CN110627817A - Imidazocyclic PAR4 antagonists and their medicinal uses - Google Patents

Abstract

The present invention relates to imidazocyclic compounds represented by formula (I) or formula (II), or pharmaceutically acceptable salts, esters or solvates thereof. The compounds of the present invention can be used in the preparation of medicaments for the prevention or treatment of thromboembolic disorders.

Description

Imidazocyclic PAR4 antagonists and their medicinal uses

technical field

The invention relates to the field of biomedicine, in particular to an imidazocyclic compound with PAR4 antagonistic activity, and also relates to a preparation method of the compound and its medical use as a PAR4 antagonist.

Background technique

Thromboembolic disease is a disease that seriously threatens human health. The activation and aggregation of platelets play a vital role in thrombus formation. α-Thrombin is the strongest known platelet activator, which can make fibrinogen Transform into fibrin, promote the formation of pathological thrombus. Thrombin receptors PAR1 (protease-activated receptor 1) and PAR4 (protease-activated receptor 4) are expressed on the surface of human platelets. In atherosclerotic thrombosis, PAR1 mediates the transmission of physiological hemostatic signals, while PAR4 It helps to stabilize the formation of thrombus, thus playing an important role in the formation of pathological thrombus. Therefore, clinically, by antagonizing the function of PAR4 and retaining the function of PAR1, it is possible to effectively inhibit the formation of thrombus and significantly reduce the risk of bleeding. Thereby improving the safety of antiplatelet therapy (Sci.Trans.Med.2017, 9, eaaf5294). The PAR1 antagonist Vorapasa did not significantly reduce cardiovascular events, but significantly increased the risk of major bleeding (N.Eng.J.Med.366,20). Indazole (Bioorgan.Med.Chem.2008,16,1262) and indole (Bioorg.Med.Chem.Lett.2014,24,4708; J.Med.Chem.2016,59,7690) PAR4 antagonists They are currently in the preclinical research stage. BMS-986120, an oral imidazothiadiazole PAR4 antagonist developed by Bristol-Myers Squibb, has completed phase I clinical research, but its half-life in humans is only 4 hours (Arterioscl.Throm.Vas.biol.2018, 38,287). The oral PAR4 antagonist BMS-986141, also developed by Bristol-Myers Squibb, has completed phase II clinical evaluation (NCT03035734). So far no oral small molecule PAR4 antagonists have been marketed.

To sum up, there is still an urgent need to develop new PAR4 antagonists with stronger activity and better pharmacokinetic performance in clinical practice.

Contents of the invention

The object of the present invention is to provide an imidazocyclic compound with PAR4 antagonistic activity.

Another object of the present invention is to provide the medical use of the imidazocyclic compound as a PAR4 antagonist. The compounds have significant antagonistic activity to PAR4 in an in vitro anti-platelet aggregation experiment, thereby strongly inhibiting platelet aggregation, and thus can be used to prepare drugs for preventing or treating various thromboembolic diseases.

For realizing the purpose, technical scheme of the present invention is as follows:

The compound represented by the following formula (I) or formula (II) described in the present invention, its pharmaceutically acceptable salt or ester or solvate:

in,

R is selected from ^: H, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, phenoxy, phenylthio, alkyl NH-, alkyloxyalkyl, tetrahydrofuran-2- radical, alkylcarbonyl, alkylsulfonyl, (alkyl) _2N- , cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, haloalkoxy, haloalkylthio, alkoxycarbonylalkane Oxygen, alkoxycarbonylalkylthio;

R ² is selected from: H, halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, cycloalkyl, haloalkyl, haloalkoxy, haloalkylthio, halocycloalkyl, heterocycloalkyl;

E is selected from: S, O, NH, -CR ³ =CR ⁴ -, -N=CR ⁴ -, -CR ³ =N-, -N=N-;

R ³ and R ⁴ are independently selected from: H, halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O) NH ₂ , R ^3a , OR ^3a , NHR ^3a , NH(CO)R ^3a , C(O)R ^3a , C(O)OR ^3a , OC(O)R ^3a , C(O)NHR ^3a , C(O)R 3a , C(O)R 3a , )NR ^3b R ^3c , NR ^3b R ^3c , -(CR ^3d R ^3e ) _n -R ^3g , -(CHR ^3f ) _n -R ^3g , -(CR ^3d R ^3e ) _n -OR ^3g , -(CHR ^3f ) _n -OR ^3g 、

R ^3a is selected from: alkyl, alkenyl, alkynyl; each of said alkyl, alkenyl, alkynyl is unsubstituted or substituted by one or two or three substituents independently selected from the following : Halogen, CN, NO ₂ , NH ₂ , OH, (O), CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , alkyl NH-, (alkyl) ₂ N-;

R ^3b and R ^3c are selected from: alkyl, alkenyl, alkynyl, aryl, or a nitrogen atom bound to it to form a 4- to 8-membered heterocycle, and the heterocycle contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0～ 2 additional heteroatoms selected from N, N-(alkyl), O, S(O) and S(O) ₂ ;

R ^3d , R ^3e and R ^3f are selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkane NH-, (alkyl) ₂ N-; wherein R ^3d and R ^3e can form a 3-8-membered ring with the carbon atoms connected to it, and the ring does not contain heteroatoms or contains 0-3 independently selected from halogen , CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl;

X ¹ is selected from: CR ⁵ , N;

R ⁵ is selected from: H, halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , alkyl , alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl Each of which is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , cycloalkyl, hydroxyalkyl, OR ^5a , COOR ^5a , SO ₂ R ^5a , O(C=O)R ^5a , (C=O )OR ^5a , N(R ^5a )(C=O)R ^5a , (C=O)NR ^5b R ^5c , NR ^5b R ^5c , SO ₂ NR ^5b R ^5c , -(CH ₂ ) _n -heteroaryl, -(CH ₂ ) _n -phenyl, -(CH ₂ ) _n -O-heteroaryl, -(CH ₂ ) _n -O-phenyl;

R ^is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl;

R ^5b and R ^5c are selected from: an alkyl group or a 4- to 8-membered heterocycle formed by a nitrogen atom bound to it, and the heterocycle contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , and OCHF ₂ , OCH ₂ F, 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional selected from N, N - heteroatoms of (alkyl), O, S(O) and S(O) ₂ ;

X ² is selected from: O, S, NR ⁶ ;

R ⁶ is selected from: H, R ^6a , C(O)R ^6a , S(O)R ^6a , S(O) ₂ R ^6a , -(CR ^6b R ^6c ) _n -R ^6e , -(CHR ^6d ) _n -R ^6e , -(CR ^6b R ^6c ) _n -OR ^6e , -(CHR ^6d ) _n -OR ^6e ;

R ^6a is selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl; wherein, the alkyl, alkenyl, alkynyl is unsubstituted or replaced by one or Two or three substituents independently selected from the following substituents are substituted: halogen, haloalkyl; wherein, the cycloalkyl, aryl, heteroaryl, heterocycloalkyl are unsubstituted or replaced by one or two Or three substituents independently selected from the following: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C( O) NH ₂ ;

R ^6b , R ^6c and R ^6d are selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkane NH-, (alkyl) ₂ N-; wherein R ^6b and R ^6c can form a 3-8-membered ring with the carbon atoms connected to it, and the ring does not contain heteroatoms or contains 0-3 independently selected from halogen , CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl;

X ³ is selected from: CR ⁷ , N;

R ⁷ is selected from: H, halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , COOH, C(O)NH ₂ , R ^7a , OR ^7a , SR ^7a , COOR ^7a , SO ₂ R ^7a , O(C=O)R ^7a , (C=O)OR ^7a , N(R ^7a )(C=O)R ^7a , (C=O)NR ^7b R ^7c , NR ^7b R ^7c , SO ₂ NR ^7b R ^7c , -(CR ^7d R ^7e ) _n -R ^7g , -(CHR ^7f ) _n -R ^7g , -(CR ^7d R ^7e ) _n -OR ^7g , -(CHR ^7f ) _n -OR ^7g ;

R ^7a is selected from: alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl; wherein, the alkyl, alkenyl, alkynyl is unsubstituted or replaced by one or Two or three substituents independently selected from the following substituents are substituted: halogen, haloalkyl; the aryl, cycloalkyl, heteroaryl, heterocycloalkyl are unsubstituted or replaced by one or two or three Substituents independently selected from the following substituents: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O) _NH2 ;

R ^7b and R ^7c are selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; wherein, R ^7b and R ^7c can form a 3- 8-membered ring containing 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkane A carbon atom substituted by a radical, an alkyl group and an alkoxy group, and 0 to 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^7d , R ^7e and R ^7f are selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkane NH-, (alkyl) ₂ N-; wherein, R ^7d and R ^7e can form a 3-8-membered ring with the carbon atoms connected to it, and the ring does not contain heteroatoms or contains 0-3 independently selected from Carbon atoms substituted by halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups , and 0 to 2 additional heteroatoms selected from N, N (alkyl), O, S (O) and S (O) ₂ ;

R ^7g is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl; wherein, the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl Cycloalkyl, heterocycloalkenyl is unsubstituted or substituted by one or two or three substituents independently selected from the following: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF _3. OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ;

X ⁴ and X ⁵ can be independently selected from: O, S, S(O), S(O) ₂ , CHR ⁸ , CR ⁹ R ¹⁰ , NR ¹¹ ;

R ⁸ , R ⁹ , R ¹⁰ are selected from: H, halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , COOH, R ^8a , OR ^8a , SR ^8a , C(O)R ^8a , S(O)R ^8a , S(O) ₂ R ^8a , -(CR ^8b R ^8c ) _n -R ^8e , -(CHR ^8d ) _n -R ^8e , -(CR ^8b R ^8c ) _n -OR ^8e , -(CHR ^8d ) _n -OR ^8e ;

R ^8a is selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl; wherein, the alkyl, alkenyl, alkynyl is unsubstituted or replaced by one or Two or three substituents independently selected from the following substituents are substituted: halogen, haloalkyl; said cycloalkyl, aryl, heteroaryl, heterocycloalkyl are unsubstituted or replaced by one or two or three Substituents independently selected from the following substituents: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O) _NH2 ;

R ^8b , R ^8c and R ^8d are selected from: H, F, Cl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl , Alkyl NH-, (Alkyl) ₂ N-; wherein, R ^8b and R ^8c can form a 3-8 membered ring with the carbon atoms connected to it, and the ring does not contain heteroatoms or contains 0 to 3 independently Substituted by a group selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy A carbon atom, and 0 to 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl; wherein, the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl Cycloalkyl, heterocycloalkenyl is unsubstituted or substituted by one or two or three substituents independently selected from the following: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF _3. OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ;

R ¹¹ is selected from: H, R ^11a , S(O)R ^11a , S(O) ₂ R ^11a , C(O)R ^11a , -(CR ^11b R ^11c ) _n -R ^11e , -(CHR ^11d ) _n -R ^11e , -(CR ^11b R ^11c ) _n -OR ^11e , -(CHR ^11d ) _n -OR ^11e ;

R ^11a is selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl; wherein, the alkyl, alkenyl, alkynyl is unsubstituted or replaced by one or Two or three substituents independently selected from the following substituents are substituted: halogen, haloalkyl; wherein, the cycloalkyl, aryl, heteroaryl, heterocycloalkyl are unsubstituted or replaced by one or two Or three substituents independently selected from the following: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C( O) NH ₂ ;

R ^11b , R ^11c and R ^11d are selected from the group consisting of: H, F, Cl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl , alkyl NH-, (alkyl) ₂ N-; wherein, R ^11b and R ^11c can form a 3-8-membered ring with the carbon atoms connected to it, and the ring does not contain heteroatoms or contains 0 to 3 independently Substituted by a group selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy A carbon atom, and 0 to 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^11e is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl; wherein, the aryl, heteroaryl, cycloalkyl, cycloalkenyl, hetero Cycloalkyl, heterocycloalkenyl is unsubstituted or substituted by one or two or three substituents independently selected from the following: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF _3. OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ;

R ¹² and R ¹³ are selected from: H, deuterium, halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , SO ₂ NH ₂ , COOH, C(O )NH ₂ , R ^12a , OR ^12a , SR ^12a , S(O)R ^12a , S(O) ₂ R ^12a , C(O)R ^12a , C(O)OR ^12a , OC(O)R ^12a , NHR ^12a , C(O)NHR ^12a , NH(CO)R ^12a , NR ^12a (CO)R ^12a , NH(CO)OR ^12a , NR ^12a (CO)OR ^12a , SO ₂ NHR ^12a , NHSO ₂ R ^12a , NR ^12a SO ₂ R ^12a , NR ^12b R ^12c , C(O)NR ^12b R ^12c , SO ₂ NR ^12b R ^12c , R ^12d ; wherein R ^12b and R ^12c combine to form 4 to 8 membered when attached to the same nitrogen A heterocyclic ring containing 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl , carbon atoms substituted by groups of alkyl and alkoxy groups, and 0 to 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^12a , R ^12b and R ^12c are selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; said alkyl, Alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl each of which is unsubstituted or is independently selected from one or two or three The following substituents are substituted: H, halogen, OH, (O), CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , SO ₂ NH ₂ , COOH, C(O)NH ₂ , NHC(O)NH ₂ , R ^12aa , OR ^12aa , SR ^12aa , S(O)R ^12aa , OS(O) ₂ R ^12aa , S(O) ₂ R ^12aa , NHR ^12aa , C (O)R ^12aa , C(O)OR ^12aa , OC(O)R ^12aa , OC(O)NHR ^12aa , C(O)NHR ^12aa , NR ^12aa C(O)R ^12aa , NHSO ₂ R ^12aa , NHC( O)OR ^12aa , S(O) ₂ NHR ^12aa , NHC(O)R ^12aa , NHC(O)NHR ^12aa , OC(O)NR ^12ab R ^12ac , NR ^12ab R ^12ac , C(O)NR ^12ab R ^12ac , SO ₂ NR ^12ab R ^12ac ;

R ^12aa is selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; said alkyl, alkenyl, alkynyl, Each of aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl is unsubstituted or substituted by one or two or three substituents independently selected from : H, Halogen, OH, (O), CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , SO ₂ NH ₂ , COOH, C(O)NH ₂ , NHC(O)NH ₂ , R ^12aaa , OR ^12aaa , SR ^12aaa , S(O)R ^12aaa , S(O) ₂ R ^12aaa , NHR ^12aaa , C(O)R ^12aaa , C(O)OR ^12aaa , OC (O)R ^12aaa , C(O)NHR ^12aaa , NR ^12aaa C(O)R ^12aaa , NHSO ₂ R ^12aaa , NHC(O)OR ^12aaa , S(O) ₂ NHR ^12aaa , NHC(O)R ^12aaa , NHC (O)NHR ^12aaa , NR ^12aab R ^12aac , C(O)NR ^12aab R ^12aac , SO ₂ NR ^12aab R ^12aac ;

R ^{12aaa is} selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; said alkyl, alkenyl, alkynyl, Aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ;

R ^12aab and R ^12aac are selected from: an alkyl group, or when attached to the same nitrogen, combine to form a 4 to 8 membered heterocycle containing 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF _3. Carbon atoms substituted by OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups, and 0 to 2 additional optional Heteroatoms from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^12ab and R ^12ac are selected from: an alkyl group, or when attached to the same nitrogen, combine to form a 4 to 8 membered heterocycle containing 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF _3. Carbon atoms substituted by OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups, and 0 to 2 additional optional Heteroatoms from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^12d is selected from: -(CR ^12da R ^12db ) _n -R ^12dd , -(CHR ^12dc ) _n -R ^12dd , -(CR ^12da R ^12db ) _n -OR ^12dd , -(CHR ^12dc ) _n -OR ^12dd ;

R ^12da , R ^12db , R ^12dc are selected from: H, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heteroaryl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl; Wherein, each of the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl is unsubstituted or is independently selected from the following by one or two or three Substituents substituted by: halogen, CN, NO ₂ , NH ₂ , OH, alkoxy, haloalkoxy, alkyl, haloalkyl, cycloalkyl, hydroxyalkyl; the carbon to which R ^12da and R ^12db can be attached Atoms form a 3-8 membered ring, the ring does not contain heteroatoms or contains 0 to 3 heteroaryls independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5 or 6 members group, OH, oxo, hydroxyalkyl, alkyl and alkoxy group substituted carbon atoms, and 0 to 2 additional ones selected from N, N(alkyl), O, S(O) and Heteroatoms of S(O) ₂ ;

R ^{12dd is} selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl;

Ring A is selected from: 4-20 membered heterocycles with an unsaturation degree of 1 that does not contain heteroatoms, 4-20 membered heterocycles with a degree of unsaturation greater than 1 that does not contain heteroatoms, 4-20 membered heterocycles that contain O, N or S atoms A 4-20-membered heterocycle with a saturation of 1, a 4-20-membered heterocycle with an unsaturation greater than 1 containing O, N or S atoms;

R ¹² can be arbitrarily substituted at the C atom site on the A ring;

R ^12d can be arbitrarily substituted at the N atom site on the A ring;

L is selected from: -O-, -S-, -NH-, -S(O)-, -S(O) ₂ -, -C(O)-, -C(O)O-, -OC(O )-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -R ^14a -, -(R ^14a ) _n -C(O)-, -C(O)- (R ^14a ) _n -, -C(O)-(R ^14a ) _n -O-, -C(O)-(R ^14a ) _n -O-(R ^14a ) _n -, -C(O)-( R ^14a ) _n -S-(R ^14a ) _n -, -C(O)-(R ^14a ) _n -S-, -O-(R ^14a ) _n -, -S-(R ^14a ) _n -, - (R ^14a ) _n -O-, -(R ^14a ) _n -S-, -O-(R ^14a ) _n -C(O)-, -S-(R ^14a ) _n -C(O)-, - O-(R ^14a ) _n -O-, -(R ^14a ) _n -O-(R ^14a ) _n -, -NC(O)(R ^14a ) _n -, -C(O)-(R ^14a ) _n -C(O)-, -C(O)-(R ^14a ) _n -OC(O)-, -NR ^14b -, -C(O)NR ^14b -, -NR ^14b C(O)NR ^14b -;

R ^14a is selected from: alkyl, alkenyl, alkynyl; wherein, said alkyl, alkenyl, alkynyl are all independently unsubstituted or substituted by one or two or three independently selected from the following Substituted by: H, (O), halogen, OCF ₃ , CF ₃ , OCHF ₂ , OH, CN, NO ₂ , haloalkyl, alkoxy, alkylthio, cycloalkyl, cycloalkoxy, carboxyl, Alkoxycarbonyl, alkylsulfonyl, NR ^14aa R ^14ab , C(=O)NR ^14aa R ^14ab , S(=O) ₂ NR ^14aa R ^14ab , aryl, heteroaryl, heterocycloalkyl, heterocycle Alkenyl; wherein, R ^14aa and R ^14ab are selected from: alkyl, or when connected to the same nitrogen, combined to form a 4 to 8-membered heterocyclic ring, which contains 0 to 3 independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0～ 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^is selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; Wherein, the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl are all independently unsubstituted or substituted with one or _two or three substituents independently selected from the group consisting of halogen, CN, NO2, _NH2 , OH, alkoxy, haloalkoxy, alkyl, haloalkane radical, cycloalkyl, hydroxyalkyl;

R ^is selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; Wherein, the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl are all independently unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of H, halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , NH(CO)NH ₂ , SO ₂ NH ₂ , R ^15a , OR ^15a , SR ^15a , S(O)R ^15a , S(O ) ₂ R ^15a , C(O)R ^15a , C(O)OR ^15a , OC(O)R ^15a , OC(O)NHR ^15a , NHR ^15a , C(O)NHR ^15a , NH(CO)R ^15a , NR ^15a (CO)R ^15a , NH(CO)OR ^15a , NR ^15a (CO)OR ^15a , NH(CO)NHR ^15a , NR ^15a (CO)NHR ^15a , S(O) ₂ NHR ^15a , NHS(O) ₂ R ^15a , NR ^15a S(O) ₂ R ^15a , NHS(O) ₂ NHR ^15a , NR ^15a S(O) ₂ NHR ^15a , OC(O)NR ^15b R ^15c , C(O)NHNOR ^15a , C( O)NHS(O) ₂ R ^15a , NR ^15a S(O) ₂ NR ^15b R ^15c , NR ^15b R ^15c , C(O)NR ^15b R ^15c , NH(CO)NR ^15b R ^15c , NR ^15a (CO) NR ^15b R ^15c , S(O) ₂ NR ^15b R ^15c , NHS(O) ₂ NR ^15b R ^15c , -(CR ^15d R ^15e ) _n -R ^15g , -(CHR ^15f ) _n -R ^15g , -(CR ^15d R ^15e ) _n -OR ^15g , -(CHR ^15f ) _n -OR ^15g ;

R ^15a , R ^15b , R ^15c are selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkane wherein, each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl is Unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , NHC(O)NH ₂ , R ^15aa , OR ^15aa , SR ^15aa , S(O)R ^15aa , S(O) ₂ R ^15aa , NHR ^15aa , C( O)R ^15aa , C(O)NHR ^15aa , NHC(O)R ^15aa , NR ^15aa C(O)R ^15aa , NHS(O) ₂ R ^15aa , NHC(O)OR ^15aa , SO ₂ NHR ^15aa , NHC( O) NHR ^15aa , SO ₂ NR ^15ab R ^15ac , NCR ^15ab R ^15ac , NR ^15ab R ^15ac , C(O)NR ^15ab R ^15ac ; wherein, when R ^15b , R ^15c are attached to the same nitrogen, combine to form 4 to An 8-membered heterocycle containing 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5 or 6-membered heteroaryl, OH, oxo, hydroxyl Alkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to ₂ additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ;

R ^15aa , R ^15ab , R ^15ac are selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkane group; wherein, when R ^15ab and R ^15ac are connected to the same nitrogen, they are combined to form a 4 to 8 membered heterocyclic ring, which contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF _2. Carbon atoms substituted by OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups, and 0 to 2 additional members selected from N, N(alkyl), O, S(O) and S(O ₎ heteroatoms;

R ^15d , R ^15e , R ^15f are selected from: H, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero Cycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein, the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, hetero Spirocycloalkyl each of which is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, hydroxyalkyl; among them, R ^15d and R ^15e can form a 4 to 8-membered ring with the carbon to which it is attached, and the ring does not contain heteroatoms or contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5 Or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional selected from N, N (alkyl), O , S(O) and S(O) ₂ heteroatoms;

R ^15g is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein, the aryl, heteroaryl group, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl, each of which is unsubstituted or is independently selected from The following substituents are substituted: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH, alkyl, Haloalkyl, alkoxy, haloalkoxy, cycloalkyl, hydroxyalkyl;

n is selected from: 1, 2, 3, 4, 5, 6.

In some preferred embodiments, the compound of formula (I) or formula (II) of the present invention or a pharmaceutically acceptable salt or ester or solvate thereof:

R is selected from: H, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl NH-, alkyloxyalkyl, tetrahydrofuran- ² -yl, alkylcarbonyl, alkyl Sulfonyl, (alkyl) _2N- , cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, haloalkoxy, haloalkylthio;

R ² is selected from: H, halogen, CN, NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , alkyl, alkoxy, alkylthio, cycloalkyl, haloalkyl, Haloalkoxy, haloalkylthio, halocycloalkyl, heterocycloalkyl;

E is selected from: S, O, -CR ³ =CR ⁴ -, -N=CR ⁴ -, -CR ³ =N-, -N=N-;

R ³ and R ⁴ are independently selected from: H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , R ^3a , OR ^3a , NH(CO)R ^3a , C(O)R ^3a , C(O)OR ^3a , OC(O)R ^3a , C(O)NHR ^3a , C(O)NR ^3b R ^3c , -(CR ^3d R ^3e ) _n -R ^3g , -(CHR ^3f ) _n -R ^3g , -(CR ^3d R ^3e ) _n -OR ^3g , -(CHR ^3f ) _n -OR ^3g , R ^3a are selected from the group consisting of: alkyl, alkenyl, Alkynyl; said alkyl, alkenyl, and alkynyl are each unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, OH, (O), CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , alkyl NH-, (alkyl) ₂ N-;

R ^3b and R ^3c are selected from: an alkyl group or a 4-6 membered heterocycle formed by the nitrogen atom bound to it, and the heterocycle contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional selected from N, N - heteroatoms of (alkyl), O, S(O) and S(O) ₂ ;

R ^3d , R ^3e and R ^3f are selected from the group consisting of: H, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkylNH-, (alk group) ₂ N-; wherein R ^3d and R ^3e can form a 3-8 membered ring with the carbon atoms connected to it, and the ring does not contain heteroatoms or contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional A heteroatom selected from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^3g is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl;

X ¹ is selected from: CR ⁵ , N;

R ⁵ is selected from: H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , alkyl, alkenyl, alkynyl, ring Alkyl, heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl are each unsubstituted or replaced by one or two or three independently selected from the following Substituents substituted by: halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , cycloalkyl, hydroxyalkyl, OR ^5a , COOR ^5a , SO ₂ R ^5a , N(R ^5a )(C=O)R ^5a , (C=O)NR ^5b R ^5c , NR ^5b R ^5c , SO ₂ NR ^5b R ^5c ;

R ^is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl;

R ^5b and R ^5c are selected from: alkyl;

X ² is selected from: O, S, NR ⁶ ;

R ⁶ is selected from: H, R ^6a , C(O)R ^6a , S(O)R ^6a , S(O) ₂ R ^6a , -(CR ^6b R ^6c ) _n -R ^6e , -(CHR ^6d ) _n -R ^6e , -(CR ^6b R ^6c ) _n -OR ^6e , -(CHR ^6d ) _n -OR ^6e ;

R ^6a is selected from: alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl; wherein, the alkyl, alkenyl, alkynyl is unsubstituted or replaced by one or two or three independently Substituents selected from the following substituents are substituted: halogen, haloalkyl; wherein, the cycloalkyl and heterocycloalkyl are unsubstituted or substituted by one or two or three substituents independently selected from the following: Halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ;

R ^6b , R ^6c and R ^6d are selected from the group consisting of: H, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkylNH-, (alk group) ₂ N-; wherein R ^6b and R ^6c can form a 3-6-membered ring with the carbon atoms connected to it, and the ring does not contain heteroatoms or contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional A heteroatom selected from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl;

X ³ is selected from: CR ⁷ , N;

R ⁷ is selected from: H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , COOH, C(O)NH ₂ , R ^7a , OR ^7a , SR ^7a , N(R ^7a ) (C=O)R ^7a , (C=O)NR ^7b R ^7c , NR ^7b R ^7c , SO ₂ NR ^7b R ^7c , -(CR ^7d R ^7e ) _n -R ^7g , -(CHR ^7f ) _n -R ^7g , -(CR ^7d R ^7e ) _n -OR ^7g , -(CHR ^7f ) _n -OR ^7g ;

R ^7a is selected from: alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl; wherein, the alkyl, alkenyl, alkynyl is unsubstituted or replaced by one or Two or three substituents independently selected from the following substituents are substituted: halogen, haloalkyl; the aryl, cycloalkyl, heteroaryl, heterocycloalkyl are unsubstituted or replaced by one or two or three Substituents independently selected from the following substituents: halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ;

R ^7b and R ^7c are selected from: alkyl, alkenyl, alkynyl, cycloalkyl; wherein, R ^7b and R ^7c can form a 3-6-membered ring with the nitrogen atom connected to it, which contains 0-3 Groups independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy Substituted carbon atoms, and 0 to 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^7d , R ^7e and R ^7f are selected from the group consisting of: H, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkylNH-, (alk group) ₂ N-; wherein, R ^7d and R ^7e can form a 3-6-membered ring with the carbon atom connected to it, and the ring does not contain heteroatoms or contains 0-3 independently selected from halogen, CF ₃ , CHF _2. Carbon atoms substituted by OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups, and 0 to 2 Additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^7g is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl; wherein, the aryl, heteroaryl, cycloalkyl, heterocycloalkyl is unsubstituted or replaced by one or two Or three substituents independently selected from the following substituents: halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ;

X ⁴ and X ⁵ can be independently selected from: O, S, CHR ⁸ , CR ⁹ R ¹⁰ , NR ¹¹ ;

R ⁸ , R ⁹ , R ¹⁰ are selected from: H, halogen, CN, NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , COOH, R ^8a , OR ^8a , SR ^8a , C (O)R ^8a , S(O)R ^8a , S(O) ₂ R ^8a , -(CR ^8b R ^8c ) _n -R ^8e , -(CHR ^8d ) _n -R ^8e , -(CR ^8b R ^8c ) _n -OR ^8e , -(CHR ^8d ) _n -OR ^8e ;

R ^8a is selected from: alkyl, alkenyl, alkynyl, heterocycloalkyl; wherein, the alkyl, alkenyl, alkynyl is unsubstituted or one or two or three are independently selected from the following Substituents substituted by: halogen, haloalkyl; said heterocycloalkyl is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ;

R ^8b , R ^8c and R ^8d are selected from the group consisting of: H, F, Cl, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkylNH-, (Alkyl) ₂ N-; wherein, R ^8b and R ^8c can form a 3-6-membered ring with the carbon atoms connected to them, and the ring does not contain heteroatoms or contains 0 to 3 independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0～ 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^8e is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl; wherein, the aryl, heteroaryl, cycloalkyl, heterocycloalkyl is unsubstituted or replaced by one or two Or three substituents independently selected from the following substituents: halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ;

R ¹¹ is selected from: H, R ^11a , S(O)R ^11a , S(O) ₂ R ^11a , C(O)R ^11a , -(CR ^11b R ^11c ) _n -R ^11e , -(CHR ^11d ) _n -R ^11e , -(CR ^11b R ^11c ) _n -OR ^11e , -(CHR ^11d ) _n -OR ^11e ;

R ^11a is selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl; wherein, the alkyl, alkenyl, alkynyl is unsubstituted or replaced by one or Two or three substituents independently selected from the following substituents are substituted: halogen, haloalkyl; wherein, the cycloalkyl, aryl, heteroaryl, heterocycloalkyl are unsubstituted or replaced by one or two Or three substituents independently selected from the following: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C( O) NH ₂ ;

R ^11b , R ^11c and R ^11d are selected from the group consisting of: H, F, Cl, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkylNH-, (Alkyl) ₂ N-; Wherein, R ^11b and R ^11c can form a 3-6 membered ring with the carbon atoms connected to it, and the ring does not contain heteroatoms or contains 0 to 3 independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0～ 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^11e is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl; wherein, the aryl, heteroaryl, cycloalkyl, heterocycloalkyl is unsubstituted or replaced by one or two Or three substituents independently selected from the following substituents: halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ;

R ¹² and R ¹³ are selected from: H, deuterium, halogen, CN, NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , SO ₂ NH ₂ , COOH, C(O)NH ₂ , R ^12a , OR ^12a , S(O)R ^12a , S(O) ₂ R ^12a , C(O)R ^12a , NHR ^12a , C(O)NHR ^12a , NH(CO)R ^12a , NR ^12a (CO )R ^12a , SO ₂ NHR ^12a , NHSO ₂ R ^12a , NR ^12b R ^12c , C(O)NR ^12b R ^12c , SO ₂ NR ^12b R ^12c , R ^12d ; wherein R ^12b and R ^12c when attached to the same nitrogen , combined to form a 4- to 8-membered heterocycle containing 0-3 independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5 or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional ones selected from N, N(alkyl), O, S(O) and S( O) a heteroatom of ₂ ;

R ^12a , R ^12b and R ^12c are selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; each of said alkyl, alkenyl or alkynyl is Unsubstituted or substituted by one or two or three substituents independently selected from H, halogen, OH, (O), CN, NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , SO ₂ NH ₂ , COOH, C(O)NH ₂ , NHC(O)NH ₂ , R ^12aa , OR ^12aa , S(O)R ^12aa , OS(O) ₂ R ^12aa , S( O) ₂ R ^12aa , NHR ^12aa , C(O)R ^12aa , C(O)NHR ^12aa , C(O)OR ^12aa , OC(O)R ^12aa , OC(O)NHR ^12aa , OC(O)NR ^12ab R ^12ac , NR ^12aa C(O)R ^12aa , NHSO ₂ R ^12aa , S(O) ₂ NHR ^12aa , NHC(O)R ^12aa , NHC(O)NHR ^12aa , NR ^12ab R ^12ac , C(O)NR ^12ab R ^12ac , SO ₂ NR ^12ab R ^12ac ;

R ^12aa is selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkane group, or heterocycloalkyl, each of which is unsubstituted or substituted by one or two or three substituents independently selected from the following: H, halogen, OH, (O), CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , SO ₂ NH ₂ , COOH, C(O)NH ₂ , NHC(O)NH ₂ , R ^12aaa , OR ^12aaa , SR ^12aaa , S(O)R ^12aaa , S(O) ₂ R ^12aaa , NHR ^12aaa , C(O)R ^12aaa , C(O)OR ^12aaa , OC(O)R ^12aaa , C(O)NHR ^12aaa , NR ^12aaa C( O)R ^12aaa , NHSO ₂ R ^12aaa , NHC(O)OR ^12aaa , S(O) ₂ NHR ^12aaa , NHC(O)R ^12aaa , NHC(O)NHR ^12aaa , NR ^12aab R ^12aac , C(O)NR ^12aaa R ^12aac , SO ₂ NR ^12aab R ^12aac ;

R ^{12aaa is} selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; said alkyl, alkenyl, alkynyl, Aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ;

R ^12aab and R ^12aac are selected from: an alkyl group, or when attached to the same nitrogen, combine to form a 4 to 6 membered heterocycle containing 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF _3. Carbon atoms substituted by OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups, and 0 to 2 additional optional Heteroatoms from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^12ab and R ^12ac are selected from: an alkyl group, or when attached to the same nitrogen, combine to form a 4-6 membered heterocycle containing 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF _3. Carbon atoms substituted by OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups, and 0 to 2 additional optional Heteroatoms from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^12d is selected from: -(CR ^12da R ^12db ) _n -R ^12dd , -(CHR ^12dc ) _n -R ^12dd , -(CR ^12da R ^12db ) _n -OR ^12dd , -(CHR ^12dc ) _n -OR ^12dd ;

R ^12da , R ^12db , R ^12dc are selected from: H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl; wherein, each of the cycloalkyl and heterocycloalkyl is unsubstituted or replaced by one Or two or three substituents independently selected from the following substituents: halogen, CN, NH ₂ , OH, alkoxy, haloalkoxy, alkyl, haloalkyl, cycloalkyl, hydroxyalkyl; R ^12da and R ^12db can form a 3-6 membered ring with the carbon atom connected to it, and the ring does not contain heteroatoms or contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5 or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy group substituted carbon atoms, and 0 to 2 additional selected from N, N (alkyl ), O, S(O) and S(O) ₂ heteroatoms;

R ^{12dd is} selected from: aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl;

Ring A is selected from: 4-10 membered heterocyclic rings with an unsaturation degree of 1 that does not contain heteroatoms, 4-10 membered heterocyclic rings with a degree of unsaturation greater than 1 that does not contain heteroatoms, and unsaturated rings that contain O, N or S atoms A 4-10 membered heterocycle with a degree of saturation of 1, a 4-10 membered heterocycle with an unsaturation greater than 1 containing O, N or S atoms;

R ¹² can be arbitrarily substituted at the C atom site on the A ring;

R ^12d can be arbitrarily substituted at the N atom site on the A ring;

L is selected from: -O-, -S-, -NH-, -S(O)-, -S(O)2-, -C(O)-, -C(O)NH-, -NHC(O )-, -NHC(O)NH-, -R ^14a -, -(R ^14a ) _n -C(O)-, -C(O)-(R ^14a ) _n -, -C(O)-(R ^14a ) _n -O-, -C(O)-(R ^14a ) _n -O-(R ^14a ) _n -, -O-(R ^14a ) _n -, -(R ^14a ) _n -O-, -O -(R ^14a ) _n -C(O)-, -O-(R ^14a ) _n -O-, -(R ^14a ) _n -O-(R ^14a ) _n -, -NC(O)(R ^14a ) _n -, -C(O)-(R ^14a ) _n -C(O)-, -NR ^14b -, -C(O)NR ^14b -, -NR ^14b C(O)NR ^14b -;

R ^14a is selected from: alkyl, alkenyl, alkynyl; wherein, said alkyl, alkenyl, alkynyl are all independently unsubstituted or substituted by one or two or three independently selected from the following Substituted by: H, (O), halogen, OCF ₃ , CF ₃ , OCHF ₂ , OH, CN, haloalkyl, alkoxy, alkylthio, cycloalkoxy, carboxyl, alkoxycarbonyl, alkyl Sulfonyl, NR ^14aa R ^14ab , C(=O)NR ^14aa R ^14ab , S(=O) ₂ NR ^14aa R ^14ab , heteroaryl, heterocycloalkyl, heterocycloalkenyl; wherein, R ^14aa and R ^14ab selected from: alkyl;

R ^14b is selected from: alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, heterospirocycloalkyl; wherein, the alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycle Alkenyl, heterospirocycloalkyl are independently unsubstituted or substituted by one or two or three substituents independently selected from the following: halogen, CN, _NH2 , OH, alkoxy, haloalkane Oxygen, haloalkyl;

R ^is selected from: alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein, The alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl are independently Unsubstituted or substituted by one or two or three substituents independently selected from H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH , C(O)NH ₂ , NH(CO)NH ₂ , SO ₂ NH ₂ , R ^15a , OR ^15a , SR ^15a , S(O)R ^15a , S(O) ₂ R ^15a , C(O)R ^15a , NHR ^15a , C(O)NHR ^15a , NH(CO)R ^15a , NR ^15a (CO)R ^15a , NH(CO)OR ^15a , NR ^15a (CO)OR ^15a , NH(CO)NHR ^15a , NR ^15a (CO)NHR ^15a , S(O) ₂ NHR ^15a , NHS(O) ₂ R ^15a , NR ^15a S(O) ₂ R ^15a , NHS(O) ₂ NHR ^15a , NR ^15a S(O) ₂ NHR ^15a , C(O)NHNOR ^15a , C(O)NHS(O) ₂ R ^15a , NR ^15b R ^15c , C(O)NR ^15b R ^15c , S(O) ₂ NR ^15b R ^15c , -(CR ^15d R ^15e ) _n -R ^15g , -(CHR ^15f ) _n -R ^15g , -(CR ^15d R ^15e ) _n -OR ^15g , -(CHR ^15f ) _n -OR ^15g ;

R ^15a , R ^15b , R ^15c are selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkane wherein, each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl is Unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , R ^15aa , OR ^15aa , SR ^15aa , S(O)R ^15aa , S(O) ₂ R ^15aa , NHR ^15aa , C(O)R ^15aa , C( O)NHR ^15aa , NHC(O)R ^15aa , NR ^15aa C(O)R ^15aa , NHS(O) ₂ R ^15aa , SO ₂ NHR ^15aa , SO ₂ NR ^15ab R ^15ac , NCR ^15ab R ^15ac , NR ^15ab R ^15ac , C(O)NR ^15ab R ^15ac ; wherein, when R ^15b and R ^15c are connected to the same nitrogen, they combine to form a 4- to 8-membered heterocycle, which contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0～ 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^15aa , R ^15ab , R ^15ac are selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkane group; wherein, when R ^15ab and R ^15ac are connected to the same nitrogen, they are combined to form a 4-6 membered heterocyclic ring, which contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF _2. Carbon atoms substituted by OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups, and 0 to 2 additional members selected from N, N(alkyl), O, S(O) and S(O ₎ heteroatoms;

R ^15d , R ^15e , and R ^15f are selected from: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl; wherein, the heteroaryl, heterocycloalkane each of which is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of: halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , haloalkyl, alkoxy, haloalkoxy; wherein, wherein, R ^15d and R ^15e can form a 4- to 8-membered ring with the carbon to which they are attached, and the ring Does not contain heteroatoms or contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkane A carbon atom substituted by a radical, an alkyl group and an alkoxy group, and 0 to 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^15g is selected from: aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, heterospirocycloalkyl; wherein, the aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkyl Spirocycloalkyl each of which is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH, haloalkyl, alkoxy, haloalkoxy;

n is selected from: 1, 2, 3.

In some preferred embodiments, the compound of formula (I) or formula (II) of the present invention or a pharmaceutically acceptable salt or ester or solvate thereof:

R1 is selected from: H, halogen, alkoxy, alkylthio, alkylNH-, alkyloxyalkyl, tetrahydrofuran- ² -yl, alkylcarbonyl, alkylsulfonyl, (alkyl ₎ 2N -, haloalkyl, halocycloalkyl, haloalkoxy, haloalkylthio;

R ² is selected from: H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , alkoxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halocycloalkane base, heterocycloalkyl;

E is selected from: S, O, -CR ³ =CR ⁴ -, -N=CR ⁴ -, -CR ³ =N-, -N=N-;

R ³ and R ⁴ are independently selected from: H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , R ^3a , OR ^3a , NH(CO)R ^3a , C(O)R ^3a , C(O)NHR ^3a , C(O)NR ^3b R ^3c , -(CR ^3d R ^3e ) _n -R ^3g , -(CHR ^3f ) _n -R ^3g , -(CR ^3d R ^3e ) _n -OR ^3g , -(CHR ^3f ) _n -OR ^3g ,

R ^3a is selected from: alkyl; each of the alkyl groups is substituted by one, two or three substituents independently selected from the following: halogen, CN, OH, (O), CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ ;

R ^3b and R ^3c are selected from: alkyl;

R ^3d , R ^3e and R ^3f are selected from the group consisting of: H, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkylNH-, (alk base) ₂ N-;

R ^3g is selected from: heteroaryl, heterocycloalkyl;

X ¹ is selected from: CR ⁵ , N;

R ⁵ is selected from: H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , alkyl, cycloalkyl, heterocycloalkyl; wherein the alkyl, cycloalkyl, hetero Cycloalkyl each of which is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , Cycloalkyl, OR ^5a , COOR ^5a , SO ₂ R ^5a , N(R ^5a )(C=O)R ^5a , (C=O)NR ^5b R ^5c , NR ^5b R ^5c , SO ₂ NR ^5b R ^5c ;

R ^5a is selected from alkyl, alkenyl, alkynyl;

R ^5b and R ^5c are selected from: alkyl;

X ² is selected from: O, S, NR ⁶ ;

R ⁶ is selected from: H, R ^6a , -(CR ^6b R ^6c ) _n -R ^6e , -(CHR ^6d ) _n -R ^6e , -(CR ^6b R ^6c ) _n -OR ^6e , -(CHR ^6d ) _n -OR ^6e ;

R ^is selected from: alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl;

R ^6b , R ^6c and R ^6d are selected from: H, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy;

R ^is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl;

X ³ is selected from: CR ⁷ , N;

R ⁷ is selected from: H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , R ^7a , OR ^7a , N(R ^7a )(C=O)R ^7a , (C=O )NR ^7b R ^7c , NR ^7b R ^7c , SO ₂ NR ^7b R ^7c , -(CR ^7d R ^7e ) _n -R ^7g , -(CHR ^7f ) _n -R ^7g , -(CR ^7d R ^7e ) _n -OR ^7g , -(CHR ^7f ) _n -OR ^7g ;

R ^is selected from: alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl;

R ^7b and R ^7c are selected from: alkyl, alkenyl, alkynyl, cycloalkyl;

R ^7d , R ^7e and R ^7f are selected from: H, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy;

R ^is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl;

X ⁴ and X ⁵ can be independently selected from: O, S, CHR ⁸ , CR ⁹ R ¹⁰ , NR ¹¹ ;

R ⁸ , R ⁹ , R ¹⁰ are selected from: H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , R ^8a , OR ^8a , C(O)R ^8a , -(CR ^8b R ^8c ) _n -R ^8e , -(CHR ^8d ) _n -R ^8e , -(CR ^8b R ^8c ) _n -OR ^8e , -(CHR ^7d ) _n -OR ^8e ;

R ^{8a is} selected from: alkyl, heterocycloalkyl;

R ^8b , R ^8c and R ^8d are selected from: H, F, Cl, alkyl, alkoxy, haloalkyl, haloalkoxy;

R ^is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl;

R ¹¹ is selected from: H, R ^11a , S(O)R ^11a , S(O) ₂ R ^11a , C(O)R ^11a , -(CR ^11b R ^11c ) _n -R ^11e , -(CHR ^11d ) _n -R ^11e , -(CR ^11b R ^11c ) _n -OR ^11e , -(CHR ^11d ) _n -OR ^11e ;

R ^11a is selected from: alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl;

R ^11b , R ^11c and R ^11d are selected from: H, F, Cl, alkyl, alkoxy, haloalkyl, haloalkoxy;

R ^11e is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl;

R ¹² and R ¹³ are selected from the group consisting of: H, deuterium, halogen, CN, NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , R ^12a , OR ^12a , S(O)R ^12a , S(O) ₂ R ^12a , C(O)R ^12a , NHR ^12a , C(O)NHR ^12a , NH(CO)R ^12a , NR ^12a (CO)R ^12a , NR ^12b R ^12c , C(O)NR ^12b R ^12c , R ^12d ; wherein when R ^12b and R ^12c are connected to the same nitrogen, they combine to form a 4- to 8-membered heterocyclic ring, which contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional A heteroatom selected from N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^12a , R ^12b and R ^12c are selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; each of said alkyl, alkenyl or alkynyl is Unsubstituted or substituted by one or two or three substituents independently selected from H, halogen, OH, (O), CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , R ^12aa , OR ^12aa , C(O)OR ^12aa , OC(O)R ^12aa , OC(O)NHR ^12aa , OC(O)NR ^12ab R ^12ac , S(O)R ^12aa , S(O) ₂ R ^12aa , OS(O) ₂ R ^12aa , NHR ^12aa , C(O)R ^12aa , C(O)NHR ^12aa , NR ^12aa C(O)R ^12aa , NHC(O)R ^12aa , NR ^12ab R ^12ac , C( O) NR ^12ab R ^12ac ;

R ^12aa is selected from: alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is not Substituted or substituted by one or two or three substituents independently selected from H, halogen, OH, (O), CN, NO ₂ , NH ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , R ^12aaa , OR ^12aaa , NHR ^12aaa , C(O)R ^12aaa , NR ^12aaa C(O)R ^12aaa , NHC(O)OR ^12aaa , NHC(O)R ^12aaa , NR ^12aab R ^12aac , C(O)NR ^12aab R ^12aac ;

R ^{12aaa is} selected from: alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; said alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl are unsubstituted or replaced by Substituted by one or two or three substituents independently selected from the following: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O) OH, C(O)NH ₂ ;

R ^12aab and R ^12aac are selected from: alkyl;

R ^12ab and R ^12ac are selected from: alkyl;

R ^12d is selected from: -(CR ^12da R ^12db ) _n -R ^12dd , -(CHR ^12dc ) _n -R ^12dd , -(CR ^12da R ^12db ) _n -OR ^12dd , -(CHR ^12dc ) _n -OR ^12dd ;

R ^12da , R ^12db , R ^12dc are selected from: H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl;

R ^{12dd is} selected from: aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl;

Ring A is selected from: 4-10 membered heterocyclic rings with an unsaturation degree of 1 that does not contain heteroatoms, 4-10 membered heterocyclic rings with a degree of unsaturation greater than 1 that does not contain heteroatoms, and unsaturated rings that contain O, N or S atoms A 4-10 membered heterocycle with a degree of saturation of 1, a 4-10 membered heterocycle with an unsaturation greater than 1 containing O, N or S atoms;

R ¹² can be arbitrarily substituted at the C atom site on the A ring;

R ^12d can be arbitrarily substituted at the N atom site on the A ring;

L is selected from: -O-, -S-, -NH-, -NHC(O)-, -R ^14a -, -(R ^14a ) _n -C(O)-, -O-(R ^14a ) _n - , -(R ^14a ) _n -O-, -O-(R ^14a ) _n -C(O)-, -O-(R ^14a ) _n -O-, -(R ^14a ) _n -O-(R ^14a ) _n -, -NC(O)(R ^14a ) _n -, -NR ^14b -;

R ^14a is selected from: alkyl, alkenyl; wherein, the alkyl, alkenyl are independently unsubstituted or substituted by one or two or three substituents independently selected from the following: H, (O), halogen, OCF ₃ , CF ₃ , OCHF ₂ , OH, CN, haloalkyl, NR ^14aa R ^14ab , heteroaryl, heterocycloalkyl, heterocycloalkenyl; wherein, R ^14aa and R ^14ab are selected from :alkyl;

R ^14b is selected from: alkyl, alkenyl, alkynyl;

R ^is selected from: alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein, The alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl are independently Unsubstituted or substituted by one or two or three substituents independently selected from H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH , C(O)NH ₂ , R ^15a , OR ^15a , SR ^15a , S(O)R ^15a , S(O) ₂ R ^15a , C(O)R ^15a , NHR ^15a , C(O)NHR ^15a , NH (CO)R ^15a , NR ^15a (CO)R ^15a , S(O) ₂ NHR ^15a , NHS(O) ₂ R ^15a , NR ^15a S(O) ₂ R ^15a , NR ^15b R ^15c , C(O)NR ^15b R ^15c , S(O) ₂ NR ^15b R ^15c , -(CR ^15d R ^15e ) _n -R ^15g , -(CHR ^15f ) _n -R ^15g , -(CR ^15d R ^15e ) _n -OR ^15g , -( CHR ^15f ) _n -OR ^15g ;

R ^15a , R ^15b , R ^15c are selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkane wherein, each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl is Unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH , C(O)NH ₂ , R ^15aa , OR ^15aa , SR ^15aa , S(O)R ^15aa , S(O) ₂ R ^15aa , NHR ^15aa , C(O)R ^15aa , C(O)NHR ^15aa , NHC (O)R ^15aa , NR ^15aa C(O)R ^15aa , NHS(O) ₂ R ^15aa , SO ₂ NHR ^15aa , SO ₂ NR ^15ab R ^15ac , NCR ^15ab R ^15ac , NR ^15ab R ^15ac , C(O)NR ^15ab R ^15ac ; wherein, when R ^15b and R ^15c are connected to the same nitrogen, they combine to form a 4- to 8-membered heterocyclic ring, which contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional selected from Heteroatoms of N, N(alkyl), O, S(O) and S(O) ₂ ;

R ^15aa , R ^15ab , R ^15ac are selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkane group; wherein, when R ^15ab and R ^15ac are connected to the same nitrogen, they are combined to form a 4-6 membered heterocyclic ring, which contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF _2. Carbon atoms substituted by OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups, and 0 to 2 additional members selected from N, N(alkyl), O, S(O) and S(O ₎ heteroatoms;

R ^15d , R ^15e , R ^15f are selected from: H, alkyl, haloalkyl;

R ^15g is selected from: aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, heterospirocycloalkyl; wherein, the aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkyl Spirocycloalkyl each of which is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH, haloalkyl, alkoxy, haloalkoxy;

n is selected from: 1, 2, 3.

In some more preferred embodiments, the compound of formula (I) or formula (II) of the present invention or a pharmaceutically acceptable salt or ester or solvate thereof:

Table 1. Structure and naming of compounds

The compounds of the present invention are also available as pharmaceutically acceptable salts. The salt may be a salt of at least one of the following acids: galactaric acid, D-glucuronic acid, glycerophosphate, hippuric acid, isethionic acid, lactobionic acid, maleic acid, 1,5-naphthalene Disulfonic acid, naphthalene-2-sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecylsulfuric acid, benzenesulfonic acid, citric acid, D-glucose, glycolic acid, lactic acid, Malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulfuric acid, tartaric acid, succinic acid, formic acid, hydroiodic acid, hydrobromic acid, methanesulfonic acid, niacin, nitric acid, orotic acid, oxalic acid, bitters Acid, L-pyroglutamic acid, saccharic acid, salicylic acid, gentisic acid, p-toluenesulfonic acid, valeric acid, palmitic acid, sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid, carbonic acid, 4-Benzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid, fumaric acid, 3-hydroxynaphthalene-2-carboxylic acid, 1-hydroxynaphthalene-2-carboxylic acid, oleic acid, undecylenic acid, ascorbic acid, Camphoric Acid, Camphorsulfonic Acid, Dichloroacetic Acid, Ethanesulfonic Acid. On the other hand, the salt can also be a salt formed between the compound of the present invention and metal (including sodium, potassium, calcium, etc.) ions or pharmaceutically acceptable amines (including ethylenediamine, tromethamine, etc.) or ammonium ions .

The compounds of the present invention can also be formulated into pharmaceutical compositions in the form of esters, prodrugs, or solvates thereof.

The present inventors have found that the compound of the above formula (I) or formula (II) or its pharmaceutically acceptable salt or ester or solvate is a novel PAR4 antagonist, which may inhibit platelet aggregation by antagonizing platelet PAR4, and thus can be used to prepare Drugs for the prevention and treatment of thromboembolic diseases.

The compounds of the present invention are useful in the prevention and treatment of a variety of thromboembolic disorders including, but not limited to: acute coronary syndrome, unstable angina, stable angina, ST-elevated myocardium Infarction, non-ST-elevation myocardial infarction, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, Arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, cancer-related thrombosis, and thrombosis due to medical implants, devices, and procedures in which blood is exposed to artificial surfaces caused by thrombosis.

The present invention also provides a pharmaceutical composition for preventing and treating the above-mentioned diseases, which contains a therapeutically effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt or ester or solvate thereof as an active ingredient and pharmaceutically acceptable carrier. Optionally mixable carriers may vary depending on dosage form, administration form and the like. Examples of carriers include excipients, binders, disintegrants, lubricants, correctives, fragrances, colorants, sweeteners and the like. The pharmaceutical composition can be in the form of capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories and patches, etc.

The compound of the present invention can be used in combination with one or more other types of drugs for the prevention or treatment of thromboembolic diseases, including but not limited to the following combinations.

Other types of prophylactic or therapeutic drugs that can optionally be used in combination with the compounds of the present invention can be one or more antiplatelet drugs, including abciximab, eptifibatide, tirofiban, clopidogrel, prazia Glycol, ticlopidine, cangrelor, enoxagrelor, ticagrelor, beraprost sodium, prostacyclin, iloprost, treprostinil, aspirin, aloprim, carbasalate calcium , indobufen, trifluxal, dipyridamole, pecotamide, terutroban, cilostazol, cloclomonade, or didazol.

Other types of prophylactic or therapeutic drugs that can optionally be used in combination with the compounds of the present invention can be one or more anticoagulant drugs, including acenocoumarol, dicoumarol, dihydroxycoumarin ethyl acetate, benzene Propylhydroxycoumarin, warfarin, chlorindione, dipheninone, phenindione, ticlocoumarin, bemiparin, certoparin, dalteparin, enoxaparin, nadroparin, Paparin, reviparin, tinzaparin, fondaparinux, idraparin, danaparin, sulodexide, dermatan sulfate, apixaban, betrixaban, edoxaban, omega Shaban, rivaroxaban, bivalirudin, lepirudin, hirudin, argatroban, dabigatran, melagatran, ximelagatran, defibrotide, ramatroban, anti Thrombin or Drotrecogin alfa;

Other types of prophylactic or therapeutic drugs that can be selected to be used in combination with the compounds of the present invention can be one or more thrombolytic drugs, such as alteplase, reteplase, tenecteplase, urokinase, saruprase Enzyme, streptokinase, anistreplase, monteplase, ancrodase, fibrinolysin, or fibrinolytic enzyme.

Other types of prophylactic or therapeutic drugs that can be selected to be used in combination with the compounds of the present invention can be one or more blood lipid-lowering drugs, including niacin, statins (such as lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin, atorvastatin, cerivastatin, rosvastatin and pitavastatin), cholesterol absorption inhibitors (such as ezetimibe, etc.), fibrates (such as clofibrate, benzalkonium Bate, fenofibrate, etc.).

The preparation method of the compound of the present invention refers to the embodiment method or improved method.

Description of drawings

Figure 1 is a test chart of the inhibition rate of compound 11 on platelet aggregation filtered in vitro;

Fig. 2 is a test chart of the inhibition rate of compound 88 on platelet aggregation filtered in vitro.

Detailed ways

The content of the present invention is specifically described below by way of examples. In the present invention, the following examples are for better illustration of the present invention, and are not intended to limit the scope of the present invention. Various changes and modifications of the present invention can be made without departing from the spirit and scope of the invention.

Example 1

6-(7,8-Dihydro-6H-indeno[4,5-b]furan-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thia Oxadiazole (compound 1)

Compound 1-1 (535 mg, 3.61 mmol) was weighed and dissolved in methanol (8 mL) and tetrahydrofuran (2 mL), and palladium hydroxide (carbon-supported, 20% Pd, 25 mg, 0.18 mmol) was added to exchange the air in the system with hydrogen, Treat the device anaerobically. The system was reacted at room temperature overnight, ethyl acetate (10 mL) was added to dilute the reaction solution, the solids in the system were removed by suction filtration, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate Ester=20:1-15:1) was purified to obtain compound 1-2 (colorless oil, 324mg).

Weigh paraformaldehyde (218mg, 7.2mmol) and anhydrous magnesium chloride (460mg, 4.8mmol) into a 50mL two-necked bottle, insert a condenser, exchange the air in the system with argon, and treat the device anaerobically. Then anhydrous THF (20 mL), triethylamine (0.67 mL, 4.8 mmol), compound 1-2 (324 mg, 2.4 mmol) in dry THF (5 mL) were added sequentially via syringe. The system was reacted under reflux for 4h. After the reaction, the system was adjusted to pH=1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (20mL x 3), the organic phase was combined, the organic phase was washed with saturated brine (20mL x 1), and dried over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=100:1) to obtain compound 1-3 (white solid, 232 mg).

Compound 1-3 (512mg, 3.2mmol) was weighed and dissolved in acetone (25mL), then potassium carbonate (654mg, 4.7mmol) and 1-chloroacetone (330μL, 4.1mmol) were added sequentially. The system was reacted under reflux for 5h. After the reaction was completed, ethyl acetate (10 mL) was added to dilute the reaction solution, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate=50: 1-30:1) purification to obtain compound 1-4 (white solid, 430mg).

Weigh copper bromide (620mg, 2.8mmol) and place it in a 250mL three-necked flask, add ethyl acetate (80mL), dissolve compound 1-4 (429mg, 2.14mmol) in ethyl acetate (20mL), and drop With the funnel under reflux conditions, the ethyl acetate solution of compound 1-4 was added dropwise into the reaction system, and the reflux was continued for 6 hours after the addition was completed. After the reaction, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=4:1) to obtain compound 1-5 (white solid, 310 mg).

Weigh compound 1-5 (124mg, 0.44mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (96mg, 0.53mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 100 mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue containing compound 1-6 was directly used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the previous step containing compound 1-6 was dissolved in a mixed solvent of dichloromethane (15 mL) and methanol (5 mL), and then a methanol solution of sodium methoxide (4M, 260 μL) was added to react at room temperature 1h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (10mL), the aqueous phase was extracted with ethyl acetate (10mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (20mL x 1), anhydrous sulfuric acid Dry over sodium, evaporate the solvent under reduced pressure, and purify the residue by column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to obtain compound 1 (gray solid, 20mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.44(s,1H),7.40(d,J=7.9Hz,1H),7.14(d,J=7.9Hz,1H),7.05(s,1H),4.21(s,3H),3.10 (t, J=7.3Hz, 2H), 2.99(t, J=7.3Hz, 2H), 2.22-2.08(m, 2H).ESI-MS: m/z 334.1[M+Na] ⁺ .

Example 2

6-(7,8-Dihydro-6H-indeno[4,5-b]furan-2-yl)-2-(methylthio)imidazo[2,1-b][1,3,4 ] Thiadiazole (compound 2)

Weighed compound 1-5 (91mg, 0.33mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (58mg, 0.39mmol) into a 15mL pressure-resistant reaction tube, and then added Water N,N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80° C. for 3 h, the reaction was continued at 110° C. for 3 h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: petroleum ether/ethyl acetate = 10:1) to obtain compound 2 (brown solid, 33 mg): ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.56 (s, 1H), 7.41(d, J=8.0Hz, 1H), 7.15(d, J=8.1Hz, 1H), 7.10(s, 1H), 3.10(t, J=7.3Hz, 2H), 2.99(t, J=7.3 Hz,2H),2.80(s,3H),2.22-2.07(m,2H).ESI-MS:m/z 350.1[M+Na] ⁺ .

Example 3

2-Methoxy-6-(6,7,8,9-tetrahydronaphtho[1,2-b]furan-2-yl)imidazo[2,1-b][1,3,4] Thiadiazole (Compound 3)

Weigh paraformaldehyde (460mg, 15.3mmol) and anhydrous magnesium chloride (324mg, 3.4mmol) into a 50mL two-necked bottle, insert a condenser, exchange the air in the system with argon, and treat the device anaerobically. Then anhydrous tetrahydrofuran (20 mL), triethylamine (1.2 mL, 8.5 mmol), and a solution of compound 3-1 (300 mg, 2.27 mmol) in anhydrous tetrahydrofuran (5 mL) were added sequentially via syringe. The system was reacted under reflux for 4h. After the reaction, the system was adjusted to pH=1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (20mL x 3), the organic phase was combined, the organic phase was washed with saturated brine (20mL x 1), and dried over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=400:1) to obtain compound 3-2 (white solid, 300 mg).

Compound 3-2 (300mg, 1.87mmol) was weighed and dissolved in acetone (20mL), then potassium carbonate (388mg, 2.81mmol) and 1-chloroacetone (180μL, 2.25mmol) were added sequentially. The system was reacted under reflux for 5h. After the reaction, ethyl acetate (10 mL) was added to dilute the reaction solution, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate=400: 1-80:1) purification to obtain compound 3-3 (yellow-white solid, 260 mg).

Weigh copper bromide (353mg, 1.58mmol) and place it in a 100mL three-necked flask, add ethyl acetate (40mL), dissolve compound 3-3 (260mg, 1.2mmol) in ethyl acetate (15mL), and drop With the funnel under reflux conditions, the ethyl acetate solution of compound 3-3 was added dropwise into the reaction system, and the reflux was continued for 6 hours after the addition was complete. After the reaction, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=4:1) to obtain compound 3-4 (white solid, 203 mg).

Weigh compound 3-4 (115mg, 0.39mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (85mg, 0.47mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 5h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 100 mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue containing compound 3-5 was directly used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the previous step containing compound 3-5 was dissolved in a mixed solvent of dichloromethane (15 mL) and methanol (5 mL), and then a methanol solution of sodium methoxide (4M, 230 μL) was added to react at room temperature 1h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (10mL), the aqueous phase was extracted with ethyl acetate (10mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (20mL x 1), anhydrous sulfuric acid The sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate 20:1-10:1) to obtain compound 3 (brown solid, 36 mg): ¹ H NMR ( 300MHz, CDCl ₃ )δ8.44(s,1H),7.37(d,J=7.9Hz,1H),7.03(s,1H),6.99(d,J=7.9Hz,1H),4.25(s,3H ),2.98(m,2H),2.86(m,2H).1.86(m,4H).ESI-MS: m/z 348.1[M+Na] ⁺ .

Example 4

2-Methylthio-6-(6,7,8,9-tetrahydronaphtho[1,2-b]furan-2-yl)imidazo[2,1-b][1,3,4] Thiadiazole (Compound 4)

Weigh compound 3-4 (81mg, 0.28mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (49mg, 0.33mmol) into a 15mL pressure-resistant reaction tube, and then add Water N,N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80° C. for 3 h, the reaction was continued at 110° C. for 3 h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: petroleum ether/ethyl acetate=20:1-10:1) to obtain compound 4 (brown solid, 25 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.03(s, 1H ), 7.31(d, J=7.9Hz, 1H), 7.00(s, 1H), 6.96(d, J=7.9Hz, 1H), 3.04(t, J=6.1Hz, 2H), 2.88((t, J=6.1Hz, 2H), 2.77(s, 3H), 1.89(m, 4H). ESI-MS: m/z 364.1[M+Na] ⁺ .

Example 5

6-(7,8-Dihydrobenzo[1,2-b:3,4-b']difuran-2-yl)-2-methoxyimidazo[2,1-b][1, 3,4] Thiadiazole (compound 5)

Under the protection of argon, compound 5-1 (5 g, 24.4 mmol) was weighed and dissolved in anhydrous tetrahydrofuran (50 mL), cooled to 0 ° C, and 1 M borane solution in tetrahydrofuran (36.6 mL, 36.6 mmol) was slowly added dropwise, After the dropwise addition was completed, it was raised to room temperature and stirred overnight. After the reaction was completed, water was slowly added dropwise to quench the reaction, transferred to a separatory funnel, extracted with ethyl acetate (50mL x 3), the combined organic phases were washed with saturated sodium bicarbonate solution (15mL×3) and saturated brine (15mL×3) washed the organic phase, dried over anhydrous sodium sulfate, evaporated the solvent under reduced pressure, and obtained compound 5-2 (white solid, 3.40g) without further purification.

Under the protection of argon, weigh compound 5-2 (0.5g, 2.62mmol) and dissolve it in anhydrous toluene (8mL), add sodium hydride (0.131g, 3.28mmol), heat up to 40°C and stir for 15min, then react The solution was cooled to room temperature, and cuprous chloride (13mg, 0.131mmol) was added, then toluene (2mL) and ethyl acetate (0.013mL) were added, and the temperature was raised to 120°C and refluxed for 24h. After the reaction was completed, the reaction solution was cooled to room temperature, Slowly add ice water to quench sodium hydride, filter to remove insoluble matter, dilute the filtrate with water, transfer to a separatory funnel, extract with methyl tert-butyl ether (10mL x 3), combine the organic phases, wash with saturated brine (5mL x 3) The organic phase was washed, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=50:1) to obtain compound 5-3 (light yellow liquid, 0.25 g).

Under argon protection, weigh bis(dibenzylideneacetone)palladium (0.603g, 1.05mmol) and triphenylphosphine (0.706g, 2.52mmol) into a 300mL pressure-resistant tube, add dimethyl sulfoxide ( 50mL), stirred at room temperature for 1 hour, then added compound 5-3 (2.7g, 17.5mmol), potassium acetate (2.57g, 26.2mmol) and biboronic acid pinacol ester (8.87g, 34.9mmol), and added two Methyl sulfoxide (50 mL), heated to 150 ° C for 10 h, after the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth to remove insoluble matter, the filtrate was diluted with water (150 mL), extracted with ethyl acetate (70 mL x 3) , combined the organic phases, washed the organic phase with saturated brine (30mL x 3), dried over anhydrous sodium sulfate, evaporated the solvent under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate=100: 1) Purification to obtain compound 5-4 (light yellow liquid, 2.7g).

Weigh compound 5-4 (2.7g, 11mmol) and dissolve it in dioxane (30mL), add 50% aqueous solution of N-methylmorpholine-N-oxide (2.5mL, 12.1mmol), and heat up to Heat at 80°C for 1 h. After the reaction is complete, cool the reaction solution to room temperature, dilute with water (30 mL), add 1N hydrochloric acid solution to acidify the system to pH = 1, transfer to a separatory funnel, and extract with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (10mL x 3), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate=4:1 ) to obtain compound 5-5 (white solid, 1.0 g).

Under the protection of argon, weigh compound 5-5 (0.1g, 0.73mmol) and dissolve it in anhydrous dichloromethane (10mL), add 1,1-dichloromethyl ether (0.13mL, 1.47mmol), cool to -20°C, slowly add titanium tetrachloride (0.24mL, 2.19mmol) dropwise. After the dropwise addition, keep the temperature constant and continue to stir for 1h. After the reaction is complete, add 1N hydrochloric acid (20mL) to dilute and transfer to a separatory funnel , extracted with dichloromethane (10mL x 3), combined the organic phases, washed the organic phase with saturated brine (10mL x 3), dried over anhydrous sodium sulfate, evaporated the solvent under reduced pressure, and the residue was subjected to column chromatography (elution Reagent: petroleum ether/ethyl acetate=20:1) to obtain compound 5-6 (white solid, 0.1 g).

Weigh compound 5-6 (0.67g, 4.08mmol) and dissolve it in acetone (20mL), add potassium carbonate (0.73g, 5.3mmol), slowly add 1-chloroacetone (0.39mL, 4.9mmol), dropwise After that, the temperature was raised to reflux for 7 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=1:1) , to obtain compound 5-7 (colorless transparent oil, 596 mg).

Weigh copper bromide (0.79g, 3.54mmol) and place it in a 250mL three-necked flask, add ethyl acetate (50mL), dissolve compound 5-7 (0.596g, 2.95mmol) in ethyl acetate (30mL), pass Add the ethyl acetate solution of compound 5-7 into the reaction system drop by drop under the reflux condition of the dropping funnel, and continue to reflux for 8 hours after the addition is completed. After the reaction, the solids in the system were removed by suction filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=1:2) to obtain compound 5-8 (yellow solid, 0.451 g).

Weigh compound 5-8 (200mg, 0.71mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (154mg, 0.853mmol) into a 35mL pressure-resistant reaction tube, then add isopropanol (10 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 100 mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue containing compound 5-9 was directly used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the previous step containing compound 5-9 was dissolved in a mixed solvent of dichloromethane (120 mL) and methanol (30 mL), and then a methanol solution of sodium methoxide (4M, 350 μL) was added to react at room temperature 1h. After the reaction was finished, quench the reaction with saturated ammonium chloride solution (60mL), extract the aqueous phase (20mL x 3) with dichloromethane, combine the organic phases, wash the organic phase with saturated brine (10mL x 1), and wash with anhydrous sulfuric acid Dry over sodium, evaporate the solvent under reduced pressure, and purify the residue by column chromatography (eluent: petroleum ether/ethyl acetate=6:1) to obtain compound 5 (white solid, 30mg): ¹ H NMR (300MHz, CDCl ₃ )δ7.87(s,1H),7.30(d,J=8.3Hz,1H),6.95(s,1H),6.77(d,J=8.2Hz,1H),4.68(t,J=8.7Hz, 3H), 4.20(s, 4H), 3.46(t, J=8.6Hz, 3H). ESI-MS: m/z 314.1[M+H] ⁺ .

Example 6

6-(7,8-Dihydrobenzo[1,2-b:3,4-b']difuran-2-yl)-2-(methylthio)imidazo[2,1-b][ 1,3,4] Thiadiazole (Compound 6)

Weigh compound 5-8 (100mg, 0.356mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (63mg, 0.427mmol) into a 15mL pressure-resistant reaction tube, and then add Water N,N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 110°C for 2h. After the reaction, the reaction system was transferred into a 25mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=4:1) to obtain compound 6 (yellow solid, 56 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ7.99(s, 1H), 7.31(d, J=8.3Hz, 1H), 6.99(s, 1H), 6.77(d, J= 8.3Hz, 1H), 4.69(t, J=8.7Hz, 2H), 3.46(t, J=8.7Hz, 2H), 2.76(s, 3H).ESI-MS: m/z 330.1[M+H] ⁺ .

Example 7

6-(8,9-Dihydro-7H-furo[2,3-f]chromen-2-yl)-2-methoxyimidazo[2,1-b][1,3,4] Thiadiazole (Compound 7)

Compound 7-1 (20g, 115.6mmol) and allyl bromide (18g, 150.3mmol) were weighed and dissolved in acetonitrile (100mL), then potassium carbonate (48g, 347mmol) was added, and the system was reacted under reflux for 3h. After the reaction, filter with suction to remove the solids, evaporate acetonitrile under reduced pressure, and purify the residue by column chromatography (eluent: petroleum ether/ethyl acetate=500:1) to obtain compound 7-2 (without Color oil, 15g).

Compound 7-2 (3.53 g, 16.57 mmol) was weighed and dissolved in N,N-diethylaniline (10 mL), and reacted at 200° C. for 3 h. After the reaction was completed, ethyl acetate (30 mL) was added to dilute the reaction system, the organic phase was washed with 1N hydrochloric acid (10 mL x 3) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the residue Purified by column chromatography (eluent: petroleum ether/ethyl acetate=50:1) to obtain compound 7-3 (colorless oil, 1.4 g).

Under argon atmosphere, compound 7-3 (1335mg, 6.27mmol) was dissolved in anhydrous tetrahydrofuran (20mL), and 9-borabicyclo[3.3.1]nonane (0.5M in THF, 12.54mL), the system continued to react at -78°C for 10h, then slowly added saturated sodium bicarbonate solution (10mL) to the above system under ice-bath conditions, and continued to react for 10min under ice-bath conditions. Under this condition, 30% hydrogen peroxide solution was added to the above system, raised to room temperature, and continued to react for 2 h. After the reaction was complete, the aqueous phase was extracted with ethyl acetate (30mL x 3), the organic phases were combined, the organic phase was washed with saturated brine (10mL x 1), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purification by chromatography (eluent: petroleum ether/ethyl acetate=3:1) gave compound 7-4 (white solid, 911 mg).

Under argon atmosphere, compound 7-4 (100 mg, 0.433 mmol) and tributylphosphine (216 μL, 0.866 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and azodicarbonyl di A solution of piperidine (218 mg, 0.866 mmol) in anhydrous THF (4 mL) was added dropwise to the above system, warmed to room temperature, and the reaction was continued overnight. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=1:0-300:1-100:1) to obtain compound 7-5 (yellow oil substance, 47mg).

Weigh compound 7-5 (220mg, 1.03mmol), pinacol diborate (526mg, 2.07mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane The complex (84mg, 0.103mmol) and potassium acetate (304mg, 3.1mmol) were placed in a 15mL pressure-resistant reaction tube, anhydrous dioxane (5mL) was added, and argon gas was bubbled and purged for 5min. Under the condition of ℃, react for 1.5h. After the reaction, ethyl acetate (20 mL) was added to dilute the reaction system, suction filtered, the insolubles were filtered off, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate=300:1 ) to obtain compound 7-6 (yellow oil, 228mg).

Weigh compound 7-6 (220mg, 0.85mmol) and dissolve it in dioxane (8mL), add 50% aqueous solution of N-methyl-N-morpholine oxide (200μL), and react the system at 80°C for 1h , and added 50% N-methyl-N-morpholine oxide aqueous solution (50 μL) again, and continued to react at 80° C. for 2 h. After the reaction was completed, add 1N hydrochloric acid solution to acidify the system to pH = 1, extract the aqueous phase with ethyl acetate (20mL x 3), combine the organic phases, wash the organic phase with saturated salt (10mL x 1) water, and dry over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=30:1-15:1) to obtain compound 7-7 (white cream solid, 80 mg).

Compound 7-7 (200 mg, 1.33 mmol) was weighed and dissolved in a mixed solvent of acetic acid (5 mL) and trifluoroacetic acid (5 mL), and urotropine (187 mg, 1.33 mmol) was added, and the system was reacted under reflux for 4 h. After the reaction, add 6N hydrochloric acid solution (30mL), continue to stir at room temperature for 30min, then add saturated sodium bicarbonate solution to adjust the pH of the solution to about 7, extract the aqueous phase with dichloromethane (20mL x 3), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=10:1-8:1) to obtain compound 7-8 (white solid, 90 mg).

Compound 7-8 (50 mg, 0.28 mmol) was weighed and dissolved in acetone (10 mL), and then potassium carbonate (77 mg, 0.56 mmol) and 1-chloroacetone (25 μL, 0.31 mmol) were added sequentially. The system was reacted under reflux for 6h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate=8: 1-7:1) was purified to obtain compound 7-9 (white solid, 40 mg).

Weigh copper bromide (335mg, 1.5mmol) and place it in a 100mL three-necked flask, add ethyl acetate (20mL), dissolve compound 7-9 (216mg, 1mmol) in ethyl acetate (20mL), and pass through the dropping funnel Under the condition of reflux, the ethyl acetate solution of compound 7-9 was added dropwise into the reaction system, after the addition was completed, the reflux was continued for 8h. After the reaction, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=1:1) to obtain compound 7-10 (yellow solid, 213 mg).

Weigh compound 7-10 (80mg, 0.271mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (59mg, 0.325mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 100 mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue containing compound 7-11 was directly used in the next step without further reaction.

The crude compound 7-11 obtained in the previous reaction was dissolved in a mixed solvent of dichloromethane (6 mL) and methanol (2 mL), and then a methanol solution of sodium methoxide (4M, 100 μL) was added to react at room temperature for 1 h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (10mL), the aqueous phase was extracted with ethyl acetate (10mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (20mL x 1), anhydrous sulfuric acid Dry over sodium, evaporate the solvent under reduced pressure, and purify the residue by column chromatography (eluent: dichloromethane/ethyl acetate=100:1-70:1) to obtain compound 7 (brown solid, 15mg): ¹ H NMR (300MHz, CDCl ₃ )δ7.87(s,1H),7.28(d,J=8.4Hz,1H),6.92(s,1H),6.74(d,J=8.4Hz,1H),4.24(t, J=5.0Hz, 2H), 4.20(s, 3H), 3.04(t, J=6.2Hz, 2H), 2.13-2.04(m, 2H).ESI-MS: m/z 350.1[M+Na] ⁺ .

Example 8

6-(8,9-Dihydro-7H-furo[2,3-f]chromen-2-yl)-2-(methylthio)imidazo[2,1-b][1,3, 4] Thiadiazole (Compound 8)

Weigh compound 7-10 (80mg, 0.27mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (48mg, 0.325mmol) into a 15mL pressure-resistant reaction tube, and then add N , N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 110°C for 2h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: petroleum ether/ethyl acetate=9:1-7:1) to obtain compound 8 (brown solid, 31 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.01(s, 1H ), 7.31(d, J=8.4Hz, 1H), 6.99(s, 1H), 6.77(d, J=8.4Hz, 1H), 4.27(t, J=4.9Hz, 2H), 3.06(t, J =6.5Hz, 2H), 2.79(s, 3H), 2.14-2.10(m, 2H).ESI-MS: m/z 366.1[M+Na] ⁺ .

Example 9

6-([1,3]dioxole[4,5-g]benzofuran-7-yl)-2-methoxyimidazo[2,1-b][1,3, 4] Thiadiazole (Compound 9)

Weigh compound 9-1 (2.76g, 20mmol) and diiodomethane (8.04g, 30mmol) and dissolve in N,N-dimethylformamide (100mL), then add copper oxide (79.5mg, 1mmol) and Potassium carbonate (8.28 g, 60 mmol). The system was reacted at 130°C for 4.5h, ethyl acetate (200mL) was added to dilute the reaction solution, the organic phase was washed with water (100mL x 3) and saturated brine (100mL x 2), dried over anhydrous sodium sulfate, and evaporated under reduced pressure The solvent and the residue were purified by column chromatography (eluent: petroleum ether/ethyl acetate=7:1-5:1) to obtain compound 9-2 (yellow oil, 2.6 g).

Weigh compound 9-2 (2.6g, 17.3mmol) and dissolve it in dichloromethane (100mL), add m-chloroperoxybenzoic acid (3.6g, 20.8mmol) in batches under ice-bath conditions, then remove the ice-bath, and the system After returning to room temperature, move to an oil bath, react under reflux for 12h, add ethyl acetate (200mL) to dilute the reaction solution, wash the organic phase with water (100mL x 3) and saturated brine (100mL x 1), and dry over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=1:1) to obtain compound 9-3 (brown solid, 2.9 g).

Compound 9-3 (2.8 g, 16.9 mmol) was weighed and dissolved in methanol (10 mL), and 10% potassium hydroxide solution (80 mL) was slowly added in an ice bath, and reacted at room temperature for 6 h. After the reaction, the system was adjusted to pH=1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (30mL x 3), the organic phase was combined, and the organic phase was washed with water (20mL x 3) and saturated brine (20mL x1) , dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=10:1:1-6:1:1) to obtain Compound 9-4 (colorless oil, 2.03 g).

Weigh paraformaldehyde (1.33g, 44mmol) and anhydrous magnesium chloride (2.79g, 29mmol) into a 100mL two-necked bottle, insert a condenser, exchange the air in the system with argon, and treat the device anaerobically. Then anhydrous tetrahydrofuran (30 mL), triethylamine (4.09 mL, 29 mmol), and a solution of compound 9-4 (2.03 g, 14.7 mmol) in anhydrous tetrahydrofuran (5 mL) were added sequentially via syringe. The system was reacted under reflux for 4h. After the reaction, the system was adjusted to pH=1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (20mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (20mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue containing compound 9-5 was directly used in the next reaction without further purification.

The residue obtained from the previous post-reaction treatment containing compound 9-5 was dissolved in acetone (20 mL), and then potassium carbonate (2.07 g, 15 mmol) and 1-chloroacetone (1.2 mL, 15 mmol) were added in sequence. The system was reacted under reflux for 6h. After the reaction was finished, ethyl acetate (50 mL) was added to dilute the reaction solution, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate/dichloro Methane=10:1:1-6:1:1) to obtain compound 9-6 (yellow solid, 600mg).

Weigh copper bromide (984mg, 4.41mmol) and place it in a 250mL three-necked flask, add ethyl acetate (80mL), dissolve compound 9-6 (600mg, 2.94mmol) in ethyl acetate (100mL), and drop With the funnel under reflux conditions, the ethyl acetate solution of compound 9-6 was added dropwise into the reaction system. After the addition was complete, the reflux was continued for 8 hours. After the reaction, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=1:1) to obtain compound 9-7 (brown solid, 575 mg).

Weigh compound 9-7 (180mg, 0.636mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (137mg, 0.763mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 100 mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue containing compound 9-8 was directly used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the previous step containing compound 9-8 was dissolved in a mixed solvent of dichloromethane (12 mL) and methanol (4 mL), and then a methanol solution of sodium methoxide (4M, 239 μL) was added to react at room temperature 1h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (10mL), the aqueous phase was extracted with ethyl acetate (10mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (20mL x 1), anhydrous sulfuric acid Dry over sodium, evaporate the solvent under reduced pressure, and purify the residue by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=10:1:1-6:1:1) to obtain a crude product, which is purified by Preparative plate chromatography (chromatographic solution: petroleum ether/ethyl acetate/dichloromethane=10:1:1/6:1:1) gave compound 9 (yellow solid, 20mg): ¹ HNMR (300MHz, CDCl ₃ ) δ7.92(s,1H),7.03(d,J=8.1Hz,1H),6.99(s,1H),6.84(d,J=8.2Hz,1H),6.07(s,2H),4.21(s ,3H).ESI-MS: m/z 338.0[M+Na] ⁺ .

Example 10

6-([1,3]dioxole[4,5-g]benzofuran-7-yl)2-(methylthio)imidazo[2,1-b][1,3 ,4] Thiadiazole (compound 10)

Weigh compound 9-7 (150mg, 0.53mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (86mg, 0.583mmol) into a 15mL pressure-resistant reaction tube, and then add Water N,N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 110°C for 2h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=7:3:0.2) to obtain compound 10 (yellow solid, 72mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.04(s ,1H),7.06-7.03(m,2H),6.85(d,J＝8.2Hz,1H),6.08(s,2H),2.77(s,3H).ESI-MS:m/z354.0[M +Na] ⁺ .

Example 11

6-(2,3-Dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-2-methoxyimidazo[2,1 -b][1,3,4]thiadiazole (compound 11)

Weigh compound 11-1 (15g, 98.68mmol), sodium acetate (16.2g, 197.56mmol) and iron powder (450mg, 8.03mmol) in a 250mL round bottom flask, add acetic acid (150mL), and then pass through the dropping funnel A solution of bromine (5.5 mL, 107 mmol) in acetic acid (18 mL) was added dropwise at room temperature. After the addition was complete, the reaction was carried out at room temperature for 16 h. After the reaction was completed, most of the acetic acid solution was distilled off under reduced pressure, ethyl acetate (200mL) was added to form a suspension, filtered with suction, the solids were removed by filtration, the filtrate was collected, and the filtrate was mixed with water (50mL x 3) and saturated saline (50mL x 1) Wash, dry over anhydrous sodium sulfate, evaporate the solvent again under reduced pressure, and purify the residue by column chromatography (eluent: dichloromethane/methanol=200:1-100:1) to obtain compound 11-2 ( Gray solid, 9.12 g).

Compound 11-2 (2.13g, 10mmol) was weighed and dissolved in dichloromethane (15mL), and boron tribromide (1M in DCM, 30mL) was added dropwise under ice-bath conditions. After the addition was complete, the reaction was carried out overnight at room temperature. After the reaction was completed, water (50 mL) was slowly added in an ice bath to quench the reaction, the aqueous phase was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (20 mL x 1). After drying over sodium sulfate, the solvent was evaporated under reduced pressure, and the residue containing compound 11-3 (2.15 g) was directly used in the next reaction without further purification.

Weigh the reaction residue from the previous step containing compound 11-3 and dissolve it in N,N-dimethylformamide (20 mL), add 1,2-dibromoethane (872 μL, 10.11 mmol) and cesium carbonate (6.52 g , 20mmol), the system was reacted at 130°C for 8h, ethyl acetate (50mL) was added to dilute the reaction solution, the organic phase was washed with water (20mL x 3) and saturated brine (20mL x 2), dried over anhydrous sodium sulfate, and reduced pressure The solvent was evaporated, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=14:1) to obtain compound 11-4 (white solid, 1.56 g).

Weigh compound 11-4 (243mg, 1mmol), diborate boronate (508mg, 2mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (81.7mg, 0.1mmol) and potassium acetate (300mg, 3mmol) were placed in a 15mL pressure-resistant reaction tube, anhydrous 1,4-dioxane (10mL) was added, and argon bubbles were purged for 5min, and the system was React at 100°C for 8 h, add ethyl acetate (30 mL) to dilute the reaction solution, filter with suction, filter off the solid, evaporate the solvent under reduced pressure, and the residue is subjected to column chromatography (eluent: petroleum ether/ethyl acetate = 13 :1-10:1) purification to obtain compound 11-5 (white solid, 163 mg).

Weigh compound 11-5 (1125mg, 3.87mmol) and dissolve it in dioxane (20mL), add 50% N-methyl-N-morpholine oxide aqueous solution (885μL), and react the system at 80°C for 1h , and added 50% N-methyl-N-morpholine oxide aqueous solution (89 μL) again, and continued to react at 80° C. for 2 h. After the reaction was completed, add 1N hydrochloric acid solution to acidify the system to pH = 1, extract the aqueous phase with ethyl acetate (20mL x 3), combine the organic phases, wash the organic phase with saturated salt (10mL x 1) water, and dry over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=16:1) to obtain compound 11-6 (light yellow solid, 524 mg).

Compound 11-6 (260 mg, 1.44 mmol) was weighed and dissolved in acetone (10 mL), and then potassium carbonate (260 mg, 1.88 mmol) and 1-chloroacetone (145 μL, 1.81 mmol) were added sequentially. The system was reacted under reflux for 6h. After the reaction, ethyl acetate (30 mL) was added to dilute the reaction solution, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate=16: 1) Purification to obtain compound 11-7 (yellow solid, 126 mg).

Weigh copper bromide (295mg, 1.32mmol) and place it in a 100mL three-necked flask, add ethyl acetate (20mL), dissolve compound 11-7 (262mg, 1.20mmol) in ethyl acetate (20mL), and drop With the funnel under reflux conditions, the ethyl acetate solution of compound 11-7 was added dropwise into the reaction system, and the reflux was continued for 8 hours after the addition was completed. After the reaction, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=1:1) to obtain compound 11-8 (yellow solid, 162 mg).

Weigh compound 11-8 (240mg, 0.808mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (174mg, 0.969mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 100mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=4.5:4.5:1 ) was purified to obtain compound 11-9 (yellow solid, 185 mg).

Compound 11-9 (185mg, 0.49mmol) was weighed and dissolved in a mixed solvent of dichloromethane (6mL) and methanol (2mL), then sodium methoxide in methanol (4M, 181μL) was added and reacted for 1h at room temperature. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (10mL), the aqueous phase was extracted with ethyl acetate (10mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (20mL x 1), anhydrous sulfuric acid Dry over sodium, evaporate the solvent under reduced pressure, and purify the residue by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=9:1-6:1) to obtain compound 11 (yellow solid, 120mg): ¹ H NMR (300MHz, CDCl ₃ ) δ7.95(s, 1H), 7.02(d, J=8.4Hz, 1H), 6.96(s, 1H), 6.81(d, J=8.4Hz, 1H), 4.45 -4.42(m,2H),4.37-4.34(m,2H),4.20(s,3H).ESI-MS: m/z 352.1[M+Na] ⁺ .

Example 12

6-(2,3-Dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-2-(methylthio)imidazo[2 ,1-b][1,3,4]thiadiazole (compound 12)

Weigh compound 11-8 (100mg, 0.34mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (60mg, 0.4mmol) into a 15mL pressure-resistant reaction tube, and then add Water N,N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 110°C for 2h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=15:1:1-10:1:1) to obtain compound 12 (yellow solid, 64mg): ¹ H NMR (300MHz, CDCl ₃ )δ8.07(s,1H),7.02(d,J=8.4Hz,1H),7.01(s,1H),6.81(d,J=8.4Hz,1H),4.47-4.31(m,4H), 2.77(s,3H).ESI-MS: m/z 368.0[M+Na] ⁺ .

Example 13

6-(3,4-Dihydro-2H-[1,4]oxepino[2,3-g]benzofuran-9-yl)-2-methoxyimidazo[2,1-b ][1,3,4]thiadiazole (compound 13)

Weigh compound 9-1 (1.95g, 14.1mmol) and dissolve it in anhydrous N,N-dimethylformamide (50mL), add potassium carbonate (4.09g, 29.6mmol) and 1,3-diiodopropane ( 5g, 16.9mmol), under argon atmosphere, heated to 110°C for 4h. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (60mL), and an appropriate amount of 1N hydrochloric acid was added to make the aqueous phase weakly acidic, extracted with ethyl acetate (40mL x 3), the combined organic phases were washed with saturated brine (10mL x 3) The organic phase was washed, dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=20:1) to obtain compound 13-1 (yellow oil , 1.3g).

Compound 13-1 (1.30g, 7.30mmol) was weighed and dissolved in dichloromethane (30mL), m-chloroperoxybenzoic acid (1.51g, 8.75mmol) was added, and the system was heated under reflux for 12h. TLC detected that the reaction process did not increase. The solids in the reaction solution were removed by filtration, the filtrate was diluted with dichloromethane (20 mL), and the organic phase was washed with saturated sodium bicarbonate solution (10 mL x 3) and saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure The filtrate and the residue were purified by column chromatography (eluent: petroleum ether/ethyl acetate=8:1) to obtain compound 13-2 (white solid, 1.08 g).

Weigh compound 13-2 (1.08g, 5.56mmol) and dissolve it in methanol (20mL), add 10% potassium hydroxide aqueous solution (20mL), and stir at room temperature for 1h. After the reaction was complete, add 1N hydrochloric acid solution to make the aqueous phase acidic, extract with dichloromethane (20mL x 3), combine the organic phases, wash the organic phase with saturated saline solution (10mL x 1), dry over anhydrous sodium sulfate, and reduce pressure The filtrate was concentrated, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to obtain compound 13-3 (white solid, 0.84 g).

Under the protection of argon, anhydrous magnesium chloride (0.96g, 10.1mmol) and paraformaldehyde (0.455g, 15.2mmol) were dissolved in anhydrous tetrahydrofuran (20mL), triethylamine (1.4mL, 10.1mmol) was added, After stirring at room temperature for 15 min, the temperature was raised to reflux, and anhydrous tetrahydrofuran solution (10 mL) of compound 13-3 (0.84 g, 5.05 mmol) was slowly added dropwise to the reaction system. After the addition was completed, heating was continued under reflux for 5 h, and the reaction progress was detected by TLC. No increase, the reaction solution was cooled to room temperature, the aqueous phase was adjusted to pH=1 by adding 1N hydrochloric acid, the reaction was quenched by adding (30 mL) water, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, and washed with saturated saline solution ( 10mL x 1) the organic phase was washed, dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=1:2) to obtain compound 13-4 (shallow Yellow oil, 0.15 g).

Weigh compound 13-4 (0.15g, 0.77mmol) and dissolve it in acetone (10mL), add potassium carbonate (0.138g, 1mmol), slowly add chloroacetone (74μL, 0.92mmol) dropwise, after the dropwise addition is completed, heat up to reflux 7h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered to remove insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=1:2) to obtain compound 13-5 (colorless oil, 60 mg).

Weigh copper bromide (70mg, 0.312mmol) and place it in a 25mL three-necked flask, add ethyl acetate (10mL), dissolve compound 13-5 (60mg, 0.26mmol) in ethyl acetate (5mL), and drop With the funnel under reflux conditions, the ethyl acetate solution of compound 13-5 was added dropwise into the reaction system, and the reflux was continued for 4 hours after the addition was complete. After the reaction, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=1:1) to obtain compound 13-6 (shallow yellow solid, 60 mg).

Weigh compound 13-6 (210mg, 0.67mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (144mg, 0.804mmol) into a 35mL pressure-resistant reaction tube, then add isopropanol (10 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 100 mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue (containing compound 13-7) was directly used in the next reaction without further purification.

Dissolve the residue containing compound 13-7 obtained in the previous reaction post-treatment in a mixed solvent of dichloromethane (39 mL) and methanol (13 mL), then add a methanol solution of sodium methoxide (4M, 550 μL), and react at room temperature 1h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (60mL), extracted with dichloromethane (20mL x 3), the organic phases were combined, washed with saturated brine (10mL x 1), dried over anhydrous sodium sulfate, The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to obtain compound 13 (white solid, 20mg): ¹ H NMR (300MHz, CDCl ₃ )δ7 .97(s,1H),7.07(d,J=8.3Hz,1H),6.96(s,1H),6.90(d,J=8.1Hz,1H),4.41(t,J=5.2Hz,2H) ,4.27(t,J=5.2Hz,2H),4.21(s,3H),2.28(m,2H).ESI-MS:m/z 344.1[M+H] ⁺ .

Example 14

6-(3,4-Dihydro-2H-[1,4]oxepino[2,3-g]benzofuran-9-yl)-2-(methylthio)imidazo[2,1 -b][1,3,4]thiadiazole (compound 14)

Weigh compound 13-7 (60mg, 0.19mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (33mg, 0.23mmol) into a 15mL pressure-resistant reaction tube, and then add N , N-dimethylformamide (3 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 110°C for 2h. After the reaction, the reaction system was transferred into a 25 mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to obtain compound 14 (yellow solid, 22 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.09(s, 1H), 7.08(d, J=8.4Hz, 1H), 7.00(s, 1H), 6.90(d, J= 8.4Hz, 1H), 4.41(t, J=5.6Hz, 2H), 4.28(t, J=5.6Hz, 2H), 2.77(s, 3H).ESI-MS: m/z 360.1[M+H] ⁺ .

Example 15

2-(Methylthio)-6-(7,8,9,10-tetrahydro-[1,4]dioxocatriene[2,3-g]benzofuran-2-yl)imidazole And[2,1-b][1,3,4]thiadiazole (compound 15)

Weigh compound 11-3 (9.4g, 43.11mmol) and dissolve it in N,N-dimethylformamide (125mL), add 1,4-diiodobutane (6.82mL, 51.73mmol) and potassium carbonate ( 13.68g, 99.15mmol), the system was reacted at 80°C for 8h, ethyl acetate (300mL) was added to dilute the reaction solution, the organic phase was washed with water (100mL x 3) and saturated brine (100mL x 2), and dried over anhydrous sodium sulfate , the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=20:1) to obtain compound 15-1 (yellow solid, 6.7 g).

Weigh compound 15-1 (3.46g, 12.5mmol), pinacol diborate (6.37g, 25.1mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride Chloromethane complex (1.03g, 1.25mmol) and potassium acetate (3.7g, 37.6mmol) were placed in a 350mL pressure-resistant reaction tube, anhydrous 1,4-dioxane (100mL) was added, and argon was bubbled Purge for 5 min, react the system at 100°C for 8 h, add ethyl acetate (150 mL) to dilute the reaction solution, filter with suction, filter off the solid, evaporate the solvent under reduced pressure, and the residue is subjected to column chromatography (eluent: petroleum ether /ethyl acetate=20:1) was purified to obtain compound 15-2 (yellow oily liquid, 2.47g).

Weigh compound 15-2 (2.47g, 7.62mmol) and dissolve it in dioxane (40mL), add 50% aqueous solution of N-methyl-N-morpholine oxide (2.35mL), and react the system at 80°C 4h. After the reaction was completed, add 1N hydrochloric acid solution to acidify the system to pH = 1, extract the aqueous phase with ethyl acetate (30mL x 3), combine the organic phases, wash the organic phase with saturated brine (30mL x 1), and dry over anhydrous sodium sulfate , the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=20:1) to obtain compound 15-3 (yellow oily liquid, 896 mg).

Compound 15-3 (208mg, 0.98mmol) was weighed and dissolved in acetone (10mL), and then potassium carbonate (176mg, 1.27mmol) and 1-chloroacetone (95μL, 1.2mmol) were added sequentially. The system was reacted under reflux for 6h. After the reaction was completed, ethyl acetate (30 mL) was added to dilute the reaction solution, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate=20: 1) Purification to obtain compound 15-4 (yellow solid, 123 mg).

Weigh copper bromide (216mg, 0.97mmol) and place it in a 100mL three-necked flask, add ethyl acetate (15mL), dissolve compound 15-4 (187mg, 0.75mmol) in ethyl acetate (30mL), and drop With the funnel under reflux conditions, the ethyl acetate solution of compound 15-4 was added dropwise into the reaction system. After the addition was complete, the reflux was continued for 8 hours. After the reaction, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=1:1) to obtain compound 15-5 (yellow solid, 74 mg).

Weigh compound 15-5 (74mg, 0.22mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (40mg, 0.27mmol) into a 35mL pressure-resistant reaction tube, and then add Water N,N-dimethylformamide (7 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 90°C for 4h, the reaction was continued at 120°C for 3h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=15:1:1-10:1:1) to obtain compound 15 (yellow solid, 20mg): ¹ H NMR (300MHz, CDCl ₃ )δ8.10(s,1H),7.10(d,J=8.4Hz,1H),7.01(s,1H),6.89(d,J=8.4Hz,1H),4.60(t,J=5.4Hz, 2H), 4.35(t, J=5.4Hz, 2H), 2.77(s, 3H), 2.07-2.00(m, 2H), 1.98-1.90(m, 2H). ESI-MS: m/z396.1[ M+Na] ⁺ .

Example 16

2-Methoxy-6-(7,8,9,10-tetrahydro-[1,4]dioxoctatriene[2,3-g]benzofuran-2-yl)imidazo[ 2,1-b][1,3,4]thiadiazole (compound 16)

Weigh compound 15-5 (101mg, 0.311mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (67mg, 0.373mmol) into a 35mL pressure-resistant reaction tube, then add isopropanol (50 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 100 mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue containing compound 16-1 was directly used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the previous step containing compound 16-1 was dissolved in a mixed solvent of dichloromethane (15 mL) and methanol (5 mL), and then a methanol solution of sodium methoxide (4M, 185 μL) was added to react at room temperature 1h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (10mL), the aqueous phase was extracted with dichloromethane (15mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (10mL x 1), anhydrous sulfuric acid Dry over sodium, evaporate the solvent under reduced pressure, and purify the residue by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=10:1:1) to obtain compound 16 (gray solid, 20 mg): ¹ H NMR(300MHz, CDCl ₃ )δ7.97(s,1H),7.09(d,J=8.3Hz,1H),6.96(s,1H),6.89(d,J=8.3Hz,1H),4.62-4.58 (m,2H),4.36-4.32(m,2H),4.21(s,3H),2.04-1.89(m,4H).ESI-MS:m/z352.1[M+Na] ⁺ .

Example 17

2-(methylthio)-6-(2,3,5,6-tetrahydro-[1,4,7]trioxacyclononatrienyl[2,3-g]benzofuran-11-yl ) imidazo[2,1-b][1,3,4]thiadiazole (compound 17)

Weigh compound 11-3 (10.74g, 49.5mmol) and dissolve it in N,N-dimethylformamide (150mL), add diethylene glycol bis-p-toluenesulfonate (24.62g, 59.4mmol) and potassium carbonate (15.71g, 114mmol), the system was reacted at 80°C for 8h, ethyl acetate (350mL) was added to dilute the reaction solution, the organic phase was washed with water (120mL x 3) and saturated brine (120mL x 2), and dried over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=20:1) to obtain compound 17-1 (white solid, 3.55 g).

Weigh compound 17-1 (1.9g, 6.6mmol), pinacol diborate (3.37g, 13.3mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride Chloromethane complex (542mg, 0.66mmol) and potassium acetate (1.95g, 19.9mmol) were placed in a 120mL pressure-resistant reaction tube, anhydrous 1,4-dioxane (30mL) was added, and argon bubbled Sweep for 5min, react the system at 100°C for 8h, add ethyl acetate (60mL) to dilute the reaction solution, filter with suction, filter off the solid, evaporate the solvent under reduced pressure, and the residue is subjected to column chromatography (eluent: petroleum ether/ Ethyl acetate=10:1) was purified to obtain compound 17-2 (yellow oily liquid, 1.33 g).

Weigh compound 17-2 (1.34g, 4mmol) and dissolve it in dioxane (20mL), add 50% aqueous solution of N-methyl-N-morpholine oxide (1.3mL), and react the system at 80°C for 4h . After the reaction was complete, add 1N hydrochloric acid solution to acidify the system to pH=1, extract the aqueous phase with ethyl acetate (10mL x 3), combine the organic phases, wash the organic phase with saturated brine (15mL x 1), and dry over anhydrous sodium sulfate , the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to obtain compound 17-3 (white solid, 270 mg).

Compound 17-3 (153mg, 0.68mmol) was weighed and dissolved in acetone (6mL), and then potassium carbonate (123mg, 0.89mmol) and 1-chloroacetone (70μL, 0.82mmol) were added sequentially. The system was reacted under reflux for 6h. After the reaction, ethyl acetate (20 mL) was added to dilute the reaction solution, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate=20: 1) Purification to obtain compound 17-4 (yellow solid, 115 mg).

Weigh copper bromide (127mg, 0.57mmol) and place it in a 50mL three-necked flask, add ethyl acetate (10mL), dissolve compound 17-4 (115mg, 0.44mmol) in ethyl acetate (15mL), and drop With the funnel under reflux conditions, the ethyl acetate solution of compound 17-4 was added dropwise into the reaction system. After the addition was complete, the reflux was continued for 8 hours. After the reaction, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=1:1) to obtain compound 17-5 (yellow solid, 45 mg).

Weigh compound 17-5 (41mg, 0.12mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (22mg, 0.15mmol) into a 15mL pressure-resistant reaction tube, and then add Water N,N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 90°C for 4h, the reaction was continued at 120°C for 3h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=15:1:1) to obtain compound 17 (yellow solid, 10 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.07(s ,1H),7.14(d,J=8.4Hz,1H),7.00(s,1H),6.92(d,J=8.4Hz,1H),4.58(dd,J=5.2,3.3Hz,2H),4.38 (dd,J=5.3,3.3Hz,2H),4.01(dd,J=5.1,3.5Hz,2H),3.97(dd,J=5.2,3.4Hz,2H),2.77(s,3H).ESI- MS: m/z 412.1[M+Na] ⁺ .

Example 18

6-(7,7-Dimethyl-7H-furo[2,3-f]chromen-2-yl)-2-methoxyimidazo[2,1-b][1,3,4 ] Thiadiazole (compound 18)

Weigh compound 18-1 (2g, 14.5mmol) and dissolve it in pyridine (2.5mL), add 3-methyl-2-butenal (2.78mL, 28.8mmol), and react the system at 140°C for 10h. After completion, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=300:5-300:10) to obtain compound 18-2 (brown oil, 31 mg).

Compound 18-2 (610 mg, 3 mmol) was weighed and dissolved in acetone (10 mL), and then potassium carbonate (621 mg, 4.5 mmol) and 1-chloroacetone (290 μL, 1.16 mmol) were added sequentially. The system was reacted under reflux for 6h. After the reaction was completed, ethyl acetate (30 mL) was added to dilute the reaction solution, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate=14: 1) Purification to obtain compound 18-3 (yellow oil, 240 mg).

Weigh copper bromide (270mg, 1.2mmol) and place it in a 100mL three-necked flask, add ethyl acetate (20mL), dissolve compound 18-3 (242mg, 1mmol) in ethyl acetate (20mL), and pass through the dropping funnel Under the condition of reflux, the ethyl acetate solution of compound 18-3 was added dropwise into the reaction system, after the addition was completed, the reflux was continued for 8h. After the reaction, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=3:2) to obtain compound 18-4 (yellow oil, 122 mg).

Weigh compound 18-4 (122mg, 0.38mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (82mg, 0.456mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 100mL flask with dichloromethane, and the solvent was evaporated under reduced pressure, and the residue containing compound 18-5 was directly used in the next step without further reaction.

The crude compound 18-5 obtained in the previous reaction was dissolved in a mixed solvent of dichloromethane (6 mL) and methanol (2 mL), and then a methanol solution of sodium methoxide (4M, 185 μL) was added to react at room temperature for 1 h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (10mL), the aqueous phase was extracted with ethyl acetate (10mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (20mL x 1), anhydrous sulfuric acid Dry over sodium, evaporate the solvent under reduced pressure, and purify the residue by preparative thin-layer chromatography (chromatographic solvent: petroleum ether/ethyl acetate=5:1) to obtain compound 18 (brown solid, 12 mg): ¹ H NMR (300MHz, CDCl ₃ )δ7.87(s,1H),7.28(d,J=8.3Hz,1H),6.91(s,1H),6.87(d,J=9.8Hz,1H),6.73(d,J=8.3 Hz, 1H), 5.71(d, J=9.9Hz, 1H), 4.21(s, 3H), 1.48(s, 6H). ESI-MS: m/z 376.1[M+Na] ⁺ .

Example 19

2-(Methylthio)-6-(Naphtho[1,2-b]fur-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (Compound 19)

Compound 19-1 (500mg, 2.9mmol) was weighed and dissolved in acetone (30mL), then potassium carbonate (522mg, 3.78mmol) and 1-chloroacetone (322μL, 3.5mmol) were added sequentially. The system was reacted under reflux for 5h. After the reaction, ethyl acetate (20 mL) was added to dilute the reaction solution, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate=20: 1-15:1) purification to obtain compound 19-2 (yellow-white solid, 565 mg).

Weigh copper bromide (780mg, 3.5mmol) and place it in a 100mL three-necked flask, add ethyl acetate (40mL), dissolve compound 19-2 (565mg, 2.7mmol) in ethyl acetate (20mL), and drop With the funnel under reflux conditions, the ethyl acetate solution of compound 19-2 was added dropwise into the reaction system, and the reflux was continued for 6 hours after the addition was complete. After the reaction, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=5:1) to obtain compound 19-3 (gray solid, 350 mg).

Weigh compound 19-3 (83mg, 0.287mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (55mg, 0.373mmol) into a 15mL pressure-resistant reaction tube, and then add Water N,N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80° C. for 3 h, the reaction was continued at 110° C. for 3 h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=20:1:1-10:1:1) to obtain compound 19 (yellow solid, 38mg): ¹ H NMR (300MHz, DMSO- d ₆ )δ8.70(s,1H),8.30(d,J=8.3Hz,1H),8.04(d,J=8.3Hz,1H),7.77(m,2H),7.68(t,J=7.5 Hz, 1H), 7.55(t, J=7.5Hz, 1H), 7.29(s, 1H), 2.82(s, 3H). ESI-MS: m/z 360.1[M+Na] ⁺ .

Example 20

2-(Methoxy)-6-(Naphtho[1,2-b]fur-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (Compound 20)

Weigh compound 19-3 (350mg, 1.21mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (261mg, 1.45mmol) into a 135mL pressure-resistant reaction tube, then add isopropanol (20 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 100 mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue containing compound 20-1 was directly used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the previous step containing compound 20-1 was dissolved in a mixed solvent of dichloromethane (27 mL) and methanol (9 mL), and then a methanol solution of sodium methoxide (4M, 765 μL) was added to react at room temperature 1h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (20mL), the aqueous phase was extracted with dichloromethane (20mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (10mL x 1), anhydrous sulfuric acid Sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=20:1:1-10:1:1) to obtain compound 20 (white solid , 100mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.37(d, J=8.2Hz, 1H), 8.02(s, 1H), 7.92(d, J=8.1Hz, 1H), 7.66(s, 2H), 7.61-7.56(m,1H), 7.49-7.44(m,1H), 7.15(s,1H), 4.22(s,3H). ESI-MS: m/z 344.1[M+Na] ⁺ .

Example 21

5-Bromo-6-(2,3-dihydro-[1,4]dioxine[2,3-g]benzofuran-8-yl)-2-(methylthio)imidazo [2,1-b][1,3,4]thiadiazole (compound 21)

Weigh compound 12 (144mg, 0.42mmol) and dissolve it in tetrahydrofuran (20mL), and dissolve N-bromosuccinimide (90mg, 0.50mmol) in tetrahydrofuran (5mL). A solution of bromosuccinimide in tetrahydrofuran (5 mL) was added dropwise into the reaction system. After the addition was complete, the mixture was raised to room temperature and stirred overnight. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=50:150:2-50:150:3) to obtain compound 21 ( Pale yellow solid, 150mg): ¹ H NMR (300MHz, CDCl ₃ ) δ7.13(s, 1H), 7.04(d, J=9Hz, 1H), 6.83(d, J=9Hz, 1H), 4.41-4.34 (m,4H),2.81(s,3H).ESI-MS:m/z 424.0[M+H] ⁺ .

Example 22

6-(2,3-Dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-2-(trifluoromethyl)imidazo[ 2,1-b][1,3,4]thiadiazole (compound 22)

Weigh compound 11-8 (100mg, 0.34mmol) and 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (74mg, 0.44mmol) into a 15mL pressure-resistant reaction tube, and then add Ethanol (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath and reacted at 80°C for 4h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=20:1:1-10:1:1) to obtain compound 22 ( Yellow solid, 30 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.26(s, 1H), 7.11(s, 1H), 7.06(d, J=8.4Hz, 1H), 6.84(d, J=8.5 Hz,1H), 4.47-4.34(m,4H).ESI-MS: m/z 390.1[M+Na] ⁺ .

Example 23

2-(2,3-Dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-6-methylimidazo[1,2- b] Pyridazine (compound 23)

Weigh compound 11-8 (100mg, 0.34mmol) and 3-amino-6-methylpyridazine (39mg, 0.35mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5mL), and The mixture solution was purged for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=10:1:1-2:1:1) to obtain compound 23 ( Yellow solid, 42mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.29(s, 1H), 7.81(d, J=9.3Hz, 1H), 7.21(s, 1H), 7.06(d, J=8.4 Hz,1H),6.93(d,J=9.3Hz,1H),6.83(d,J=8.4Hz,1H),4.50-4.33(m,4H),2.58(s,3H).ESI-MS:m /z 330.1[M+Na] ⁺ .

Example 24

6-bromo-2-(2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)imidazo[1,2-b ] Pyridazine (compound 24)

Weigh compound 11-8 (100mg, 0.34mmol) and 6-bromo-3-pyrazinamine (70.3mg, 0.404mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (10mL), and The mixture solution was purged for 5 min. The system was moved into an oil bath, and after reacting at 80° C. for 5 h, the reaction was continued at 120° C. for 3 h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=10:1:1-2:1:1) to obtain compound 24 ( Yellow solid, 30 mg): ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.74(s, 1H), 8.12(d, J=9.5Hz, 1H), 7.50(d, J=9.5Hz, 1H), 7.31(s,1H),7.12(d,J=8.4Hz,1H),6.84(d,J=8.4Hz,1H),4.44-4.33(m,4H).ESI-HRMS:calcd.for C ₁₆ H ₁₁ BrN ₃ O ₃ [M+H] ⁺ 373.9958, found: 373.9961.

Example 25

2-(2,3-Dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-6-methoxyimidazo[1,2 -b] pyridazine (compound 25)

Compound 24 (313mg, 0.842mmol) was weighed and dissolved in a mixed solvent of dichloromethane (2mL) and methanol (12mL), and a methanol solution of sodium methoxide (4M, 375μL, 1.5mmol) was added, reacted at room temperature for 2h, and then refluxed for 2h. After the reaction was completed, quenched by adding saturated ammonium chloride (20 mL), extracted with ethyl acetate (15 mL x 3), combined the organic phases, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and evaporated the solvent under reduced pressure , the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=50:150:2-50:150:8) to obtain compound 25 (light yellow solid, 120 mg): ¹ H NMR (300MHz, CDCl ₃ )δ8.16(s, 1H), 7.77(d, J=9.7Hz, 1H), 7.15(s, 1H), 7.05(d, J=8.4Hz, 1H), 6.83(d, J＝8.4Hz, 2H), 6.71(d, J＝9.7Hz, 2H), 4.56-4.35(m, 4H), 4.01(s, 3H).ESI-MS: m/z 324.0[M+H] ⁺ .

Example 26

6-(2,3-Dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)imidazo[1,2-b][1, 2,4] Triazine (compound 26)

Weigh compound 11-8 (100mg, 0.34mmol) and 1,2,4-triazin-3-amine (48.5mg, 0.51mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5mL), The mixture solution was purged with argon for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=10:1:1-2:1:1) to obtain compound 26 ( Orange solid, 40 mg). ¹ H NMR (300MHz, CDCl ₃ ) δ8.44(d, J=1.4Hz, 1H), 8.39(s, 1H), 8.33(d, J=1.4Hz, 1H), 7.43(s, 1H), 7.11 (d, J=8.5Hz, 1H), 6.86(d, J=8.4Hz, 1H), 4.50-4.34(m, 4H). ESI-MS: m/z 317.1[M+Na] ⁺ .

Example 27

6-Methyl-2-(7,8,9,10-tetrahydro-[1,4]dioxoctatriene[2,3-g]benzofuran-2-yl)imidazo[1 ,2-b]pyridazine (compound 27)

Weigh compound 15-5 (97mg, 0.299mmol) and 3-amino-6-methylpyridazine (49mg, 0.448mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5mL), and The mixture solution was purged for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=10:1:1-3:1:1) to obtain compound 27 ( Yellow solid, 60mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.31(s, 1H), 7.82(d, J=7.3Hz, 1H), 7.21(s, 1H), 7.13(d, J=9.3 Hz,1H),6.95-6.91(m,2H),4.62(s,2H),4.37(s,2H),2.58(s,3H),2.03-1.94(m,4H).ESI-HRMS: calcd. for C ₁₉ H ₁₈ N ₃ O ₃ [M+H] ⁺ 336.1343, found: 336.1348.

Example 28

6-Methyl-2-(Naphtho[1,2-b]furan-2-yl)imidazo[1,2-b]pyridazine (Compound 28)

Weigh compound 19-3 (81mg, 0.28mmol) and 3-amino-6-methylpyridazine (37mg, 0.336mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5mL), and The mixture solution was purged for 5 min. The system was moved into an oil bath and reacted at 80°C for 10h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane/methanol=300:1-100:1) to obtain compound 28 (yellow solid, 18 mg). ¹ H NMR (300MHz, CDCl ₃ ) δ8.43(d, J=8.2Hz, 1H), 8.36(s, 1H), 7.94(d, J=8.1Hz, 1H), 7.86(d, J=9.3Hz ,1H),7.69(s,2H),7.64-7.59(m,1H),7.53-7.48(m,1H),7.40(s,1H),6.95(d,J=9.3Hz,1H),2.60( s,3H).ESI-MS: m/z 322.1[M+Na] ⁺ .

Example 29

6-(Naphtho[1,2-b]furan-2-yl)imidazo[1,2-b][1,2,4]triazine (Compound 29)

Weigh compound 19-3 (83mg, 0.287mmol) and 1,2,4-triazin-3-amine (41mg, 0.43mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5mL) to The mixture solution was purged with argon for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=10:1:1-4:1:1) to obtain compound 29 ( Yellow solid, 28 mg): ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.01(s, 1H), 8.74(d, J=2.0Hz, 1H), 8.67(d, J=2.0Hz, 1H), 8.43(d, J=8.1Hz, 1H), 8.11(d, J=8.1Hz, 1H), 7.86(m, 2H), 7.75(t, J=7.0Hz, 1H), 7.68(s, 1H), 7.62 (t, J=7.0Hz, 1H).ESI-MS: m/z 309.1[M+Na] ⁺ .

Example 30

5-(6-Fluoro-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-2-methoxyimidazo [1,2-b][1,2,4]thiadiazole (compound 30)

Compound 30-1 (1.02 g, 5.33 mmol) was weighed and dissolved in trifluoroacetic acid (7 mL), and hexatropine (1.5 g, 10.66 mmol) was added in portions. The system reacted under reflux for 10h. After the reaction, the system was adjusted to pH=1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (15mL x 3), the organic phases were combined, washed with saturated brine (10mL x 1), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=100:1-80:1) to obtain compound 30-2 (yellow solid, 739 mg).

A solution of 30-2 (350 mg, 1.6 mmol) dissolved in sodium hydroxide (83 mg, 2.08 mmol) in water (5 mL) was weighed. A solution of hydrogen peroxide (190 μL, 6.18 mmol) in water (5 mL) was then slowly added dropwise. The system was reacted for 2h at room temperature. After the reaction, the system was adjusted to pH=1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (20mL x 2), the organic phases were combined, and the organic phase was washed with saturated brine (10mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=10:1-8:1) to obtain compound 30-3 (yellow solid, 258 mg).

Weigh 30-3 (250mg, 1.2mmol) and dissolve it in N,N-dimethylformamide (8mL), add 1,2-dibromoethane (156μL, 1.82mmol) and potassium carbonate (358mg, 2.66mmol ). The system was reacted at 105°C for 3h. After the reaction was completed, water (10mL) was added, and the aqueous phase was extracted with ethyl acetate (10mL x 3). ), and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=100:1-80:1) to obtain compound 30-4 (yellow solid, 225 mg).

Under the protection of argon, 30-4 (3g, 12.88mmol) was dissolved in anhydrous tetrahydrofuran (25mL), and n-butyllithium (5.7mL, 14.16mmol) was added dropwise at -78°C, and stirred at -78°C for 30min Finally, trimethyl borate (1.72mL, 15.5mmol) was added, and after stirring at -78°C for 60min, the solution containing 30-5 was warmed to 0°C, and acetic acid (2.5mL, 14.2mmol) and 48% peroxide Hydrogen solution (1.6mL, 51.5mmol), react overnight at natural temperature, add water (10ml), extract the aqueous phase with ethyl acetate (20mL x 3), combine the organic phases, organic phase with water (15mL x 3) and saturated brine ( 10mL x1), washed with anhydrous sodium sulfate, evaporated the solvent under reduced pressure, and purified the residue by column chromatography (eluent: petroleum ether/ethyl acetate=50:1-8:1) to obtain compound 30-6 (yellow solid, 1.58 g).

Under argon protection, anhydrous dichloromethane (30mL), 1,1-dichloromethyl ether (1.68mL, 18.54mmol) were added successively, the temperature was lowered to 0°C, and titanium tetrachloride (2.44mL, 22.25mmol), add dropwise the solution of compound 30-6 (1.58g, 9.27mmol) in anhydrous dichloromethane (10mL), after the dropwise addition, keep the temperature constant and continue to stir for 1h, after the reaction is complete, add 1N hydrochloric acid (10mL ), transferred to a separatory funnel, extracted with dichloromethane (10mL x 3), combined the organic phases, washed the organic phase with saturated brine (10mL x 1), dried over anhydrous sodium sulfate, and evaporated the solvent under reduced pressure. The residue containing compound 30-7 was directly used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the previous step containing compound 30-7 was dissolved in acetone (40mL), potassium carbonate (1.92g, 13.9mmol) was added, 1-chloroacetone (970μL, 12.05mmol) was slowly added dropwise, and After the addition was completed, the temperature was raised to reflux for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane =20:1:1-10:1:1) to obtain compound 30-8 (white solid, 442 mg).

Weigh copper bromide (246mg, 1.1mmol) and place it in a 100mL three-necked flask, add ethyl acetate (20mL), dissolve compound 30-8 (200mg, 0.85mmol) in ethyl acetate (20mL), and drop With the funnel under reflux conditions, the ethyl acetate solution of compound 30-8 was added dropwise into the reaction system, and the reflux was continued for 8 hours after the addition was complete. After the reaction, the solids in the system were removed by suction filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=2:1) to obtain compound 30-9 (yellow solid, 156 mg).

Weigh compound 30-9 (90mg, 0.28mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (62mg, 0.34mmol) into a 35mL pressure-resistant reaction tube, then add isopropanol (50 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 100 mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue containing compound 30-10 was directly used in the next reaction without further purification.

Dissolve the residue obtained from the post-reaction treatment of the previous step containing compound 30-10 in a mixed solvent of dichloromethane (15 mL) and methanol (5 mL), then add a methanol solution of sodium methoxide (4M, 185 μL), and react at room temperature 1h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (10mL), the aqueous phase was extracted with dichloromethane (15mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (10mL x 1), anhydrous sulfuric acid The sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=8:1:1) to obtain compound 30 (white solid, 28 mg): ¹ H NMR(300MHz, CDCl ₃ )δ7.96(s,1H),7.05(s,1H),6.57(d,J=9.8Hz,1H),4.53-4.31(m,4H),4.23(s,3H) .ESI-MS: m/z 370.0[M+Na] ⁺ .

Example 31

5-(6-Fluoro-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-2-methylthioimidazo [1,2-b][1,2,4]thiadiazole (compound 31)

Weigh compound 30-9 (90mg, 0.3mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (50mg, 0.343mmol) into a 15mL pressure-resistant reaction tube, and then add N , N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 4h, the reaction was continued at 110°C for 3h. After the reaction was completed, water (15 mL) was added to dilute the reaction solution, extracted with ethyl acetate (10 mL x 3), the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and reduced pressure The solvent was evaporated, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=20:1:1-8:1:1) to obtain compound 31 (orange solid, 70mg) : ¹ H NMR (300MHz, CDCl ₃ ) δ8.07(s, 1H), 7.07(s, 1H), 6.56(d, J=9.9Hz, 1H), 4.38(d, J=7.4Hz, 4H), 2.77(s,3H).ESI-MS: m/z 386.0[M+Na] ⁺ .

Example 32

2-(6-fluoro-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-6-methylimidazo[ 1,2-b]pyridazine (compound 32)

Weigh compound 30-9 (90mg, 0.3mmol) and 3-amino-6-methylpyridazine (50mg, 0.343mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5mL), and The mixture solution was purged for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=20:1:1-8:1:1) to obtain compound 32 ( Orange solid, 70 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.27(s, 1H), 7.81(d, J=9.3Hz, 1H), 7.26(s, 1H), 6.94(d, J= 9.3Hz, 1H), 6.57(d, J=9.8Hz, 1H), 4.38(dd, J=12.6, 5.2Hz, 4H), 2.58(s, 3H).ESI-MS: m/z 348.2[M+ Na] ⁺ .

Example 33

6-(6-fluoro-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)imidazo[1,2-b ][1,2,4]triazine (compound 33)

Weigh compound 30-9 (62mg, 0.197mmol) and 1,2,4-triazin-3-amine (28mg, 0.295mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5mL) to The mixture solution was purged with argon for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=10:1:1-3:1:1) to obtain compound 33 ( Yellow solid, 25 mg): 1H NMR (300MHz, CDCl ₃ ) δ8.46(s, 1H), 8.38(s, 1H), 8.35(s, 1H), 7.48(s, 1H), 6.60(d, J= 9.8Hz,1H),4.47-4.34(m,4H).ESI-MS:m/z335.1[M+Na] ⁺ .

Example 34

6-(6-Chloro-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-2-methoxyimidazo [2,1-b][1,3,4]thiadiazole (compound 34)

Compound 34-1 (10 g, 66 mmol) was weighed and dissolved in acetic acid (60 mL), N-chlorosuccinimide (8.8 g, 66 mmol) was added, and the system was reacted at 105° C. for 0.5 h. Then cooled to room temperature and continued stirring for 2.5h. After the reaction, the resulting slurry was poured into ice water (200mL), and a large amount of yellow solids were precipitated immediately. The aqueous phase was extracted with ethyl acetate (40mL x 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride (40mL x 3), dried over anhydrous sodium sulfate, evaporated the solvent under reduced pressure, and recrystallized from ethanol (15mL) to obtain compound 34-2 (yellow solid, 6.6g).

Compound 34-2 (6.83g, 36.6mmol) was weighed and dissolved in dichloromethane (40mL), and boron tribromide (2M in DCM, 46mL) was added dropwise through the dropping funnel under ice bath conditions, and the addition was completed. Rise to room temperature to react overnight. After the reaction, the system was slowly poured into ice water (100mL), the layers were static, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (40mL x 3), the organic phase was combined, and the organic phase was washed with saturated sodium chloride (50mL x 2) Wash, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and the residue containing compound 34-3 is directly used in the next reaction without further purification.

The residue containing compound 34-3 obtained in the previous step reaction was dissolved in N,N-dimethylformamide (60mL), potassium carbonate (22.5g, 163mmol) and 1,2-dibromoethane (9.14 mL, 106mmol), and the system was reacted at 85°C for 4h. After the reaction was completed, ethyl acetate (200 mL) was added to dilute the reaction solution, the organic phase was washed with water (100 mL x 3) and saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purification by chromatography (eluent: petroleum ether/ethyl acetate=20:1-6:1) gave compound 34-4 (yellow solid, 5.46 g).

Compound 34-4 (5.46g, 27.5mmol) was weighed and dissolved in dichloromethane (60mL), m-chloroperoxybenzoic acid (6.7g, 33mmol, 85%) was added in batches under ice-cooling conditions, and then warmed to room temperature After reacting overnight, most of the solvent was distilled off under reduced pressure, and the residue containing compound 34-5 was directly used in the next reaction without further treatment.

The residue containing compound 34-5 obtained in the previous step reaction was dissolved in methanol (30 mL), and 10% potassium hydroxide solution (140 mL) was slowly added under ice-cooling conditions, and reacted at room temperature for 3 h. After the reaction, the system was adjusted to pH=1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (50mL x 3), the organic phase was combined, and the organic phase was washed with saturated sodium bicarbonate solution (50mL x 3) and saturated saline (50mL x 1), washed with anhydrous sodium sulfate, evaporated the solvent under reduced pressure, and purified the residue by column chromatography (eluent: petroleum ether/ethyl acetate=20:1-4:1:1) to obtain Compound 34-6 (yellow oil, 3.7 g).

Under argon atmosphere, compound 34-6 (3.7g, 19.83mmol) was dissolved in anhydrous dichloromethane (50mL), dichloromethyl ether (3.6mL, 39.66mmol) was added, and at 0°C , added a solution of titanium tetrachloride (5.22 mL, 47.6 mmol) dropwise, after the addition was complete, warmed up to room temperature and stirred for 2 h. After the reaction was complete, 1N hydrochloric acid solution (20mL) was added to quench the reaction under ice-bath conditions, the aqueous phase was extracted with dichloromethane (25mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (30mL x 1), After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue containing compound 34-7 was directly used in the next reaction without further purification.

The residue containing compound 34-7 obtained in the previous reaction was dissolved in acetone (40 mL), and then potassium carbonate (4.3 g, 31 mmol) and 1-chloroacetone (2 mL, 25 mmol) were added in sequence. The system was reacted under reflux for 6h. After the reaction was completed, ethyl acetate (40 mL) was added to dilute the reaction solution, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate=10: 1-4:1) was purified to obtain compound 34-8 (yellow solid, 1.93g).

Weigh copper bromide (2.21g, 9.9mmol) and place it in a 250mL three-necked flask, add ethyl acetate (20mL), dissolve compound 34-8 (1.925g, 7.62mmol) in ethyl acetate (80mL), pass Add the ethyl acetate solution of compound 34-8 into the reaction system dropwise under the reflux condition of the dropping funnel, and continue to reflux for 5 hours after the addition is completed. After the reaction, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=2:1-1:1) to obtain compound 34 -9 (yellow solid, 1 g).

Weigh compound 34-9 (100mg, 0.3mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (65mg, 0.36mmol) into a 35mL pressure-resistant reaction tube, then add isopropanol (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 100mL flask with dichloromethane, and the solvent was evaporated under reduced pressure, and the residue containing compound 34-10 was directly used in the next step without further reaction.

The crude compound 34-10 obtained in the previous reaction was dissolved in a mixed solvent of dichloromethane (9 mL) and methanol (3 mL), and then a methanol solution of sodium methoxide (4M, 185 μL) was added to react at room temperature for 1 h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (15mL), the aqueous phase was extracted with dichloromethane (10mL x 3), the organic phase was combined, and the organic phase was washed with saturated brine (20mL x 1), anhydrous sulfuric acid The sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane/petroleum ether/ethyl acetate=150:50:1-150:50:2) to obtain compound 34 (yellow White solid, 21 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ7.95(s, 1H), 7.04(s, 1H), 6.84(s, 1H), 4.42-4.33(m, 4H), 4.21(s ,3H).ESI-MS: m/z 386.1[M+Na] ⁺ .

Example 35

6-(6-Chloro-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-2-methylthioimidazo [2,1-b][1,3,4]thiadiazole (compound 35)

Weigh compound 34-9 (100mg, 0.3mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (53mg, 0.362mmol) into a 35mL pressure-resistant reaction tube, and then add Water N,N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 90°C for 4h, the reaction was continued at 120°C for 3h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=15:1:1-10:1:1-8:1:1) to obtain compound 35 (yellow-white solid, 55 mg). ¹ H NMR (300MHz, CDCl ₃ )δ8.09(s,1H),7.10(s,1H),6.86(s,1H),4.47-4.40(m,2H),4.40-4.34(m,2H), 2.79(s,3H).ESI-MS: m/z 402.0[M+Na] ⁺ .

Example 36

2-(6-Chloro-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-6-methylimidazo[ 1,2-b]pyridazine (compound 36)

Weigh compound 34-9 (100mg, 0.3mmol) and 3-amino-6-methylpyridazine (40mg, 0.362mmol) into a 35mL pressure-resistant reaction tube, then add isopropanol (5mL), and The mixture solution was purged for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=15:1:1-3:1:1) to obtain compound 36 ( Yellow-white solid, 70 mg). ¹ H NMR (300MHz, CDCl ₃ )δ8.30(s,1H),7.84(d,J=9.3Hz,1H),7.31(s,1H),6.97(d,J=9.3Hz,1H),6.88 (s,1H),4.50-4.34(m,4H),2.61(s,3H).ESI-MS: m/z 364.2[M+Na] ⁺ .

Example 37

6-(6-Chloro-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)imidazo[1,2-b ][1,2,4]triazine (compound 37)

Weigh compound 34-9 (100mg, 0.3mmol) and 1,2,4-triazin-3-amine (43.5mg, 0.452mmol) into a 35mL pressure-resistant reaction tube, then add isopropanol (5mL), The mixture solution was purged with argon for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (eluent: dichloromethane/petroleum ether/ethyl acetate=150:50:2-150:50:5-150:50:7) Purification gave compound 37 (orange solid, 45 mg): ¹ HNMR (300MHz, DMSO-d ₆ ) δ8.89(s, 1H), 8.70(s, 1H), 8.63(s, 1H), 7.41(s, 1H), 7.02(s,1H), 4.47-4.35(m,4H).ESI-MS: m/z 327.1[MH] ⁺ .

Example 38

6-(6-Bromo-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-2-methoxyimidazo [2,1-b][1,3,4]thiadiazole (Compound 38)

Weigh compound 34-1 (30.1g, 198mmol) and dissolve it in acetic acid (450mL), add sodium acetate (24.6g, 300mmol), at room temperature, pass the solution of liquid bromine (10.1mL) in acetic acid (30mL) through the dropping funnel Slowly added to the above system, continue to stir for 1h. After the reaction, the obtained slurry was poured into ice water (1000mL), and a large amount of yellow solids were precipitated immediately, filtered with suction, and the filter cake was compacted, and the obtained filter cake was vacuum-dried overnight to obtain compound 38-1 (yellow solid, 43 g).

Weigh compound 38-1 (5g, 21.6mmol) and dissolve it in dichloromethane (50mL), and add boron tribromide (1M in DCM, 43.3mL) dropwise through the dropping funnel at -50°C, and the addition is complete , react overnight at room temperature. After the reaction, the system was slowly poured into ice water (100mL), the layers were static, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (50mL x 3), the organic phase was combined, and the organic phase was washed with saturated sodium chloride (50mL x 2) Wash, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and the residue containing compound 38-2 is directly used in the next reaction without further purification.

The residue containing compound 38-2 obtained in the previous step reaction was dissolved in N,N-dimethylformamide (50mL), and potassium carbonate (8.97g, 65mmol) and 1,2-dibromoethane (2.83 mL, 32.5mmol), and the system was reacted at 85°C for 4h. After the reaction was completed, ethyl acetate (200 mL) was added to dilute the reaction solution, the organic phase was washed with water (100 mL x 3) and saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purification by chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=20:1:1-8:1:1) gave compound 38-3 (yellow solid, 2.26 g).

Weighed compound 38-3 (3.5g, 14.4mmol) and dissolved it in dichloromethane (30mL), added m-chloroperoxybenzoic acid (3.52g, 17.3mmol, 85%) in batches under ice-bath conditions, and then removed the ice After the system returned to room temperature, it was transferred to an oil bath and reacted under reflux for 12 hours. Most of the solvent was evaporated under reduced pressure, and the residue containing compound 38-4 was directly used in the next reaction without further treatment.

The residue containing compound 38-4 obtained in the previous step reaction was dissolved in methanol (10 mL), and 10% potassium hydroxide solution (80 mL) was slowly added under ice-cooling conditions, and reacted at room temperature for 6 h. After the reaction, the system was adjusted to pH=1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (30mL x 3), the organic phase was combined, and the organic phase was washed with saturated sodium bicarbonate solution (20mL x 3) and saturated brine ( 20mL x 1) was washed, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=10:1:1-6:1: 1) Purification to obtain compound 38-5 (yellow oil, 3.2 g).

Under argon atmosphere, compound 38-5 (3.2g, 13.9mmol) was dissolved in anhydrous dichloromethane, dichloromethyl ether (1.88mL, 20.8mmol) was added dropwise at 0°C A dichloromethane (4 mL) solution of titanium tetrachloride (3.04 mL, 27.7 mmol) was added dropwise, and after the addition was complete, it was stirred at room temperature for 48 h. After the reaction was complete, 1N hydrochloric acid solution (10mL) was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (10mL x 3), the organic phase was combined, and the organic phase was washed with saturated brine (10mL x 1) and dried over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue containing compound 38-6 was directly used in the next reaction without further purification.

The residue containing compound 38-6 obtained in the previous reaction was dissolved in acetone (20 mL), and then potassium carbonate (2 g, 14.5 mmol) and 1-chloroacetone (553 μL, 6.95 mmol) were added sequentially. The system was reacted under reflux for 6h. After the reaction was finished, ethyl acetate (30 mL) was added to dilute the reaction solution, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate/dichloro Methane=20:1:1-8:1:1) was purified to obtain compound 38-7 (yellow solid, 860 mg).

Weigh copper bromide (335mg, 1.5mmol) and place it in a 100mL three-necked flask, add ethyl acetate (20mL), dissolve compound 38-7 (297mg, 1mmol) in ethyl acetate (20mL), and pass through the dropping funnel Under the condition of reflux, the ethyl acetate solution of compound 38-7 was added dropwise into the reaction system, after the addition was completed, the reflux was continued for 8h. After the reaction, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=3:2-1:1) to obtain compound 38 -8 (yellow solid, 230 mg).

Weigh compound 38-8 (150mg, 0.4mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (86mg, 0.48mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 100 mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue containing compound 38-9 was directly used in the next step without further reaction.

The crude compound 38-9 obtained in the previous reaction was dissolved in a mixed solvent of dichloromethane (6 mL) and methanol (2 mL), and then a methanol solution of sodium methoxide (4M, 100 μL) was added to react at room temperature for 1 h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (10mL), the aqueous phase was extracted with ethyl acetate (10mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (20mL x 1), anhydrous sulfuric acid The sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=12:1:1-9:1:1), and the obtained crude product ( 40 mg) was recrystallized in methanol/dichloromethane system to obtain compound 38 (white solid, 10 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ7.94(s, 1H), 6.99(s, 2H), 4.42- 4.32(m,4H),4.21(s,3H).ESI-MS(ESI):m/z 430.0[M+Na] ⁺ .

Example 39

6-(6-Bromo-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-2-(methylthio) Imidazo[2,1-b][1,3,4]thiadiazole (Compound 39)

Weighed compound 38-8 (80mg, 0.213mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (35mg, 0.234mmol) into a 15mL pressure-resistant reaction tube, and then added Water N,N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 110°C for 2h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: petroleum ether/ethyl acetate=10:1-8:1) to obtain compound 39 (yellow solid, 50 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.07(s, 1H ),7.03(s,1H),7.00(s,1H),4.43-4.36(m,4H),2.77(s,3H).ESI-MS(ESI):m/z 446.0[M+Na] ⁺ .

Example 40

2-(6-Bromo-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-6-methylimidazo[ 1,2-b]pyridazine (compound 40)

Weigh compound 38-8 (100mg, 0.266mmol) and 3-amino-6-methylpyridazine (32mg, 0.293mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5mL), and The mixture solution was purged for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane/methanol=300:1-100:1) to obtain compound 40 (yellow solid, 70 mg): ¹ H NMR (300MHz, CDCl ₃ )δ8.28(s,1H),7.82(d,J=9.3Hz,1H),7.24(s,1H),7.02(s,1H),6.95(d,J=9.3Hz, 1H), 4.44-4.34(m,4H), 2.59(s,3H).ESI-MS: m/z 408.1[M+Na] ⁺ .

Example 41

6-(6-Bromo-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)imidazo[1,2-b ][1,2,4]triazine (Compound 41)

Weigh compound 38-8 (100mg, 0.266mmol) and 1,2,4-triazin-3-amine (28mg, 0.293mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5mL) to The mixture solution was purged with argon for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=10:1:1-6:1:1) to obtain compound 41 ( Brown solid, 52mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.46(d, J=1.9Hz, 1H), 8.38(s, 1H), 8.35(d, J=1.8Hz, 1H), 7.44( s,1H),7.04(s,1H),4.44-4.36(m,4H).ESI-MS: m/z 395.0[M+Na] ⁺ .

Example 42

2-Methoxy-5-(6-(trifluoromethyl)-2,3-dihydro[1,4]dioxino[2,3-g]benzofuran-8- base) imidazo[1,2-b][1,2,4]thiadiazole (compound 42)

Compound 42-1 (200 mg, 0.83 mmol) was weighed and dissolved in trifluoroacetic acid (5 ml), and hexatropine (233 mg, 1.66 mmol) was added in portions. The system reacted under reflux for 10h. After the reaction, the system was adjusted to pH=1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (15mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (10mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=50:1) to obtain compound 42-2 (white solid, 115 mg).

A solution of 42-2 (3.74 g, 13.9 mmol) dissolved in sodium hydroxide (724 mg, 18.1 mmol) in water (30 mL) was weighed. Then a solution of hydrogen peroxide (1.7 mL, 55.6 mmol) in water (10 mL) was slowly added dropwise, and the system was reacted at room temperature for 2 h. After the reaction, the system was adjusted to pH=1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (20mL x 2), the organic phases were combined, and the organic phase was washed with saturated brine (10mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=50:1-5:1) to obtain compound 42-3 (colorless oil, 3.18 g).

Weigh 42-3 (2.43g, 9.46mmol) and dissolve it in N,N-dimethylformamide (20mL), add 1,2-dibromoethane (1.22mL, 14.19mmol) and potassium carbonate (2.88g , 20.81 mmol). The system was reacted at 100°C for 3h. After the reaction was completed, water (50mL) was added, and the aqueous phase was extracted with ethyl acetate (20mL x 3). ), and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=150:1-100:1) to obtain compound 42-4 (white solid, 1.87 g).

Under argon protection, 42-4 (1.5g, 5.3mmol) was dissolved in anhydrous tetrahydrofuran (15mL), and n-butyllithium (2.33mL, 5.83mmol) was added dropwise at -78°C, stirred at -78°C After 30min, trimethyl borate (0.71mL, 6.36mmol) was added, and after stirring at -78°C for 60min, the solution containing compound 42-5 was warmed to 0°C, and acetic acid (1mL, 5.83mmol) and peroxide Hydrogen solution (0.715mL, 23.32mmol), react overnight at natural temperature, add water (10mL), extract the aqueous phase with ethyl acetate (20mL x 3), combine the organic phase, the organic phase with water (15mL x 3) and saturated saline ( 10mL x 1) was washed, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=20:1-5:1) to obtain compound 42- 6 (brown oil, 888 mg).

Compound 42-6 (99 mg, 0.45 mmol) was weighed and dissolved in trifluoroacetic acid (5 mL), and hexatropine (126 mg, 0.9 mmol) was added in portions. The system was reacted under reflux for 4h. After the reaction, the system was adjusted to pH=1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (8mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (5mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=8:1) to obtain compound 42-7 (white solid, 61 mg).

Weigh compound 42-7 (60mg, 0.24mmol) and dissolve it in acetone (8mL), add potassium carbonate (45mg, 0.323mmol), slowly add 1-chloroacetone (30μL, 0.363mmol) dropwise, after the dropwise addition is completed, heat up Reflux for 4 hours, after the reaction is completed, cool the reaction solution to room temperature, filter to remove insoluble matter, concentrate the filtrate under reduced pressure, and the residue is subjected to column chromatography (eluent: petroleum ether/ethyl acetate=10:1-8:1) Purification afforded compound 42-8 (white solid, 54 mg).

Weigh copper bromide (69mg, 0.308mmol) and place it in a 50mL three-necked flask, add ethyl acetate (8mL), dissolve compound 42-8 (44mg, 0.154mmol) in ethyl acetate (5mL), and drop With the funnel under reflux conditions, the ethyl acetate solution of compound 42-8 was added dropwise into the reaction system, and the reflux was continued for 8 hours after the addition was complete. After the reaction, the solids in the system were removed by suction filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=1:1) to obtain compound 42-9 (white solid, 33 mg).

Weigh compound 42-9 (95mg, 0.26mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (56mg, 0.31mmol) into a 35mL pressure-resistant reaction tube, then add isopropanol (6 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 50 mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue containing compound 42-10 was directly used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the previous step containing compound 42-10 was dissolved in a mixed solvent of dichloromethane (15 mL) and methanol (5 mL), and then a methanol solution of sodium methoxide (4M, 170 μL) was added to react at room temperature 1h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (10mL), the aqueous phase was extracted with dichloromethane (15mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (10mL x 1), anhydrous sulfuric acid The sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=7:1:1) to obtain compound 42 (yellow solid, 25 mg): ¹ H NMR(300MHz, CDCl ₃ )δ7.97(s,1H),7.15(d,J=1.4Hz,1H),7.11(s,1H),4.51-4.44(m,2H),4.41-4.34(m, 2H), 4.21(s,3H). ESI-MS: m/z 420.0[M+Na] ⁺ .

Example 43

2-Methylthio-5-(6-(trifluoromethyl)-2,3-dihydro[1,4]dioxino[2,3-g]benzofuran-8- base) imidazo[1,2-b][1,2,4]thiadiazole (compound 43)

Weigh compound 42-9 (100mg, 0.274mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (48mg, 0.33mmol) into a 15mL pressure-resistant reaction tube, and then add Water N,N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 120°C for 2h. After the reaction was completed, water (15 mL) was added to dilute the reaction solution, extracted with ethyl acetate (10 mL x 3), the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and reduced pressure The solvent was evaporated, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=15:1:1-12:1:1) to obtain compound 43 (yellow solid, 83 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.11(s, 1H), 7.21(d, J=1.3Hz, 1H), 7.13(s, 1H), 4.51-4.46(m, 2H), 4.42-4.37( m,2H),2.79(s,3H).ESI-MS:m/z 436.1[M+Na] ⁺ .

Example 44

6-Methyl-2-(6-(trifluoromethyl)-2,3-dihydro[1,4]dioxino[2,3-g]benzofuran-8-yl ) imidazo[1,2-b]pyridazine (compound 44)

Weigh compound 42-9 (70mg, 0.2mmol) and 3-amino-6-methylpyridazine (22mg, 0.2mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5mL), and The mixture solution was purged for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=15:1:1-3:1:1) to obtain compound 44 ( White solid, 50 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.31(s, 1H), 7.83(d, J=9.3Hz, 1H), 7.40(d, J=1.3Hz, 1H), 7.14( s,1H),6.96(d,J=9.3Hz,1H),4.52-4.46(m,2H),4.42-4.36(m,2H),2.59(s,3H).ESI-MS:m/z 398.2 [M+Na] ⁺ .

Example 45

6-(6-(trifluoromethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)imidazo[ 1,2-b][1,2,4]triazine (compound 45)

Weigh compound 42-9 (95mg, 0.26mmol) and 1,2,4-triazin-3-amine (37mg, 0.39mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (6mL) to The mixture solution was purged with argon for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=10:1:1-3:1:1) to obtain compound 45 ( Yellow solid, 25mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.52(d, J=1.9Hz, 1H), 8.44(s, 1H), 8.40(d, J=1.9Hz, 1H), 7.64( d, J=1.4Hz, 1H), 7.21(s, 1H), 4.58-4.39(m, 4H). ESI-MS: m/z 385.1[M+Na] ⁺ .

Example 46

6-(2,3-Dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl-6-d)-2-(methylthio) Imidazo[2,1-b][1,3,4]thiadiazole (Compound 46)

Weigh compound 38-3 (5.66g, 23.27mmol), pinacol diboronate (11.82g, 46.54mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride Chloromethane complex (1.9g, 2.33mmol) and potassium acetate (6.85g, 69.8mmol) were placed in a 300mL pressure-resistant reaction tube, anhydrous 1,4-dioxane (80mL) was added, and argon was bubbled Purge for 5 minutes, react the system at 100°C for 5 hours, add ethyl acetate (100 mL) to dilute the reaction solution, filter with suction, filter off the solids, evaporate the solvent under reduced pressure, and the residue is subjected to column chromatography (eluent: petroleum ether /ethyl acetate=20:1-10:1) to obtain compound 46-1 (yellow solid, 6.2 g).

Weigh compound 46-1 (290mg, 1mmol) and dissolve it in a mixed solvent of deuterated methanol (3mL) and deuterium water (3mL), then add triethylamine (138μL, 1mmol) and silver nitrate (170mg, 1mmol) successively, at 80°C Under the condition of reflux for 2h. After the reaction was complete, the system was cooled to room temperature, suction filtered through diatomaceous earth, the filtrate was collected, ethyl acetate (20 mL) was added to dilute the filtrate, the organic phase was washed with saturated sodium chloride (5 mL x 2), dried over anhydrous sodium sulfate, The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate: 20:1:1-18:1:1) to obtain compound 46-2 (white solid, 85mg).

Compound 46-2 (2g, 12.12mmol) was weighed and dissolved in dichloromethane (50mL), m-chloroperoxybenzoic acid (2.96g, 14.55mmol, 85%) was added in batches under ice bath conditions, and then the ice bath was removed , after the system returned to room temperature, reacted for 12 hours, evaporated most of the solvent under reduced pressure, and the residue containing compound 46-3 was directly used in the next reaction without further treatment.

To the residue containing compound 46-3 obtained in the previous step reaction, 10% potassium hydroxide solution (30 mL) was slowly added under ice-bath conditions, and reacted at room temperature for 2 h. After the reaction, the system was adjusted to pH=1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (50mL x 3), the organic phase was combined, and the organic phase was washed with saturated sodium bicarbonate solution (20mL x 4) and saturated salt Wash with water (20mL x 2), dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and purify the residue by column chromatography (eluent: petroleum ether/ethyl acetate/=10:1-5:1) to obtain Compound 46-4 (yellow oil, 1.72 g).

Weigh paraformaldehyde (785.5mg, 26.18mmol) and anhydrous magnesium chloride (1660mg, 17.34mmol) into a 50mL two-necked bottle, insert a condenser, exchange the air in the system with argon, and perform anaerobic treatment on the device. Anhydrous tetrahydrofuran (20 mL) was then added via syringe. The system was moved into an oil bath, and triethylamine (2.42mL, 17.34mmol) was slowly added at 70°C under weak reflux, followed by a solution of compound 46-4 (1.33g, 8.67mmol) in anhydrous tetrahydrofuran (20mL). After the addition, keep the reaction at 70°C for 5h. After the reaction, cool the system to room temperature, add 1N hydrochloric acid solution (20mL), stir for 10min, extract with ethyl acetate (20mL x 3), combine the organic phases, wash with saturated brine (20mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 20:1-16:1) to obtain compound 46-5 (light yellow oil, 655 mg).

Weigh compound 46-5 (655mg, 3.62mmol) and dissolve it in acetone (20mL), add potassium carbonate (750mg, 5.43mmol), slowly add 1-chloroacetone (350μL, 4.34mmol) dropwise, after the dropwise addition is completed, heat up Reflux for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=20:1: 1-10:1:1) to obtain compound 46-6 (white solid, 470 mg).

Compound 46-6 (227mg, 0.74mmol) was weighed and dissolved in a 50mL two-neck bottle, the air in the system was exchanged with argon, the device was anaerobically treated, and then anhydrous dichloromethane (7mL) was added through a syringe. Under ice bath conditions, a solution of N,N-diisopropylethylamine (370 μL, 2.22 mmol) in anhydrous dichloromethane (2 mL) was slowly added, and the system was reacted under ice bath conditions for 0.5 h. A solution of triisopropylsilyl triflate (300 μL, 1.11 mmol) in anhydrous dichloromethane (2 mL) was then added dropwise under ice-bath conditions. After the addition was completed, it was raised to room temperature and stirred overnight. After the reaction, the system was quenched with saturated sodium bicarbonate solution (15mL), the aqueous phase was extracted with dichloromethane (10mL x 3), the organic phase was combined, and the organic phase was washed with saturated sodium bicarbonate solution (10mL x 1) and saturated It was washed with brine (10 mL x 1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue containing compound 46-7 was directly used in the next reaction without further purification.

The 50mL two-neck bottle exchanged the air in the system with argon, and treated the device anaerobically, and then added anhydrous tetrahydrofuran (7mL) solution containing the residue obtained from the previous step reaction of compound 46-7 through a syringe, and placed it in an ice bath. Under conditions, a solution of N-bromosuccinimide (145 mg, 0.81 mmol) in anhydrous THF (2 mL) was added dropwise. After addition, rise to room temperature and stir for 3h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=1:1-1:8) to obtain compound 46-8 (yellow oily liquid, 230mg) .

Weigh compound 46-8 (90mg, 0.3mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (50mg, 0.343mmol) into a 15mL pressure-resistant reaction tube, and then add N , N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 4h, the reaction was continued at 120°C for 3h. After the reaction was completed, water (15 mL) was added to dilute the reaction solution, extracted with ethyl acetate (10 mL x 3), the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and reduced pressure The solvent was evaporated, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=20:1:1-8:1:1) to obtain compound 46 (white solid, 38mg). ¹ H NMR (300MHz,DMSO-d ₆ )δ8.07(s,1H),7.01(s,1H),6.81(s,1H),4.45-4.35(m,4H),2.77(s,3H). ESI-HRMS: calcd.for C ₁₅ H ₁₁ DN ₃ O ₃ S ₂ [M+H] ⁺ 347.0377, found: 347.0375.

Example 47

6-(2,3-Dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl-6-d)-2-(methoxy) Imidazo[2,1-b][1,3,4]thiadiazole (Compound 47)

Compound 46 (50 mg, 0.145 mmol) was weighed and dissolved in tetrahydrofuran (5 mL), m-chloroperoxybenzoic acid (purity 85%, 147 mg, 0.723 mmol) was slowly added at room temperature, and the reaction was maintained at room temperature for 6 h. After the reaction was complete, dichloromethane (20 mL) was added to dilute the reaction system, the organic phase was washed with saturated sodium bicarbonate (5 mL x 3) and saturated brine (5 mL), dried over anhydrous sodium sulfate, and the organic phase was distilled off under reduced pressure, containing The residue of compound 47-1 was directly put into the next reaction without further purification.

The crude compound 47-1 obtained in the previous step was dissolved in a mixed solvent of dichloromethane (3 mL) and methanol (1 mL), and sodium methoxide in methanol (4M, 55 μL) was added at room temperature, and kept at room temperature for 1 h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (5 mL), the aqueous phase was extracted with ethyl acetate (5 mL x 3), the organic phases were combined, the organic phase was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=50:150:1-50:150:6) to obtain compound 47 (yellow solid, 8mg) : ¹ H NMR (300MHz,DMSO-d ₆ )δ7.95(s,1H),6.97(s,1H),6.81(s,1H),4.44-4.37(m,4H),4.21(s,3H) .ESI-HRMS:calcd.forC ₁₅ H ₁₁ DN ₃ O ₄ S[M+H] ⁺ 347.0606,found: 331.0608.

Example 48

6-(6-(Benzyloxy)-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-2- Bromoimidazo[2,1-b][1,3,4]thiadiazole (Compound 48)

Weigh compound 46-1 (6.2g, 21.37mmol) and dissolve it in dioxane (120mL), add 50% aqueous solution of N-methyl-N-morpholine oxide (5.3mL), and react the system at 80°C After 6 h, 50% N-methyl-N-morpholine oxide aqueous solution (530 μL) was added again, and the reaction was continued at 80° C. for 2 h. After the reaction was completed, add 1N hydrochloric acid solution to acidify the system to pH = 1, extract with ethyl acetate (50mL x 3), combine the organic phases, wash the organic phase with saturated brine (20mL x 2), dry over anhydrous sodium sulfate, and reduce pressure The solvent was evaporated, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=20:1-10:1) to obtain compound 48-1 (light yellow solid, 3.45 g).

Weigh compound 48-1 (3.43g, 19.04mmol) and dissolve it in N,N-dimethylformamide (70mL), add potassium carbonate (3.42g, 24.75mmol) and benzyl bromide (2.94mL, 24.75mmol) , the system was stirred at room temperature for 7h. After the reaction was complete, ethyl acetate (200 mL) was added to dilute the reaction solution, the organic phase was washed with water (50 mL x 3) and saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purification by chromatography (eluent: petroleum ether/ethyl acetate=20:1-8:1) gave compound 48-2 (light yellow solid, 4.49 g).

Weighed compound 48-2 (4.49g, 16.62mmol) and dissolved it in dichloromethane (100mL), added m-chloroperoxybenzoic acid (4.05g, 19.94mmol, 85%) in batches under ice-cooling conditions, and then removed the ice After the system returned to room temperature, it was transferred to an oil bath and reacted under reflux for 12 hours. Most of the solvent was evaporated under reduced pressure, and the residue containing compound 48-3 was directly used in the next reaction without further treatment.

The residue containing compound 48-3 obtained in the previous step reaction was dissolved in methanol (5 mL), and 10% potassium hydroxide solution (10 mL) was slowly added under ice-cooling conditions, and reacted at room temperature for 6 h. After the reaction, the system was adjusted to pH=1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (50mL x 3), the organic phase was combined, and the organic phase was washed with saturated sodium bicarbonate solution (50mL x 2) and saturated brine ( 50mL x 1) was washed, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=20:1-15:1), Compound 48-4 (yellow oil, 1.82 g) was obtained.

Weigh paraformaldehyde (2.39g, 79.77mmol) and anhydrous magnesium chloride (5.06g, 53.18mmol) into a 250mL two-necked bottle, insert a condenser, exchange the air in the system with argon, and treat the device anaerobically . Then anhydrous THF (100 mL), triethylamine (7.39 mL, 53.18 mmol), compound 48-4 (4.9 g, 26.59 mmol) in dry THF (10 mL) were added sequentially via syringe. The system was reacted under reflux for 6h. After the reaction, the system was adjusted to pH=1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (50mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (50mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=10:1-3:1) to obtain compound 48-5 (yellow solid, 4.03 g).

Compound 48-5 (4.43g, 15.47mmol) was weighed and dissolved in acetone (50mL), then potassium carbonate (5.34g, 38.7mmol) and 1-chloroacetone (1.48mL, 18.6mmol) were added sequentially. The system was reacted under reflux for 6h. After the reaction was completed, ethyl acetate (100 mL) was added to dilute the reaction solution, the solids in the system were removed by suction filtration, the filtrate was evaporated under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate=9: 1-4:1) was purified to obtain compound 48-6 (yellow solid, 4.52 g).

Weigh copper bromide (4.67g, 20.9mmol) and place it in a 250mL three-necked flask, add ethyl acetate (80mL), dissolve compound 48-6 (4.52g, 13.94mmol) in ethyl acetate (100mL), pass Add the ethyl acetate solution of compound 48-6 into the reaction system drop by drop under the reflux condition of the dropping funnel, and continue to reflux for 8 hours after the addition is complete. After the reaction, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=1:1) to obtain compound 48-7 (yellow solid, 2.12 g).

Weigh compound 48-7 (1008mg, 2.5mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (540mg, 3mmol) into a 300mL pressure-resistant reaction tube, then add isopropanol ( 50 mL), the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 250mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=10:1-1:3) , to obtain compound 48 (yellow solid, 700 mg). ¹ H NMR (300MHz, CDCl ₃ )δ8.64(s,1H),7.50-7.33(m,5H),7.07(s,1H),6.48(s,1H),5.18(s,2H),4.32( s,4H).ESI-HRMS:calcd.ForC ₂₁ H ₁₅ BrN ₃ O ₄ S[M+H] ⁺ 485.9941,found:485.9931.

Example 49

6-(6-(Benzyloxy)-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-2- Methoxyimidazo[2,1-b][1,3,4]thiadiazole (compound 49)

Compound 48 (80mg, 0.165mmol) was weighed and dissolved in a mixed solvent of dichloromethane (6mL) and methanol (2mL), then sodium methoxide in methanol (4M, 45μL) was added and reacted for 1h at room temperature. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (10mL), the aqueous phase was extracted with ethyl acetate (10mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (20mL x 1), anhydrous sulfuric acid The sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=10:1:1-7:1:1) to obtain compound 49 ( White solid, 36 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ7.92(s, 1H), 7.48-7.31(m, 5H), 7.14(s, 1H), 6.36(s, 1H), 5.13(s ,2H), 4.38-4.33(m,4H), 4.20(s,3H).ESI-MS: m/z 458.1[M+Na] ⁺ .

Example 50

6-(6-(Benzyloxy)-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-2- (Methylthio)imidazo[2,1-b][1,3,4]thiadiazole (compound 50)

Weigh compound 48-7 (201mg, 0.5mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (81mg, 0.55mmol) into a 15mL pressure-resistant reaction tube, and then add N , N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 110°C for 2h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: dichloromethane/ethyl acetate=100:1) to obtain compound 50 (brown solid, 159 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.04(s, 1H), 7.48 -7.32(m,5H),7.18(s,1H),6.36(s,1H),5.13(s,2H),4.38-4.33(m,4H),2.77(s,3H).ESI-MS:m /z474.1[M+Na] ⁺ .

Example 51

2-(6-(Benzyloxy)-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-6- Methylimidazo[1,2-b]pyridazine (compound 51)

Weigh compound 48-7 (35mg, 0.087mmol) and 3-amino-6-methylpyridazine (10mg, 0.09mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (8mL), and The mixture solution was purged for 5 min. The system was moved into an oil bath and reacted at 65°C for 12h. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=10:1-4:1) to obtain compound 51 (yellow solid, 9 mg): ¹ H NMR(300MHz, CDCl ₃ )δ8.26(s,1H),7.80(d,J=9.3Hz,1H),7.48-7.30(m,6H),6.92(d,J=9.3Hz,1H),6.37 (s,1H),5.14(s,2H),4.46-4.29(m,4H),2.58(s,3H).ESI-MS: m/z 436.1[M+Na] ⁺ .

Example 52

6-(6-(Benzyloxy)-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)imidazo[ 1,2-b][1,2,4]triazine (compound 52)

Weigh compound 48-7 (101mg, 0.25mmol) and 1,2,4-triazin-3-amine (36mg, 0.36mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5mL) to The mixture solution was purged with argon for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=10:1:1-2:1:1) to obtain compound 52 ( Yellow solid, 26 mg): ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.83(s, 1H), 8.70(d, J=1.7Hz, 1H), 8.63(d, J=1.7Hz, 1H), 7.55-7.33(m,6H),6.56(s,1H),5.24(s,2H),4.38(m,4H).ESI-MS: m/z 423.1[M+Na] ⁺ .

Example 53

6-(6-(Benzyloxy)-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-2- Methoxyimidazo[2,1-b][1,3,4]thiadiazole (Compound 53)

Compound 48 (80mg, 0.165mmol) was weighed and dissolved in a mixed solvent of dichloromethane (6mL) and methanol (2mL), then sodium methoxide in methanol (4M, 45μL) was added and reacted for 1h at room temperature. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (10 mL), the aqueous phase was extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 1), and dried over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=10:1:1-7:1:1) to obtain compound 53 (white solid , 36 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ7.92(s, 1H), 7.48-7.31(m, 5H), 7.14(s, 1H), 6.36(s, 1H), 5.13(s, 2H ), 4.38-4.33(m,4H), 4.20(s,3H).ESI-MS: m/z 458.1[M+Na] ⁺ .

Example 54

8-(2-Methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2,3-dihydro-[1,4]dioxane Dieno[2,3-g]benzofuran-6-ol (Compound 54)

Under an argon atmosphere, compound 49 (204 mg, 0.468 mmol) and pentamethylbenzene (485 mg, 3.276 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL), the system was placed at -78 ° C, and three After the addition of boron chloride (1M in DCM, 1.17mL, 1.17mmol), the reaction was continued at -78°C for 1.5h. After the reaction was completed, sodium bicarbonate solution (0.7M in DCM, 10 mL) was added at -78°C to quench the reaction, raised to room temperature, continued to stir for 1 h, filtered with suction, washed the filter cake with toluene (5 mL), and dried in vacuo. Compound 54 (white solid, 130mg) was obtained: ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.49(s, 1H), 8.33(s, 1H), 6.98(s, 1H), 6.17(s, 1H) ,4.28(s,4H),4.20(s,3H).

Example 55

6-(6-Cyclopropyl-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-2-methoxy Imidazo[2,1-b][1,3,4]thiadiazole (Compound 55)

Weigh compound 38-3 (486mg, 2mmol), cyclopropylboronic acid (224mg, 2.6mmol), anhydrous potassium phosphate (1484mg, 7mmol), tricyclohexylphosphine (224mg, 0.8mmol), palladium acetate (90mg, 0.4 mmol) were placed in a 15 mL pressure-resistant reaction tube, toluene (10 mL) and water (0.5 mL) were added, argon was bubbled and purged for 5 min, sealed, and the system was reacted at 85° C. for 4 h. After the reaction was completed, ethyl acetate (50 mL) was added to dilute the reaction system, suction filtered, the solids were filtered off, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (10 mL x 2). Dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and purify the residue by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=15:1:1) to obtain compound 55-1 (yellow solid , 337 mg).

Compound 55-1 (330 mg, 1.62 mmol) was weighed and dissolved in dichloromethane (20 mL), and m-chloroperoxybenzoic acid (395 mg, 1.94 mmol, 85%) was added in batches under ice-bath conditions, and then the ice bath was removed. After the system returned to room temperature, it was transferred to an oil bath and reacted under reflux for 12 hours. Most of the solvent was evaporated under reduced pressure, and the residue containing compound 55-2 was directly used in the next reaction without further treatment.

The residue containing compound 55-2 obtained in the previous reaction was dissolved in methanol (5 mL), and 10% potassium hydroxide solution (20 mL) was slowly added under ice-cooling conditions, and reacted at room temperature for 6 h. After the reaction, the system was adjusted to pH=1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (20mL x 3), the organic phase was combined, and the organic phase was washed with saturated sodium bicarbonate solution (10mL x 2) and saturated brine ( 10mL x 1) was washed, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=10:1:1-6:1: 1) Purification to obtain compound 55-3 (yellow oil, 125 mg).

Under an argon atmosphere, dissolve compound 55-3 (125 mg, 0.65 mmol) in anhydrous dichloromethane, add dichloromethyl methyl ether (88 μL, 0.98 mmol), and add dropwise at 0°C A solution of titanium tetrachloride (143 μL, 1.3 mmol) in dichloromethane (4 mL) was added and stirred at room temperature for 48 h. After the reaction was complete, 1N hydrochloric acid solution (10mL) was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (10mL x 3), the organic phase was combined, and the organic phase was washed with saturated brine (10mL x 1) and dried over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue containing compound 55-4 was directly used in the next reaction without further purification.

The residue containing compound 55-4 obtained in the previous reaction was dissolved in acetone (20 mL), and then potassium carbonate (226 mg, 1.64 mmol) and 1-chloroacetone (85 μL, 1.06 mmol) were added sequentially. The system was reacted under reflux for 6h. After the reaction was finished, ethyl acetate (30 mL) was added to dilute the reaction solution, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate/dichloro Methane=20:1:1-10:1:1) was purified to obtain compound 55-5 (light green solid, 55 mg).

Weigh copper bromide (1082mg, 4.85mmol) and place it in a 100mL three-necked flask, add ethyl acetate (20mL), dissolve compound 55-5 (500mg, 1.94mmol) in ethyl acetate (20mL), and drop With the funnel under reflux conditions, the ethyl acetate solution of compound 55-5 was added dropwise into the reaction system, and the reflux was continued for 8 hours after the addition was complete. After the reaction, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=3:2-1:1) to obtain compound 55 -6 (yellow solid, 320 mg).

Weigh compound 55-6 (92.5mg, 0.274mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (59.4mg, 0.33mmol) into a 15mL pressure-resistant reaction tube, then add iso Propanol (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction was completed, the reaction system was transferred into a 100 mL flask with dichloromethane, and the solvent was evaporated under reduced pressure. The residue containing compound 55-7 was directly used in the next step without further reaction.

The crude compound 55-7 obtained in the previous reaction was dissolved in a mixed solvent of dichloromethane (15 mL) and methanol (5 mL), and then a methanol solution of sodium methoxide (4M, 163 μL) was added to react at room temperature for 1 h. After the reaction, quench the reaction with saturated ammonium chloride solution (10mL), extract with ethyl acetate (10mL x 3), combine the organic phases, wash the organic phase with saturated brine (20mL x 1), and dry over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=20:1:1-10:1:1) to obtain compound 55 (yellow solid , 15mg): ¹ H NMR (300MHz, CDCl ₃ ) δ7.94(s, 1H), 7.15(s, 1H), 6.46(s, 1H), 4.40-4.37(m, 2H), 4.33-4.29(m ,2H),4.21(s,3H),2.08-2.00(m,1H),0.99-0.90(m,2H),0.78-0.69(m,2H).ESI-MS: m/z 392.1[M+Na ] ⁺ .

Example 56

6-(6-Cyclopropyl-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-2-(methylthio base) imidazo[2,1-b][1,3,4]thiadiazole (compound 56)

Weigh compound 55-6 (75mg, 0.222mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (40mg, 0.267mmol) into a 15mL pressure-resistant reaction tube, and then add N , N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 110°C for 2h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=15:1:1-10:1:1) to obtain compound 56 (yellow solid, 80mg): ¹ H NMR (300MHz, CDCl ₃ )δ8.06(s,1H),7.19(s,1H),6.46(s,1H),4.41-4.31(m,4H),2.76(s,3H),2.09-2.00(m,1H),0.98 -0.92(m,2H),0.77-0.71(m,2H).ESI-MS: m/z 408.1[M+Na] ⁺ .

Example 57

2-(6-Cyclopropyl-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-6-methylimidazole And[1,2-b]pyridazine (compound 57)

Weigh compound 55-6 (75mg, 0.222mmol) and 3-amino-6-methylpyridazine (30mg, 0.267mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5mL), and The mixture solution was purged for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=15:1:1-10:1:1) to obtain compound 57 ( Yellow solid, 60 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.27(s, 1H), 7.80(d, J=9.3Hz, 1H), 7.40(s, 1H), 6.92(d, J=9.3 Hz,1H),6.48(s,1H),4.42-4.32(m,4H),2.57(s,3H),2.11-2.02(m,1H),0.99-0.93(m,2H),0.78-0.73( m,2H).ESI-MS: m/z 370.1[M+Na] ⁺ .

Example 58

6-(6-Cyclopropyl-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)imidazo[1,2 -b][1,2,4]triazine (compound 58)

Weigh compound 55-6 (80mg, 0.24mmol) and 1,2,4-triazin-3-amine (34mg, 0.353mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5mL) to The mixture solution was purged with argon for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=10:1:1-2:1:1) to obtain compound 58 ( Orange solid, 20 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.44(d, J=1.7Hz, 1H), 8.38(s, 1H), 8.33(d, J=1.8Hz, 1H), 7.62 (s,1H),6.49(s,1H),4.46-4.32(m,4H),2.08(dd,J＝9.4,4.0Hz,1H),1.04-0.95(m,2H),0.80-0.73(m ,2H).ESI-MS: m/z 357.1[M+Na] ⁺ .

Example 59

6-(6-(Cyclohex-1-en-1-yl)-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8 -yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole (Compound 59)

Weigh compound 38-7 (1g, 3.4mmol), cyclohexen-1-ylboronic acid (933mg, 7.4mmol), palladium acetate (378mg, 1.7mmol), triphenylphosphine (883mg, 3.4mmol), potassium carbonate (2.8g, 20.2mmol) was placed in a 125mL thick-walled pressure bottle, added toluene (30mL) and water (3.3mL), purged with argon for 5min, sealed, and placed at 90°C for 8h. After the reaction is complete, add ethyl acetate (50mL) to dilute the reaction system, filter with suction, remove the solids in the system, extract with ethyl acetate (30mL x 2), wash with saturated brine (20mL x 1), and dry over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=30:1:1-25:1:1-20:1:1) to obtain Compound 59-1 (yellow solid, 700 mg).

Compound 59-1 (577 mg, 2 mmol) was weighed and placed in a 100 mL two-neck bottle, the air in the system was exchanged with argon to treat the device anaerobically, and then anhydrous dichloromethane (20 mL) was added through a syringe. Under ice bath conditions, a solution of N,N-diisopropylethylamine (748 mg, 5.8 mmol) in anhydrous dichloromethane (5 mL) was slowly added, and the system was reacted under ice bath conditions for 0.5 h. A solution of triisopropylsilyl triflate (888 mg, 3 mmol) in anhydrous dichloromethane (5 mL) was then added dropwise under ice-bath conditions. After the addition was completed, it was raised to room temperature and stirred overnight. After the reaction, the system was quenched with saturated sodium bicarbonate solution (30mL), the aqueous phase was extracted with dichloromethane (15mL x 3), the organic phases were combined, and saturated sodium bicarbonate solution (20mL x 1) and saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, evaporated the solvent under reduced pressure, and the residue containing compound 59-2 was directly used in the next reaction without further purification.

The 100mL two-neck bottle exchanged the air in the system with argon, and treated the device anaerobically, and then added anhydrous tetrahydrofuran (25mL) solution containing the residue obtained from the previous step reaction of compound 59-2 through a syringe, and placed it in an ice bath. Under conditions, a solution of N-bromosuccinimide (534 mg, 3 mmol) in anhydrous THF (10 mL) was added dropwise. After addition, rise to room temperature and stir for 3h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=2:1-1:1) to obtain compound 59-3 (yellow solid, 250 mg).

Weigh compound 59-3 (123mg, 0.33mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (71mg, 0.39mmol) into a 35mL pressure-resistant reaction tube, then add isopropanol (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 100 mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue containing compound 59-4 was directly used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the previous step containing compound 59-4 was dissolved in a mixed solvent of dichloromethane (12 mL) and methanol (4 mL), and then a methanol solution of sodium methoxide (4M, 200 μL) was added. Reaction 1h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (10 mL), the aqueous phase was extracted with dichloromethane (10 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 1), and dried over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=30:1:1-15:1:1) to obtain compound 59 (white solid, 20mg ): ¹ H NMR (300MHz, CDCl ₃ ) δ7.94(s,1H),7.18(s,1H),6.72(s,1H),6.08(m,1H),4.43-4.35(m,4H), 4.21(s,3H),2.42(m,2H),2.22(m,2H),1.83-1.67(m,4H).

Example 60

6-(6-(Cyclohex-1-en-1-yl)-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8 -yl)-2-methylthioimidazo[2,1-b][1,3,4]thiadiazole (compound 60)

Weigh compound 59-3 (120mg, 0.32mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (56mg, 0.38mmol) into a 35mL pressure-resistant reaction tube, and then add Water N,N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 90°C for 4h, the reaction was continued at 120°C for 3h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=10:1:1-8:1:1) to obtain compound 60 (white solid, 30mg): ¹ H NMR (300MHz, CDCl ₃ )δ8.06(s,1H),7.22(s,1H),6.72(s,1H),6.08(s,1H),4.47-4.31(m,4H),2.77(s,3H),2.47-2.37 (m,2H),2.28-2.19(m,2H),1.85-1.63(m,4H).ESI-MS:m/z 448.1[M+Na] ⁺ .

Example 61

2-(6-(Cyclohex-1-en-1-yl)-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8 -yl)-6-methylimidazo[1,2-b]pyridazine (compound 61)

Weigh compound 59-3 (30mg, 0.08mmol) and 3-amino-6-methylpyridazine (11mg, 0.095mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5mL), and The mixture solution was purged for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=10:1:1-4:1:1) to obtain compound 61 ( Yellow solid, 12 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.31(s, 1H), 7.83(d, J=9.3Hz, 1H), 7.45(s, 1H), 6.95(d, J=9.3 Hz,1H),6.76(s,1H),6.12(s,1H),4.50-4.33(m,4H),2.60(s,3H),2.51-2.40(m,2H),2.31-2.20(m, 2H), 1.88-1.79(m,2H), 1.78-1.67(m,2H).ESI-MS: m/z 410.2[M+Na] ⁺ .

Example 62

6-(6-(Cyclohex-1-en-1-yl)-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8 -yl) imidazo[1,2-b][1,2,4]triazine (compound 62)

Weigh compound 41 (25mg, 0.07mmol), cyclohexen-1-ylboronic acid (20mg, 0.15mmol), palladium acetate (8mg, 0.03mmol), triphenylphosphine (18mg, 0.07mmol), potassium carbonate (56mg , 0.40 mmol) into a 15 mL thick-walled pressure-resistant bottle, added toluene (3 mL) and water (300 μL), purged with argon for 5 min, sealed, and placed at 90 ° C for 8 h. After the reaction was complete, ethyl acetate (20 mL) was added to dilute the reaction system, the solids in the system were removed by suction filtration, extracted with ethyl acetate (10 mL x 2), washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=50:150:1-50:150:5) to obtain compound 62 (orange solid, 15 mg): ¹ HNMR (300MHz, CDCl ₃ ) δ8.44(s, 1H), 8.38(s, 1H), 8.33(s, 1H), 7.65(s, 1H), 6.76(s, 1H), 6.11( s,1H),4.45-4.37(m,4H),2.44(s,2H),2.25(s,2H),1.82-1.71(m,4H).ESI-MS:m/z 397.1[M+Na] ⁺ .

Example 63

6-Methyl-2-(6-phenyl-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)imidazo [1,2-b]pyridazine (Compound 63)

Weigh compound 40 (66mg, 0.2mmol), phenylboronic acid (46mg, 0.4mmol), palladium acetate (20mg, 0.1mmol), triphenylphosphine (45mg, 0.2mmol), potassium carbonate (142mg, 1.0mmol) in Toluene (5 mL) and water (555 μL) were added to a 35 mL thick-walled pressure-resistant bottle, purged with argon for 5 min, sealed, and placed at 90° C. for 8 h. After the reaction was complete, ethyl acetate (20 mL) was added to dilute the reaction system, the solids in the system were removed by suction filtration, extracted with ethyl acetate (10 mL x 2), washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=20:1:1-5:1:1) to obtain compound 63 (yellow solid, 50mg ). ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.61(s, 1H), 8.01(d, J=9.3Hz, 1H), 7.64(d, J=7.5Hz, 2H), 7.52(t, J= 7.6Hz, 2H), 7.40(t, J=7.3Hz, 1H), 7.34(s, 1H), 7.20(d, J=9.5Hz, 1H), 6.97(s, 1H), 4.48-4.38(m, 4H), 2.54(s,3H).ESI-MS: m/z 406.2[M+Na] ⁺ .

Example 64

2-Methoxy-6-(6-(p-tolyl)-2,3-dihydro[1,4]dioxino[2,3-g]benzofuran-8- base) imidazo[2,1-b][1,3,4]thiadiazole (compound 64)

Weigh compound 38-7 (267mg, 0.9mmol), 4-methylphenylboronic acid (269mg, 2.0mmol), palladium acetate (100mg, 0.45mmol), triphenylphosphine (236mg, 0.9mmol), potassium carbonate (745mg , 5.4 mmol) into a 35 mL thick-walled pressure-resistant bottle, added toluene (5 mL) and water (555 μL), purged with argon for 5 min, sealed, and placed at 90 ° C for 8 h. After the reaction is complete, add ethyl acetate (20mL) to dilute the reaction system, filter with suction, filter off the solids in the system, extract with ethyl acetate (10mL x 2), wash with saturated brine (10mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=20:1-10:1) to obtain compound 64-1 (yellow-green solid, 203 mg).

Weigh copper bromide (191mg, 0.86mmol) and place it in a 100mL three-necked flask, add ethyl acetate (15mL), dissolve compound 64-1 (203mg, 0.66mmol) in ethyl acetate (30mL), and drop With the funnel under reflux, add the ethyl acetate solution of compound 64-1 into the reaction system dropwise. After the addition, continue to reflux for 8 hours. After the reaction, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/dichloromethane=4:1-3:1-2:1-1 :1) purification to obtain compound 64-2 (yellow-white solid, 187 mg).

Weigh compound 64-2 (92.5mg, 0.239mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (52mg, 0.287mmol) into a 15mL pressure-resistant reaction tube, then add isopropyl alcohol (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 100 mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue containing compound 64-3 was directly used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the previous step containing compound 64-3 was dissolved in a mixed solvent of dichloromethane (15 mL) and methanol (5 mL), and then a methanol solution of sodium methoxide (4M, 155 μL) was added to react at room temperature 1h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (10 mL), the aqueous phase was extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 1), and dried over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=20:1:1-15:1:1-10:1:1-8:1 :1) Compound 64 was purified (yellow solid, 40 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ7.96(s, 1H), 7.52(d, J=7.9Hz, 2H), 7.24(s, 1H) ,7.21(m,2H),6.92(s,1H),4.52-4.35(m,4H),4.21(s,3H),2.41(s,3H).ESI-MS: m/z 420.0[M+H ] ⁺ .

Example 65

2-Methylthio-6-(6-(p-tolyl)-2,3-dihydro[1,4]dioxino[2,3-g]benzofuran-8- base) imidazo[2,1-b][1,3,4]thiadiazole (compound 65)

Weigh compound 64-2 (72mg, 0.2mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (35mg, 0.24mmol) into a 15mL pressure-resistant reaction tube, and then add Water N,N-dimethylformamide (3 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 90°C for 4h, the reaction was continued at 120°C for 3h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=20:1:1-10:1:1-8:1:1) to obtain compound 65 (yellow solid, 54 mg): ¹ H NMR(300MHz, CDCl ₃ )δ8.08(s,1H),7.51(d,J=7.9Hz,2H),7.24(d,J=3.5Hz,2H),6.93(s,1H),4.51-4.36 (m,5H),2.77(s,3H),2.41(s,3H).

Example 66

6-Methyl-2-(6-(p-methylphenyl)-2,3-dihydro[1,4]dioxino[2,3-g]benzofuran-8- base) imidazo[1,2-b]pyridazine (compound 66)

Weigh compound 40 (70mg, 0.2mmol), 4-methylphenylboronic acid (55mg, 0.4mmol), palladium acetate (21mg, 0.1mmol), triphenylphosphine (48mg, 0.2mmol), potassium carbonate (151mg, 1.1 mmol) in a 35 mL thick-walled pressure-resistant bottle, added toluene (5 mL) and water (555 μL), purged with argon for 5 min, sealed, and placed at 90 ° C for 8 h. After the reaction is complete, add ethyl acetate (20mL) to dilute the reaction system, filter with suction, filter off the solids in the system, extract with ethyl acetate (10mL x 2), wash with saturated brine (10mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=20:1:1-5:1:1) to obtain compound 66 (yellow solid , 40mg): ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.60(s, 1H), 8.01(d, J=9.4Hz, 1H), 7.53(d, J=7.9Hz, 2H), 7.32( d,J=7.8Hz,2H),7.33(s,1H),7.20(d,J=9.4Hz,1H),6.93(s,1H),4.48-4.36(m,4H),2.54(s,3H ),2.38(s,3H).ESI-HRMS:calcd.for C ₂₄ H ₁₉ N ₃ O ₃ [M+Na] ⁺ 420.1319,found:420.1319.

Example 67

6-(6-(p-tolyl)-2,3-dihydro[1,4]dioxino[2,3-g]benzofuran-8-yl)imidazo[1, 2-b][1,2,4]triazine (Compound 67)

Weigh compound 41 (80mg, 0.214mmol), 4-methylphenylboronic acid (64mg, 0.471mmol), palladium acetate (24mg, 0.107mmol), triphenylphosphine (56mg, 0.214mmol), potassium carbonate (177mg, 1.284 mmol) in a 15 mL thick-walled pressure-resistant bottle, added toluene (3 mL) and water (300 μL), purged with argon for 5 min, sealed, and placed at 100 ° C for 8 h. After the reaction is complete, add ethyl acetate (20mL) to dilute the reaction system, filter with suction, filter off the solids in the system, extract with ethyl acetate (10mL x 2), wash with saturated brine (10mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=20:50:1-6:20:1) to obtain compound 67 (orange Solid, 67 mg): ¹ HNMR (300MHz, DMSO-d ₆ ) δ8.87(s, 1H), 8.70(d, J=2.0Hz, 1H), 8.63(d, J=2.0Hz, 1H), 7.57( d,J=8.0Hz,2H),7.51(s,1H),7.36(d,J=8.0Hz,2H),6.98(s,1H),4.48-4.42(m,4H),2.41(s,3H ).ESI-HRMS: calcd.for C ₂₂ H ₁₇ N ₄ O ₃ [M+H] ⁺ 385.1295, found: 385.1300.

Example 68

2-(6-(4-methoxyphenyl)-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl) -6-Methylimidazo[1,2-b]pyridazine (Compound 68)

Weigh compound 40 (66mg, 0.17mmol), 4-methoxyphenylboronic acid (57mg, 0.38mmol), palladium acetate (20mg, 0.1mmol), triphenylphosphine (45mg, 0.2mmol), potassium carbonate (142mg, 1.0 mmol) in a 35 mL thick-walled pressure-resistant bottle, added toluene (5 mL) and water (555 μL), purged with argon for 5 min, sealed, and placed at 90 ° C for 8 h. After the reaction is complete, add ethyl acetate (20mL) to dilute the reaction system, filter with suction, filter off the solids in the system, extract with ethyl acetate (10mL x 2), wash with saturated brine (10mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=20:1:1-5:1:1) to obtain compound 68 (yellow solid , 40mg). ¹ H NMR (300MHz, DMSO-d ₆ )δ8.59(s, 1H), 8.01(d, J=9.4Hz, 1H), 7.57(d, J=8.7Hz, 2H), 7.32(s, 1H) ,7.20(d,J=9.4Hz,1H),7.08(d,J=8.7Hz,2H),6.90(s,1H),4.46-4.38(m,4H),3.83(s,3H),2.54( s,3H).ESI-MS: m/z 436.2[M+Na] ⁺ .

Example 69

2-(6-(4-fluorophenyl)-2,3-dihydro[1,4]dioxino[2,3-g]benzofuran-8-yl)-6- Methylimidazo[1,2-b]pyridazine (Compound 69)

Weigh compound 40 (80mg, 0.21mmol), 4-fluorophenylboronic acid (64mg, 0.456mmol), palladium acetate (24mg, 0.104mmol), triphenylphosphine (55mg, 0.21mmol), potassium carbonate (172mg, 1.243mmol ) into a 35mL thick-walled pressure-resistant bottle, add toluene (5mL) and water (555μL), purge with argon for 5min, seal the bottle, and place it at 90°C for 8h. After the reaction is complete, add ethyl acetate (20mL) to dilute the reaction system, filter with suction, filter off the solids in the system, extract with ethyl acetate (10mL x 2), wash with saturated brine (10mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=20:1:1-5:1:1) to obtain compound 69 (yellow solid , 38 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.31(s, 1H), 7.80(d, J=9.3Hz, 1H), 7.62-7.56(m, 2H), 7.39(s, 1H), 7.14(t, J=8.7Hz, 2H), 6.94(d, J=9.4Hz, 1H), 6.91(s, 1H), 4.51-4.38(m, 4H), 2.59(s, 3H).ESI-HRMS :calcd.for C ₂₃ H ₁₇ FN ₃ O ₃ [M+H] ⁺ 402.1248, found: 402.1249.

Example 70

6-(6-(4-fluorophenyl)-2,3-dihydro[1,4]dioxino[2,3-g]benzofuran-8-yl)imidazo[ 1,2-b][1,2,4]triazine (Compound 70)

Weigh compound 41 (79mg, 0.212mmol), 4-fluorophenylboronic acid (65mg, 0.466mmol), palladium acetate (24mg, 0.107mmol), triphenylphosphine (56mg, 0.214mmol), potassium carbonate (177mg, 1.284mmol ) into a 15mL thick-walled pressure-resistant bottle, add toluene (3mL) and water (300μL), purge with argon for 5min, seal the bottle, and place it at 100°C for 8h. After the reaction is complete, add ethyl acetate (20mL) to dilute the reaction system, filter with suction, filter off the solids in the system, extract with ethyl acetate (10mL x 2), wash with saturated brine (10mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=20:50:1-6:20:1) to obtain compound 70 (orange Solid, 75 mg): ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.87(s, 1H), 8.72(d, J=2.0Hz, 1H), 8.64(d, J=2.0Hz, 1H), 7.75 -7.70(m,2H),7.52(s,1H),7.40-7.34(m,2H),7.02(s,1H),4.55-4.40(m,4H).ESI-HRMS:calcd.for C ₂₁ H ₁₄ FN ₄ O ₃ [M+H] ⁺ 389.1044, found: 389.1047.

Example 71

6-Methyl-2-(6-(4-(trifluoromethyl)phenyl)-2,3-dihydro-[1,4]dioxino[2,3-g] Benzofuran-8-yl)imidazo[1,2-b]pyridazine (Compound 71)

Weigh compound 40 (80mg, 0.207mmol), 4-trifluoromethylphenylboronic acid (43mg, 0.228mmol), palladium acetate (12mg, 0.052mmol), triphenylphosphine (27mg, 0.104mmol), potassium carbonate (86mg , 0.621 mmol) into a 15 mL thick-walled pressure-resistant bottle, added toluene (5 mL) and water (250 μL), purged with argon for 5 min, sealed, and placed at 100 ° C for 8 h. After the reaction is complete, add ethyl acetate (20mL) to dilute the reaction system, filter with suction, filter off the solids in the system, extract with ethyl acetate (10mL x 2), wash with saturated brine (10mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=20:1:1-10:1:1) to obtain compound 71 (yellow green Solid, 20 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.31 (s, 1H), 7.82-7.69 (m, 5H), 7.41 (s, 1H), 6.98-6.93 (m, 2H), 4.50- 4.41(m,4H),2.59(s,3H).ESI-HRMS:calcd.for C ₂₄ H ₁₇ F ₃ N ₃ O ₃ [M+H] ⁺ 402.1217,found:402.1218.

Example 72

6-(6-(4-(trifluoromethyl)phenyl)-2,3-dihydro[1,4]dioxino[2,3-g]benzofuran-8- base) imidazo[1,2-b][1,2,4]triazine (compound 72)

Weigh compound 41 (48mg, 0.129mmol), 4-trifluoromethylphenylboronic acid (54mg, 0.283mmol), palladium acetate (14mg, 0.064mmol), triphenylphosphine (34mg, 0.128mmol), potassium carbonate (106g , 0.772mmol) into a 15mL thick-walled pressure-resistant bottle, added toluene (3mL) and water (300μL), purged with argon for 5min, sealed, and placed at 100°C for 8h. After the reaction is complete, add ethyl acetate (20mL) to dilute the reaction system, filter with suction, filter off the solids in the system, extract with ethyl acetate (10mL x 2), wash with saturated brine (10mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=20:50:1-6:20:1) to obtain compound 72 (orange Solid, 34 mg): ¹ HNMR (300MHz, CDCl ₃ ) δ8.88(s, 1H), 8.71(d, J=2.0Hz, 1H), 8.64(d, J=2.0Hz, 1H), 7.98-7.83( m,4H),7.59(s,1H),7.13(s,1H),4.56-4.40(m,4H).ESI-HRMS:calcd.for C ₂₂ H ₁₄ F ₃ N ₄ O ₃ [M+H] ⁺ 439.1013,found: 439.1012.

Example 73

2-(Methylthio)-6-(6-(pyrrolidin-1-yl)-2,3-dihydro[1,4]dioxino[2,3-g]benzo Furan-8-yl)imidazo[2,1-b][1,3,4]thiadiazole (Compound 73)

Compound 38-7 (1.91g, 6.43mmol) was weighed and dissolved in toluene (25mL), p-toluenesulfonic acid (245mg, 1.29mmol) was added, the water separator was connected, and the system was reacted under reflux for 8h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (20 mL x 2) and saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purification by chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=20:1:1-15:1:1) gave compound 73-1 (white solid, 1.624 g).

Weigh compound 73-1 (233mg, 0.683mmol), tetrahydropyrrole (67μL, 0.82mmol), tris(dibenzylideneacetone) dipalladium (62mg, 0.07mmol), 2-dicyclohexylphosphine-2,4 , 6-triisopropylbiphenyl (82mg, 0.17mmol), sodium tert-butoxide (79mg, 0.82mmol) were placed in a 35mL thick-walled pressure-resistant bottle, anhydrous toluene (5mL) was added, frozen pumped 3 times, and placed Reaction at 90°C for 6h. After the reaction is complete, add ethyl acetate (20mL) to dilute the reaction system, filter with suction, filter off the solids in the system, extract with ethyl acetate (10mL x 2), wash with saturated brine (10mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=10:1:1) to obtain compound 73-2 (red solid, 149 mg).

Weighed compound 73-2 (149 mg, 0.45 mmol) and dissolved it in acetone (10 mL), added 2N hydrochloric acid solution (5 mL), and reacted at room temperature for 1 h. After the reaction, the system was adjusted to alkaline with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10mL x 2), the organic phases were combined, and the organic phase was washed with saturated brine (10mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue containing compound 73-3 was directly used in the next reaction without further treatment.

The residue containing compound 73-3 obtained in the previous step reaction was placed in a 25 mL two-necked bottle, the air in the system was exchanged with argon, the device was anaerobically treated, and then anhydrous dichloromethane (5 mL) was added through a syringe. Under ice bath conditions, a solution of N,N-diisopropylethylamine (230 μL, 1.39 mmol) in anhydrous dichloromethane (1 mL) was slowly added, and the system was reacted under ice bath conditions for 0.5 h. A solution of triisopropylsilyl triflate (186 μL, 0.69 mmol) in anhydrous dichloromethane (1 mL) was then added dropwise under ice-bath conditions. After the addition was completed, it was raised to room temperature and stirred overnight. After the reaction, the system was quenched with saturated sodium bicarbonate solution (10mL), the aqueous phase was extracted with dichloromethane (8mL x 3), the organic phase was combined, and the organic phase was washed with saturated sodium bicarbonate solution (10mL x 1) and saturated It was washed with brine (10 mL x 1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue containing compound 73-4 was directly used in the next reaction without further purification.

The 25mL two-neck bottle exchanged the air in the system with argon, and treated the device anaerobically, and then added anhydrous tetrahydrofuran (5mL) solution containing the residue obtained from the previous step reaction of compound 73-4 through a syringe, and placed it in an ice bath. Under conditions, a solution of N-bromosuccinimide (90 mg, 0.51 mmol) in anhydrous THF (1 mL) was added dropwise. After addition, rise to room temperature and stir for 3h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=15:1:1) to obtain compound 73-5 (red solid, 60mg ).

Weigh compound 73-5 (60mg, 0.164mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (29mg, 0.197mmol) into a 35mL pressure-resistant reaction tube, and then add Water N,N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 90°C for 4h, the reaction was continued at 120°C for 3h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=4:1:1) to obtain compound 73 (yellow solid, 23 mg): 1H NMR (300MHz, CDCl ₃ ) δ8.03(s, 1H),5.91(s,1H),4.51-4.24(m,4H),3.82-3.17(m,4H),2.76(s,3H),2.11-1.87(m,4H).ESI-MS:m/ z437.1[M+Na] ⁺ .

Example 74

2-Bromo-6-(6-(piperidin-1-yl)-2,3-dihydro[1,4]dioxino[2,3-g]benzofuran-8- base) imidazo[2,1-b][1,3,4]thiadiazole (compound 74)

Weigh compound 73-1 (200mg, 0.586mmol), piperidine (64μL, 0.703mmol), tris(dibenzylideneacetone) dipalladium (54mg, 0.06mmol), 2-dicyclohexylphosphine-2,4, 6-triisopropylbiphenyl (70mg, 0.147mmol), sodium tert-butoxide (68mg, 0.703mmol) were placed in a 35mL thick-walled pressure-resistant bottle, anhydrous toluene (5mL) was added, frozen for 3 times, and placed in React at 90°C for 6h. After the reaction is complete, add ethyl acetate (20mL) to dilute the reaction system, filter with suction, filter off the solids in the system, extract with ethyl acetate (10mL x 2), wash with saturated brine (10mL x 1), and dry over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=10:1:1) to obtain compound 74-1 (red solid, 152 mg).

Weighed compound 74-1 (152 mg, 0.44 mmol) and dissolved it in acetone (8 mL), added 2N hydrochloric acid solution (6 mL), and reacted at room temperature for 1 h. After the reaction, the system was adjusted to be alkaline with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10mL x 2), the organic phases were combined, washed with saturated brine (10mL x 1), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue containing compound 74-2 was directly used in the next reaction without further treatment.

The residue containing compound 74-2 obtained in the previous step reaction was placed in a 25 mL two-necked bottle, the air in the system was exchanged with argon, and the device was anaerobically treated, and then anhydrous dichloromethane (8 mL) was added through a syringe. Under ice bath conditions, a solution of N,N-diisopropylethylamine (218 μL, 1.32 mmol) in anhydrous dichloromethane (2 mL) was slowly added, and the system was reacted under ice bath conditions for 0.5 h. A solution of triisopropylsilyl triflate (177 μL, 0.66 mmol) in anhydrous dichloromethane (2 mL) was then added dropwise under ice-bath conditions. After the addition was completed, it was raised to room temperature and stirred overnight. After the reaction, the system was quenched with saturated sodium bicarbonate solution (10mL), the aqueous phase was extracted with dichloromethane (10mL x 3), the organic phases were combined, and saturated sodium bicarbonate solution (10mL x 1) and saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, evaporated the solvent under reduced pressure, and the residue containing compound 74-3 was directly used in the next reaction without further purification.

The 25mL two-neck bottle exchanged the air in the system with argon, and treated the device anaerobically, and then added anhydrous tetrahydrofuran (6mL) solution containing the residue obtained after the previous step reaction of compound 74-3 through a syringe, and placed it in an ice bath. Under conditions, a solution of N-bromosuccinimide (86 mg, 0.483 mmol) in anhydrous THF (2 mL) was added dropwise. After addition, rise to room temperature and stir for 3h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=15:1:1) to obtain compound 74-4 (red solid, 58mg ).

Weigh compound 74-4 (100mg, 0.264mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (57mg, 0.32mmol) into a 35mL pressure-resistant reaction tube, then add isopropanol (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 5h, the reaction was continued at 130°C for 3h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=15:1:1) to obtain compound 74 (yellow solid, 23mg): ¹ H NMR (300MHz, CDCl ₃ )δ8.15(s,1H),7.12(s,1H),6.31(s,1H),4.39(d,J=5.0Hz,2H),4.35(d,J=5.2 Hz,2H),3.12-3.03(m,4H),1.82-1.73(m,4H),1.65-1.58(m,2H).ESI-MS: m/z 485.1[M+Na] ⁺ .

Example 75

2-Methoxy-6-(6-(piperidin-1-yl)-2,3-dihydro[1,4]dioxino[2,3-g]benzofuran- 8-yl)imidazo[2,1-b][1,3,4]thiadiazole (compound 75)

Compound 74 (122mg, 0.264mmol) was weighed and dissolved in a mixed solvent of dichloromethane (15mL) and methanol (5mL), then sodium methoxide in methanol (4M, 160μL) was added and reacted for 1h at room temperature. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (15 mL), the aqueous phase was extracted with dichloromethane (10 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=10:1:1) to obtain compound 75 (orange solid, 24 mg): ¹ H NMR ( 300MHz, CDCl ₃ )δ7.93(s,1H),7.05(s,1H),6.29(s,1H),4.38(d,J＝4.8Hz,2H),4.34(d,J＝5.0Hz,2H ),4.20(s,3H),3.11-3.00(m,4H),1.75(d,J＝4.3Hz,4H),1.63-1.57(m,2H).ESI-MS:m/z435.1[M +Na] ⁺ .

Example 76

2-Methylthio-6-(6-(piperidin-1-yl)-2,3-dihydro[1,4]dioxino[2,3-g]benzofuran- 8-yl)imidazo[2,1-b][1,3,4]thiadiazole (Compound 76)

Weighed compound 74-4 (55mg, 0.145mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (26mg, 0.174mmol) into a 35mL pressure-resistant reaction tube, and then added Water N,N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 90°C for 4h, the reaction was continued at 120°C for 3h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=10:1:1-4:1:1) to obtain compound 76 (red solid, 27mg): ¹ H NMR (300MHz, CDCl ₃ )δ8.05(s,1H),7.09(s,1H),6.29(s,1H),4.45-4.25(m,4H),3.12-2.97(m,4H),2.76(s,3H),1.84 -1.68(m,4H),1.65-1.57(m,2H).ESI-MS: m/z 451.2[M+Na] ⁺ .

Example 77

6-Methyl-2-(6-(piperidin-1-yl)-2,3-dihydro[1,4]dioxino[2,3-g]benzofuran-8 -yl) imidazo[1,2-b]pyridazine (compound 77)

Weigh compound 74-4 (84mg, 0.222mmol) and 3-amino-6-methylpyridazine (29mg, 0.266mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5mL), and The mixture solution was purged for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=1:1:1) to obtain compound 77 (yellow solid, 34 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.28(s, 1H), 7.81(d, J=9.3Hz, 1H), 7.30(s, 1H), 6.92(d, J=9.3Hz, 1H), 6.31 (s,1H),4.48-4.31(m,4H),3.15-3.03(m,4H),2.58(s,3H),1.84-1.71(m,4H),1.64-1.57(m,2H).ESI -MS: m/z 413.2[M+Na] ⁺ .

Example 78

6-(6-(piperidin-1-yl)-2,3-dihydro[1,4]dioxino[2,3-g]benzofuran-8-yl)imidazo [1,2-b][1,2,4]triazine (Compound 78)

Weigh compound 74-4 (125mg, 0.33mmol) and 1,2,4-triazin-3-amine (48mg, 0.5mmol) into a 35mL pressure-resistant reaction tube, then add isopropanol (5mL) to The mixture solution was purged with argon for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=10:1:1-1:1:1) to obtain compound 78 ( Red solid, 39 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.43(d, J=1.9Hz, 1H), 8.38(s, 1H), 8.33(d, J=1.9Hz, 1H), 7.54( s,1H),6.32(s,1H),4.41(d,J=4.9Hz,2H),4.37(d,J=5.0Hz,2H),3.15-3.06(m,4H),1.84-1.75(m ,4H), 1.62 (dd, J=11.1, 6.1Hz, 2H).ESI-MS: m/z 400.2[M+Na] ⁺ .

Example 79

4-(8-(2-Methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2,3-dihydro-[1,4]dioxo Heterocyclohexadieno[2,3-g]benzofuran-6-yl)morpholine (compound 79)

Weigh compound 73-1 (402mg, 1.178mmol), morpholine (122μL, 1.41mmol), tris(dibenzylideneacetone) dipalladium (108mg, 0.118mmol), 2-dicyclohexylphosphine-2,4, 6-Triisopropylbiphenyl (140mg, 0.295mmol), sodium tert-butoxide (135mg, 1.41mmol) were placed in a 35mL thick-walled pressure-resistant bottle, anhydrous toluene (5mL) was added, frozen for 3 times, and placed in React at 90°C for 6h. After the reaction is complete, add ethyl acetate (20mL) to dilute the reaction system, filter with suction, filter off the solids in the system, extract with ethyl acetate (10mL x 2), wash with saturated brine (10mL x 1), and dry over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=4:1:1) to obtain compound 79-1 (yellow solid, 312 mg).

Weighed compound 79-1 (312 mg, 0.90 mmol) and dissolved it in acetone (10 mL), added 2N hydrochloric acid solution (8 mL), and reacted for 1 h at room temperature. After the reaction, the system was adjusted to be alkaline with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10mL x 2), the organic phases were combined, washed with saturated brine (10mL x 1), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue containing compound 79-2 was directly used in the next reaction without further treatment.

The residue containing compound 79-2 obtained in the previous step reaction was placed in a 50 mL two-necked bottle, the air in the system was exchanged with argon, and the device was anaerobically treated, and then anhydrous dichloromethane (15 mL) was added through a syringe. Under ice bath conditions, a solution of N,N-diisopropylethylamine (490 μL, 2.967 mmol) in anhydrous dichloromethane (2 mL) was slowly added, and the system was reacted under ice bath conditions for 0.5 h. A solution of triisopropylsilyl triflate (397 μL, 1.48 mmol) in anhydrous dichloromethane (2 mL) was then added dropwise under ice-bath conditions. After the addition was completed, it was raised to room temperature and stirred overnight. After the reaction, the system was quenched with saturated sodium bicarbonate solution (15mL), the aqueous phase was extracted with dichloromethane (10mL x 3), the organic phases were combined, and saturated sodium bicarbonate solution (10mL x 1) and saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, evaporated the solvent under reduced pressure, and the residue containing compound 79-3 was directly used in the next reaction without further purification.

The 50mL two-neck bottle exchanged the air in the system with argon, and treated the device anaerobically, and then added anhydrous tetrahydrofuran (10mL) solution containing the residue obtained from the post-reaction treatment of the previous step of compound 79-3 through a syringe. Under conditions, a solution of N-bromosuccinimide (194 mg, 1.1 mmol) in anhydrous THF (5 mL) was added dropwise. After addition, rise to room temperature and stir for 3h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=4:1:1) to obtain compound 79-4 (orange solid, 180mg).

Weigh compound 79-4 (82mg, 0.2mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (46mg, 0.26mmol) into a 35mL pressure-resistant reaction tube, then add isopropanol (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction was completed, the reaction system was transferred into a 100 mL flask with dichloromethane, and the solvent was evaporated under reduced pressure. The residue containing compound 79-5 was directly used in the next step without further reaction.

The crude compound 79-5 obtained in the previous reaction was dissolved in a mixed solvent of dichloromethane (9 mL) and methanol (3 mL), and then a methanol solution of sodium methoxide (4M, 150 μL) was added to react at room temperature for 1 h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (15 mL), the aqueous phase was extracted with dichloromethane (10 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 1), and dried over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=5:1:1-1:1:1) to obtain compound 79 (orange red solid , 34 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ7.94(s, 1H), 7.02(s, 1H), 6.33(s, 1H), 4.45-4.31(m, 4H), 4.21(s, 3H ), 3.96-3.83(m,4H), 3.19-3.03(m,4H).ESI-MS: m/z 437.1[M+Na] ⁺ .

Example 80

4-(8-(2-Methylthioimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2,3-dihydro-[1,4]dioxo Heterocyclohexa[2,3-g]benzofuran-6-yl)morpholine (Compound 80)

Weigh compound 79-4 (100mg, 0.262mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (46mg, 0.314mmol) into a 35mL pressure-resistant reaction tube, and then add Water N,N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 90°C for 4h, the reaction was continued at 120°C for 3h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=4:1:1) to obtain compound 80 (red solid, 28mg): ¹ H NMR (300MHz, CDCl ₃ ) δ7.92(s ,1H),8.06(s,1H),7.06(s,1H),6.31(s,1H),4.40-4.36(m,4H),3.91-3.89(m,4H),3.13-3.11(m,4H ), 2.77(s,3H).ESI-MS: m/z 453.1[M+Na] ⁺ .

Example 81

4-(8-(6-Methylimidazo[1,2-b]pyridazin-2-yl)-2,3-dihydro-[1,4]dioxino[2, 3-g]benzofuran-6-yl)morpholine (compound 81)

Weigh compound 79-4 (51mg, 0.133mmol) and 3-amino-6-methylpyridazine (17mg, 0.16mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5mL), and The mixture solution was purged for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=1:5:5) to obtain compound 81 (yellow solid, 28 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.28(s, 1H), 7.81(d, J=9.3Hz, 1H), 7.27(s, 1H), 6.94(d, J=9.3Hz, 1H), 6.33 (s,1H),4.49-4.30(m,4H),3.98-3.83(m,4H),3.22-3.04(m,4H),2.58(s,3H).ESI-MS: m/z 415.2[M +Na] ⁺ .

Example 82

4-(8-(imidazo[1,2-b][1,2,4]triazin-6-yl)-2,3-dihydro[1,4]dioxino[ 2,3-g]benzofuran-6-yl)morpholine (Compound 82)

Weigh compound 79-4 (70mg, 0.183mmol) and 1,2,4-triazin-3-amine (26mg, 0.275mmol) into a 35mL pressure-resistant reaction tube, then add isopropanol (5mL) to The mixture solution was purged with argon for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=1:1:1-1:5:5) to obtain compound 82 ( Red solid, 16 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.43(s, 1H), 8.37(s, 1H), 8.33(d, J=1.7Hz, 1H), 7.50(s, 1H), 6.34(s,1H),4.47-4.32(m,4H),3.96-3.87(m,4H),3.22-3.08(m,4H).ESI-MS: m/z 402.1[M+Na] ⁺ .

Example 83

4-(8-(6-Methylimidazo[1,2-b]pyridazin-2-yl)-2,3-dihydro-[1,4]dioxin[2,3-g]benzene Furan-6-yl)thiomorpholine 1,1-dioxide (Compound 83)

Weigh compound 73-1 (300mg, 0.88mmol), thiomorpholine-1,1-dioxide (143mg, 1.06mmol), tris(dibenzylideneacetone) dipalladium (81mg, 0.088mmol), 2 -Dicyclohexylphosphonium-2,4,6-triisopropylbiphenyl (105mg, 0.22mmol), sodium tert-butoxide (102mg, 1.06mmol) were placed in a 35mL thick-walled pressure-resistant bottle, and anhydrous toluene ( 5mL), frozen for 3 times, and placed at 90°C for 6h. After the reaction is complete, add ethyl acetate (20mL) to dilute the reaction system, filter with suction, filter off the solids in the system, extract with ethyl acetate (10mL x 2), wash with saturated brine (10mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=5:1:1) to obtain compound 83-1 (yellow solid, 90 mg).

Compound 83-1 (85 mg, 0.215 mmol) was weighed and dissolved in acetone (5 mL), 2N hydrochloric acid solution (2.5 mL) was added, and reacted at room temperature for 1 h. After the reaction, the system was adjusted to alkaline with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10mL x 2), the organic phase was combined, and the organic phase was washed with saturated brine (10mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue containing compound 83-2 was directly used in the next reaction without further treatment.

The residue containing compound 83-2 obtained in the previous step reaction was placed in a 25 mL two-necked bottle, the air in the system was exchanged with argon, and the device was anaerobically treated, and then anhydrous dichloromethane (5 mL) was added through a syringe. Under ice bath conditions, a solution of N,N-diisopropylethylamine (110 μL, 0.65 mmol) in anhydrous dichloromethane (1 mL) was slowly added, and the system was reacted under ice bath conditions for 0.5 h. A solution of triisopropylsilyl triflate (90 μL, 0.32 mmol) in anhydrous dichloromethane (1 mL) was then added dropwise under ice-bath conditions. After the addition was completed, it was raised to room temperature and stirred overnight. After the reaction, the system was quenched with saturated sodium bicarbonate solution (10mL), the aqueous phase was extracted with dichloromethane (8mL x 3), the organic phases were combined, and saturated sodium bicarbonate solution (10mL x 1) and saturated brine ( 10 mL x 1) was washed, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue containing compound 83-3 was directly used in the next reaction without further purification.

The 25mL two-neck bottle exchanged the air in the system with argon, and treated the device anaerobically, and then added anhydrous tetrahydrofuran (7mL) solution containing the residue obtained from the previous step reaction of compound 83-3 through a syringe, and placed it in an ice bath. Under conditions, a solution of N-bromosuccinimide (42 mg, 0.24 mmol) in anhydrous THF (2 mL) was added dropwise. After addition, rise to room temperature and stir for 3h. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=5:1:1) to obtain compound 83-4 (orange solid, 36 mg).

Weigh compound 83-4 (36mg, 0.084mmol) and 3-amino-6-methylpyridazine (11mg, 0.1mmol) into a 15mL pressure-resistant reaction tube, then add isopropanol (5mL), and The mixture solution was purged for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=4:1:1-1:1:1) to obtain compound 83 ( Yellow solid, 24 mg): ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.52(s, 1H), 8.01(d, J=9.4Hz, 1H), 7.35(s, 1H), 7.20(d, J =9.4Hz,1H),6.44(s,1H),4.34(m,4H),3.51(m,4H),3.34(m,4H),2.54(s,3H).ESI-MS:m/z 339.3 [MH] ⁺ .

Example 84

2-Methoxy-6-(6-(3-methoxypropoxy)-2,3-dihydro-[1,4]dioxino[2,3-g]benzene Furan-8-yl)imidazo[2,1-b][1,3,4]thiadiazole (compound 84)

Compound 48-6 (1.4g, 4.32mmol) was weighed and dissolved in a mixed solvent of methanol (10mL) and tetrahydrofuran (10mL), and then 10% palladium/carbon (1.8g, 17.14mmol) and cyclohexene (18mL) were added successively . The system was reacted under reflux for 5h. After the reaction, the solids in the system were removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 8:1) to obtain compound 84-1 (yellow solid, 809 mg).

Weigh compound 84-1 (100mg, 0.43mmol) and dissolve it in N,N-dimethylformamide (15mL), add potassium carbonate (177mg, 1.3mmol) and 1-bromo-3-methoxypropane (145μL , 1.3mmol), the system was reacted at 50°C for 3h. After the reaction, add water (20ml) to dilute the reaction solution, extract the aqueous phase with dichloromethane (10mL x 3), combine the organic phases, wash with water (10mL x 3) and saturated brine (10mL x 1), and dry over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=15:1:1-10:1:1) to obtain compound 84-2 (yellow solid, 118 mg).

Compound 84-2 (227mg, 0.74mmol) was weighed and dissolved in a 50mL two-neck bottle, the air in the system was exchanged with argon, the device was anaerobically treated, and then anhydrous dichloromethane (7mL) was added through a syringe. Under ice bath conditions, a solution of N,N-diisopropylethylamine (370 μL, 2.22 mmol) in anhydrous dichloromethane (2 mL) was slowly added, and the system was reacted under ice bath conditions for 0.5 h. A solution of triisopropylsilyl triflate (300 μL, 1.11 mmol) in anhydrous dichloromethane (2 mL) was then added dropwise under ice-bath conditions. After the addition was complete, it was raised to room temperature and stirred overnight. After the reaction, the system was quenched with saturated sodium bicarbonate solution (15mL), the aqueous phase was extracted with dichloromethane (10mL x 3), the organic phases were combined, and saturated sodium bicarbonate solution (10mL x 1) and saturated brine ( 10 mL x 1) was washed, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue containing compound 84-3 was directly used in the next reaction without further purification.

The 50mL two-neck bottle exchanged the air in the system with argon, and treated the device anaerobically, and then added anhydrous tetrahydrofuran (7mL) solution containing the residue obtained from the post-reaction treatment of the previous step of compound 84-3 through a syringe. Under conditions, a solution of N-bromosuccinimide (145 mg, 0.81 mmol) in anhydrous THF (2 mL) was added dropwise. After addition, rise to room temperature and stir for 3h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=1:1-8:1) to obtain compound 84-4 (yellow oily liquid, 230 mg) .

Weigh compound 84-4 (114mg, 0.3mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (64mg, 0.355mmol) into a 35mL pressure-resistant reaction tube, then add isopropanol (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 100 mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue containing compound 84-5 was directly used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the previous step containing compound 84-5 was dissolved in a mixed solvent of dichloromethane (15 mL) and methanol (5 mL), and then a methanol solution of sodium methoxide (4M, 180 μL) was added to react at room temperature 1h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (10 mL), the aqueous phase was extracted with dichloromethane (15 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 1), and dried over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=8:1:1-4:1:1) to obtain compound 84 (yellow solid, 28mg ): ¹ H NMR (300MHz, CDCl ₃ ) δ7.91(s,1H),7.07(s,1H),6.29(s,1H),4.38-4.33(m,4H),4.20(s,3H), 4.12-4.08(m,2H),3.61-3.57(m,2H),3.36(s,3H),2.11-2.03(m,2H).ESI-MS: m/z 440.2[M+Na] ⁺ .

Example 85

2-Methylthio-6-(6-(3-methoxypropoxy)-2,3-dihydro-[1,4]dioxino[2,3-g]benzene Furan-8-yl)imidazo[2,1-b][1,3,4]thiadiazole (compound 85)

Weigh compound 84-4 (80mg, 0.269mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (48mg, 0.323mmol) into a 15mL pressure-resistant reaction tube, and then add N , N-dimethylformamide (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 110°C for 2h. After the reaction was completed, water (15 mL) was added to dilute the reaction solution, extracted with ethyl acetate (10 mL x 3), the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and reduced pressure The solvent was evaporated, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=10:1:1-3:1:1) to obtain compound 85 (yellow solid, 20 mg): ¹ H NMR (300MHz, CDCl ₃ )δ8.04(s,1H),7.12(s,1H),6.30(s,1H),4.44-4.30(m,4H),4.11(t,J=6.1Hz, 2H), 3.59(t, J=6.2Hz, 2H), 3.36(s, 3H), 2.77(s, 3H), 2.14-2.00(m, 2H). ESI-MS: m/z 456.1 [M+Na ] ⁺ .

Example 86

4-(2–(8-((2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2,3-dihydro-[1, 4] Dioxin [2,3-g] benzofuran-6-yl) oxy) ethyl) morpholine (compound 86)

Under argon protection, compound 54 (50 mg, 0.145 mmol) was dissolved in anhydrous N,N-dimethylformamide (7 mL), sodium tert-butoxide (42 mg, 0.434 mmol) was added, and 4-(2 -Bromoethyl)morpholine hydrobromide (48 mg, 0.174 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL), added dropwise to the above system, and stirred at room temperature for 1.5 hours. After the reaction was complete, water (15ml) was added to the system, the aqueous phase was extracted with ethyl acetate (10mL x 2), the organic phases were combined, and the organic phase was washed with water (10mL x3) and saturated brine (10mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=2:1:1-1:2:2) to obtain compound 86 (yellow solid , 28 mg): ¹ HNMR (300MHz, CDCl ₃ ) δ7.92(s, 1H), 7.05(s, 1H), 6.28(s, 1H), 4.41–4.31(m, 4H), 4.20(s, 3H) ,4.16(t,2H),3.78-3.69(m,4H),2.84(t,2H),2.67-2.56(m,4H).ESI-MS: m/z 459.0[M+H] ⁺ .

Example 87

4-(2–(8-((2-Methylthioimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2,3-dihydro-[1, 4] Dioxin[2,3-g]benzofuran-6-yl)oxy)ethyl)morpholine (Compound 87)

Under argon atmosphere, compound 50 (204mg, 0.468mmol) and pentamethylbenzene (485mg, 3.276mmol) were dissolved in anhydrous tetrahydrofuran (10mL), the system was placed at -78°C, and three After the addition of boron chloride (1M in DCM, 1.17mL, 1.17mmol), the reaction was continued at -78°C for 1.5h. After the reaction was completed, sodium bicarbonate solution (0.7M in DCM, 10 mL) was added at -78°C to quench the reaction, raised to room temperature, continued to stir for 1 h, filtered with suction, washed the filter cake with toluene (5 mL), and dried in vacuo. Compound 87-1 (white solid, 130 mg) was obtained

Under argon protection, compound 87-1 (55 mg, 0.152 mmol) was dissolved in anhydrous N,N-dimethylformamide (6 mL), sodium tert-butoxide (44 mg, 0.457 mmol) was added, and 4- (2-Bromoethyl)morpholine hydrobromide (51 mg, 0.183 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL), added dropwise to the above system, and stirred at room temperature for 1.5 hours. After the reaction was complete, water (15ml) was added to the system, the aqueous phase was extracted with ethyl acetate (10mL x 2), the organic phases were combined, and the organic phase was washed with water (10mL x 3) and saturated brine (10mL x 1), and anhydrous sulfuric acid Sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=2:1:1-1:2:2) to obtain compound 87 (yellow Solid, 50 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.04(s, 1H), 7.10(s, 1H), 6.28(s, 1H), 4.36(d, J=4.9Hz, 4H), 4.17 (t, J=5.4Hz, 2H), 3.77-3.69(m, 4H), 2.84(t, J=5.4Hz, 2H), 2.77(s, 3H), 2.64-2.61(m, 4H).ESI- MS: m/z 475.2[M+H] ⁺ .

Example 88

4-(4-(((8-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2,3-dihydro-[1 ,4] dioxane[2,13-g]benzofuran-6-yl)oxy)methyl)-5-methylthiazol-2-yl)morpholine (compound 88)

Weigh copper bromide (5.76g, 25.8mmol) and add it to ethyl acetate (20mL), heat up to reflux, and dissolve compound 88-1 (1.5g, 12.9mmol) in chloroform (4mL) and add it dropwise to the above system , continue heating under reflux for 1 hour, a large amount of white solids are produced during the reaction. After the reaction was completed, the reaction liquid was cooled to room temperature, filtered through celite to remove insoluble matter, and the filtrate was concentrated under reduced pressure to obtain a crude product containing compound 88-2 (dark green oil, 8 g).

To a solution of compound 88-3 (3.32 mL, 38.1 mmol) in chloroform (20 mL) was added dropwise trimethylsilyl isothiocyanate (2.68 mL, 19.1 mmol) at room temperature, immediately producing a large amount of white solid, Stirring was continued for 1 hour. After the reaction was completed, it was filtered, the filter cake was washed with chloroform (2 mL x 3), and the filter cake was vacuum-dried overnight to obtain compound 88-4 (white solid, 2.5 g).

Compound 88-2 (3.33 g, 17.1 mmol) and compound 88-4 (2.5 g, 17.1 mmol) were weighed and dissolved in methanol (30 mL), heated to reflux for 1 hour. After the reaction was completed, the solution was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to obtain compound 88-5 (yellow transparent oil, 1.7 g).

Under the protection of argon, the compound 88-5 (0.41g, 1.69mmol) was dissolved in anhydrous tetrahydrofuran (10mL), and at 0°C, a 2M solution of lithium borohydride in tetrahydrofuran (1.69mL) was slowly added dropwise to the above system , 3.38mmol), after the dropwise addition was completed, it was raised to room temperature and stirred overnight. After the reaction was completed, methanol (2mL) was added dropwise in the reaction solution to stop the reaction, until no bubbles were generated in the reaction solution, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: sherwood oil: ethyl acetate =1:2) to obtain compound 88-6 (white solid, 217 mg).

Compound 88-6 (0.25 g, 1.16 mmol) was dissolved in anhydrous dichloromethane (5 mL), and phosphorus tribromide (60 μL, 0.580 mmol) was dissolved in dichloromethane (1 mL) under ice-cooling conditions, Dropwise into the above system, after the dropwise addition, react at room temperature for 4 hours. After the reaction was complete, add saturated sodium bicarbonate solution (10 mL) to quench the reaction, extract with dichloromethane (5 mL x 3), combine the organic phases, wash the organic phase with saturated brine (5 mL x 3), and dry over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 8:1) to obtain compound 88-7 (white crystals, 145 mg).

Under argon protection, compound 54 (80mg, 0.25mmol) was dissolved in anhydrous N,N-dimethylformamide (5mL), sodium tert-butoxide (26mg, 0.28mmol) was added, compound 88-7 (76mg, 0.28mmol) was dissolved in anhydrous N,N-dimethylformamide (1mL), added dropwise to the above system, and stirred at room temperature for 2.5 hours. After the reaction was complete, ethyl acetate (20 mL) was added to dilute the system, the organic phase was washed with water (5 mL x 3) and saturated brine (5 mL x 3) successively, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was washed with silica gel Purified by column chromatography (eluent: petroleum ether: dichloromethane: ethyl acetate = 6:4:1) to obtain compound 88 (white solid, 49 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ7.91( s,1H),7.10(s,1H),6.45(s,1H),4.98(s,2H),4.38-4.33(m,4H),4.20(s,3H),3.82-3.79(m,4H) ,3.43-3.40(m,4H),2.34(s,3H).ESI-MS: m/z 564.1[M+Na] ⁺ .

Example 89

2-Methoxy-6-(6-((2-thiomorpholinothiazol-4-yl)methoxy)-2,3-dihydro[1,4]dioxino [2,3-g]benzofuran-8-yl)imidazo[2,1-b][1,3,4]thiadiazole (compound 89)

Compound 89 was obtained by referring to the method of Example 88: ¹ H NMR (300MHz, CDCl ₃ ) δ7.92(s, 1H), 7.13(s, 1H), 6.58(s, 1H), 6.39(s, 1H), 5.03(s,2H),4.38-4.33(m,4H),4.20(s,3H),3.87-3.83(m,4H),2.75-2.72(m,4H) _.ESI -HRMS: calcd. H ₂₁ N ₅ O ₅ S ₃ [M+Na] ⁺ 566.0597,found:566.0598.

Example 90

2-methoxy-6-(6-((5-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)methoxy)-2,3-dihydro[ 1,4]dioxino[2,3-g]benzofuran-8-yl)imidazo[2,1-b][1,3,4]thiadiazole (Compound 90)

Compound 90-1 (2.05 g, 10 mmol) and methyl 3-bromopyruvate (1.33 mL, 10 mmol, 80%) were weighed and dissolved in methanol (50 mL), heated to reflux for 2 hours. After the reaction was completed, the solution was distilled off under reduced pressure, and the residue was not purified to obtain a crude product of compound 90-2 (yellow oil, 2.45 g).

Under the protection of argon, the crude product of compound 90-2 (2.45 g, 8.53 mmol) obtained in the previous step reaction was dissolved in anhydrous tetrahydrofuran (30 mL), and 2M hydroboration was slowly added dropwise to the above system at 0°C. Lithium tetrahydrofuran solution (17mL, 34mmol), after the dropwise addition, was raised to room temperature and stirred overnight. After the reaction was completed, methanol (20mL) was added dropwise in the reaction solution to stop the reaction. After no bubbles were generated in the reaction solution, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether: ethyl acetate = 8:1-3:1) to obtain compound 90-3 (white solid, 1.44 g).

Compound 90-3 (519 mg, 2 mmol) was dissolved in anhydrous dichloromethane (10 mL), and phosphorus tribromide (188 μL, 2 mmol) was dissolved in dichloromethane (2 mL) under ice-cooling conditions, dropwise Dropped into the above system, the dropwise addition was completed, and reacted at room temperature for 4 hours. After the reaction is complete, add saturated sodium bicarbonate solution (10mL) to quench the reaction, extract with dichloromethane (5mL x 3), combine the organic phases, wash the organic phase with saturated brine (5mL x 3), and dry over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 20:1-10:1) to obtain compound 90-4 (white solid, 200 mg).

Under argon protection, compound 54 (70 mg, 0.20 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), sodium tert-butoxide (23 mg, 0.244 mmol) was added, and compound 90-4 (85mg, 0.26mmol) was dissolved in anhydrous N,N-dimethylformamide (1mL), added dropwise to the above system, and stirred at room temperature for 2.5 hours. After the reaction was complete, ethyl acetate (20 mL) was added to dilute the system, the organic phase was washed with water (5 mL x 3) and saturated brine (5 mL x 3) successively, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purified by chromatography (eluent: petroleum ether: dichloromethane: ethyl acetate = 15:1:1-5:1:1), and repurified by recrystallization (ethyl acetate/THF/methanol/dichloromethane) , to obtain compound 90 (white solid, 15 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.10(d, J=7.8Hz, 2H), 7.96(s, 1H), 7.73(d, J=7.7Hz, 2H),7.46(s,1H),7.18(s,1H),6.44(s,1H),5.36(s,2H),4.41-4.37(m,4H),4.23(s,3H).ESI-HRMS :calcd.for C ₂₆ H ₁₇ F ₃ N ₄ O ₅ S ₂ [M+Na] ⁺ 609.0479, found: 609.0483.

Example 91

4-(4-(((8-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2,3-dihydro-[1 ,4]dioxino[2,3-g]benzofuran-6-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide ( Compound 91)

Weigh 91-1 (100μL, 0.98mmol) into a 50mL bottle, exchange the air in the system with argon, treat the device anaerobically, add anhydrous N,N-dimethylformamide (5mL), and then 0 ℃, were added dropwise a solution of imidazole (133mg, 1.96mmol) in anhydrous N,N-dimethylformamide (1mL), tert-butyldimethylsilyl chloride (221mg, 1.47mmol) in anhydrous N,N-dimethylformamide Methylformamide (1 mL) solution. The system was reacted for 6h at room temperature. After the reaction, add water (10ml) to the system, extract the aqueous phase with ethyl acetate (8mL x 3), combine the organic phases, wash the organic phase with water (8mL x 3) and saturated brine (8mL x 1), anhydrous sodium sulfate After drying, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=100:1) to obtain compound 91-2 (colorless oily liquid, 272 mg).

Weigh compound 91-2 (105mg, 0.341mmol), 4-(N,N-dimethylcarbamoyl) phenylboronic acid (99mg, 0.512mmol), [1,1'-bis(diphenylphosphine) Iron] dichloropalladium dichloromethane complex (28mg, 0.034mmol), sodium carbonate (44mg, 0.42mmol) was placed in a 35mL thick-walled pressure bottle, and toluene (3mL), water (200 μL) and ethanol ( 1 mL), purged with argon for 5 min, sealed, and placed at 95°C for 4 h. After the reaction is complete, add saturated sodium bicarbonate (10 mL), extract with ethyl acetate (6 mL x 3), wash with saturated brine (5 mL x 1), dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and pass the residue through column Purification by chromatography (eluent: petroleum ether/ethyl acetate=4:1-2:1) gave compound 91-3 (yellow oily liquid, 116 mg).

Compound 91-3 (116 mg, 0.31 mmol) was weighed and dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride (770 μL, 0.77 mmol) was slowly added at room temperature, and reacted overnight at room temperature. After the reaction, add saturated sodium chloride (10mL), extract with ethyl acetate (10mL x 3), wash with saturated brine (10mL x 1), dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and pass the residue through column layer (eluent: petroleum ether/ethyl acetate=2:1-1:1) to obtain compound 91-4 (white solid, 63 mg).

Dissolve compound 91-4 (60g, 0.28mmol) in anhydrous dichloromethane (4mL), and dissolve phosphorus tribromide (21μL, 0.224mmol) in dichloromethane (0.5mL) under ice-cooling conditions , dropwise into the above system, the dropwise addition was completed, and reacted at room temperature for 4 hours. After the reaction was complete, add saturated sodium bicarbonate solution (10mL) to quench the reaction, extract with dichloromethane (6mL x 3), combine the organic phases, wash the organic phase with saturated brine (5mL x 1), and dry over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to obtain compound 91-5 (yellow oily liquid, 51 mg).

Under argon protection, compound 54 (48mg, 0.139mmol) was dissolved in anhydrous N,N-dimethylformamide (4mL), sodium tert-butoxide (20mg, 0.208mmol) was added, compound 91-5 (54mg, 0.167mmol) was dissolved in anhydrous N,N-dimethylformamide (1mL), added dropwise to the above system, and stirred at room temperature for 1.5 hours. After the reaction was complete, water (10ml) was added to the system, the aqueous phase was extracted with ethyl acetate (8mL x 3), the organic phases were combined, and the organic phase was washed with water (5mL x 3) and saturated brine (5mL x 1), and anhydrous sulfuric acid Sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=2:1:1-1:5:5) to obtain compound 91 (white Solid, 45 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.03(d, J=8.2Hz, 2H), 7.96(s, 1H), 7.53(d, J=8.1Hz, 2H), 7.41(s ,1H),7.18(s,1H),6.44(s,1H),5.35(s,2H),4.46-4.34(m,4H),4.23(s,3H),3.16(s,3H),3.04( s,3H).ESI-MS:m/z612.2[M+Na] ⁺ .

Example 92

4-(4-(((8-(2-Methylthioimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2,3-dihydro-[1 ,4]dioxino[2,3-g]benzofuran-6-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide ( Compound 92)

Under argon protection, compound 87-1 (22 mg, 0.061 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL), sodium tert-butoxide (9 mg, 0.09 mmol) was added, and compound 91 -5 (24 mg, 0.073 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL), added dropwise to the above system, and stirred at room temperature for 1.5 hours. After the reaction was complete, water (15ml) was added to the system, the aqueous phase was extracted with ethyl acetate (10mL x 2), the organic phases were combined, and the organic phase was washed with water (10mL x 3) and saturated brine (10mL x 1), and anhydrous sulfuric acid Dry over sodium, evaporate the solvent under reduced pressure, and purify the residue by column chromatography (eluent: dichloromethane/methanol=100:1-50:1) to obtain compound 92 (yellow-white solid, 10 mg): ¹ H NMR (300MHz, CDCl ₃ )δ8.05(s,1H),8.00(d,J=8.2Hz,2H),7.51(d,J=8.1Hz,2H),7.39(s,1H),7.20(s, 1H), 6.42(s,1H), 5.33(s,2H), 4.44-4.31(m,4H), 3.13(s,3H), 3.01(s,3H), 2.76(s,3H).ESI-MS :m/z628.2[M+Na] ⁺ .

Example 93

6-(6-((4-((4-bromobenzyl)oxy)benzyl)oxy)-2,3-dihydro-[1,4]dioxino[2, 3-g]benzofuran-8-yl)imidazo[1,2-b][1,2,4]triazine (compound 93)

Weigh compound 84-1 (234.6mg, 1.002mmol) and dissolve it in N,N-dimethylformamide (20mL), add 1-bromo-4-[[4-(bromomethyl)phenoxy]methanol Base]-benzene (461.1 mg, 1.303 mmol) and potassium carbonate (180.1 mg, 1.303 mmol), and the system was stirred overnight at room temperature. After the reaction was completed, ethyl acetate (50 mL) was added to dilute the reaction solution, the organic phase was washed with water (20 mL x 3) and saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was passed through a column Purification by chromatography (eluent: petroleum ether/ethyl acetate=20:1) gave compound 93-1 (yellow solid, 458 mg).

Under the protection of argon, weigh compound 93-1 (175 mg, 0.34 mmol) and dissolve it in anhydrous tetrahydrofuran (20 mL), slowly add benzyltrimethylammonium dichloroiodate (144 mg, 0.41 mmol) dropwise at room temperature After the addition of anhydrous tetrahydrofuran solution (10 mL), the system was transferred to an oil bath and reacted overnight at 45°C. After the reaction was complete, diethyl ether (10mL) and ethyl acetate (10mL) were added to dilute the reaction solution, and the organic phase was diluted with dilute sodium bicarbonate (20mL x 2), saturated sodium thiosulfate (20mL x 2) and saturated brine (20mL x 2) Wash, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and the residue containing compound 93-2 is directly used in the next reaction without further purification.

Put the residue obtained from the post-reaction treatment of the previous step containing compound 93-2 and 1,2,4-triazin-3-amine (53.2mg, 0.55mmol) in a 15mL pressure-resistant reaction tube, and then add isopropanol (5 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=10:1:1-2:1:1) to obtain compound 93 ( Orange solid, 10 mg). ¹ HNMR (300MHz, CDCl ₃ ) δ8.42(d, J=1.8Hz, 1H), 8.35(s, 1H), 8.32(d, J=1.8Hz, 1H), 7.57(s, 1H), 7.52( d,J=8.3Hz,2H),7.39(d,J=8.5Hz,2H),7.32(d,J=8.4Hz,2H),6.98(d,J=8.3Hz,2H),6.38(s, 1H), 5.06(d, J＝8.5Hz, 4H), 4.43-4.33(m, 4H).ESI-HRMS: calcd.for C ₂₉ H ₂₁ BrN ₄ O ₅ [M+H] ⁺ 609.0567, found: 609.0564.

Example 94

2-((8-(2-Methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2,3-dihydro-[1,4]di Oxine[2,3-g]benzofuran-6-yl)oxy)-1-(pyrrolidin-1-yl)ethan-1-one (compound 94)

Under argon protection, tetrahydropyrrole (130 μL, 1.58 mmol) was weighed and dissolved in anhydrous dichloromethane (2 mL), and triethylamine (264 μL, 1.89 mmol) and bromoacetyl chloride (145 μL, 1.74 mmol) in anhydrous dichloromethane (2 mL), and stirred overnight at room temperature. After the reaction was complete, water (15mL) was added to the reaction solution, extracted with dichloromethane (10mL x 2), washed with saturated sodium bicarbonate (8mL x 2) and saturated sodium chloride (5mL x 1), dried over anhydrous sodium sulfate , the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=8:1-2:1) to obtain compound 94-1 (yellow oily liquid, 112 mg).

Under argon protection, compound 54 (22 mg, 0.062 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL), sodium tert-butoxide (9 mg, 0.09 mmol) was added, and compound 94-1 (14 mg, 0.075 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL), added dropwise to the above system, and stirred at room temperature for 1.5 hours. After the reaction was complete, water (15ml) was added to the system, the aqueous phase was extracted with ethyl acetate (10mL x 2), the organic phases were combined, and the organic phase was washed with water (8mL x 3) and saturated brine (5mL x 1), and anhydrous sulfuric acid Sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=2:1:1-1:3:3) to obtain compound 94 (yellow Solid, 14 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ7.92(s, 1H), 7.08(s, 1H), 6.33(s, 1H), 4.67(s, 2H), 4.42-4.29(m, 4H), 4.20(s,3H), 3.63-3.49(m,4H), 2.00-1.80(m,4H).ESI-MS: m/z 479.2[M+Na] ⁺ .

Example 95

2-((8-(2-Methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2,3-dihydro-[1,4]di Oxine[2,3-g]benzofuran-6-yl)oxy)-1-(piperidin-1-yl)ethan-1-one (compound 95)

Under the protection of argon, piperidine (100 μL, 1.58 mmol) was weighed and dissolved in anhydrous dichloromethane (2 mL), and triethylamine (263 μL, 1.89 mmol) and bromoacetyl chloride (131 μL, 1.58 mmol) in anhydrous dichloromethane (2 mL), stirred overnight at room temperature. After the reaction was complete, water (15mL) was added to the reaction solution, extracted with dichloromethane (10mL x 2), washed with saturated sodium bicarbonate (8mL x 2) and saturated sodium chloride (5mL x 1), dried over anhydrous sodium sulfate , the solvent was distilled off under reduced pressure, and the residue containing compound 95-1 was directly used in the next step without further reaction.

Under argon protection, compound 54 (25 mg, 0.072 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL), sodium tert-butoxide (10 mg, 0.11 mmol) was added, and compound 95-1 (18 mg, 0.083 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL), added dropwise to the above system, and stirred at room temperature for 1.5 hours. After the reaction was complete, water (10mL) was added to the system, the aqueous phase was extracted with ethyl acetate (8mL x 2), the organic phases were combined, and the organic phase was washed with water (6mL x 3) and saturated brine (6mL x 1), washed with anhydrous sulfuric acid The sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=5:1:1-1:1:1) to obtain compound 95 (yellow White solid, 30 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ7.93(s, 1H), 7.06(s, 1H), 6.35(s, 1H), 4.71(s, 2H), 4.42-4.30(m ,4H), 4.20(s,3H), 3.64-3.44(m,4H), 1.72-1.60(m,6H).ESI-MS: m/z 493.2[M+Na] ⁺ .

Example 96

1-(4,4-difluoropiperidin-1-yl)-2-((8-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6 -yl)-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-6-yl)oxy)ethan-1-one (compound 96 )

Under the protection of argon, weigh 4,4-difluoropiperidine hydrochloride (207mg, 1.3mmol) and dissolve it in anhydrous dichloromethane (3mL), and add triethylamine (548μL, 3.94mmol) dropwise at 0°C ), bromoacetyl chloride (120 μL, 1.45 mmol) in anhydrous dichloromethane (2 mL), stirred at room temperature overnight. After the reaction was complete, water (15 mL) was added to the reaction solution, extracted with dichloromethane (10 mL x 2), washed with saturated sodium bicarbonate (8 mL x 2) and saturated sodium chloride (5 mL x 1), dried over anhydrous sodium sulfate, The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=10:1:1-6:1:1) to obtain compound 96-1 (yellow oil liquid, 119 mg).

Under argon protection, compound 54 (22 mg, 0.062 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL), sodium tert-butoxide (9 mg, 0.093 mmol) was added, and compound 96-1 (18 mg, 0.075 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL), added dropwise to the above system, and stirred at room temperature for 1.5 hours. After the reaction was complete, water (10mL) was added to the system, the aqueous phase was extracted with ethyl acetate (8mL x 2), the organic phases were combined, and the organic phase was washed with water (6mL x 2) and saturated brine (5mL x 1), and anhydrous sulfuric acid Sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=3:1:1-1:1:1) to obtain compound 96 (white Solid, 20 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ7.93(s, 1H), 7.02(s, 1H), 6.36(s, 1H), 4.75(s, 2H), 4.43-4.27(m, 4H), 4.21(s,3H), 3.86-3.65(m,4H), 2.10-1.86(m,4H).ESI-MS: m/z 529.3[M+Na] ⁺ .

Example 97

2-((8-(2-Methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2,3-dihydro-[1,4]di Oxino[2,3-g]benzofuran-6-yl)oxy)-1-morpholinoethan-1-one (compound 97)

Under the protection of argon, weigh morpholine (600 μL, 6.9 mmol) and dissolve it in anhydrous dichloromethane (8 mL), and drop triethylamine (960 μL, 6.9 mmol) and bromoacetyl chloride (580 μL, 6.9 mmol) in anhydrous dichloromethane (4 mL), stirred overnight at room temperature. After the reaction was complete, water (15 mL) was added to the reaction solution, extracted with dichloromethane (15 mL x 2), washed with saturated sodium bicarbonate (8 mL x 2) and saturated sodium chloride (10 mL x 1), dried over anhydrous sodium sulfate , the solvent was distilled off under reduced pressure, and the residue containing compound 97-1 was directly used in the next step without further reaction.

Under argon protection, compound 54 (25 mg, 0.072 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL), sodium tert-butoxide (10 mg, 0.11 mmol) was added, and compound 97-1 (20mg, 0.087mmol) was dissolved in anhydrous N,N-dimethylformamide (1mL), added dropwise to the above system, and stirred at room temperature for 1.5 hours. After the reaction was complete, water (10mL) was added to the system, the aqueous phase was extracted with ethyl acetate (8mL x 2), the organic phases were combined, and the organic phase was washed with water (6mL x 3) and saturated brine (6mL x 1), washed with anhydrous sulfuric acid The sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=5:1:1-1:1:1) to obtain compound 97 (yellow White solid, 24 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ7.91(s, 1H), 7.01(s, 1H), 6.34(s, 1H), 4.72(s, 2H), 4.39-4.29(m ,4H), 4.19(s,3H), 3.68-3.59(m,8H).ESI-MS: m/z 495.2[M+Na] ⁺ .

Example 98

2-((8-(2-Methylthioimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2,3-dihydro-[1,4]di Oxino[2,3-g]benzofuran-6-yl)oxy)-1-morpholinoethan-1-one (compound 98)

Under argon protection, compound 87-1 (53 mg, 0.147 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), sodium tert-butoxide (21 mg, 0.22 mmol) was added, and compound 97 -1 (37 mg, 0.176 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL), added dropwise to the above system, and stirred at room temperature for 1.5 hours. After the reaction was complete, water (10mL) was added to the system, the aqueous phase was extracted with ethyl acetate (8mL x 2), the organic phases were combined, and the organic phase was washed with water (6mL x 3) and saturated brine (6mL x 1), washed with anhydrous sulfuric acid The sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=3:1:1-1:2:2) to obtain compound 98 (yellow White solid, 20 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.09(s, 1H), 7.11(s, 1H), 6.40(s, 1H), 4.78(s, 2H), 4.46-4.35(m ,4H), 3.78-3.62(m,8H), 2.81(s,3H).ESI-MS: m/z 489.1[M+Na] ⁺ .

Example 99

1-(1,1-disulfur dioxide)-2-((8-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2, 3-Dihydro-[1,4]dioxino[2,3-g]benzofuran-6-yl)oxy)ethan-1-one (Compound 99)

Under the protection of argon, weigh thiomorpholine-1,1-dioxide (300mg, 2.22mmol) and dissolve it in anhydrous dichloromethane (2mL), drop triethylamine (370μL, 2.66 mmol), bromoacetyl chloride (185 μL, 2.22 mmol) in anhydrous dichloromethane (2 mL), stirred overnight at room temperature. After the reaction was complete, water (15 mL) was added to the reaction solution, extracted with dichloromethane (10 mL x 5), washed with saturated sodium bicarbonate (5 mL x 2) and saturated sodium chloride (5 mL x 1), dried over anhydrous sodium sulfate, The solvent was distilled off under reduced pressure, and the residue containing compound 99-1 was directly used in the next step without further reaction.

Under argon protection, compound 54 (30mg, 0.087mmol) was dissolved in anhydrous N,N-dimethylformamide (3mL), sodium tert-butoxide (13mg, 0.13mmol) was added, compound 99-1 (27mg, 0.104mmol) was dissolved in anhydrous N,N-dimethylformamide (1mL), added dropwise to the above system, and stirred at room temperature for 1.5 hours. After the reaction was complete, water (10mL) was added to the system, the aqueous phase was extracted with ethyl acetate (8mL x 2), the organic phases were combined, and the organic phase was washed with water (6mL x 3) and saturated brine (6mL x 1), washed with anhydrous sulfuric acid The sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=1:1:1-1:2:2) to obtain compound 99 (yellow White solid, 24 mg): 1H NMR (300MHz, DMSO-d ₆ ) δ8.39(s, 1H), 6.96(s, 1H), 6.44(s, 1H), 4.96(s, 2H), 4.37-4.27( m,4H),4.21(s,3H),3.95-3.83(m,4H),3.27-3.14(m,4H).ESI-MS:m/z543.1[M+Na] ⁺ .

Example 100

(8-(2-Methoxyimidazo[1,2-b][1,2,4]thiadiazol-5-yl)-2,3-dihydro-[1,4]dioxane Hexadieno[2,3-g]benzofuran-3-yl)methanol (compound 100)

Under argon protection, weigh sodium hydride (147 mg, 3.67 mmol) and dissolve it in dimethyl sulfoxide (8 mL), and add compound 9-1 (203 mg, 1.47 mmol) in dimethyl sulfoxide ( 2mL) solution, the system was stirred at room temperature for 1 hour, benzyl bromide (175μL, 0.98mmol) was added dropwise at 0°C, the system was stirred overnight at room temperature, after the reaction was completed, ice water (10mL) was added to quench the reaction, and an appropriate amount of 1N hydrochloric Adjust the phase to pH=1, extract with dichloromethane (10mL x 3), combine the organic phases, wash with saturated brine (10mL x1), dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and the residue is subjected to column chromatography (Eluent: petroleum ether/ethyl acetate=20:1) was purified to obtain compound 100-1 (yellow solid, 140 mg).

Weigh compound 100-1 (135mg, 0.59mmol) and dissolve it in N,N-dimethylformamide (6mL), add potassium carbonate (106mg, 0.77mmol) and epibromohydrin (63μl, 0.77mmol), heat up Heated to 50°C for 6h. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (15mL), extracted with ethyl acetate (8mL x 3), the organic phases were combined, washed with water (6mL x3) and saturated brine (6mL x 1), anhydrous Dry over sodium sulfate, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (eluent: petroleum ether/ethyl acetate=20:1-6:1) to obtain compound 100-2 (colorless oil, 148mg) .

Compound 100-2 (202mg, 0.71mmol) was weighed and dissolved in dichloromethane (8mL), m-chloroperoxybenzoic acid (202mg, 0.995mmol, 85%) was added in batches under ice-bath conditions, and then the ice-bath was removed, The system was reacted at room temperature for 12 hours, the insoluble matter was removed by suction filtration, the filtrate was washed with saturated sodium bicarbonate (10mL x 2) and saturated brine (8mL x 1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, containing compound 100 The residue of -3 was directly used in the next reaction without further treatment.

The residue containing compound 100-3 obtained in the previous step reaction was dissolved in methanol (7 mL), and anhydrous potassium carbonate (294 mg, 2.13 mmol) was slowly added in an ice bath, and reacted at room temperature for 3 h. After the reaction, the system was adjusted to pH=1 with 1N hydrochloric acid solution, extracted with dichloromethane (10mL x 2), the organic phases were combined, washed with saturated brine (8mL x 1), dried over anhydrous sodium sulfate, The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=10:1-2:1) to obtain compound 100-4 (colorless oil, 111 mg).

Under argon atmosphere, compound 100-4 (110 mg, 0.404 mmol) was dissolved in anhydrous tetrahydrofuran, triethylamine (140 μL, 1.01 mmol) was added at 0°C, and acetyl chloride (36 μL, 0.505 mmol) in anhydrous tetrahydrofuran (1 mL), after the addition was complete, stir at room temperature overnight. After the reaction was complete, water (6 mL) was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (6 mL x 2), the organic phase was combined, and the organic phase was washed with saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, and reduced pressure The solvent was evaporated, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=6:1) to obtain compound 100-5 (colorless oil, 113 mg).

Compound 100-5 (110 mg, 0.35 mmol) was weighed and dissolved in ethyl acetate (6 mL), and 10% palladium/carbon (24 mg, 0.23 mmol) was added to exchange the air in the system with hydrogen to treat the device anaerobically. The system was reacted at room temperature overnight, ethyl acetate (10 mL) was added to dilute the reaction solution, the solids in the system were removed by suction filtration, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate Ester=2:1) was purified to obtain compound 100-6 (colorless oil, 73 mg).

Under the protection of argon, add anhydrous dichloromethane (14mL), 1,1-dichloromethyl ether (525μL, 5.8mmol) successively, cool down to 0°C, and then slowly add titanium tetrachloride (763μL, 6.96mmol) ), add dropwise a solution of compound 100-6 (650mg, 2.9mmol) in anhydrous dichloromethane (8mL), after the dropwise addition, keep the temperature constant and continue to stir for 1h, after the reaction is complete, add 1N hydrochloric acid (10mL) to dilute, Transfer to a separatory funnel, extract with dichloromethane (10mL x 3), combine the organic phases, wash the organic phase with saturated brine (10mL x 1), dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure, containing compound 100 The residue of -7 was directly used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the previous step containing compound 100-7 was dissolved in acetone (20 mL), potassium carbonate (520 mg, 3.77 mmol) was added, 1-chloroacetone (302 μL, 3.77 mmol) was slowly added dropwise, and After the completion, the temperature was raised to reflux for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate=8:1- 5:1) purification to obtain compound 100-8 (yellow oily liquid, 314mg).

Weigh copper bromide (116mg, 0.52mmol) and place it in a 50mL three-necked flask, add ethyl acetate (15mL), dissolve compound 100-8 (105mg, 0.4mmol) in ethyl acetate (8mL), and drop With the funnel under reflux conditions, the ethyl acetate solution of compound 100-8 was added dropwise into the reaction system, and the reflux was continued for 4 h after the addition was completed. After the reaction, the solids in the system were removed by suction filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane=2:1-1:9) to obtain compound 100 -9 (yellow oily liquid, 72 mg).

Weigh compound 100-9 (100mg, 0.271mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (58mg, 0.325mmol) into a 35mL pressure-resistant reaction tube, then add isopropanol (6 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 130°C for 3h. After the reaction, the reaction system was transferred into a 100 mL flask with dichloromethane, the solvent was evaporated under reduced pressure, and the residue containing compound 100-10 was directly used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the previous step containing compound 100-10 was dissolved in a mixed solvent of dichloromethane (15 mL) and methanol (5 mL), and then a methanol solution of sodium methoxide (4M, 170 μL) was added to react at room temperature 1h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (10mL), the aqueous phase was extracted with dichloromethane (15mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (10mL x 1), anhydrous sulfuric acid Dry over sodium, evaporate the solvent under reduced pressure, and purify the residue by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=8:1:1) to obtain compound 100 (white solid, 18 mg): ¹ H NMR(300MHz,DMSO-d ₆ )δ8.39(s,1H),7.04(d,J=8.4Hz,1H),6.98(s,1H),6.80(d,J=8.4Hz,1H),5.10 (m,1H),4.51(m,1H),4,21(s,3H),4.17(m,2H),3.68(m,2H).ESI-MS: m/z 360.1[M+H] ⁺ .

Example 101

(8-(2-(methylthio)imidazo[1,2-b][1,2,4]thiadiazol-5-yl)-2,3-dihydro-[1,4]dioxo Heterocyclohexadieno[2,3-g]benzofuran-3-yl)methyl acetate (compound 101)

Weigh compound 100-9 (67mg, 0.181mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (32mg, 0.22mmol) into a 15mL pressure-resistant reaction tube, and then add N , N-dimethylformamide (4 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 80°C for 6h, the reaction was continued at 110°C for 2h. After the reaction was completed, water (15 mL) was added to dilute the reaction solution, extracted with ethyl acetate (10 mL x 3), the organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and reduced pressure The solvent was evaporated, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=8:1:1-4:1:1) to obtain compound 101 (white solid, 42 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.09(s, 1H), 7.08(d, J=8.4Hz, 1H), 7.03(s, 1H), 6.87(d, J=8.4Hz, 1H), 4.57 -4.45(m,2H),4.45-4.34(m,2H),4.31-4.17(m,1H),2.79(s,3H),2.16(s,3H).ESI-HRMS:calcd.for C ₁₈ H ₁₅ N ₃ O ₅ S ₂ [M+H] ⁺ 418.0487, found: 418.0528.

Example 102

(8-(2-(methylthio)imidazo[1,2-b][1,2,4]thiadiazol-5-yl)-2,3-dihydro-[1,4]dioxo Heterocyclohexadieno[2,3-g]benzofuran-3-yl)methanol (compound 102)

Under argon protection, compound 101 (34 mg, 0.0815 mmol) was weighed and dissolved in methanol (2 mL) and tetrahydrofuran (2 mL), and lithium hydroxide monohydrate (4.5 mg, 0.106 mmol) in water ( 0.2mL) solution, the system was stirred at room temperature for 1 hour, the solids in the system were removed by suction filtration, the filter cake was washed with water and ethanol, and the solvent was removed by vacuum drying to obtain compound 102 (white solid, 24mg): ¹ H NMR (300MHz, DMSO-d ₆ )δ8.53(s,1H),7.09(d,J=8.4Hz,1H),7.05(s,1H),6.84(d,J=8.4Hz,1H),5.12(t,J ＝5.6Hz,1H),4.57-4.46(m,1H),4.31-4.22(m,1H),4.21-4.10(m,1H),3.79-3.66(m,2H),2.82(s,3H). ESI-HRMS: calcd.for C ₁₆ H ₁₃ N ₃ O ₄ S ₂ [M+H] ⁺ 376.0381, found: 376.0420

Example 103

(8-(2-(methylthio)imidazo[1,2-b][1,2,4]thiadiazol-5-yl)-2,3-dihydro-[1,4]dioxo Heterocyclohexadieno[2,3-g]benzofuran-3-yl)methyl 4-methylbenzenesulfonate (Compound 103)

Weigh compound 102 (104mg, 0.277mmol) and dissolve it in pyridine (13mL), add 4-toluenesulfonyl chloride (106mg, 0.554mmol) in batches at 0°C, react overnight at room temperature, add saturated saline (5mL ), extracted with dichloromethane (10mL x 3), combined the organic phases, washed the organic phase with 2N hydrochloric acid (10mL x 3) and saturated brine (10mL x 1), dried over anhydrous sodium sulfate, and concentrated the filtrate under reduced pressure, The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=8:1:1-4:1:1) to obtain compound 103 (yellow solid, 85 mg): ¹ H NMR ( 300MHz, CDCl ₃ )δ8.05(s,1H),7.81(d,J=8.1Hz,2H),7.35(d,J=7.9Hz,2H),7.05-6.94(m,2H),6.71(d , J=8.4Hz, 1H), 4.55-4.13(m, 5H), 2.77(s, 3H), 2.45(s, 3H). ESI-MS: m/z 313.1[M+Na] ⁺ .

Example 104

5-(3-(bromomethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]benzofuran-8-yl)-2-( Methylthio)imidazo[1,2-b][1,2,4]thiadiazole (compound 104)

Weigh compound 100-8 (511mg, 1.76mmol) and dissolve it in methanol (8mL), add a solution of sodium hydroxide (84mg, 2.11mmol) in water (2mL) dropwise at 0°C, after the addition is complete, stir at room temperature overnight. After the reaction was complete, 1N hydrochloric acid was added to adjust the pH of the solution to 1, the aqueous phase was extracted with dichloromethane (6mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (5mL x 1), dried over anhydrous sodium sulfate, and reduced The solvent was evaporated under pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to obtain compound 104-1 (yellow solid, 300 mg).

Under argon atmosphere, compound 104-1 (81 mg, 0.297 mmol) was dissolved in anhydrous dichloromethane (8 mL), triethylamine (103 μL, 0.744 mmol) was added at 0°C, and 4 -Toluenesulfonyl chloride (85 mg, 0.446 mmol) in anhydrous dichloromethane (2 mL) was added, stirred at room temperature overnight. After the reaction was complete, water (6 mL) was added to quench the reaction, the aqueous phase was extracted with dichloromethane (6 mL x 3), the organic phases were combined, and the organic phase was washed with saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, and reduced The solvent was evaporated under pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=5:1) to obtain compound 104-2 (white solid, 104 mg).

Weigh copper bromide (40mg, 0.175mmol) and place it in a 50mL three-necked flask, add ethyl acetate (8mL), dissolve compound 104-2 (50mg, 0.134mmol) in ethyl acetate (10mL), and drop With the funnel under reflux conditions, the ethyl acetate solution of compound 104-2 was added dropwise into the reaction system, and the reflux was continued for 4 h after the addition was complete. After the reaction, the solids in the system were removed by suction filtration, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=8:1:1-6:1 : 1) purification to obtain compound 104-3 (white solid, 35 mg).

Weigh compound 104-3 (55mg, 0.114mmol) and 5-methylthio-1,3,4-thiadiazol-2-amine (20mg, 0.137mmol) into a 15mL pressure-resistant reaction tube, and then add N , N-dimethylformamide (4 mL), and the mixture solution was purged with argon for 5 min. The system was moved into an oil bath, and after reacting at 90°C for 5h, the reaction was continued at 120°C for 3h. After the reaction was completed, water (15 mL) was added to dilute the reaction solution, extracted with ethyl acetate (8 mL x 3), the organic phase was washed with water (5 mL x 3) and saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, and reduced pressure The solvent was evaporated, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate=8:1:1-7:1:1) to obtain compound 104 (yellow solid, 22 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.07(s, 1H), 7.06(d, J=8.4Hz, 1H), 7.01(s, 1H), 6.84(d, J=8.4Hz, 1H), 4.60 -4.46(m,2H),4.42-4.31(m,1H),3.69-3.53(m,2H),2.77(s,3H).ESI-HRMS:calcd.forC ₁₆ H ₁₂ BrN ₃ O ₃ S ₂ [ M+H] ⁺ 437.9503, found: 437.9576

Example 105

(8-(6-Methylimidazo[1,2-b]pyridazin-2-yl)-2,3-dihydro-[1,4]dioxine[2,3-g] Benzofuran-3-yl)methyl 4-methylbenzenesulfonate (Compound 105)

Weigh compound 104-3 (102mg, 0.212mmol) and 3-amino-6-methylpyridazine (35mg, 0.318mmol) into a 35mL pressure-resistant reaction tube, then add isopropanol (10mL), and The mixture solution was purged for 5 min. The system was moved into an oil bath and reacted at 85°C for 12h. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=8:1:1-2:1:1) to obtain compound 105 ( Yellow solid, 58 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.27(s, 1H), 7.87-7.78(m, 3H), 7.35(d, J=8.0Hz, 2H), 7.19(s, 1H ), 7.05(d, J=8.5Hz, 1H), 6.94(d, J=9.3Hz, 1H), 6.74(d, J=8.5Hz, 1H), 4.55-4.39(m, 2H), 4.38-4.18 (m,3H),2.58(s,3H),2.45(s,3H).ESI-HRMS: calcd.for C ₂₅ H ₂₁ N ₃ O ₃ S[M+H] ⁺ 492.1224, found: 492.1224.

Example 106

(8-(2-(Methylthio)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2,3-dihydro-[1,4]dioxo Heterocyclohexadieno[2,3-g]benzofuran-3-yl)methylthiomorpholine-4-carboxylate 1,1-dioxide (compound 106)

Compound 102 (48 mg, 0.128 mmol) was weighed and dissolved in anhydrous tetrahydrofuran (5 mL), triethylamine (500 μL, 0.32 mmol) was added at 0°C, and p-nitrophenyl chloroformate ( 52 mg, 0.256 mmol) in anhydrous tetrahydrofuran (1 mL), after the addition was complete, stir at room temperature overnight. After the reaction is complete, add water (15mL) to quench the reaction, adjust the pH of the aqueous phase with 1N hydrochloric acid to 1, extract the aqueous phase with dichloromethane (10mL x 3), combine the organic phases, and wash the organic phase with saturated brine (10mL x 1) After washing, drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=8:1:1-4:1:1), Compound 106-1 (yellow solid, 17 mg) was obtained.

Weigh compound 106-1 (30mg, 0.056mmol) and dissolve it in anhydrous N,N-dimethylformamide (5mL), and add N,N-diisopropylethylamine (14μL, 0.083mmol ), thiomorpholine-1,1-dioxide (9mg, 0.067mmol), after addition, stirred overnight at room temperature. After the reaction was complete, dilute with water (15mL), extract the aqueous phase with ethyl acetate (8mL x 3), combine the organic phases, wash the organic phase with water (8mL x 3) and saturated brine (8mL x 1), and wash with anhydrous sulfuric acid Sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=8:1:1-1:1:1) to obtain compound 106 (white Solid, 12 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.08(s, 1H), 7.08(d, J=8.5Hz, 1H), 7.03(s, 1H), 6.85(d, J=8.4Hz ,1H),4.57-4.46(m,4H),4.28-4.22(m,1H),4.05-3.94(m,4H),3.09-2.96(m,4H),2.79(s,3H).ESI-MS :m/z 537.1[M+H] ⁺ .

Example 107

(8-(2-(Methylthio)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2,3-dihydro-[1,4]dioxo Heterocyclohexadieno[2,3-g]benzofuran-3-yl)methyl(2-(4-methylpiperazin-1-yl)ethyl)carbamate (Compound 107)

Weigh compound 106-1 (25mg, 0.046mmol) and dissolve it in anhydrous N,N-dimethylformamide (4mL), and add N,N-diisopropylethylamine (11μL, 0.07mmol ), 4-methyl-1-piperazineethylamine (9 μL, 0.056 mmol), after the addition was complete, stir at room temperature overnight. After the reaction was complete, dilute with water (10mL), extract the aqueous phase with ethyl acetate (10mL x 3), combine the organic phases, wash the organic phase with water (10mL x 3) and saturated brine (10mL x 1), and wash with anhydrous sulfuric acid Sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=1:1:1-1:3:3) to obtain compound 107 (yellow Solid, 25 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.06(s, 1H), 7.05(d, J=8.5Hz, 1H), 7.01(s, 1H), 6.85(d, J=8.4Hz ,1H),5.31(s,1H),4.55-4.33(m,4H),4.28-4.18(m,1H),3.39-3.25(m,2H),2.77(s,3H),2.73-2.48(m ,10H),2.41(s,3H).ESI-MS:m/z545.2[M+H] ⁺ .

Example 108

(8-(2-(Methylthio)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2,3-dihydro-[1,4]dioxo Heterocyclohexadieno[2,3-g]benzofuran-3-yl)methyl(2-(4-methylpiperazin-1-yl)ethyl)carbamate (Compound 108)

Weigh compound 106-1 (24mg, 0.045mmol) and dissolve it in anhydrous N,N-dimethylformamide (4mL), and add N,N-diisopropylethylamine (11μL, 0.067mmol ), morpholine (5 μL, 0.0533 mmol), after the addition was complete, stir overnight at room temperature. After the reaction was complete, dilute with water (15mL), extract the aqueous phase with ethyl acetate (8mL x 2), combine the organic phases, wash the organic phase with water (8mL x 3) and saturated brine (8mL x 1), and wash with anhydrous sulfuric acid Sodium was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=6:1:1-1:1:1) to obtain compound 108 (white Solid, 18 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.06(s, 1H), 7.05(d, J=8.4Hz, 1H), 7.01(s, 1H), 6.85(d, J=8.4Hz ,1H),4.55-4.40(m,4H),4.28-4.18(m,1H),3.72-3.60(m,4H),3.53-3.43(m,4H),2.77(s,3H).ESI-MS :m/z 511.1[M+Na] ⁺ .

Example 109

Evaluation of Antiplatelet Aggregation Activity in Vitro

Test principle: AYP is a specific agonist peptide of PAR4, the sequence is AYPGKF-NH ₂ , which can selectively activate PAR4 and cause platelet aggregation. The compound of the present invention can antagonize platelet PAR4, thereby inhibiting platelet aggregation. The platelet aggregation inhibition rate can reflect the activity of the compound. The test used filtered platelets taken from mouse arterial plasma.

Platelet aggregation assay: draw 300 μL of Tyrode's buffer and place it in the test area of the platelet aggregation instrument to adjust to zero, then draw 270 μL of filtered platelets and place them in the preheating tank, add 20 μL of each test sample (compound concentration: 20 nM), and preheat at 37°C for 5 minutes After placing it in the test area, add test beads and 10 μL AYP, and measure the maximum aggregation rate of platelets within 5 minutes. The negative control group was normal saline. The aggregation inhibition rate of platelets was calculated by the following formula. Calculation formula: platelet aggregation inhibition rate=[(X-Y)/X]*100%, wherein X is the maximum platelet aggregation rate of the normal saline group, and Y is the maximum platelet aggregation rate of the compound. The experimental results of some compounds are shown in Table 2.

Table 2. Inhibition rate of compounds on platelet aggregation induced by AYP

The experimental results (Table 2) show that when the inducer AYP concentration is 100 μM and the compound concentration is at 20 nM, compounds 5, 8, 10, 11, 12, 13, 14, 23, 30, 31, 32, 46, 47, 54 , 55, 75, 76, 86, 88, 89, 91, 92, 94, 96, 98 all surpassed BMS-986120 in the inhibition rate of in vitro filtered platelet aggregation, showing that the compound of the present invention has excellent anti-platelet aggregation activity . For example, the test charts of the inhibition rate of compound 11 and compound 88 on in vitro filtered platelet aggregation are shown in Figure 1 and Figure 2, respectively.

Example 110

Metabolic Stability of Compounds in Human Liver Microsomes

Evaluation of the metabolic stability of human liver microsomes is an important means for preclinical evaluation of the pharmacokinetic properties of candidate compounds in drug development.

The experimental incubation system (250 μL in volume, n=3) consists of liver microsomes, working solution of the test substance and phosphate buffer solution. The incubation system was co-incubated at 37°C for one hour, and the timing started after adding NADPH solution. The time point is to stop the reaction by adding the stop solution, and the sampling intervals are 0, 5, 15, 30, and 60 min, a total of 5 points. Negative control without NADPH, the sampling time point is 0, 60min. Use LC-MS/MS to analyze, the absolute value k of the slope measured by the natural logarithm of the percentage of the remaining amount of the test substance plotted against time is calculated according to the following formula: T _1/2 (half-life period)=ln2/k = 0.693/k. The experimental results are shown in Table 3.

Table 3. Studies on metabolic stability of some compounds in human liver microsomes

The experimental results (Table 3) show that the metabolic stability of liver microsomes of compounds 9, 11, 13, 30, 31, 38, 47, 86, and 88 of the present invention are all improved compared with BMS-986120, and T _1/2 has increased, and the stability of compounds 30, 38, and 86 improved significantly. This indicates that some compounds of the present invention have better metabolic stability in organisms, which may reduce the hepatic first-pass effect of drugs, and show that the compounds of the present invention have better pharmacokinetic properties.

Example 111

tablet

Compound 11 (50g) prepared in Example 11, hydroxypropylmethylcellulose E (150g), starch (200g), an appropriate amount of povidone K30 and magnesium stearate (1g) were mixed, granulated, and compressed into tablets .

Claims (7)

1. The compound shown in formula (I) or formula (II) or its pharmaceutically acceptable salt or ester or solvate: in, R is selected from ^: H, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, phenoxy, phenylthio, alkyl NH-, alkyloxyalkyl, tetrahydrofuran-2- radical, alkylcarbonyl, alkylsulfonyl, (alkyl) _2N- , cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, haloalkoxy, haloalkylthio, alkoxycarbonylalkane Oxygen, alkoxycarbonylalkylthio; R ² is selected from: H, halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, cycloalkyl, haloalkyl, haloalkoxy, haloalkylthio, halocycloalkyl, heterocycloalkyl; E is selected from: S, O, NH, -CR ³ =CR ⁴ -, -N=CR ⁴ -, -CR ³ =N-, -N=N-; R ³ and R ⁴ are independently selected from: H, halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O) NH ₂ , R ^3a , OR ^3a , NHR ^3a , NH(CO)R ^3a , C(O)R ^3a , C(O)OR ^3a , OC(O)R ^3a , C(O)NHR ^3a , C(O)R 3a , C(O)R 3a , )NR ^3b R ^3c , NR ^3b R ^3c , -(CR ^3d R ^3e ) _n -R ^3g , -(CHR ^3f ) _n -R ^3g , -(CR ^3d R ^3e ) _n -OR ^3g , -(CHR ^3f ) _n -OR ^3g 、 R ^3a is selected from: alkyl, alkenyl, alkynyl; each of said alkyl, alkenyl, alkynyl is unsubstituted or substituted by one or two or three substituents independently selected from the following : Halogen, CN, NO ₂ , NH ₂ , OH, (O), CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , alkyl NH-, (alkyl) ₂ N-; R ^3b and R ^3c are selected from: alkyl, alkenyl, alkynyl, aryl, or a nitrogen atom bound to it to form a 4- to 8-membered heterocycle, and the heterocycle contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0～ 2 additional heteroatoms selected from N, N-(alkyl), O, S(O) and S(O) ₂ ; R ^3d , R ^3e and R ^3f are selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkane NH-, (alkyl) ₂ N-; wherein R ^3d and R ^3e can form a 3-8-membered ring with the carbon atoms connected to it, and the ring does not contain heteroatoms or contains 0-3 independently selected from halogen , CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl; X ¹ is selected from: CR ⁵ , N; R ⁵ is selected from: H, halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , alkyl , alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl Each of which is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , cycloalkyl, hydroxyalkyl, OR ^5a , COOR ^5a , SO ₂ R ^5a , O(C=O)R ^5a , (C=O )OR ^5a , N(R ^5a )(C=O)R ^5a , (C=O)NR ^5b R ^5c , NR ^5b R ^5c , SO ₂ NR ^5b R ^5c , -(CH ₂ ) _n -heteroaryl, -(CH ₂ ) _n -phenyl, -(CH ₂ ) _n -O-heteroaryl, -(CH ₂ ) _n -O-phenyl; R ^is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl; R ^5b and R ^5c are selected from: an alkyl group or a 4- to 8-membered heterocycle formed by a nitrogen atom bound to it, and the heterocycle contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , and OCHF ₂ , OCH ₂ F, 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional selected from N, N - heteroatoms of (alkyl), O, S(O) and S(O) ₂ ; X ² is selected from: O, S, NR ⁶ ; R ⁶ is selected from: H, R ^6a , C(O)R ^6a , S(O)R ^6a , S(O) ₂ R ^6a , -(CR ^6b R ^6c ) _n -R ^6e , -(CHR ^6d ) _n -R ^6e , -(CR ^6b R ^6c ) _n -OR ^6e , -(CHR ^6d ) _n -OR ^6e ; R ^6a is selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl; wherein, the alkyl, alkenyl, alkynyl is unsubstituted or replaced by one or Two or three substituents independently selected from the following substituents are substituted: halogen, haloalkyl; wherein, the cycloalkyl, aryl, heteroaryl, heterocycloalkyl are unsubstituted or replaced by one or two Or three substituents independently selected from the following: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C( O) NH ₂ ; R ^6b , R ^6c and R ^6d are selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkane NH-, (alkyl) ₂ N-; wherein R ^6b and R ^6c can form a 3-8-membered ring with the carbon atoms connected to it, and the ring does not contain heteroatoms or contains 0-3 independently selected from halogen , CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl; X ³ is selected from: CR ⁷ , N; R ⁷ is selected from: H, halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , COOH, C(O)NH ₂ , R ^7a , OR ^7a , SR ^7a , COOR ^7a , SO ₂ R ^7a , O(C=O)R ^7a , (C=O)OR ^7a , N(R ^7a )(C=O)R ^7a , (C=O)NR ^7b R ^7c , NR ^7b R ^7c , SO ₂ NR ^7b R ^7c , -(CR ^7d R ^7e ) _n -R ^7g , -(CHR ^7f ) _n -R ^7g , -(CR ^7d R ^7e ) _n -OR ^7g , -(CHR ^7f ) _n -OR ^7g ; R ^7a is selected from: alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl; wherein, the alkyl, alkenyl, alkynyl is unsubstituted or replaced by one or Two or three substituents independently selected from the following substituents are substituted: halogen, haloalkyl; the aryl, cycloalkyl, heteroaryl, heterocycloalkyl are unsubstituted or replaced by one or two or three Substituents independently selected from the following substituents: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O) _NH2 ; R ^7b and R ^7c are selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; wherein, R ^7b and R ^7c can form a 3- 8-membered ring containing 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkane A carbon atom substituted by a radical, an alkyl group and an alkoxy group, and 0 to 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^7d , R ^7e and R ^7f are selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkane NH-, (alkyl) ₂ N-; wherein, R ^7d and R ^7e can form a 3-8-membered ring with the carbon atoms connected to it, and the ring does not contain heteroatoms or contains 0-3 independently selected from Carbon atoms substituted by halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups , and 0 to 2 additional heteroatoms selected from N, N (alkyl), O, S (O) and S (O) ₂ ; R ^7g is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl; wherein, the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl Cycloalkyl, heterocycloalkenyl is unsubstituted or substituted by one or two or three substituents independently selected from the following: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF _3. OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ; X ⁴ and X ⁵ can be independently selected from: O, S, S(O), S(O) ₂ , CHR ⁸ , CR ⁹ R ¹⁰ , NR ¹¹ ; R ⁸ , R ⁹ , R ¹⁰ are selected from: H, halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , COOH, R ^8a , OR ^8a , SR ^8a , C(O)R ^8a , S(O)R ^8a , S(O) ₂ R ^8a , -(CR ^8b R ^8c ) _n -R ^8e , -(CHR ^8d ) _n -R ^8e , -(CR ^8b R ^8c ) _n -OR ^8e , -(CHR ^8d ) _n -OR ^8e ; R ^8a is selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl; wherein, the alkyl, alkenyl, alkynyl is unsubstituted or replaced by one or Two or three substituents independently selected from the following substituents are substituted: halogen, haloalkyl; said cycloalkyl, aryl, heteroaryl, heterocycloalkyl are unsubstituted or replaced by one or two or three Substituents independently selected from the following substituents: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O) _NH2 ; R ^8b , R ^8c and R ^8d are selected from: H, F, Cl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl , Alkyl NH-, (Alkyl) ₂ N-; wherein, R ^8b and R ^8c can form a 3-8 membered ring with the carbon atoms connected to it, and the ring does not contain heteroatoms or contains 0 to 3 independently Substituted by a group selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy A carbon atom, and 0 to 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl; wherein, the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl Cycloalkyl, heterocycloalkenyl is unsubstituted or substituted by one or two or three substituents independently selected from the following: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF _3. OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ; R ¹¹ is selected from: H, R ^11a , S(O)R ^11a , S(O) ₂ R ^11a , C(O)R ^11a , -(CR ^11b R ^11c ) _n -R ^11e , -(CHR ^11d ) _n -R ^11e , -(CR ^11b R ^11c ) _n -OR ^11e , -(CHR ^11d ) _n -OR ^11e ; R ^11a is selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl; wherein, the alkyl, alkenyl, alkynyl is unsubstituted or replaced by one or Two or three substituents independently selected from the following substituents are substituted: halogen, haloalkyl; wherein, the cycloalkyl, aryl, heteroaryl, heterocycloalkyl are unsubstituted or replaced by one or two Or three substituents independently selected from the following: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C( O) NH ₂ ; R ^11b , R ^11c and R ^11d are selected from the group consisting of: H, F, Cl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl , alkyl NH-, (alkyl) ₂ N-; wherein, R ^11b and R ^11c can form a 3-8-membered ring with the carbon atoms connected to it, and the ring does not contain heteroatoms or contains 0 to 3 independently Substituted by a group selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy A carbon atom, and 0 to 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^11e is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl; wherein, the aryl, heteroaryl, cycloalkyl, cycloalkenyl, hetero Cycloalkyl, heterocycloalkenyl is unsubstituted or substituted by one or two or three substituents independently selected from the following: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF _3. OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ; R ¹² and R ¹³ are selected from: H, deuterium, halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , SO ₂ NH ₂ , COOH, C(O )NH ₂ , R ^12a , OR ^12a , SR ^12a , S(O)R ^12a , S(O) ₂ R ^12a , C(O)R ^12a , C(O)OR ^12a , OC(O)R ^12a , NHR ^12a , C(O)NHR ^12a , NH(CO)R ^12a , NR ^12a (CO)R ^12a , NH(CO)OR ^12a , NR ^12a (CO)OR ^12a , SO ₂ NHR ^12a , NHSO ₂ R ^12a , NR ^12a SO ₂ R ^12a , NR ^12b R ^12c , C(O)NR ^12b R ^12c , SO ₂ NR ^12b R ^12c , R ^12d ; wherein R ^12b and R ^12c combine to form 4 to 8 membered when attached to the same nitrogen A heterocyclic ring containing 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl , carbon atoms substituted by groups of alkyl and alkoxy groups, and 0 to 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^12a , R ^12b and R ^12c are selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; said alkyl, Alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl each of which is unsubstituted or is independently selected from one or two or three The following substituents are substituted: H, halogen, OH, (O), CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , SO ₂ NH ₂ , COOH, C(O)NH ₂ , NHC(O)NH ₂ , R ^12aa , OR ^12aa , SR ^12aa , S(O)R ^12aa , OS(O) ₂ R ^12aa , S(O) ₂ R ^12aa , NHR ^12aa , C (O)R ^12aa , C(O)OR ^12aa , OC(O)R ^12aa , OC(O)NHR ^12aa , C(O)NHR ^12aa , NR ^12aa C(O)R ^12aa , NHSO ₂ R ^12aa , NHC( O)OR ^12aa , S(O) ₂ NHR ^12aa , NHC(O)R ^12aa , NHC(O)NHR ^12aa , OC(O)NR ^12ab R ^12ac , NR ^12ab R ^12ac , C(O)NR ^12ab R ^12ac , SO ₂ NR ^12ab R ^12ac ; R ^12aa is selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; said alkyl, alkenyl, alkynyl, Each of aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl is unsubstituted or substituted by one or two or three substituents independently selected from : H, Halogen, OH, (O), CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , SO ₂ NH ₂ , COOH, C(O)NH ₂ , NHC(O)NH ₂ , R ^12aaa , OR ^12aaa , SR ^12aaa , S(O)R ^12aaa , S(O) ₂ R ^12aaa , NHR ^12aaa , C(O)R ^12aaa , C(O)OR ^12aaa , OC (O)R ^12aaa , C(O)NHR ^12aaa , NR ^12aaa C(O)R ^12aaa , NHSO ₂ R ^12aaa , NHC(O)OR ^12aaa , S(O) ₂ NHR ^12aaa , NHC(O)R ^12aaa , NHC (O)NHR ^12aaa , NR ^12aab R ^12aac , C(O)NR ^12aab R ^12aac , SO ₂ NR ^12aab R ^12aac ; R ^{12aaa is} selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; said alkyl, alkenyl, alkynyl, Aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ; R ^12aab and R ^12aac are selected from: an alkyl group, or when attached to the same nitrogen, combine to form a 4 to 8 membered heterocycle containing 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF _3. Carbon atoms substituted by OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups, and 0 to 2 additional optional Heteroatoms from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^12ab and R ^12ac are selected from: an alkyl group, or when attached to the same nitrogen, combine to form a 4 to 8 membered heterocycle containing 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF _3. Carbon atoms substituted by OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups, and 0 to 2 additional optional Heteroatoms from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^12d is selected from: -(CR ^12da R ^12db ) _n -R ^12dd , -(CHR ^12dc ) _n -R ^12dd , -(CR ^12da R ^12db ) _n -OR ^12dd , -(CHR ^12dc ) _n -OR ^12dd ; R ^12da , R ^12db , R ^12dc are selected from: H, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heteroaryl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl; Wherein, each of the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl is unsubstituted or is independently selected from the following by one or two or three Substituents substituted by: halogen, CN, NO ₂ , NH ₂ , OH, alkoxy, haloalkoxy, alkyl, haloalkyl, cycloalkyl, hydroxyalkyl; the carbon to which R ^12da and R ^12db can be attached Atoms form a 3-8 membered ring, the ring does not contain heteroatoms or contains 0 to 3 heteroaryls independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5 or 6 members group, OH, oxo, hydroxyalkyl, alkyl and alkoxy group substituted carbon atoms, and 0 to 2 additional ones selected from N, N(alkyl), O, S(O) and Heteroatoms of S(O) ₂ ; R ^{12dd is} selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl; Ring A is selected from: 4-20 membered heterocycles with an unsaturation degree of 1 that does not contain heteroatoms, 4-20 membered heterocycles with a degree of unsaturation greater than 1 that does not contain heteroatoms, 4-20 membered heterocycles that contain O, N or S atoms A 4-20-membered heterocycle with a saturation of 1, a 4-20-membered heterocycle with an unsaturation greater than 1 containing O, N or S atoms; R ¹² can be arbitrarily substituted at the C atom site on the A ring; R ^12d can be arbitrarily substituted at the N atom site on the A ring; L is selected from: -O-, -S-, -NH-, -S(O)-, -S(O) ₂ -, -C(O)-, -C(O)O-, -OC(O )-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -R ^14a -, -(R ^14a ) _n -C(O)-, -C(O)- (R ^14a ) _n -, -C(O)-(R ^14a ) _n -O-, -C(O)-(R ^14a ) _n -O-(R ^14a ) _n -, -C(O)-( R ^14a ) _n -S-(R ^14a ) _n -, -C(O)-(R ^14a ) _n -S-, -O-(R ^14a ) _n -, -S-(R ^14a ) _n -, - (R ^14a ) _n -O-, -(R ^14a ) _n -S-, -O-(R ^14a ) _n -C(O)-, -S-(R ^14a ) _n -C(O)-, - O-(R ^14a ) _n -O-, -(R ^14a ) _n -O-(R ^14a ) _n -, -NC(O)(R ^14a ) _n -, -C(O)-(R ^14a ) _n -C(O)-, -C(O)-(R ^14a ) _n -OC(O)-, -NR ^14b -, -C(O)NR ^14b -, -NR ^14b C(O)NR ^14b -; R ^14a is selected from: alkyl, alkenyl, alkynyl; wherein, said alkyl, alkenyl, alkynyl are all independently unsubstituted or substituted by one or two or three independently selected from the following Substituted by: H, (O), halogen, OCF ₃ , CF ₃ , OCHF ₂ , OH, CN, NO ₂ , haloalkyl, alkoxy, alkylthio, cycloalkyl, cycloalkoxy, carboxyl, Alkoxycarbonyl, alkylsulfonyl, NR ^14aa R ^14ab , C(=O)NR ^14aa R ^14ab , S(=O) ₂ NR ^14aa R ^14ab , aryl, heteroaryl, heterocycloalkyl, heterocycle Alkenyl; wherein, R ^14aa and R ^14ab are selected from: alkyl, or when connected to the same nitrogen, combined to form a 4 to 8-membered heterocyclic ring, which contains 0 to 3 independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0～ 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^is selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; Wherein, the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl are all independently unsubstituted or substituted with one or _two or three substituents independently selected from the group consisting of halogen, CN, NO2, _NH2 , OH, alkoxy, haloalkoxy, alkyl, haloalkane radical, cycloalkyl, hydroxyalkyl; R ^is selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; Wherein, the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl are all independently unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of H, halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , NH(CO)NH ₂ , SO ₂ NH ₂ , R ^15a , OR ^15a , SR ^15a , S(O)R ^15a , S(O ) ₂ R ^15a , C(O)R ^15a , C(O)OR ^15a , OC(O)R ^15a , OC(O)NHR ^15a , NHR ^15a , C(O)NHR ^15a , NH(CO)R ^15a , NR ^15a (CO)R ^15a , NH(CO)OR ^15a , NR ^15a (CO)OR ^15a , NH(CO)NHR ^15a , NR ^15a (CO)NHR ^15a , S(O) ₂ NHR ^15a , NHS(O) ₂ R ^15a , NR ^15a S(O) ₂ R ^15a , NHS(O) ₂ NHR ^15a , NR ^15a S(O) ₂ NHR ^15a , OC(O)NR ^15b R ^15c , C(O)NHNOR ^15a , C( O)NHS(O) ₂ R ^15a , NR ^15a S(O) ₂ NR ^15b R ^15c , NR ^15b R ^15c , C(O)NR ^15b R ^15c , NH(CO)NR ^15b R ^15c , NR ^15a (CO) NR ^15b R ^15c , S(O) ₂ NR ^15b R ^15c , NHS(O) ₂ NR ^15b R ^15c , -(CR ^15d R ^15e ) _n -R ^15g , -(CHR ^15f ) _n -R ^15g , -(CR ^15d R ^15e ) _n -OR ^15g , -(CHR ^15f ) _n -OR ^15g ; R ^15a , R ^15b , R ^15c are selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkane wherein, each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl is Unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , NHC(O)NH ₂ , R ^15aa , OR ^15aa , SR ^15aa , S(O)R ^15aa , S(O) ₂ R ^15aa , NHR ^15aa , C( O)R ^15aa , C(O)NHR ^15aa , NHC(O)R ^15aa , NR ^15aa C(O)R ^15aa , NHS(O) ₂ R ^15aa , NHC(O)OR ^15aa , SO ₂ NHR ^15aa , NHC( O) NHR ^15aa , SO ₂ NR ^15ab R ^15ac , NCR ^15ab R ^15ac , NR ^15ab R ^15ac , C(O)NR ^15ab R ^15ac ; wherein, when R ^15b , R ^15c are attached to the same nitrogen, combine to form 4 to An 8-membered heterocycle containing 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5 or 6-membered heteroaryl, OH, oxo, hydroxyl Alkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to ₂ additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ; R ^15aa , R ^15ab , R ^15ac are selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkane group; wherein, when R ^15ab and R ^15ac are connected to the same nitrogen, they are combined to form a 4 to 8 membered heterocyclic ring, which contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF _2. Carbon atoms substituted by OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups, and 0 to 2 additional members selected from N, N(alkyl), O, S(O) and S(O ₎ heteroatoms; R ^15d , R ^15e , R ^15f are selected from: H, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero Cycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein, the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, hetero Spirocycloalkyl each of which is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, hydroxyalkyl; among them, R ^15d and R ^15e can form a 4 to 8-membered ring with the carbon to which it is attached, and the ring does not contain heteroatoms or contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5 Or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional selected from N, N (alkyl), O , S(O) and S(O) ₂ heteroatoms; R ^15g is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein, the aryl, heteroaryl group, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl, each of which is unsubstituted or is independently selected from The following substituents are substituted: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH, alkyl, Haloalkyl, alkoxy, haloalkoxy, cycloalkyl, hydroxyalkyl; n is selected from: 1, 2, 3, 4, 5, 6. 2. The compound of claim 1, characterized in that: R is selected from: H, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl NH-, alkyloxyalkyl, tetrahydrofuran- ² -yl, alkylcarbonyl, alkyl Sulfonyl, (alkyl) _2N- , cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, haloalkoxy, haloalkylthio; R ² is selected from: H, halogen, CN, NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , alkyl, alkoxy, alkylthio, cycloalkyl, haloalkyl, Haloalkoxy, haloalkylthio, halocycloalkyl, heterocycloalkyl; E is selected from: S, O, -CR ³ =CR ⁴ -, -N=CR ⁴ -, -CR ³ =N-, -N=N-; R ³ and R ⁴ are independently selected from: H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , R ^3a , OR ^3a , NH(CO)R ^3a , C(O)R ^3a , C(O)OR ^3a , OC(O)R ^3a , C(O)NHR ^3a , C(O)NR ^3b R ^3c , -(CR ^3d R ^3e ) _n -R ^3g , -(CHR ^3f ) _n -R ^3g , -(CR ^3d R ^3e ) _n -OR ^3g , -(CHR ^3f ) _n -OR ^3g , R ^3a is selected from: alkyl, alkenyl, alkynyl; each of said alkyl, alkenyl, alkynyl is unsubstituted or substituted by one or two or three substituents independently selected from the following : Halogen, CN, OH, (O), CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , alkyl NH-, (alkyl) ₂ N-; R ^3b and R ^3c are selected from: an alkyl group or a 4-6 membered heterocycle formed by the nitrogen atom bound to it, and the heterocycle contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional selected from N, N - heteroatoms of (alkyl), O, S(O) and S(O) ₂ ; R ^3d , R ^3e and R ^3f are selected from the group consisting of: H, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkylNH-, (alk group) ₂ N-; wherein R ^3d and R ^3e can form a 3-8 membered ring with the carbon atoms connected to it, and the ring does not contain heteroatoms or contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional A heteroatom selected from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^3g is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl; X ¹ is selected from: CR ⁵ , N; R ⁵ is selected from: H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , alkyl, alkenyl, alkynyl, ring Alkyl, heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl are each unsubstituted or replaced by one or two or three independently selected from the following Substituents substituted by: halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , cycloalkyl, hydroxyalkyl, OR ^5a , COOR ^5a , SO ₂ R ^5a , N(R ^5a )(C=O)R ^5a , (C=O)NR ^5b R ^5c , NR ^5b R ^5c , SO ₂ NR ^5b R ^5c ; R ^is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; R ^5b and R ^5c are selected from: alkyl; X ² is selected from: O, S, NR ⁶ ; R ⁶ is selected from: H, R ^6a , C(O)R ^6a , S(O)R ^6a , S(O) ₂ R ^6a , -(CR ^6b R ^6c ) _n -R ^6e , -(CHR ^6d ) _n -R ^6e , -(CR ^6b R ^6c ) _n -OR ^6e , -(CHR ^6d ) _n -OR ^6e ; R ^6a is selected from: alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl; wherein, the alkyl, alkenyl, alkynyl is unsubstituted or replaced by one or two or three independently Substituents selected from the following substituents are substituted: halogen, haloalkyl; wherein, the cycloalkyl and heterocycloalkyl are unsubstituted or substituted by one or two or three substituents independently selected from the following: Halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ; R ^6b , R ^6c and R ^6d are selected from the group consisting of: H, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkylNH-, (alk group) ₂ N-; wherein R ^6b and R ^6c can form a 3-6-membered ring with the carbon atoms connected to it, and the ring does not contain heteroatoms or contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional A heteroatom selected from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl; X ³ is selected from: CR ⁷ , N; R ⁷ is selected from: H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , COOH, C(O)NH ₂ , R ^7a , OR ^7a , SR ^7a , N(R ^7a ) (C=O)R ^7a , (C=O)NR ^7b R ^7c , NR ^7b R ^7c , SO ₂ NR ^7b R ^7c , -(CR ^7d R ^7e ) _n -R ^7g , -(CHR ^7f ) _n -R ^7g , -(CR ^7d R ^7e ) _n -OR ^7g , -(CHR ^7f ) _n -OR ^7g ; R ^7a is selected from: alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl; wherein, the alkyl, alkenyl, alkynyl is unsubstituted or replaced by one or Two or three substituents independently selected from the following substituents are substituted: halogen, haloalkyl; the aryl, cycloalkyl, heteroaryl, heterocycloalkyl are unsubstituted or replaced by one or two or three Substituents independently selected from the following substituents: halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ; R ^7b and R ^7c are selected from: alkyl, alkenyl, alkynyl, cycloalkyl; wherein, R ^7b and R ^7c can form a 3-6-membered ring with the nitrogen atom connected to it, which contains 0-3 Groups independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy Substituted carbon atoms, and 0 to 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^7d , R ^7e and R ^7f are selected from the group consisting of: H, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkylNH-, (alk group) ₂ N-; wherein, R ^7d and R ^7e can form a 3-6-membered ring with the carbon atom connected to it, and the ring does not contain heteroatoms or contains 0-3 independently selected from halogen, CF ₃ , CHF _2. Carbon atoms substituted by OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups, and 0 to 2 Additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^7g is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl; wherein, the aryl, heteroaryl, cycloalkyl, heterocycloalkyl is unsubstituted or replaced by one or two Or three substituents independently selected from the following substituents: halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ; X ⁴ and X ⁵ can be independently selected from: O, S, CHR ⁸ , CR ⁹ R ¹⁰ , NR ¹¹ ; R ⁸ , R ⁹ , R ¹⁰ are selected from: H, halogen, CN, NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , COOH, R ^8a , OR ^8a , SR ^8a , C (O)R ^8a , S(O)R ^8a , S(O) ₂ R ^8a , -(CR ^8b R ^8c ) _n -R ^8e , -(CHR ^8d ) _n -R ^8e , -(CR ^8b R ^8c ) _n -OR ^8e , -(CHR ^8d ) _n -OR ^8e ; R ^8a is selected from: alkyl, alkenyl, alkynyl, heterocycloalkyl; wherein, the alkyl, alkenyl, alkynyl is unsubstituted or one or two or three are independently selected from the following Substituents substituted by: halogen, haloalkyl; said heterocycloalkyl is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ; R ^8b , R ^8c and R ^8d are selected from the group consisting of: H, F, Cl, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkylNH-, (Alkyl) ₂ N-; wherein, R ^8b and R ^8c can form a 3-6-membered ring with the carbon atoms connected to them, and the ring does not contain heteroatoms or contains 0 to 3 independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0～ 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^8e is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl; wherein, the aryl, heteroaryl, cycloalkyl, heterocycloalkyl is unsubstituted or replaced by one or two Or three substituents independently selected from the following substituents: halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ; R ¹¹ is selected from: H, R ^11a , S(O)R ^11a , S(O) ₂ R ^11a , C(O)R ^11a , -(CR ^11b R ^11c ) _n -R ^11e , -(CHR ^11d ) _n -R ^11e , -(CR ^11b R ^11c ) _n -OR ^11e , -(CHR ^11d ) _n -OR ^11e ; R ^11a is selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl; wherein, the alkyl, alkenyl, alkynyl is unsubstituted or replaced by one or Two or three substituents independently selected from the following substituents are substituted: halogen, haloalkyl; wherein, the cycloalkyl, aryl, heteroaryl, heterocycloalkyl are unsubstituted or replaced by one or two Or three substituents independently selected from the following: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C( O) NH ₂ ; R ^11b , R ^11c and R ^11d are selected from the group consisting of: H, F, Cl, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkylNH-, (Alkyl) ₂ N-; Wherein, R ^11b and R ^11c can form a 3-6 membered ring with the carbon atoms connected to it, and the ring does not contain heteroatoms or contains 0 to 3 independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0～ 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^11e is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl; wherein, the aryl, heteroaryl, cycloalkyl, heterocycloalkyl is unsubstituted or replaced by one or two Or three substituents independently selected from the following substituents: halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ; R ¹² and R ¹³ are selected from: H, deuterium, halogen, CN, NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , SO ₂ NH ₂ , COOH, C(O)NH ₂ , R ^12a , OR ^12a , S(O)R ^12a , S(O) ₂ R ^12a , C(O)R ^12a , NHR ^12a , C(O)NHR ^12a , NH(CO)R ^12a , NR ^12a (CO )R ^12a , SO ₂ NHR ^12a , NHSO ₂ R ^12a , NR ^12b R ^12c , C(O)NR ^12b R ^12c , SO ₂ NR ^12b R ^12c , R ^12d ; wherein R ^12b and R ^12c when attached to the same nitrogen , combined to form a 4- to 8-membered heterocycle containing 0-3 independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5 or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional ones selected from N, N(alkyl), O, S(O) and S( O) a heteroatom of ₂ ; R ^12a , R ^12b and R ^12c are selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; each of said alkyl, alkenyl or alkynyl is Unsubstituted or substituted by one or two or three substituents independently selected from H, halogen, OH, (O), CN, NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , SO ₂ NH ₂ , COOH, C(O)NH ₂ , NHC(O)NH ₂ , R ^12aa , OR ^12aa , S(O)R ^12aa , OS(O) ₂ R ^12aa , S( O) ₂ R ^12aa , NHR ^12aa , C(O)R ^12aa , C(O)NHR ^12aa , C(O)OR ^12aa , OC(O)R ^12aa , OC(O)NHR ^12aa , OC(O)NR ^12ab R ^12ac , NR ^12aa C(O)R ^12aa , NHSO ₂ R ^12aa , S(O) ₂ NHR ^12aa , NHC(O)R ^12aa , NHC(O)NHR ^12aa , NR ^12ab R ^12ac , C(O)NR ^12ab R ^12ac , SO ₂ NR ^12ab R ^12ac ; R ^12aa is selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkane group, or heterocycloalkyl, each of which is unsubstituted or substituted by one or two or three substituents independently selected from the following: H, halogen, OH, (O), CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , SO ₂ NH ₂ , COOH, C(O)NH ₂ , NHC(O)NH ₂ , R ^12aaa , OR ^12aaa , SR ^12aaa , S(O)R ^12aaa , S(O) ₂ R ^12aaa , NHR ^12aaa , C(O)R ^12aaa , C(O)OR ^12aaa , OC(O)R ^12aaa , C(O)NHR ^12aaa , NR ^12aaa C( O)R ^12aaa , NHSO ₂ R ^12aaa , NHC(O)OR ^12aaa , S(O) ₂ NHR ^12aaa , NHC(O)R ^12aaa , NHC(O)NHR ^12aaa , NR ^12aab R ^12aac , C(O)NR ^12aaa R ^12aac , SO ₂ NR ^12aab R ^12aac ; R ^{12aaa is} selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; said alkyl, alkenyl, alkynyl, Aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ ; R ^12aab and R ^12aac are selected from: an alkyl group, or when attached to the same nitrogen, combine to form a 4 to 6 membered heterocycle containing 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF _3. Carbon atoms substituted by OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups, and 0 to 2 additional optional Heteroatoms from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^12ab and R ^12ac are selected from: an alkyl group, or when attached to the same nitrogen, combine to form a 4-6 membered heterocycle containing 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF _3. Carbon atoms substituted by OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups, and 0 to 2 additional optional Heteroatoms from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^12d is selected from: -(CR ^12da R ^12db ) _n -R ^12dd , -(CHR ^12dc ) _n -R ^12dd , -(CR ^12da R ^12db ) _n -OR ^12dd , -(CHR ^12dc ) _n -OR ^12dd ; R ^12da , R ^12db , R ^12dc are selected from: H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl; wherein, each of the cycloalkyl and heterocycloalkyl is unsubstituted or replaced by one Or two or three substituents independently selected from the following substituents: halogen, CN, NH ₂ , OH, alkoxy, haloalkoxy, alkyl, haloalkyl, cycloalkyl, hydroxyalkyl; R ^12da and R ^12db can form a 3-6 membered ring with the carbon atom connected to it, and the ring does not contain heteroatoms or contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5 or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy group substituted carbon atoms, and 0 to 2 additional selected from N, N (alkyl ), O, S(O) and S(O) ₂ heteroatoms; R ^{12dd is} selected from: aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl; Ring A is selected from: 4-10 membered heterocyclic rings with an unsaturation degree of 1 that does not contain heteroatoms, 4-10 membered heterocyclic rings with a degree of unsaturation greater than 1 that does not contain heteroatoms, and unsaturated rings that contain O, N or S atoms A 4-10 membered heterocycle with a degree of saturation of 1, a 4-10 membered heterocycle with an unsaturation greater than 1 containing O, N or S atoms; R ¹² can be arbitrarily substituted at the C atom site on the A ring; R ^12d can be arbitrarily substituted at the N atom site on the A ring; L is selected from: -O-, -S-, -NH-, -S(O)-, -S(O)2-, -C(O)-, -C(O)NH-, -NHC(O )-, -NHC(O)NH-, -R ^14a -, -(R ^14a ) _n -C(O)-, -C(O)-(R ^14a ) _n -, -C(O)-(R ^14a ) _n -O-, -C(O)-(R ^14a ) _n -O-(R ^14a ) _n -, -O-(R ^14a ) _n -, -(R ^14a ) _n -O-, -O -(R ^14a ) _n -C(O)-, -O-(R ^14a ) _n -O-, -(R ^14a ) _n -O-(R ^14a ) _n -, -NC(O)(R ^14a ) _n -, -C(O)-(R ^14a ) _n -C(O)-, -NR ^14b -, -C(O)NR ^14b -, -NR ^14b C(O)NR ^14b -; R ^14a is selected from: alkyl, alkenyl, alkynyl; wherein, said alkyl, alkenyl, alkynyl are all independently unsubstituted or substituted by one or two or three independently selected from the following Substituted by: H, (O), halogen, OCF ₃ , CF ₃ , OCHF ₂ , OH, CN, haloalkyl, alkoxy, alkylthio, cycloalkoxy, carboxyl, alkoxycarbonyl, alkyl Sulfonyl, NR ^14aa R ^14ab , C(=O)NR ^14aa R ^14ab , S(=O) ₂ NR ^14aa R ^14ab , heteroaryl, heterocycloalkyl, heterocycloalkenyl; wherein, R ^14aa and R ^14ab selected from: alkyl; R ^14b is selected from: alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, heterospirocycloalkyl; wherein, the alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycle Alkenyl, heterospirocycloalkyl are independently unsubstituted or substituted by one or two or three substituents independently selected from the following: halogen, CN, _NH2 , OH, alkoxy, haloalkane Oxygen, haloalkyl; R ^is selected from: alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein, The alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl are independently Unsubstituted or substituted by one or two or three substituents independently selected from H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH , C(O)NH ₂ , NH(CO)NH ₂ , SO ₂ NH ₂ , R ^15a , OR ^15a , SR ^15a , S(O)R ^15a , S(O) ₂ R ^15a , C(O)R ^15a , NHR ^15a , C(O)NHR ^15a , NH(CO)R ^15a , NR ^15a (CO)R ^15a , NH(CO)OR ^15a , NR ^15a (CO)OR ^15a , NH(CO)NHR ^15a , NR ^15a (CO)NHR ^15a , S(O) ₂ NHR ^15a , NHS(O) ₂ R ^15a , NR ^15a S(O) ₂ R ^15a , NHS(O) ₂ NHR ^15a , NR ^15a S(O) ₂ NHR ^15a , C(O)NHNOR ^15a , C(O)NHS(O) ₂ R ^15a , NR ^15b R ^15c , C(O)NR ^15b R ^15c , S(O) ₂ NR ^15b R ^15c , -(CR ^15d R ^15e ) _n -R ^15g , -(CHR ^15f ) _n -R ^15g , -(CR ^15d R ^15e ) _n -OR ^15g , -(CHR ^15f ) _n -OR ^15g ; R ^15a , R ^15b , R ^15c are selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkane wherein, each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl is Unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , R ^15aa , OR ^15aa , SR ^15aa , S(O)R ^15aa , S(O) ₂ R ^15aa , NHR ^15aa , C(O)R ^15aa , C( O)NHR ^15aa , NHC(O)R ^15aa , NR ^15aa C(O)R ^15aa , NHS(O) ₂ R ^15aa , SO ₂ NHR ^15aa , SO ₂ NR ^15ab R ^15ac , NCR ^15ab R ^15ac , NR ^15ab R ^15ac , C(O)NR ^15ab R ^15ac ; wherein, when R ^15b and R ^15c are connected to the same nitrogen, they combine to form a 4- to 8-membered heterocycle, which contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0～ 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^15aa , R ^15ab , R ^15ac are selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkane group; wherein, when R ^15ab and R ^15ac are connected to the same nitrogen, they are combined to form a 4-6 membered heterocyclic ring, which contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF _2. Carbon atoms substituted by OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups, and 0 to 2 additional members selected from N, N(alkyl), O, S(O) and S(O ₎ heteroatoms; R ^15d , R ^15e , and R ^15f are selected from: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl; wherein, the heteroaryl, heterocycloalkane each of which is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of: halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH ₂ , haloalkyl, alkoxy, haloalkoxy; wherein, wherein, R ^15d and R ^15e can form a 4- to 8-membered ring with the carbon to which they are attached, and the ring Does not contain heteroatoms or contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkane A carbon atom substituted by a radical, an alkyl group and an alkoxy group, and 0 to 2 additional heteroatoms selected from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^15g is selected from: aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, heterospirocycloalkyl; wherein, the aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkyl Spirocycloalkyl each of which is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH, haloalkyl, alkoxy, haloalkoxy; n is selected from: 1, 2, 3. 3. The compound of claim 1, characterized in that: R1 is selected from: H, halogen, alkoxy, alkylthio, alkylNH-, alkyloxyalkyl, tetrahydrofuran- ² -yl, alkylcarbonyl, alkylsulfonyl, (alkyl ₎ 2N -, haloalkyl, halocycloalkyl, haloalkoxy, haloalkylthio; R ² is selected from: H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , alkoxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halocycloalkane base, heterocycloalkyl; E is selected from: S, O, -CR ³ =CR ⁴ -, -N=CR ⁴ -, -CR ³ =N-, -N=N-; R ³ and R ⁴ are independently selected from: H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , R ^3a , OR ^3a , NH(CO)R ^3a , C(O)R ^3a , C(O)NHR ^3a , C(O)NR ^3b R ^3c , -(CR ^3d R ^3e ) _n -R ^3g , -(CHR ^3f ) _n -R ^3g , -(CR ^3d R ^3e ) _n -OR ^3g , -(CHR ^3f ) _n -OR ^3g , R ^3a is selected from: alkyl; each of the alkyl groups is substituted by one, two or three substituents independently selected from the following: halogen, CN, OH, (O), CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ ; R ^3b and R ^3c are selected from: alkyl; R ^3d , R ^3e and R ^3f are selected from the group consisting of: H, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkylNH-, (alk base) ₂ N-; R ^3g is selected from: heteroaryl, heterocycloalkyl; X ¹ is selected from: CR ⁵ , N; R ⁵ is selected from: H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , alkyl, cycloalkyl, heterocycloalkyl; wherein the alkyl, cycloalkyl, hetero Cycloalkyl each of which is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , Cycloalkyl, OR ^5a , COOR ^5a , SO ₂ R ^5a , N(R ^5a )(C=O)R ^5a , (C=O)NR ^5b R ^5c , NR ^5b R ^5c , SO ₂ NR ^5b R ^5c ; R ^5a is selected from alkyl, alkenyl, alkynyl; R ^5b and R ^5c are selected from: alkyl; X ² is selected from: O, S, NR ⁶ ; R ⁶ is selected from: H, R ^6a , -(CR ^6b R ^6c ) _n -R ^6e , -(CHR ^6d ) _n -R ^6e , -(CR ^6b R ^6c ) _n -OR ^6e , -(CHR ^6d ) _n -OR ^6e ; R ^is selected from: alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl; R ^6b , R ^6c and R ^6d are selected from: H, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy; R ^is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl; X ³ is selected from: CR ⁷ , N; R ⁷ is selected from: H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , R ^7a , OR ^7a , N(R ^7a )(C=O)R ^7a , (C=O )NR ^7b R ^7c , NR ^7b R ^7c , SO ₂ NR ^7b R ^7c , -(CR ^7d R ^7e ) _n -R ^7g , -(CHR ^7f ) _n -R ^7g , -(CR ^7d R ^7e ) _n -OR ^7g , -(CHR ^7f ) _n -OR ^7g ; R ^is selected from: alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl; R ^7b and R ^7c are selected from: alkyl, alkenyl, alkynyl, cycloalkyl; R ^7d , R ^7e and R ^7f are selected from: H, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy; R ^is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl; X ⁴ and X ⁵ can be independently selected from: O, S, CHR ⁸ , CR ⁹ R ¹⁰ , NR ¹¹ ; R ⁸ , R ⁹ , R ¹⁰ are selected from: H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , R ^8a , OR ^8a , C(O)R ^8a , -(CR ^8b R ^8c ) _n -R ^8e , -(CHR ^8d ) _n -R ^8e , -(CR ^8b R ^8c ) _n -OR ^8e , -(CHR ^7d ) _n -OR ^8e ; R ^{8a is} selected from: alkyl, heterocycloalkyl; R ^8b , R ^8c and R ^8d are selected from: H, F, Cl, alkyl, alkoxy, haloalkyl, haloalkoxy; R ^is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl; R ¹¹ is selected from: H, R ^11a , S(O)R ^11a , S(O) ₂ R ^11a , C(O)R ^11a , -(CR ^11b R ^11c ) _n -R ^11e , -(CHR ^11d ) _n -R ^11e , -(CR ^11b R ^11c ) _n -OR ^11e , -(CHR ^11d ) _n -OR ^11e ; R ^11a is selected from: alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl; R ^11b , R ^11c and R ^11d are selected from: H, F, Cl, alkyl, alkoxy, haloalkyl, haloalkoxy; R ^11e is selected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl; R ¹² and R ¹³ are selected from the group consisting of: H, deuterium, halogen, CN, NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , R ^12a , OR ^12a , S(O)R ^12a , S(O) ₂ R ^12a , C(O)R ^12a , NHR ^12a , C(O)NHR ^12a , NH(CO)R ^12a , NR ^12a (CO)R ^12a , NR ^12b R ^12c , C(O)NR ^12b R ^12c , R ^12d ; wherein when R ^12b and R ^12c are connected to the same nitrogen, they combine to form a 4- to 8-membered heterocycle, which contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional A heteroatom selected from N, N(alkyl), O, S(O) and S(O) ₂ ; R ^12a , R ^12b and R ^12c are selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; each of said alkyl, alkenyl or alkynyl is Unsubstituted or substituted by one or two or three substituents independently selected from H, halogen, OH, (O), CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , R ^12aa , OR ^12aa , C(O)OR ^12aa , OC(O)R ^12aa , OC(O)NHR ^12aa , OC(O)NR ^12ab R ^12ac , S(O)R ^12aa , S(O) ₂ R ^12aa , OS(O) ₂ R ^12aa , NHR ^12aa , C(O)R ^12aa , C(O)NHR ^12aa , NR ^12aa C(O)R ^12aa , NHC(O)R ^12aa , NR ^12ab R ^12ac , C( O) NR ^12ab R ^12ac ; R ^12aa is selected from: alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is not Substituted or substituted by one or two or three substituents independently selected from H, halogen, OH, (O), CN, NO ₂ , NH ₂ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , R ^12aaa , OR ^12aaa , NHR ^12aaa , C(O)R ^12aaa , NR ^12aaa C(O)R ^12aaa , NHC(O)OR ^12aaa , NHC(O)R ^12aaa , NR ^12aab R ^12aac , C(O)NR ^12aab R ^12aac ; R ^{12aaa is} selected from: alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; said alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl are unsubstituted or replaced by Substituted by one or two or three substituents independently selected from the following: halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O) OH, C(O)NH ₂ ; R ^12aab and R ^12aac are selected from: alkyl; R ^12ab and R ^12ac are selected from: alkyl; R ^12d is selected from: -(CR ^12da R ^12db ) _n -R ^12dd , -(CHR ^12dc ) _n -R ^12dd , -(CR ^12da R ^12db ) _n -OR ^12dd , -(CHR ^12dc ) _n -OR ^12dd ; R ^12da , R ^12db , R ^12dc are selected from: H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl; R ^{12dd is} selected from: aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl; Ring A is selected from: 4-10 membered heterocyclic rings with an unsaturation degree of 1 that does not contain heteroatoms, 4-10 membered heterocyclic rings with a degree of unsaturation greater than 1 that does not contain heteroatoms, and unsaturated rings that contain O, N or S atoms A 4-10 membered heterocycle with a degree of saturation of 1, a 4-10 membered heterocycle with an unsaturation greater than 1 containing O, N or S atoms; R ¹² can be arbitrarily substituted at the C atom site on the A ring; R ^12d can be arbitrarily substituted at the N atom site on the A ring; L is selected from: -O-, -S-, -NH-, -NHC(O)-, -R ^14a -, -(R ^14a ) _n -C(O)-, -O-(R ^14a ) _n - , -(R ^14a ) _n -O-, -O-(R ^14a ) _n -C(O)-, -O-(R ^14a ) _n -O-, -(R ^14a ) _n -O-(R ^14a ) _n -, -NC(O)(R ^14a ) _n -, -NR ^14b -; R ^14a is selected from: alkyl, alkenyl; wherein, the alkyl, alkenyl are independently unsubstituted or substituted by one or two or three substituents independently selected from the following: H, (O), halogen, OCF ₃ , CF ₃ , OCHF ₂ , OH, CN, haloalkyl, NR ^14aa R ^14ab , heteroaryl, heterocycloalkyl, heterocycloalkenyl; wherein, R ^14aa and R ^14ab are selected from :alkyl; R ^14b is selected from: alkyl, alkenyl, alkynyl; R ^is selected from: alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein, The alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl are independently Unsubstituted or substituted by one or two or three substituents independently selected from H, halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH , C(O)NH ₂ , R ^15a , OR ^15a , SR ^15a , S(O)R ^15a , S(O) ₂ R ^15a , C(O)R ^15a , NHR ^15a , C(O)NHR ^15a , NH (CO)R ^15a , NR ^15a (CO)R ^15a , S(O) ₂ NHR ^15a , NHS(O) ₂ R ^15a , NR ^15a S(O) ₂ R ^15a , NR ^15b R ^15c , C(O)NR ^15b R ^15c , S(O) ₂ NR ^15b R ^15c , -(CR ^15d R ^15e ) _n -R ^15g , -(CHR ^15f ) _n -R ^15g , -(CR ^15d R ^15e ) _n -OR ^15g , -( CHR ^15f ) _n -OR ^15g ; R ^15a , R ^15b , R ^15c are selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkane wherein, each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl is Unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH , C(O)NH ₂ , R ^15aa , OR ^15aa , SR ^15aa , S(O)R ^15aa , S(O) ₂ R ^15aa , NHR ^15aa , C(O)R ^15aa , C(O)NHR ^15aa , NHC (O)R ^15aa , NR ^15aa C(O)R ^15aa , NHS(O) ₂ R ^15aa , SO ₂ NHR ^15aa , SO ₂ NR ^15ab R ^15ac , NCR ^15ab R ^15ac , NR ^15ab R ^15ac , C(O)NR ^15ab R ^15ac ; wherein, when R ^15b and R ^15c are connected to the same nitrogen, they combine to form a 4- to 8-membered heterocyclic ring, which contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ , OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups substituted carbon atoms, and 0 to 2 additional selected from Heteroatoms of N, N(alkyl), O, S(O) and S(O) ₂ ; R ^15aa , R ^15ab , R ^15ac are selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkane group; wherein, when R ^15ab and R ^15ac are connected to the same nitrogen, they are combined to form a 4-6 membered heterocyclic ring, which contains 0 to 3 members independently selected from halogen, CF ₃ , CHF ₂ , OCF ₃ , OCHF _2. Carbon atoms substituted by OCH ₂ F, 5- or 6-membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy groups, and 0 to 2 additional members selected from N, N(alkyl), O, S(O) and S(O ₎ heteroatoms; R ^15d , R ^15e , R ^15f are selected from: H, alkyl, haloalkyl; R ^15g is selected from: aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, heterospirocycloalkyl; wherein, the aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkyl Spirocycloalkyl each of which is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of halogen, CN, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH, C(O)NH, haloalkyl, alkoxy, haloalkoxy; n is selected from: 1, 2, 3. 4. The compound of claim 1, wherein the compound or its pharmaceutically acceptable salt or ester or solvate is selected from the following compounds: 5. A pharmaceutical composition, which contains any one of the compounds as claimed in claims 1 to 4 or a pharmaceutically acceptable salt, ester or solvate thereof as an active ingredient and a pharmaceutically acceptable carrier. 6. Use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt or ester or solvate thereof in the preparation of a medicament for preventing or treating thromboembolic disorders. 7. the pharmaceutical composition as claimed in claim 5, is characterized in that, described pharmaceutical composition is capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalation, ointment, Suppository or patch.