterocyclic, halogenated phenyl, or 5-6-halogenated heteroaryl. The compound or its pharmaceutically acceptable salt according to any one of claims 1-2 or 6, wherein it has the structure shown in formula (I''-12), (I''-13), (I'-A'-6), (I'-A'-7), (I''-16), (I''-17), (I'-A'-8), or (I'-A'-9). Ra1 , Ra2 , Ra3 and Ra4 are defined as Ra ; preferably, Ra1 , Ra2 , Ra3 and Ra4 are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1 - C3 alkyl, C1 - C3 halogenated alkyl, C1 - C3 deuterated alkyl, C1 - C3 alkoxy, C1 - C3 halogenated alkoxy, C1 - C3 deuterated alkoxy. The compound or its pharmaceutically acceptable salt according to any one of claims 1-4 or 5, wherein ring B is a 5-6 member heteroaryl group, preferably acezolyl, pyrazolyl, triazolyl, thiazolyl, thiadiazolyl, or acezolyl; preferably ring B is... , , , , , , or The preferred location is Ring B. or Alternatively, ring B may be selected from the following group of substituted or unsubstituted groups: C6 - C10 aryl, 5-10-membered heteroaryl, 4-10-membered heterocyclol, C3 - C10 cycloalkyl, phenyl-5-6-membered heterocyclol, phenyl-C5 -C6 cycloalkyl , 5-6-membered heteroaryl-5-6-membered heterocyclol, or 5-6-membered heteroaryl-C5- C6 cycloalkyl ; wherein, substitution refers to being substituted by 1-4 R groups. b' substitution; preferably, ring B is a substituted or unsubstituted 5-6-membered heteroaryl group or a substituted or unsubstituted 5-6-membered heteroaryl group with a 5-6-membered heterocyclic group, preferably, ring B is a substituted or unsubstituted 5-6-membered heteroaryl group, a substituted or unsubstituted 5-membered heteroaryl group with a 5-membered heterocyclic group, a substituted or unsubstituted 5-membered heteroaryl group with a 6-membered heterocyclic group, a substituted or unsubstituted 6-membered heteroaryl group with a 5-membered heterocyclic group, or a substituted or unsubstituted 6-membered heteroaryl group with a 6-membered heterocyclic group; preferably, ring B is a substituted or Unsubstituted lower group: azolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, isothiazolyl, azidizolyl, isoazolyl, tetrazolyl, pyrroleyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyridyl, pyridoneyl, dazolyl, triazolyl; more preferably, ring B is a substituted or unsubstituted lower group: azolyl, isoazolyl, pyrazolyl, triazolyl, thiazolyl, thiadiazolyl, azidizolyl; wherein, the substitution refers to being formed by 1-4 R groups. b' substitution; wherein each of R b' is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, hydroxyl, oxo, thio, C1 -C6 alkyl, C1- C6 alkyl, C1 - C6 alkoxy, C2 - C6 alkenyl, C2 -C6 alkynyl, C1- C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyl, C3 - C10 cycloalkyl, 4-10 heterocyclic, C6-C10 aryl, 5-10 heteroaryl, C1 -C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C3 -C10 cycloalkyl, 4-10 heterocyclic, C6-C10 aryl, 5-10 heteroaryl, C1 - C6 halogenated alkyl, C1 -C6 halogenated alkoxy, C3- C10 cycloalkyl, C2 ... 10- membered halogenated cycloalkyl, 4-10-membered halogenated heterocyclic, C6 - C10 halogenated aryl, or 5-10-membered halogenated heteroaryl; preferably, ring B is selected from... Preferred locations are selected from , , , Cy3 is a 5-membered heteroaryl group; Cy2 is a 5-6-membered heterocyclic group; y'' is 0, 1, or 2; y''' is 0, 1, 2, or 3; Rb'-6 , Rb' -7 , and Rb' -8 are defined the same as Rb ' ; preferably, Rb'-6 , Rb' -7 , and Rb'-8 are each independently selected from H, deuterium, halogen, amino, cyano, nitro, hydroxyl, C1 - C6 alkyl, C1 - C6 halogenated alkyl, C1 - C6 alkoxy, or C1 - C6 halogenated alkoxy; or for or Wherein, cyclic G is selected from C3 - C8 cycloalkyl or 4-8 membered heterocyclic groups, f1 is 1, 2, 3 or 4; y' is 0, 1, 2 or 3; Rb ' and Rbb are defined as described above, and further preferably... Selected from , Wherein, Ar1 is a 5-membered heteroaryl; Ar2 is a 6-membered heteroaryl; Z2 is selected from C or N; Z3 is selected from O, S, N, NR b'-4 , CR b'-2 ; Z4 is selected from O, S, N, NR b'-4 , CR b'-3 ; Z5 is selected from C or N; Z6 is selected from O, S, N, NR b'-4 , CR b'-1 ; W1 is selected from CR b'-1 or N; W2 is selected from CR b'-2 or N; W3 is selected from CR b'-3 or N; W4 is selected from CR b'-5 or N; preferably, Selected from , , , , , , , , , , , ; wherein Rb' -1 , Rb' -2 , Rb' -3 , Rb' -4 and Rb' -5 are defined as Rb' ; preferably, Rb'-1 , Rb' -2 , Rb'- 3 and Rb' -5 are selected from H, deuterium, halogen, amino, cyano, nitro, hydroxyl, C1 - C6 alkyl, C1 - C6 halogenated alkyl, C1 - C6 alkoxy, C1 - C6 halogenated alkoxy; Rb'-4 is selected from H, C1 - C6 alkyl, C1 - C6 halogenated alkyl. The compound or its pharmaceutically acceptable salt according to any one of claims 1-8, wherein Rb is independently selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, oxo, thio, substituted or unsubstituted C1 -C6 alkyl, substituted or unsubstituted C2- C6 alkenyl, substituted or unsubstituted C2 - C6 alkynyl, substituted or unsubstituted C1 - C6 halogenated alkyl, substituted or unsubstituted C1 - C6 halogenated alkoxy, substituted or unsubstituted C1 - C6 deuterated alkyl, substituted or unsubstituted C1 - C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyl, substituted or unsubstituted C1 - C6 alkoxy, substituted or unsubstituted C3 - C6 alkoxy, substituted or unsubstituted C4-C6 alkoxy, substituted or unsubstituted C5 - C6 alkoxy, substituted or unsubstituted C6 ... 10 -cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, ( CH2 ) k OR B-1 , ( CH2 ) k NR B-1 RB -2 , ( CH2 ) k COR B-3 , ( CH2 ) k COOR B-3 , ( CH2 ) k OCOR B-3 , =NHOR B-1 , =CR B-1 RB-2 , ( CH2 ) k C(=NH)OR B-1 , ( CH2 ) k CONR B-1 RB -2 , ( CH2 ) k NR B-1 COR B-3 , ( CH2 ) k NR B-1 COOR B-3 , ( CH2 ) k C(=NH)NR B-1 RB-2 ( CH₂ ) kNRB -1C (=NH)RB -3 , ( CH₂ ) kSORB -1 , ( CH₂ )kSONRB - 1RB -2, (CH₂)kNRB-1SORB-3, (CH₂)kSO₂RB-1 , ( CH₂ ) kSO₂NRB - 1RB - 2 or ( CH₂ ) kNRB - 1SO₂RB -3 ; wherein the substitution refers to substitution by 1-4 Rbb ; Rbb is selected from hydrogen, deuterium, halogen, amino , cyano, nitro, hydroxyl, oxo, thio, C1 - C₆ alkyl, C1 -C₆ alkoxy, C2 - C₆ alkenyl, C2 -C₆ ynyl , C1 - C₆ deuterated alkyl, C1- C₆ ... 6- Deuterated alkoxy, C1 - C6 hydroxyl, C3- C10 cycloalkyl, 4-10 membered heterocyclic, C6 - C10 aryl, 5-10 membered heteroaryl, C1 - C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C3- C10 halogenated cycloalkyl, 4-10 membered heterocyclic, C6 - C10 halogenated aryl, 5-10 membered heteroaryl, ( CH2 ) j OR b-1 , ( CH2 ) j NR b-1 R b-2 , ( CH2 ) j COR b-3 , ( CH2 ) j COOR b-3 , ( CH2 ) j OCOR b-3 , =NHOR b-1 , =CR b-1 R b-2 , (CH 2 ) j C(=NH)OR b-1 , (CH 2 ) j CONR b-1 R b-2 , (CH 2 ) j NR b-1 COR b-3 , (CH 2 ) j NR b-1 COOR b-3 , (CH 2 ) j C(=NH)NR b-1 R b-2 , (CH 2 ) j NR b-1 C(=NH)R b-3 , (CH 2 ) j SOR b-1 , (CH 2 ) j SONR b-1 R b-2 , (CH 2 ) j NR b-1 SOR b-3 , (CH 2 ) j SO 2 R b-1 , (CH 2 ) j SO 2 NR b-1 R b-2 or (CH 2 ) j NR b-1 SO 2 R b-3 , wherein C 1 - C 6- alkyl, C1 - C6 alkoxy, C2 -C6 alkenyl, C2- C6 alkynyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyl, C3- C10 cycloalkyl, 4-10 membered heterocyclic, C6 - C10 aryl , 5-10 membered heteroaryl may be further substituted by 1-4 R bbb ; preferably, each R b is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, oxo, thio, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2 - C6 alkynyl, substituted or unsubstituted C1 -C 6- halogenated alkyl, substituted or unsubstituted C1 - C6- halogenated alkoxy, substituted or unsubstituted C1 - C6- deuterated alkyl, substituted or unsubstituted C1 - C6- deuterated alkoxy, substituted or unsubstituted C1 - C6- hydroxyalkyl, substituted or unsubstituted C1 - C6- alkoxy, substituted or unsubstituted C3- C8 - cycloalkyl, substituted or unsubstituted 4-8-membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10-membered heteroaryl, OR B-1 , NR B-1 RB -2 , COR B- 3, COOR B-3 , OCOR B -3, =NHOR B-1 , CONR B-1 RB -2 , NR B-1 COR B-3 , NR B-1 COOR B-3 , C(=NH)NR B-1 RB -2 , = CR B-1 RB -2 , NR B-1 C(=NH)RB -3 , SOR B-1 , SONR B-1 RB -2 , NR B-1 SOR B-3 , SO 2 RB -1 , SO 2 NR B-1 RB -2 or NR B-1 SO 2 RB -3 ; wherein, the substitution mentioned in Rb refers to substitution by 1-4 R bb , wherein R bb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1 - C6 alkyl, C1 - C6 alkoxy, C2 - C6 alkenyl, C2 - C6 alkynyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyl, C3 -C 8- membered cycloalkyl, 4-8-membered heterocyclic, phenyl, 5-6-membered heteroaryl, C1 - C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C3 - C8 halogenated cycloalkyl, 4-8-membered halogenated heterocyclic, halogenated phenyl, 5-6-membered halogenated heteroaryl, OR b-1 , NR b-1 R b-2 , COR b-1 , COOR b-1 , OCOR b-1 , CONR b-1 R b-2 , NR b-1 COR b-1 , =NHOR b-1 , NR b-1 COOR b-3 , C(=NH)NR b-1 R b-2 , NR b-1 C(=NH)R b-3 , =CR b-1 R b-2 , SOR b-1 , SONR b-1 R b-2 NR b-1 SOR b-3 , SO 2 R b-1 , SO 2 NR b-1 R b-2 , or NR b-1 SO 2 R b-3 ; preferably, each R b is independently selected from substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2 - C6 alkynyl, substituted or unsubstituted C1 - C6 halogenated alkyl, substituted or unsubstituted C1 - C6 halogenated alkoxy, substituted or unsubstituted C1 - C6 deuterated alkyl, substituted or unsubstituted C1 - C6 deuterated alkoxy, substituted or unsubstituted C1 - C6 hydroxyl, substituted or unsubstituted C1 - C6 alkoxy, substituted or unsubstituted C3 -C 8 -cycloalkyl, substituted or unsubstituted 4-8 membered heterocyclic, substituted or unsubstituted C6 - C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, OR B-1 , NR B-1 RB -2 , COR B-3 , =NHOR B-1 , CONR B-1 RB -2 , NR B-1 COR B-3 , COOR B-3 , NR B-1 COOR B-3 , C(=NH)NR B-1 RB -2 , =CR B-1 RB -2 , NR B-1 C(=NH) RB-3 , SOR B-1 , SONR B-1 RB -2 , NR B-1 SOR B-3 , SO₂ RB -1 , SO₂ NR B-1 RB -2 or NR B-1 SO₂ RB-3 ; wherein, R The substitution mentioned in b refers to substitution by 1-4 R bb , wherein R bb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1 - C6 alkyl, C1-C6 alkoxy, C2 - C6 alkenyl, C2-C6 alkynyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyl, C3- C8 cycloalkyl, 4-8 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C1 - C6 halogenated alkyl, C1 -C6 halogenated alkoxy, C3 -C8 cycloalkyl, 4-8 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C1 - C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C3-C8 cycloalkyl, C2 ... 8- membered halogenated cycloalkyl, 4-8-membered halogenated heterocyclic, halogenated phenyl, 5-6-membered halogenated heteroaryl, OR b-1 , NR b-1 R b-2 , COR b-1 , CONR b-1 R b-2 , NR b-1 COR b-1 , =NHOR b-1 , COOR b-3 , NR b-1 COOR b-3 , C(=NH)NR b-1 R b-2 , NR b-1 C(=NH)R b-3 , =CR b-1 R b-2 , SOR b-1 , SONR b-1 R b-2 , NR b- 1 SOR b-3 , SO 2 R b-1 , SO 2 NR b -1 R b-2 or NR b-1 SO 2 R b-3 , wherein the C1 - C6 alkyl, C1 -C 6- alkoxy, C2 - C6 alkenyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyalkyl, C2-C6 alkynyl, C3- C8 cycloalkyl, 4-8 membered heterocyclic, phenyl, 5-6 membered heteroaryl can be further substituted by 1-4 R bbb , where R bbb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1 - C6 alkyl, C1- C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1 -C6 deuterated alkoxy, C1- C6 hydroxyalkyl, C3 - C8 cycloalkyl, 4-8 membered heterocyclic, phenyl, 5-6 membered heteroaryl can be further substituted by 1-4 R bbb, where R bbb is selected from hydrogen, deuterium, halogen, amino, cyano , hydroxyl, nitro, oxo, thio, C1 - C6 alkyl, C1- C6 alkoxy, C2-C6 alkenyl, C2 -C6 alkynyl, C3- C8 cycloalkyl, C3 - C8 cycloalkyl, C2 - C6 ... 8- membered cycloalkyl, 4-8-membered heterocyclic, phenyl, 5-6-membered heteroaryl, C1 - C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C3 - C8 halogenated cycloalkyl, 4-8-membered heterocyclic, halogenated phenyl, 5-6-membered heteroaryl; wherein, RB-1 , RB -2 , RB -3 , Rb-1 , Rb -2 and Rb -3 are each independently selected from hydrogen, COOC 1 - C6 alkyl, SO2 C1 - C6 alkyl, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C2 - C6 alkenyl, substituted or unsubstituted C2 - C6 ynyl, substituted or unsubstituted C1 - C6 halogenated alkyl, substituted or unsubstituted C 1 -C 6- halogenated alkoxy, substituted or unsubstituted C 1 -C 6 -deuterated alkyl, substituted or unsubstituted C 1 -C 6 -deuterated alkoxy, substituted or unsubstituted C 1 -C 6 -hydroxyalkyl, substituted or unsubstituted C 3 -C 8 -cycloalkyl, substituted or unsubstituted 4-8-membered heterocyclic, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6-membered heteroaryl, C 1 -C 6- halogenated alkyl, C 3 -C 8- halogenated cycloalkyl, 4-8-membered heterocyclic, halogenated phenyl, 5-6-membered heteroaryl; wherein, substitution in RB-1 , RB -2 , RB-3 , Rb-1 , Rb-2 , and Rb -3 refers to substitution by 1-4 R bbbb , wherein R bbbb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, hydroxyl, oxo, thio, C1 - C6 alkyl, C1 - C6 alkyl, C1 - C6 alkoxy, C2- C6 alkenyl, C2 - C6 alkynyl, C1 - C6 deuterated alkyl, C1 -C6 deuterated alkoxy, C1 - C6 hydroxyl, C3- C8 cycloalkyl, 4-8 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C1 -C6 halogenated alkyl, C1 -C6 halogenated alkoxy ... 8- membered halogenated cycloalkyl, 4-8-membered halogenated heterocyclic, halogenated phenyl, 5-6-membered halogenated heteroaryl; preferably, Rb is independently... C1 - C3 alkylene OC1 - C3 alkyl, C1 - C3 alkylene OC1 - C3 halogenated alkyl, wherein ring G is selected from C3 - C6 cycloalkyl or 4-6 membered heterocyclic group, and f1 is 1, 2, 3 or 4; preferably, Rb are each independently selected from C1 - C3 alkylene OC1 - C3 alkyl, C1 - C3 alkylene OC1-C3 halogenated alkyl, C3 - C6 cycloalkyl, C3 - C6 halogenated cycloalkyl, C1 - C3 alkylene C3 - C6 cycloalkyl, C1 - C3 alkylene 4-6 membered heterocyclic group, C1 - C3 alkylene C3 - C6 halogenated cycloalkyl, C1 -C 3- alkylene 4-6-membered halogenated heterocyclic groups, C1 - C3 alkoxy-substituted C3 -C6 cycloalkyl groups, C1 - C3 halogenated alkoxy-substituted C3 - C6 cycloalkyl groups, C1 - C3 alkyl COO-substituted C3 - C6 cycloalkyl groups, C1 - C3 alkyl OCO-substituted C3 - C6 cycloalkyl groups, C1 -C3 alkyl CONH-substituted C3 - C6 cycloalkyl groups, C1 - C3 alkyl NHCO-substituted C3 - C6 cycloalkyl groups, C1 - C3 alkyl NHCOO-substituted C3 - C6 cycloalkyl groups, 4-6-membered heterocyclic groups, 4-6-membered halogenated heterocyclic groups, C1 - C3 alkoxy-substituted 4-6-membered heterocyclic groups, C1 -C3 halogenated alkoxy-substituted 4-6 membered heterocyclic groups, C1 - C3 alkyl COO-substituted 4-6 membered heterocyclic groups, C1 - C3 alkyl OCO-substituted 4-6 membered heterocyclic groups, C1 - C3 alkyl CONH-substituted 4-6 membered heterocyclic groups, C1 - C3 alkyl NHCO-substituted 4-6 membered heterocyclic groups, or C1 - C3 alkyl NHCOO-substituted 4-6 membered heterocyclic groups. The compound or its pharmaceutically acceptable salt according to any one of claims 1-9, wherein Rf is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; R f selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Preferred location, R f selected from , , , , , , , , , , , , , , , , , , , , , ; Preferred R f selected from , , , , , , , , , , , , , , , ; Better option R f selected from , , , , , , ; and/or, for or Further preferred locations for or Wherein, Ra1 , Ra2 , Ra3 , and Ra4 are defined as described above; and/or, Ra1 is selected from halogens, C1 - C3 alkyl groups, C1 - C3 halogenated alkyl groups, preferably methyl; and/or, Ra2 is selected from hydrogen or halogens (such as fluorine, chlorine, or bromine), preferably hydrogen or fluorine; and/or, Ra3 is selected from hydrogen or halogens (such as fluorine, chlorine, or bromine), preferably hydrogen or fluorine; and/or, Ra4 is selected from hydrogen; and/or, ring A is... , , , ; and/or, Ra is independently selected from hydrogen, deuterium, halogen, C1 - C3 alkyl, C1 - C3 halogenated alkyl, C1 - C3 deuterated alkyl, C1 - C3 alkoxy, C1 - C3 halogenated alkoxy, C1 - C3 deuterated alkoxy, preferably, Ra is independently selected from hydrogen, deuterium, halogen, C1 - C3 alkyl; and/or, Rb is independently selected from C1 - C3 alkyl, C1 - C3 halogenated alkyl, C2 - C4 alkenyl, C2 - C4 halogenated alkenyl, C2 -C4 alkynyl, C2 -C4 halogenated alkynyl, COC1 - C3 alkyl, CH=NOH, CH= NOC1 - C3 alkyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; The preferred choices R and b are each selected independently. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , R b is the preferred choice ; and/or, cyclic B is selected from the subgroup, whether substituted or unsubstituted: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Wherein, the substitution refers to substitution by 1, 2, or 3 Rb ' ; and/or, Rb ' is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1 - C3 alkyl, C1 - C3 halogenated alkyl, C1 - C3 deuterated alkyl, C1 - C3 alkoxy, C1 - C3 halogenated alkoxy, C1 - C3 deuterated alkoxy; and/or, cycloG is selected from C3 - C6 cycloalkyl or 4-6 membered heterocyclic groups, preferably. , , , , , , , , , , , , , , , , ; and/or, R bb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1 - C3 alkyl, C1 - C3 halogenated alkyl, C1 - C3 alkoxy, C1 - C3 halogenated alkoxy, C1 - C3 alkyl COO, C1-C3 alkyl OCO, C1 - C3 alkyl CONH, C1 - C3 alkyl NHCO, C1 - C3 alkyl NHCOO, C1 - C3 halogenated alkyl COO, C1 - C3 halogenated alkyl OCO, C1 - C3 halogenated alkyl CONH, C1 - C3 halogenated alkyl NHCO , C1 - C3 halogenated alkyl NHCOO; and/or, L 2 is selected from NH or NHCOO; and/or, R p is selected from C1 - C6 alkyl, C2 - C6 alkenyl, C2- C6 alkoxy, C1 - C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C1 -C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyalkyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclic, C6- C10 aryl, 5-6 membered heteroaryl; wherein, the C1 -C6 alkyl, C2 - C6 alkenyl, C2- C6 alkoxy, C1 - C6 halogenated alkyl, C1 - C6 halogenated alkoxy, C1 -C6 deuterated alkyl, C1 - C6 hydroxyalkyl, C3 -C6 cycloalkyl, 4-6 membered heterocyclic, C6 - C10 aryl, 5-6 membered heteroaryl . 6- Deuterated alkoxy, C1 - C6 hydroxyl, C3- C6 cycloalkyl, 4-6 -membered heterocyclic, C6 - C10 aryl, 5-6-membered heteroaryl are optionally further substituted by one or more of hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1 - C3 alkyl, C1 - C3 halogenated alkyl, C1 - C3 alkoxy, and C1 - C3 halogenated alkoxy; preferably, Rp is selected from methyl, ethyl, propyl, cyclopropyl, ... , , , , ; and/or, L1 is selected from key, NH, O, CO, CONH, L1 is the preferred key; and/or, X1 is N; and/or, X2 is N; and/or, X5 is N; and/or, X7 is N; and/or, X2 and X7 are N; and/or, X1 , X2 and X7 are N; and/or, X2 , X5 and X7 are N ; and/or, X3 is CR3r ; and/or, X4 is CR4r ; and/or, X6 is CR6r ; and / or, Y1 is selected from S or O; and/or, Y2 is selected from CR9r ; and/or, Y3 is selected from CR10r ; and/or, X8 is N; and/or, R1r , R2r , R3r , R4 r , R5r , R6r , R7r , R8r , R9r , and R10r are each independently selected from hydrogen , deuterium , halogen, amino, cyano, nitro, hydroxyl, C1 - C3 alkyl, C1 - C3 alkoxy, C1 - C3 halogenated alkyl, C1 - C3 halogenated alkoxy, C1 -C3 deuterated alkyl, C1 - C3 deuterated alkoxy, C1 - C3 hydroxyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C1 - C3 alkylene- R21 , ( CH2 ) OR21 , ( CH2 ) NR21R22 , and ( CH2 ) COR23. ( CH₂ )COOR 21 , ( CH₂ )CONR 21 R 22 , ( CH₂ )NR 21 COR 23 , ( CH₂ )NR 21 COOR 22 , ( CH₂ )SOR 23 , ( CH₂ )SONR 21 R 22 , ( CH₂ ) SO₂ R 21 , ( CH₂ ) SO₂NR 21 R 22 ; wherein, the C₁ - C₃ alkyl, C₁ - C₃ alkoxy, C₁ - C₃ halogenated alkyl, C₁ - C₃ halogenated alkoxy, C₁ - C₃ deuterated alkyl, C₁ - C₃ deuterated alkoxy, C₁ - C₃ hydroxylated, C₃ ... The 6- cycloalkyl, 4-6 heterocyclic, phenyl, and 5-6 heteroaryl groups may optionally be further substituted by one or more of deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 halogenated alkyl, C1 - C6 deuterated alkyl, C1 - C6 deuterated alkoxy, C1 - C6 hydroxyl, and C1 - C6 halogenated alkoxy; and/or, m1 is 0, 1, 2, or 3; and/or, m2 and m3 are each independently 0 or 1, preferably 0. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, wherein the compound is selected from the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . A compound as shown below Wherein, R and N are selected from H or an amino protecting group; wherein the amino protecting group is selected from allyloxycarbonyl, trifluoroacetyl, tri-butylsulfinyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, phosphomethoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tri-butyloxycarbonyl, benzyl, or p-methoxyphenyl; Ra1 , Ra2, Ra4 , L1 , ring B, y, and Rb are defined as described in claim 3; preferably, the compound is selected from the following compounds . . A method for preparing a compound of formula (I''-10), (I''-14), or (I''-15) as described in claim 6, or of formula (I'-A'-1) as described in claim 3, or a pharmaceutically acceptable salt thereof: Method 1: Reacting the compounds shown in formula (INT-3) and (INT-2) to prepare the compound shown in formula (I''-10), Method 2: React the compounds shown in formula (INT-3) and (INT'-2) to prepare the compound shown in formula (I''-14). Method 3: React the compounds shown in formula (INT-3) and (INT''-2) to prepare the compound shown in formula (I''-15). Method 4: React the compounds shown in formula (INT-4) and (INT'''-2) to prepare the compound shown in formula (I'-A'-4). Preferably, the reactions described in methods one to four are carried out in the presence of an organic base and a catalyst, wherein the base is an amide condenser; wherein R O  is selected from OH or C<sub> 1 -C 6 alkoxy;R N  is selected from H or an amino protecting group; wherein the amino protecting group is selected from allyloxycarbonyl, trifluoroacetyl, tri-butylsulfinyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, phosphoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthalyldimethyl, tri-butyloxycarbonyl, benzyl, or p-methoxyphenyl; R 4 r , R 9 r , R 10 r , Ra, Rb , R n r The definitions of b'-1 , L1 , ring A and x are as described in claim 6; the definitions of Rf , Ra1 , Ra2 , Ra4 , L1 , ring B, y and Rb are as described in claim 3. A pharmaceutical composition comprising a therapeutically effective amount of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. Use of a compound or a pharmaceutically acceptable salt thereof from any one of claims 1-11, or a pharmaceutical composition thereof from claim 14, in the preparation of a medicament for treating a disease selected from mast cell-related diseases, respiratory diseases, inflammatory conditions, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), autoimmune diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary hypertension (PAH), or primary pulmonary hypertension (PPH); preferably, the disease is selected from asthma. For conditions such as asthma, eosinophilic esophagitis, allergic rhinitis, pulmonary hypertension (PAH), pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, chronic urticaria, spontaneous chronic urticaria, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, gastrointestinal stromal tumor, mast cell tumor, mastocytosis, allergic reaction syndrome, type I or type II diabetes, with urticaria or chronic urticaria being preferred.