CN110627817B

CN110627817B - Imidazocyclic PAR4 antagonist and medical application thereof

Info

Publication number: CN110627817B
Application number: CN201910487201.1A
Authority: CN
Inventors: 孙宏斌; 孔毅; 陈偲; 陈盼盼; 陈方君; 宋航宇; 任燊红; 刘昭君
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2018-06-25
Filing date: 2019-06-05
Publication date: 2022-03-29
Anticipated expiration: 2039-06-05
Also published as: CN110627817A

Abstract

The invention relates to an imidazo ring compound shown in a formula (I) or a formula (II), or a pharmaceutically acceptable salt, ester or solvate thereof. The compounds of the invention can be used for the preparation of medicaments for the prophylaxis or treatment of thromboembolic disorders.

Description

Imidazocyclic PAR4 antagonist and medical application thereof

Technical Field

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

Background

Thromboembolic diseases are serious human health-threatening diseases, platelet activation and aggregation play a crucial role in thrombosis, and alpha-thrombin is known as the strongest platelet activator, which converts fibrinogen into fibrin and promotes the formation of pathological thrombi. Thrombin receptors, namely PAR1 (protease activated receptor 1) and PAR4 (protease activated receptor 4), are expressed on the surface of human platelets, and PAR1 mediates the conduction of physiological hemostatic signals in atherothrombosis, and PAR4 helps to stabilize thrombus formation, thereby playing an important role in pathological thrombus formation, so that the functions of PAR4 are antagonized clinically, the function of PAR1 is retained, thrombus formation can be effectively inhibited, the bleeding risk is obviously reduced, and the safety of antiplatelet therapy is improved (Sci. Trans. Med.2017,9, eaaf 5294). The PAR1 antagonist valapasha did not significantly reduce cardiovascular events, but rather significantly increased the risk of severe bleeding (n.eng.j.med.366, 20). Indazoles (bioorgan. med. chem.2008,16,1262) and indoles (bioorg. med. chem.lett.2014,24,4708; j.med. chem.2016,59,7690) PAR4 antagonists are currently in preclinical research phase. An oral imidazothiadiazole PAR4 antagonist BMS-986120, developed by behcet masxibao corporation, has completed a first clinical study, but has a half-life of only 4 hours in humans (ariteriosccl.from.vas.biol.2018, 38,287). The oral PAR4 antagonist BMS-986141, also developed by bekken masculine, inc, has now completed a second phase clinical evaluation (NCT 03035734). To date, no oral small molecule PAR4 antagonist has been marketed.

In view of the above, there is still a need in the clinical field to develop new PAR4 antagonists with enhanced activity and better pharmacokinetic properties.

Disclosure of Invention

The invention aims to provide an imidazole ring compound with PAR4 antagonistic activity.

Another object of the present invention is to provide the pharmaceutical use of said imidazocyclic compounds as PAR4 antagonists. The compounds show obvious antagonistic activity on PAR4 in an in vitro anti-platelet aggregation experiment, thereby strongly inhibiting platelet aggregation, and can be used for preparing medicaments for preventing or treating various thromboembolic diseases.

In order to achieve the purpose, the technical scheme of the invention is as follows:

the invention relates to a compound shown as a formula (I) or a formula (II) as well as pharmaceutically acceptable salt, ester or solvate thereof:

wherein the content of the first and second substances,

R¹selected from: H. halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, phenoxy, phenylthio, alkyl NH-, alkyloxyalkyl, tetrahydrofuran-2-yl, alkylcarbonyl, alkylsulfonyl, (alkyl)₂N-, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, haloalkoxy, haloalkylthio, alkoxycarbonylalkyloxy, alkoxycarbonylalkylthio;

R²selected from: H. halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, haloalkyl, haloalkoxy, haloalkylthio, halocycloalkyl, heterocycloalkyl;

e is selected from: s, O, NH, -CR³＝CR⁴-、-N＝CR⁴-、-CR³＝N-、-N＝N-；

R³And R⁴Independently selected from: H. halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂、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)NR^3bR^3c、NR^3bR^3c、-(CR^3dR^3e)_n-R^3g、-(CHR^3f)_n-R^3g、-(CR^3dR^3e)_n-O-R^3g、-(CHR^3f)_n-O-R^3g、

R^3aSelected from: alkyl, alkenyl, alkynyl; said alkyl, alkenyl, alkynyl each of which is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, NO₂、NH₂、OH、(O)、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃Alkyl NH-, (alkyl)₂N-；

R^3bAnd R^3cSelected from: alkyl, alkenyl, alkynyl, aryl or a nitrogen atom bonded thereto form a 4-to 8-membered heterocyclic ring containing 0 to 3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N- (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^3d、R^3eand R^3fSelected from: H. halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkyl NH-, (alkyl)₂N-; wherein R is^3dAnd R^3eCan form a 3-to 8-membered ring with the carbon atoms to which they are attached, the ring being free of heteroatoms or containing groups which are 0 to 3 independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^3gis selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl;

X¹selected from: CR⁵、N；

R⁵Selected from: H. halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂Alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl are each unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂Cycloalkyl, hydroxyalkyl, OR^5a、COOR^5a、SO₂R^5a、O(C＝O)R^5a、(C＝O)OR^5a、N(R^5a)(C＝O)R^5a、(C＝O)NR^5bR^5c、NR^5bR^5c、SO₂NR^5bR^5c、-(CH₂)_n-heteroaryl, - (CH)₂)_n-phenyl, - (CH)₂)_n-O-heteroaryl, - (CH)₂)_n-O-phenyl;

R^5aselected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl;

R^5band R^5cSelected from: alkyl or a 4-to 8-membered heterocyclic ring formed with the nitrogen atom bonded thereto, the heterocyclic ring containing 0 to 3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N- (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

X²selected from: o, S, NR⁶；

R⁶Selected from: H. r^6a、C(O)R^6a、S(O)R^6a、S(O)₂R^6a、-(CR^6bR^6c)_n-R^6e、-(CHR^6d)_n-R^6e、-(CR^6bR^6c)_n-O-R^6e、-(CHR^6d)_n-O-R^6e；

R^6aSelected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, haloalkyl; wherein said cycloalkyl, aryl, heteroaryl, heterocycloalkyl is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂；

R^6b、R^6cAnd R^6dSelected from: H. halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkyl NH-, (alkyl)₂N-; wherein R is^6bAnd R^6cCan form a 3-to 8-membered ring with the carbon atoms to which they are attached, the ring being free of heteroatoms or containing groups which are 0 to 3 independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^6eselected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl;

X³selected from: CR⁷、N；

R⁷Selected from: H. halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、COOH、C(O)NH₂、R^7a、OR^7a、SR^7a、COOR^7a、SO₂R^7a、O(C＝O)R^7a、(C＝O)OR^7a、N(R^7a)(C＝O)R^7a、(C＝O)NR^7bR^7c、NR^7bR^7c、SO₂NR^7bR^7c、-(CR^7dR^7e)_n-R^7g、-(CHR^7f)_n-R^7g、-(CR^7dR^7e)_n-O-R^7g、-(CHR^7f)_n-O-R^7g；

R^7aSelected from: alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, haloalkyl; said aryl, cycloalkyl, heteroaryl, heterocycloalkyl is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂；

R^7bAnd R^7cSelected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; wherein R is^7bAnd R^7cCan form a 3-to 8-membered ring with the nitrogen atom to which it is attached, containing 0 to 3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^7d、R^7eand R^7fSelected from: H. halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkyl NH-, (alkyl)₂N-; wherein R is^7dAnd R^7eCan form a 3-to 8-membered ring with the carbon atoms to which they are attached, the ring being free of heteroatoms or containing groups which are 0 to 3 independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^7gselected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl; wherein said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl are unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂；

X⁴And X⁵Can be independently selected from: o, S, S (O), S (O)₂、CHR⁸、CR⁹R¹⁰、NR¹¹；

R⁸、R⁹、R¹⁰Selected from: H. halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、COOH、R^8a、OR^8a、SR^8a、C(O)R^8a、S(O)R^8a、S(O)₂R^8a、-(CR^8bR^8c)_n-R^8e、-(CHR^8d)_n-R^8e、-(CR^8bR^8c)_n-O-R^8e、-(CHR^8d)_n-O-R^8e；

R^8aSelected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, haloalkyl; said cycloalkyl, aryl, heteroaryl, heterocycloalkyl being unsubstitutedOr by one or two or three substituents independently selected from: halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂；

R^8b、R^8cAnd R^8dSelected from: H. f, Cl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkyl NH-, (alkyl)₂N-; wherein R is^8bAnd R^8cCan form a 3-to 8-membered ring with the carbon atoms to which they are attached, the ring being free of heteroatoms or containing groups which are 0 to 3 independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^8eselected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl; wherein said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl are unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂；

R¹¹Selected from: H. r^11a、S(O)R^11a、S(O)₂R^11a、C(O)R^11a、-(CR^11bR^11c)_n-R^11e、-(CHR^11d)_n-R^11e、-(CR^11bR^11c)_n-O-R^11e、-(CHR^11d)_n-O-R^11e；

R^11aSelected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl is unsubstituted or substituted by one or two orThree substituents independently selected from the group consisting of: halogen, haloalkyl; wherein said cycloalkyl, aryl, heteroaryl, heterocycloalkyl is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂；

R^11b、R^11cAnd R^11dSelected from: H. f, Cl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkyl NH-, (alkyl)₂N-; wherein R is^11bAnd R^11cCan form a 3-to 8-membered ring with the carbon atoms to which they are attached, the ring being free of heteroatoms or containing groups which are 0 to 3 independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^11eselected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl; wherein said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl are unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂；

R¹²And R¹³Selected from: H. deuterium, halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、SO₂NH₂、COOH、C(O)NH₂、R^12a、OR^12a、SR^12a、S(O)R^12a、S(O)₂R^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、SO₂NHR^12a、NHSO₂R^12a、NR^12aSO₂R^12a、NR^12bR^12c、C(O)NR^12bR^12c、SO₂NR^12bR^12c、R^12d(ii) a Wherein R is^12bAnd R^12cWhen linked to the same nitrogen, combine to form a 4-to 8-membered heterocyclic ring containing 0-3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^12a、R^12band R^12cSelected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl are each unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: H. halogen, OH, (O), CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、SO₂NH₂、COOH、C(O)NH₂、NHC(O)NH₂、R^12aa、OR^12aa、SR^12aa、S(O)R^12aa、OS(O)₂R^12aa、S(O)₂R^12aa、NHR^12aa、C(O)R^12aa、C(O)OR^12aa、OC(O)R^12aa、OC(O)NHR^12aa、C(O)NHR^12aa、NR^12aaC(O)R^12aa、NHSO₂R^12aa、NHC(O)OR^12aa、S(O)₂NHR^12aa、NHC(O)R^12aa、NHC(O)NHR^12aa、OC(O)NR^12abR^12ac、NR^12abR^12ac、C(O)NR^12abR^12ac、SO₂NR^12abR^12ac；

R^12aaSelected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl are each unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: H. halogen, OH, (O), CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、SO₂NH₂、COOH、C(O)NH₂、NHC(O)NH₂、R^12aaa、OR^12aaa、SR^12aaa、S(O)R^12aaa、S(O)₂R^12aaa、NHR^12aaa、C(O)R^12aaa、C(O)OR^12aaa、OC(O)R^12aaa、C(O)NHR^12aaa、NR^12aaaC(O)R^12aaa、NHSO₂R^12aaa、NHC(O)OR^12aaa、S(O)₂NHR^12aaa、NHC(O)R^12aaa、NHC(O)NHR^12aaa、NR^12aabR^12aac、C(O)NR^12aabR^12aac、SO₂NR^12aabR^12aac；

R^12aaaSelected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂；

R^12aabAnd R^12aacSelected from: alkyl, or when attached to the same nitrogen, combine to form a 4-to 8-membered heterocyclic ring containing from 0-3 substituents independently selected from halogen、CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^12aband R^12acSelected from: alkyl, or when attached to the same nitrogen, combine to form a 4-to 8-membered heterocyclic ring containing from 0-3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^12dselected from: - (CR)^12daR^12db)_n-R^12dd、-(CHR^12dc)_n-R^12dd、-(CR^12daR^12db)_n-O-R^12dd、-(CHR^12dc)_n-O-R^12dd；

R^12da、R^12db、R^12dcSelected from: H. alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heteroaryl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl; wherein said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl are each unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, NO₂、NH₂OH, alkoxy, haloalkoxy, alkyl, haloalkyl, cycloalkyl, hydroxyalkyl; r^12daAnd R^12dbCan form a 3-to 8-membered ring with the carbon atoms to which they are attached, the ring being free of heteroatoms or containing groups which are 0 to 3 independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^12ddselected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl;

the A ring is selected from: a 4-20 membered heterocyclic ring with 1 degree of unsaturation containing no heteroatom, a 4-20 membered heterocyclic ring with greater than 1 degree of unsaturation containing no heteroatom, a 4-20 membered heterocyclic ring with 1 degree of unsaturation containing O, N or an S atom, a 4-20 membered heterocyclic ring with greater than 1 degree of unsaturation containing O, N or an S atom;

R¹²can be randomly substituted on the C atom site on the A ring;

R^12dcan be randomly substituted on the site of N atom on the A ring;

l is selected from: -O-, -S-, -NH-, -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-O-C(O)-、-NR^14b-、-C(O)NR^14b-、-NR^14bC(O)NR^14b-；

R^14aSelected from: alkyl, alkenyl, alkynyl; wherein each of said alkyl, alkenyl, alkynyl is independently unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: H. (O), halogen, OCF₃、CF₃、OCHF₂、OH、CN、NO₂Haloalkyl, alkoxy, alkylthio, cycloalkyl, cycloalkoxy, carboxyl, alkoxycarbonyl, alkaneRadical sulfonyl, NR^14aaR^14ab、C(＝O)NR^14aaR^14ab、S(＝O)₂NR^14aaR^14abAryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl; wherein R is^14aaAnd R^14abSelected from: alkyl, or when attached to the same nitrogen, combine to form a 4-to 8-membered heterocyclic ring containing from 0-3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^14bselected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl are each independently unsubstituted or substituted with one or two or three substituents independently selected from: halogen, CN, NO₂、NH₂OH, alkoxy, haloalkoxy, alkyl, haloalkyl, cycloalkyl, hydroxyalkyl;

R¹⁵selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl are each independently unsubstituted or substituted with one or two or three substituents independently selected from: H. halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂、NH(CO)NH₂、SO₂NH₂、R^15a、OR^15a、SR^15a、S(O)R^15a、S(O)₂R^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)₂NHR^15a、NHS(O)₂R^15a、NR^15aS(O)₂R^15a、NHS(O)₂NHR^15a、NR^15aS(O)₂NHR^15a、OC(O)NR^15bR^15c、C(O)NHNOR^15a、C(O)NHS(O)₂R^15a、NR^15aS(O)₂NR^15bR^15c、NR^15bR^15c、C(O)NR^15bR^15c、NH(CO)NR^15bR^15c、NR^15a(CO)NR^15bR^15c、S(O)₂NR^15bR^15c、NHS(O)₂NR^15bR^15c、-(CR^15dR^15e)_n-R^15g、-(CHR^15f)_n-R^15g、-(CR^15dR^15e)_n-O-R^15g、-(CHR^15f)_n-O-R^15g；

R^15a、R^15b、R^15cSelected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, or hetero-spirocycloalkyl is each unsubstituted or substituted with one or two or three substituents independently selected from: halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂、NHC(O)NH₂、R^15aa、OR^15aa、SR^15aa、S(O)R^15aa、S(O)₂R^15aa、NHR^15aa、C(O)R^15aa、C(O)NHR^15aa、NHC(O)R^15aa、NR^15aaC(O)R^15aa、NHS(O)₂R^15aa、NHC(O)OR^15aa、SO₂NHR^15aa、NHC(O)NHR^15aa、SO₂NR^15abR^15ac、NCR^15abR^15ac、NR^15abR^15ac、C(O)NR^15abR^15ac(ii) a Wherein R is^15b、R^15cWhen linked to the same nitrogen, combine to form a 4-to 8-membered heterocyclic ring containing 0-3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^15aa、R^15ab、R^15acselected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein R is^15ab、R^15acWhen linked to the same nitrogen, combine to form a 4-to 8-membered heterocyclic ring containing 0-3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^15d、R^15e、R^15fselected from: H. alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, hetero-spirocycloalkyl are each unsubstituted or substituted with one or two or three substituents independently selected from: halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂Alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, hydroxyalkyl; wherein R is^15dAnd R^15eMay form a 4-to 8-membered ring with the carbon to which it is attached, the ring being free of heteroatoms or containing 0 to 3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^15gselected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, hetero-spirocycloalkyl are each unsubstituted or substituted with one or two or three substituents independently selected from: halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃C (O) OH, C (O) NH, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, hydroxyalkyl;

n is selected from: 1.2, 3,4, 5 and 6.

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

R¹selected from: H. halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl NH-, alkyloxyalkyl, tetrahydrofuran-2-yl, alkylcarbonyl, alkylsulfonyl, (alkyl)₂N-, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, haloalkoxy, haloalkylthio;

R²selected from: H. halogen, CN, NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃Alkyl, alkoxy, alkylthio, cycloalkyl, haloalkyl, haloalkoxy, haloalkylthio, haloCycloalkyl, heterocycloalkyl;

e is selected from: s, O, -CR³＝CR⁴-、-N＝CR⁴-、-CR³＝N-、-N＝N-；

R³And R⁴Independently selected from: H. halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂、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^3bR^3c、-(CR^3dR^3e)_n-R^3g、-(CHR^3f)_n-R^3g、-(CR^3dR^3e)_n-O-R^3g、-(CHR^3f)_n-O-R^3g、R^3aSelected from: alkyl, alkenyl, alkynyl; said alkyl, alkenyl, alkynyl each of which is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, OH, (O), CF₃、CF₂CF₃、OCF₃、OCF₂CF₃Alkyl NH-, (alkyl)₂N-；

R^3bAnd R^3cSelected from: alkyl or a 4-6 membered heterocyclic ring formed with the nitrogen atom bonded thereto, the heterocyclic ring containing 0 to 3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N- (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^3d、R^3eand R^3fSelected from: H. halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkyl NH-, (alkyl)₂N-; wherein R is^3dAnd R^3eCan form a 3-to 8-membered ring with the carbon atoms to which they are attached, the ring being free of heteroatoms or containing groups which are 0 to 3 independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^3gselected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl;

X¹selected from: CR⁵、N；

R⁵Selected from: H. halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂Alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl are each unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂Cycloalkyl, hydroxyalkyl, OR^5a、COOR^5a、SO₂R^5a、N(R^5a)(C＝O)R^5a、(C＝O)NR^5bR^5c、NR^5bR^5c、SO₂NR^5bR^5c；

R^5aSelected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl;

R^5band R^5cSelected from: an alkyl group;

X²selected from: o, S, NR⁶；

R^6aSelected from: alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl; wherein, theAlkyl, alkenyl, alkynyl are unsubstituted or substituted with one or two or three substituents independently selected from: halogen, haloalkyl; wherein said cycloalkyl, heterocycloalkyl is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂；

R^6b、R^6cAnd R^6dSelected from: H. halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkyl NH-, (alkyl)₂N-; wherein R is^6bAnd R^6cCan form a 3-6 membered ring with the carbon atoms to which they are attached, the ring being free of heteroatoms or containing groups which are 0-3 independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^6eselected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl;

X³selected from: CR⁷、N；

R⁷Selected from: H. halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、COOH、C(O)NH₂、R^7a、OR^7a、SR^7a、N(R^7a)(C＝O)R^7a、(C＝O)NR^7bR^7c、NR^7bR^7c、SO₂NR^7bR^7c、-(CR^7dR^7e)_n-R^7g、-(CHR^7f)_n-R^7g、-(CR^7dR^7e)_n-O-R^7g、-(CHR^7f)_n-O-R^7g；

R^7aSelected from: alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl; wherein the content of the first and second substances,the alkyl, alkenyl, alkynyl groups are unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, haloalkyl; said aryl, cycloalkyl, heteroaryl, heterocycloalkyl is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂；

R^7bAnd R^7cSelected from: alkyl, alkenyl, alkynyl, cycloalkyl; wherein R is^7bAnd R^7cCan form a 3-6 membered ring with the nitrogen atom to which it is attached, containing 0-3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^7d、R^7eand R^7fSelected from: H. halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkyl NH-, (alkyl)₂N-; wherein R is^7dAnd R^7eCan form a 3-6 membered ring with the carbon atoms to which they are attached, the ring being free of heteroatoms or containing groups which are 0-3 independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^7gselected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl, heterocycloalkyl is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂；

X⁴And X⁵Can be independently selected from: o, S, CHR⁸、CR⁹R¹⁰、NR¹¹；

R⁸、R⁹、R¹⁰Selected from: H. halogen, CN, NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、COOH、R^8a、OR^8a、SR^8a、C(O)R^8a、S(O)R^8a、S(O)₂R^8a、-(CR^8bR^8c)_n-R^8e、-(CHR^8d)_n-R^8e、-(CR^8bR^8c)_n-O-R^8e、-(CHR^8d)_n-O-R^8e；

R^8aSelected from: alkyl, alkenyl, alkynyl, heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, haloalkyl; the heterocycloalkyl group is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂；

R^8b、R^8cAnd R^8dSelected from: H. f, Cl, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkyl NH-, (alkyl)₂N-; wherein R is^8bAnd R^8cCan form a 3-6 membered ring with the carbon atoms to which they are attached, the ring being free of heteroatoms or containing groups which are 0-3 independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^8eselected from: aryl, heteroaryl, cycloalkyl,A heterocycloalkyl group; wherein said aryl, heteroaryl, cycloalkyl, heterocycloalkyl is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂；

R^11aSelected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, haloalkyl; wherein said cycloalkyl, aryl, heteroaryl, heterocycloalkyl is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂；

R^11b、R^11cAnd R^11dSelected from: H. f, Cl, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkyl NH-, (alkyl)₂N-; wherein R is^11bAnd R^11cCan form a 3-6 membered ring with the carbon atoms to which they are attached, the ring being free of heteroatoms or containing groups which are 0-3 independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^11eselected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl, heterocycloalkyl is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂；

R¹²And R¹³Selected from: H. deuterium, halogen, CN, NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、SO₂NH₂、COOH、C(O)NH₂、R^12a、OR^12a、S(O)R^12a、S(O)₂R^12a、C(O)R^12a、NHR^12a、C(O)NHR^12a、NH(CO)R^12a、NR^12a(CO)R^12a、SO₂NHR^12a、NHSO₂R^12a、NR^12bR^12c、C(O)NR^12bR^12c、SO₂NR^12bR^12c、R^12d(ii) a Wherein R is^12bAnd R^12cWhen linked to the same nitrogen, combine to form a 4-to 8-membered heterocyclic ring containing 0-3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^12a、R^12band R^12cSelected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; said alkyl, alkenyl or alkynyl each of which is unsubstituted or substituted with one or two or three substituents independently selected from: H. halogen, OH, (O), CN, NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、SO₂NH₂、COOH、C(O)NH₂、NHC(O)NH₂、R^12aa、OR^12aa、S(O)R^12aa、OS(O)₂R^12aa、S(O)₂R^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^12abR^12ac、NR^12aaC(O)R^12aa、NHSO₂R^12aa、S(O)₂NHR^12aa、NHC(O)R^12aa、NHC(O)NHR^12aa、NR^12abR^12ac、C(O)NR^12abR^12ac、SO₂NR^12abR^12ac；

R^12aaSelected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group is each unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: H. halogen, OH, (O), CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、SO₂NH₂、COOH、C(O)NH₂、NHC(O)NH₂、R^12aaa、OR^12aaa、SR^12aaa、S(O)R^12aaa、S(O)₂R^12aaa、NHR^12aaa、C(O)R^12aaa、C(O)OR^12aaa、OC(O)R^12aaa、C(O)NHR^12aaa、NR^12aaaC(O)R^12aaa、NHSO₂R^12aaa、NHC(O)OR^12aaa、S(O)₂NHR^12aaa、NHC(O)R^12aaa、NHC(O)NHR^12aaa、NR^12aabR^12aac、C(O)NR^12aabR^12aac、SO₂NR^12aabR^12aac；

R^12aaaSelected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl being unsubstituted or substituted by one or two or three substituents independently selected fromAnd (3) substitution: halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂；

R^12aabAnd R^12aacSelected from: alkyl, or when attached to the same nitrogen, combine to form a 4-to 6-membered heterocyclic ring containing from 0-3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^12aband R^12acSelected from: alkyl, or when attached to the same nitrogen, combine to form a 4-6 membered heterocyclic ring containing from 0 to 3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^12da、R^12db、R^12dcSelected from: H. alkyl, haloalkyl, cycloalkyl, heterocycloalkyl; wherein said cycloalkyl, heterocycloalkyl, or each of them is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, NH₂OH, alkoxy, haloalkoxy, alkyl, haloalkyl, cycloalkyl, hydroxyalkyl; r^12daAnd R^12dbCan form a 3-6 membered ring with the carbon atoms to which they are attached, the ring being free of heteroatoms or containing groups which are 0-3 independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^12ddselected from: aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl;

the A ring is selected from: a 4-10 membered heterocyclic ring with 1 degree of unsaturation containing no heteroatom, a 4-10 membered heterocyclic ring with greater than 1 degree of unsaturation containing no heteroatom, a 4-10 membered heterocyclic ring with 1 degree of unsaturation containing O, N or an S atom, a 4-10 membered heterocyclic ring with greater than 1 degree of unsaturation containing O, N or an S atom;

R¹²can be randomly substituted on the C atom site on the A ring;

R^12dcan be randomly substituted on the site of N atom 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 (O) -, and^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^14bC(O)NR^14b-；

R^14aselected from: alkyl, alkenyl, alkynyl; wherein each of said alkyl, alkenyl, alkynyl is independently unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: H. (O), halogen, OCF₃、CF₃、OCHF₂OH, CN, haloalkyl, alkoxy, alkylthio, cycloalkoxy, carboxyl, alkoxycarbonyl, alkylsulfonyl, NR^14aaR^14ab、C(＝O)NR^14aaR^14ab、S(＝O)₂NR^14aaR^14abHeteroaryl, heterocycloalkyl, heterocycloalkenyl; wherein R is^14aaAnd R^14abSelected from: an alkyl group;

R^14bselected from: alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, heterospirocycloalkyl; wherein said alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, heterospirocycloalkyl are each independently unsubstituted or substituted with one or two or three substituents independently selected from: halogen, CN, NH₂OH, alkoxy, haloalkoxy, haloalkyl;

R¹⁵selected from: alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl are each independently unsubstituted or substituted with one or two or three substituents independently selected from: H. halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂、NH(CO)NH₂、SO₂NH₂、R^15a、OR^15a、SR^15a、S(O)R^15a、S(O)₂R^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)₂NHR^15a、NHS(O)₂R^15a、NR^15aS(O)₂R^15a、NHS(O)₂NHR^15a、NR^15aS(O)₂NHR^15a、C(O)NHNOR^15a、C(O)NHS(O)₂R^15a、NR^15bR^15c、C(O)NR^15bR^15c、S(O)₂NR^15bR^15c、-(CR^15dR^15e)_n-R^15g、-(CHR^15f)_n-R^15g、-(CR^15dR^15e)_n-O-R^15g、-(CHR^15f)_n-O-R^15g；

R^15a、R^15b、R^15cSelected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, or hetero-spirocycloalkyl is each unsubstituted or substituted with one or two or three substituents independently selected from: halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂、R^15aa、OR^15aa、SR^15aa、S(O)R^15aa、S(O)₂R^15aa、NHR^15aa、C(O)R^15aa、C(O)NHR^15aa、NHC(O)R^15aa、NR^15aaC(O)R^15aa、NHS(O)₂R^15aa、SO₂NHR^15aa、SO₂NR^15abR^15ac、NCR^15abR^15ac、NR^15abR^15ac、C(O)NR^15abR^15ac(ii) a Wherein R is^15b、R^15cWhen linked to the same nitrogen, combine to form a 4-to 8-membered heterocyclic ring containing 0-3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^15aa、R^15ab、R^15acselected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein R is^15ab、R^15acWhen linked to the same nitrogen, combine to form a 4-6 membered heterocyclic ring containing an amino group modified by 0 to E3 are independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^15d、R^15e、R^15fselected from: H. alkyl, alkenyl, alkynyl, haloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl; wherein each of said heteroaryl, heterocycloalkyl, heterocycloalkenyl is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂Haloalkyl, alkoxy, haloalkoxy; wherein, R is^15dAnd R^15eMay form a 4-to 8-membered ring with the carbon to which it is attached, the ring being free of heteroatoms or containing 0 to 3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^15gselected from: aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, heterospirocycloalkyl; wherein said aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, hetero-spirocycloalkyl are each unsubstituted or substituted with one or two or three substituents independently selected from: halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃C (O) OH, C (O) NH, haloalkyl, alkoxy, haloalkoxy;

n is selected from: 1.2 and 3.

R¹selected from: H. halogen, alkylOxy, alkylthio, alkyl NH-, alkyloxyalkyl, tetrahydrofuran-2-yl, alkylcarbonyl, alkylsulfonyl, (alkyl)₂N-, haloalkyl, halocycloalkyl, haloalkoxy, haloalkylthio;

R²selected from: H. halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃Alkoxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halocycloalkyl, heterocycloalkyl;

R³And R⁴Independently selected from: H. halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、R^3a、OR^3a、NH(CO)R^3a、C(O)R^3a、C(O)NHR^3a、C(O)NR^3bR^3c、-(CR^3dR^3e)_n-R^3g、-(CHR^3f)_n-R^3g、-(CR^3dR^3e)_n-O-R^3g、-(CHR^3f)_n-O-R^3g、

R^3aSelected from: an alkyl group; each of said alkyl groups being substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, OH, (O), CF₃、CF₂CF₃、OCF₃、OCF₂CF₃；

R^3bAnd R^3cSelected from: an alkyl group;

R^3d、R^3eand R^3fSelected from: H. halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, alkylcarbonyl, alkyl NH-, (alkyl)₂N-；

R^3gSelected from: heteroaryl, heterocycloalkyl;

X¹selected from: CR⁵、N；

R⁵Selected from: H. halogen, CN,CF₃、CF₂CF₃、OCF₃、OCF₂CF₃Alkyl, cycloalkyl, heterocycloalkyl; wherein said alkyl, cycloalkyl, heterocycloalkyl are each unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃Cycloalkyl, OR^5a、COOR^5a、SO₂R^5a、N(R^5a)(C＝O)R^5a、(C＝O)NR^5bR^5c、NR^5bR^5c、SO₂NR^5bR^5c；

R^5aSelected from alkyl, alkenyl, alkynyl;

R^5band R^5cSelected from: an alkyl group;

X²selected from: o, S, NR⁶；

R⁶Selected from: H. r^6a、-(CR^6bR^6c)_n-R^6e、-(CHR^6d)_n-R^6e、-(CR^6bR^6c)_n-O-R^6e、-(CHR^6d)_n-O-R^6e；

R^6aSelected from: alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl;

R^6b、R^6cand R^6dSelected from: H. halogen, alkyl, alkoxy, haloalkyl, haloalkoxy;

R^6eselected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl;

X³selected from: CR⁷、N；

R⁷Selected from: H. halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、R^7a、OR^7a、N(R^7a)(C＝O)R^7a、(C＝O)NR^7bR^7c、NR^7bR^7c、SO₂NR^7bR^7c、-(CR^7dR^7e)_n-R^7g、-(CHR^7f)_n-R^7g、-(CR^7dR^7e)_n-O-R^7g、-(CHR^7f)_n-O-R^7g；

R^7aSelected from: alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl;

R^7band R^7cSelected from: alkyl, alkenyl, alkynyl, cycloalkyl;

R^7d、R^7eand R^7fSelected from: H. halogen, alkyl, alkoxy, haloalkyl, haloalkoxy;

R^7gselected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl;

R⁸、R⁹、R¹⁰Selected from: H. halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、R^8a、OR^8a、C(O)R^8a、-(CR^8bR^8c)_n-R^8e、-(CHR^8d)_n-R^8e、-(CR^8bR^8c)_n-O-R^8e、-(CHR^7d)_n-O-R^8e；

R^8aSelected from: alkyl, heterocycloalkyl;

R^8b、R^8cand R^8dSelected from: H. f, Cl, alkyl, alkoxy, haloalkyl, haloalkoxy;

R^8eselected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl;

R^11aSelected from: alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl;

R^11b、R^11cand R^11dSelected from: H. f, Cl, alkyl, alkoxy, haloalkyl, haloalkoxy;

R^11eselected from: aryl, heteroaryl, cycloalkyl, heterocycloalkyl;

R¹²and R¹³Selected from: H. deuterium, halogen, CN, NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、R^12a、OR^12a、S(O)R^12a、S(O)₂R^12a、C(O)R^12a、NHR^12a、C(O)NHR^12a、NH(CO)R^12a、NR^12a(CO)R^12a、NR^12bR^12c、C(O)NR^12bR^12c、R^12d(ii) a Wherein R is^12bAnd R^12cWhen linked to the same nitrogen, combine to form a 4-to 8-membered heterocyclic ring containing 0-3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^12a、R^12band R^12cSelected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; said alkyl, alkenyl or alkynyl each of which is unsubstituted or substituted with one or two or three substituents independently selected from: H. halogen, OH, (O), CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、R^12aa、OR^12aa、C(O)OR^12aa、OC(O)R^12aa、OC(O)NHR^12aa、OC(O)NR^12abR^12ac、S(O)R^12aa、S(O)₂R^12aa、OS(O)₂R^12aa、NHR^12aa、C(O)R^12aa、C(O)NHR^12aa、NR^12aaC(O)R^12aa、NHC(O)R^12aa、NR^12abR^12ac、C(O)NR^12abR^12ac；

R^12aaSelected from: alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; the alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group is each unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: H. halogen, OH, (O), CN, NO₂、NH₂、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、R^12aaa、OR^12aaa、NHR^12aaa、C(O)R^12aaa、、NR^12aaaC(O)R^12aaa、NHC(O)OR^12aaa、NHC(O)R^12aaa、NR^12aabR^12aac、C(O)NR^12aabR^12aac；

R^12aaaSelected from: alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; said alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: halogen, CN, NO₂、NH₂、OH、CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂；

R^12aabAnd R^12aacSelected from: an alkyl group;

R^12aband R^12acSelected from: an alkyl group;

R^12da、R^12db、R^12dcSelected from: H. alkyl, haloalkyl, cycloalkyl, heterocycloalkyl;

R^12ddselected from: aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl;

R¹²can be randomly substituted on the C atom site on the A ring;

R^12dcan be randomly substituted on the site of N atom 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^14aSelected from: alkyl, alkenyl; wherein each of said alkyl, alkenyl is independently unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of: H. (O), halogen, OCF₃、CF₃、OCHF₂OH, CN, haloalkyl, NR^14aaR^14abHeteroaryl, heterocycloalkyl, heterocycloalkenyl; wherein R is^14aaAnd R^14abSelected from: an alkyl group;

R^14bselected from: alkyl, alkenyl, alkynyl;

R¹⁵selected from: alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl are each independently unsubstituted or substituted with one or two or three substituents independently selected from: H. halogen, CN, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂、R^15a、OR^15a、SR^15a、S(O)R^15a、S(O)₂R^15a、C(O)R^15a、NHR^15a、C(O)NHR^15a、NH(CO)R^15a、NR^15a(CO)R^15a、S(O)₂NHR^15a、NHS(O)₂R^15a、NR^15aS(O)₂R^15a、NR^15bR^15c、C(O)NR^15bR^15c、S(O)₂NR^15bR^15c、-(CR^15dR^15e)_n-R^15g、-(CHR^15f)_n-R^15g、-(CR^15dR^15e)_n-O-R^15g、-(CHR^15f)_n-O-R^15g；

R^15a、R^15b、R^15cSelected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, or hetero-spirocycloalkyl is each unsubstituted or substituted with one or two or three substituents independently selected from: halogen, CN, OH, CF₃、CF₂CF₃、OCF₃、OCF₂CF₃、C(O)OH、C(O)NH₂、R^15aa、OR^15aa、SR^15aa、S(O)R^15aa、S(O)₂R^15aa、NHR^15aa、C(O)R^15aa、C(O)NHR^15aa、NHC(O)R^15aa、NR^15aaC(O)R^15aa、NHS(O)₂R^15aa、SO₂NHR^15aa、SO₂NR^15abR^15ac、NCR^15abR^15ac、NR^15abR^15ac、C(O)NR^15abR^15ac(ii) a Wherein R is^15b、R^15cWhen linked to the same nitrogen, combine to form a 4-to 8-membered heterocyclic ring containing 0-3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^15aa、R^15ab、R^15acselected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, heterospirocycloalkyl; wherein R is^15ab、R^15acWhen linked to the same nitrogen, combine to form a 4-6 membered heterocyclic ring containing from 0 to 3 substituents independently selected from halogen, CF₃、CHF₂、OCF₃、OCHF₂、OCH₂F. 5 or 6 membered heteroaryl, OH, oxo, hydroxyalkyl, alkyl and alkoxy, and 0-2 additional carbon atoms selected from the group consisting of N, N (alkyl), O, S (O) and S (O)₂A heteroatom of (a);

R^15d、R^15e、R^15fselected from: H. alkyl, haloalkyl;

n is selected from: 1.2 and 3.

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

TABLE 1 Structure and nomenclature of Compounds

The compounds of the present invention may also be used as pharmaceutically acceptable salts. The salt may be an acid salt of at least one of the following acids: galactaric acid, D-glucuronic acid, glycerophosphoric acid, hippuric acid, isethionic acid, lactobionic acid, maleic acid, 1, 5-naphthalenedisulfonic 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, nicotinic acid, nitric acid, orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharinic 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. Alternatively, the salts may be formed with metal (including sodium, potassium, calcium, etc.) ions or pharmaceutically acceptable amine (including ethylenediamine, tromethamine, etc.) or ammonium ions of the compounds of the present invention.

The compounds of the present invention may also be comprised in pharmaceutical compositions in the form of esters, prodrugs, or solvates thereof.

The present inventors have found that a compound of formula (I) or formula (II) as above, or a pharmaceutically acceptable salt or ester or solvate thereof, is a novel PAR4 antagonist which inhibits platelet aggregation by antagonizing platelet PAR4, and thus can be used for the preparation of a medicament 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 myocardial infarction, non-ST-elevated myocardial infarction, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, cancer-related thrombosis, and thrombosis resulting from medical implants, devices, and procedures in which blood is exposed to artificial surfaces to promote thrombosis.

The invention also provides a pharmaceutical composition for preventing and treating the diseases, which comprises 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 a pharmaceutically acceptable carrier. The carrier which can be arbitrarily mixed may vary depending on the dosage form, administration form and the like. Examples of carriers include excipients, binders, disintegrants, lubricants, flavoring agents, coloring agents, sweetening agents, and the like. The pharmaceutical composition can be in the form of capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories, patches and other pharmaceutically conventional preparations.

The compounds of the present invention may be used in combination with one or more other types of agents for the prophylaxis or treatment of thromboembolic disorders, including, but not limited to, the following combinations.

Other types of prophylactic or therapeutic agents that may be selected for use in combination with the compounds of the present invention may be one or more antiplatelet agents including abciximab, eptifibatide, tirofiban, clopidogrel, prasugrel, ticlopidine, cangrelor, enoogrel, ticagrelor, beraprost sodium, prostacyclin, iloprostil, treprostinil, aspirin, aloprine, carbapirine calcium, indobufen, triflusal, dipyridamole, picotamide, terutraban, cilostazol, clomontam or ditozole.

Other types of prophylactic or therapeutic agents that may optionally be used in combination with the compounds of the invention may be one or more anticoagulant drugs including coumaryl acetate, dicoumarin acetate, hydrocinnamal, warfarin, clidanone, benzindone, thiocoumarin, bemiparin, sertorubin, dalteparin, enoxaparin, nadroparin, heparin, tinzaparin, fondaparinux sodium, heparin, danaparoid, sulodexide, dermatan sulfate, apixaban, betrixaban, edoxaban, omixaban, rivaroxaban, bivalirudin, lepirudin, hirudin, argatroban, dabigatran, melagatran, ximegagatran, defibrinide, ramatroban, antithrombin or dreecogin alfa;

other types of prophylactic or therapeutic agents that may optionally be used in combination with the compounds of the present invention may be one or more thrombolytic agents, such as alteplase, reteplase, tenecteplase, urokinase, sareprplase, streptokinase, anistreplase, monteplase, ancrod, fibrinolytic enzymes, or plasmin.

Other types of prophylactic or therapeutic agents that may optionally be used in combination with the compounds of the present invention may be one or more hypolipidemic agents, including nicotinic acid, statins (e.g., lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin, and pitavastatin), cholesterol absorption inhibitors (e.g., ezetimibe, etc.), fibrates (e.g., clofibrate, bezafibrate, fenofibrate, etc.).

The compounds of the invention are prepared by processes according to the examples or by modifications.

Drawings

FIG. 1 is a graph showing the inhibition of in vitro filtered platelet aggregation by Compound 11;

FIG. 2 is a graph showing the inhibition of in vitro filtered platelet aggregation by Compound 88.

Detailed Description

The present invention will be described in detail with reference to examples. In the present invention, the following examples are given for better illustration of the present invention and are not intended to limit the scope of the present invention. Various changes and modifications may be made to the invention 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] thiadiazole (Compound 1)

Compound 1-1(535mg, 3.61mmol) was weighed out and dissolved in methanol (8mL) and tetrahydrofuran (2mL), palladium hydroxide (carbon supported, 20% Pd, 25mg, 0.18mmol) was added and the apparatus was treated anaerobically with exchange of air in the system. The reaction was carried out overnight at room temperature, ethyl acetate (10mL) was added to dilute the reaction mixture, the solid content in the reaction mixture was filtered off by suction filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate 20:1-15:1) to give compound 1-2 (colorless oil, 324 mg).

Paraformaldehyde (218mg, 7.2mmol) and anhydrous magnesium chloride (460mg, 4.8mmol) were weighed into a 50mL two-necked flask, a condenser tube was inserted, and the apparatus was treated oxygen-free by exchanging air in the system with argon. Then, a solution of anhydrous tetrahydrofuran (20mL), triethylamine (0.67mL, 4.8mmol), and compound 1-2(324mg, 2.4mmol) in anhydrous tetrahydrofuran (5mL) was added sequentially via syringe. The system is reacted for 4h under reflux. After the reaction was completed, the pH of the system was adjusted to 1 with 1N hydrochloric acid solution, the aqueous phase (20mL × 3) was extracted with ethyl acetate, the organic phases were combined, the organic phase was washed with saturated brine (20mL × 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 100:1) to obtain compound 1-3 (white solid, 232 mg).

Compound 1-3(512mg, 3.2mmol) was weighed out and dissolved in acetone (25mL), followed by the addition of potassium carbonate (654mg, 4.7mmol), 1-chloropropanone (330. mu.L, 4.1mmol) in that order. The system is reacted for 5h under reflux. After the reaction, ethyl acetate (10mL) was added to dilute the reaction solution, the solid content in the system was filtered off 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: 50:1-30:1) to obtain compound 1-4 (white solid, 430 mg).

Copper bromide (620mg, 2.8mmol) was weighed into a 250mL three-necked flask, ethyl acetate (80mL) was added, compounds 1-4(429mg, 2.14mmol) were dissolved in ethyl acetate (20mL), and the ethyl acetate solution of compounds 1-4 was added dropwise to the reaction system through a dropping funnel under reflux conditions, and after the addition was completed, reflux was continued for 6 h. After the reaction, the solid content in the system was filtered off 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).

Compound 1-5(124mg, 0.44mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (96mg, 0.53mmol) were weighed into a 15mL pressure-resistant reaction tube, then isopropanol (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred into a 100mL flask with methylene chloride, and the solvent was distilled off under reduced pressure, and the residue containing compounds 1 to 6 was used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the above step containing the compounds 1 to 6 was dissolved in a mixed solvent of dichloromethane (15mL) and methanol (5mL), followed by addition of a methanol solution of sodium methoxide (4M, 260. mu.L) and reaction at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (10mL), the aqueous phase (10mL × 3) was extracted with ethyl acetate, the organic phases were combined, the organic phase was washed with a saturated saline solution (20mL × 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) to obtain compound 1 (gray solid, 20 mg):¹H NMR(300MHz,CDCl₃)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)

Compound 1-5(91mg, 0.33mmol) and 5-methylthio-1, 3, 4-thiadiazol-2-amine (58mg, 0.39mmol) were weighed into a 15mL pressure-resistant reaction tube, and then anhydrous N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after reaction for 3 hours at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 110 ℃. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 2), 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) to give compound 2 (brown solid, 33 mg):¹H NMR(300MHz,DMSO-d₆)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＝7.3Hz,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)

Paraformaldehyde (460mg, 15.3mmol) and anhydrous magnesium chloride (324mg, 3.4mmol) were weighed into a 50mL two-necked flask, a condenser tube was inserted, and the apparatus was oxygen-free by exchanging air in the system with argon. Then, a solution of anhydrous tetrahydrofuran (20mL), triethylamine (1.2mL, 8.5mmol), and compound 3-1(300mg, 2.27mmol) in anhydrous tetrahydrofuran (5mL) was added sequentially via syringe. The system is reacted for 4h under reflux. After the reaction was completed, the pH of the system was adjusted to 1 with 1N hydrochloric acid solution, the aqueous phase (20mL × 3) was extracted with ethyl acetate, the organic phases were combined, the organic phase was washed with saturated brine (20mL × 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 400:1) to obtain compound 3-2 (white solid, 300 mg).

Compound 3-2(300mg, 1.87mmol) was weighed out and dissolved in acetone (20mL), followed by the addition of potassium carbonate (388mg, 2.81mmol), 1-chloropropanone (180. mu.L, 2.25mmol) in that order. The system is reacted for 5h under reflux. After the reaction, ethyl acetate (10mL) was added to dilute the reaction solution, the solid content in the system was filtered off 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: 400:1-80:1) to obtain compound 3-3 (yellow-white solid, 260 mg).

Copper bromide (353mg, 1.58mmol) is weighed and placed in a 100mL three-necked flask, ethyl acetate (40mL) is added, compound 3-3(260mg, 1.2mmol) is dissolved in ethyl acetate (15mL), an ethyl acetate solution of compound 3-3 is added dropwise into the reaction system through a dropping funnel under the reflux condition, and after the addition is finished, the reflux is continued for 6 h. After the reaction, the solid content in the system was filtered off 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).

Compound 3-4(115mg, 0.39mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (85mg, 0.47mmol) were weighed into a 15mL pressure-resistant reaction tube, then isopropanol (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 5 hours of reaction at 80 ℃, the reaction is continued for 3 hours at 130 ℃. After completion of the reaction, the reaction system was transferred into a 100mL flask with methylene chloride, the solvent was distilled off under reduced pressure, and the residue containing the compound 3-5 was used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the above step containing the compounds 3 to 5 was dissolved in a mixed solvent of dichloromethane (15mL) and methanol (5mL), followed by addition of a methanol solution of sodium methoxide (4M, 230. mu.L) and reaction at room temperature for 1 hour. After the reaction, quenching the reaction with saturated ammonium chloride solution (10mL), extracting the aqueous phase (10mL x3) with ethyl acetate, combining the organic phases, washing the organic phase with saturated saline (20mL x1), drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and purifying the residue by column chromatography (eluent: petroleum ether/ethyl acetate 20:1-10:1) to obtain the compoundSubstance 3 (brown solid, 36 mg):¹H NMR(300MHz,CDCl₃)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)

Compound 3-4(81mg, 0.28mmol) and 5-methylthio-1, 3, 4-thiadiazol-2-amine (49mg, 0.33mmol) were weighed into a 15mL pressure-resistant reaction tube, and then anhydrous N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after reaction for 3 hours at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 110 ℃. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 2), 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 20:1-10:1) to give compound 4 (brown solid, 25 mg):¹H NMR(300MHz,CDCl₃)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)

Weighing compound 5-1(5g, 24.4mmol) and dissolving in anhydrous tetrahydrofuran (50mL) under the protection of argon, cooling to 0 ℃, slowly adding 1M borane in tetrahydrofuran (36.6mL, 36.6mmol) dropwise, after the dropwise addition is completed, raising the temperature to room temperature and stirring overnight, after the reaction is completed, slowly adding water dropwise to quench the reaction, transferring to a separating funnel, extracting with ethyl acetate (50mL x3), combining organic phases, washing the organic phases with saturated sodium bicarbonate solution (15mL x3) and saturated saline solution (15mL x3), respectively, drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and obtaining compound 5-2 (white solid, 3.40g) without further purification.

Weighing compound 5-2(0.5g, 2.62mmol) and dissolving in anhydrous toluene (8mL) under the protection of argon, adding sodium hydride (0.131g, 3.28mmol), heating to 40 ℃ and stirring for 15min, cooling the reaction solution to room temperature, adding cuprous chloride (13mg, 0.131mmol), adding toluene (2mL) and ethyl acetate (0.013mL), heating to 120 ℃ and refluxing for 24h, after the reaction is completed, cooling the reaction solution to room temperature, slowly adding ice water dropwise to quench sodium hydride, filtering to remove insoluble substances, adding water to dilute the filtrate, transferring to a separating funnel, extracting with methyl tert-butyl ether (10mL x3), combining the organic phases, washing the organic phase with saturated saline (5mL x3), drying with anhydrous sodium sulfate, removing the solvent under reduced pressure, purifying the residue by column chromatography (eluent: petroleum ether/ethyl acetate ═ 50:1) to obtain compound 5-3 (pale yellow liquid), 0.25 g).

Under the protection of argon, bis (dibenzylideneacetone) palladium (0.603g, 1.05mmol) and triphenylphosphine (0.706g, 2.52mmol) are weighed into a 300mL pressure resistant tube, dimethyl sulfoxide (50mL) is added, stirring is carried out at room temperature for 1 hour, then compounds 5-3(2.7g, 17.5mmol), potassium acetate (2.57g, 26.2mmol) and pinacol diboron (8.87g, 34.9mmol) are added, dimethyl sulfoxide (50mL) is added, heating is carried out at 150 ℃ for 10 hours, after the reaction is completed, the reaction liquid is cooled to room temperature, insoluble substances are removed by filtration through kieselguhr, the filtrate is diluted with water (150mL), ethyl acetate (70mL x3) is extracted, the organic phases are combined, the organic phase is washed with saturated saline (30mL x3), anhydrous sodium sulfate is dried, the solvent is removed by reduced pressure evaporation, the residue is purified by column chromatography (petroleum ether/ethyl acetate 100:1), compound 5-4 (pale yellow liquid, 2.7g) was obtained.

Compound 5-4(2.7g, 11mmol) was weighed and dissolved in dioxane (30mL), 50% aqueous solution of N-methylmorpholine-N-oxide (2.5mL, 12.1mmol) was added, the temperature was raised to 80 ℃ and heated for 1h, after completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (30mL), 1N hydrochloric acid solution was added to acidify the system to pH 1, the mixture was transferred to a separatory funnel, extracted with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated brine (10mL × 3), 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 ═ 4:1) to give compound 5-5 (white solid, 1.0 g).

Weighing compounds 5-5(0.1g, 0.73mmol) and dissolving in anhydrous dichloromethane (10mL) under the protection of argon, adding 1, 1-dichloromethyl ether (0.13mL, 1.47mmol), cooling to-20 ℃, slowly adding titanium tetrachloride (0.24mL, 2.19mmol) dropwise, after the dropwise addition is completed, keeping the temperature constant and continuing stirring for 1h, after the reaction is completed, adding 1N hydrochloric acid (20mL) for dilution, transferring to a separating funnel, extracting with dichloromethane (10mL x3), combining organic phases, washing the organic phase with saturated saline (10mL x3), drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and purifying the residue by column chromatography (eluent: petroleum ether/ethyl acetate ═ 20:1) to obtain compounds 5-6 (white solid, 0.1 g).

Compound 5-6(0.67g, 4.08mmol) was weighed, dissolved in acetone (20mL), potassium carbonate (0.73g, 5.3mmol) was added, 1-chloropropanone (0.39mL, 4.9mmol) was slowly added dropwise, after completion of the dropwise addition, reflux was raised at elevated temperature for 7 hours, after completion of the reaction, the reaction solution was cooled to room temperature, insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane ═ 1:1) to give compound 5-7 (colorless transparent oil, 596 mg).

Weighing copper bromide (0.79g, 3.54mmol), placing the copper bromide in a 250mL three-necked bottle, adding ethyl acetate (50mL), dissolving the compound 5-7(0.596g, 2.95mmol) in ethyl acetate (30mL), dropwise adding the ethyl acetate solution of the compound 5-7 into the reaction system through a dropping funnel under the reflux condition, and continuing to reflux for 8 hours after the addition is finished. After the reaction was completed, the solid matter in the system was filtered off by suction filtration, the solvent was distilled off 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).

Compound 5-8(200mg, 0.71mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (154mg, 0.853mmol) were weighed into a 35mL pressure-resistant reaction tube, followed by addition of isopropanol (10mL) and purging of the mixture solution with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred into a 100mL flask with methylene chloride, the solvent was distilled off under reduced pressure, and the residue containing compounds 5 to 9 was used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the above step containing compounds 5 to 9 was dissolved in a mixed solvent of dichloromethane (120mL) and methanol (30mL), followed by addition of a methanol solution of sodium methoxide (4M, 350. mu.L) and reaction at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (60mL), the aqueous phase (20mL × 3) was extracted with dichloromethane, the organic phases were combined, the organic phase was washed with a saturated saline solution (10mL × 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 ═ 6:1) to obtain compound 5 (white solid, 30 mg):¹H NMR(300MHz,CDCl₃)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)

Compound 5-8(100mg, 0.356mmol) and 5-methylsulfanyl-1, 3, 4-thiadiazol-2-amine (63mg, 0.427mmol) were weighed into a 15mL pressure-resistant reaction tube, and then anhydrous N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 2 hours at the temperature of 110 ℃. After the reaction was completed, the reaction system was transferred into a 25mL flask with dichloromethane, the solvent was distilled off 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):¹H NMR(300MHz,CDCl₃)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 out and dissolved in acetonitrile (100mL), followed by addition of potassium carbonate (48g, 347mmol), and the system was reacted under reflux for 3 h. After the reaction, the reaction mixture was filtered off to remove a solid, acetonitrile was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate 500:1) to obtain compound 7-2 (colorless oily substance, 15 g).

The compound 7-2(3.53g, 16.57mmol) was dissolved in N, N-diethylaniline (10mL) and reacted at 200 ℃ for 3 hours. After completion of the reaction, ethyl acetate (30mL) was added to dilute the reaction system, the organic phase was washed with 1N hydrochloric acid (10mL × 3) and saturated brine (10mL × 2), 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 give compound 7-3 (colorless oily substance, 1.4 g).

Under argon atmosphere, compound 7-3(1335mg, 6.27mmol) was dissolved in anhydrous tetrahydrofuran (20mL), 9-borabicyclo [3.3.1] nonane (0.5M in THF, 12.54mL) was added dropwise at-78 deg.C, the system was allowed to continue to react at-78 deg.C for 10h, then saturated sodium bicarbonate solution (10mL) was slowly added to the system under ice bath conditions, the ice bath conditions were maintained, the reaction was continued for 10min, then under these conditions, 30% hydrogen peroxide solution was added to the system, warmed to room temperature, and the reaction was continued for 2 h. After completion of the reaction, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phases were combined, washed with saturated brine (10mL × 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 give compound 7-4 (white solid, 911 mg).

Compound 7-4(100mg, 0.433mmol), tributylphosphine (216. mu.L, 0.866mmol) were dissolved in anhydrous tetrahydrofuran (5mL) under an argon atmosphere, and a solution of azobisformyldipiperidine (218mg, 0.866mmol) in anhydrous tetrahydrofuran (4mL) was added dropwise to the system under ice-bath conditions, warmed to room temperature, and the reaction was continued overnight. After the reaction was completed, 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 give compound 7-5 (yellow oil, 47 mg).

Weighing the compounds 7-5(220mg, 1.03mmol), pinacol diboron (526mg, 2.07mmol), palladium dichloride dichloromethane complex [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (84mg, 0.103mmol) and potassium acetate (304mg, 3.1mmol), placing the compounds in a 15mL pressure-resistant reaction tube, adding anhydrous dioxane (5mL), bubbling and purging with argon for 5min, sealing, and reacting at 100 ℃ for 1.5 h. After the reaction, ethyl acetate (20mL) was added to dilute the reaction system, and the insoluble matter was filtered off by suction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate 300:1) to give compound 7-6 (yellow oily substance, 228 mg).

Weighing the compounds 7-6(220mg, 0.85mmol) and dissolving in dioxane (8mL), adding 50% N-methyl-N-morpholine oxide aqueous solution (200 μ L), reacting at 80 deg.C for 1h, adding 50% N-methyl-N-morpholine oxide aqueous solution (50 μ L), and continuing to react at 80 deg.C for 2 h. After the reaction was completed, a 1N hydrochloric acid solution was added to acidify the system to pH 1, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated brine (10mL × 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 ═ 30:1-15:1) to obtain compounds 7 to 7 (white pasty solid, 80 mg).

Weighing the compound 7-7(200mg, 1.33mmol), dissolving in a mixed solvent of acetic acid (5mL) and trifluoroacetic acid (5mL), adding urotropin (187mg, 1.33mmol), and reacting the system under reflux for 4 h. After the reaction was completed, 6N hydrochloric acid solution (30mL) was added, stirring was continued at room temperature for 30min, then saturated sodium bicarbonate solution was added to adjust the solution pH to about 7, the aqueous phase was extracted with dichloromethane (20mL × 3), 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 10:1-8:1) to obtain compounds 7 to 8 (white solid, 90 mg).

Compounds 7-8(50mg, 0.28mmol) were weighed out and dissolved in acetone (10mL), followed by the addition of potassium carbonate (77mg, 0.56mmol), 1-chloropropanone (25. mu.L, 0.31mmol) in that order. The system is reacted for 6h under reflux condition. After the reaction, ethyl acetate (20mL) was added to dilute the reaction solution, the solid content in the system was filtered off 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 8:1-7:1) to obtain compounds 7-9 (white solid, 40 mg).

Copper bromide (335mg, 1.5mmol) was weighed into a 100mL three-necked flask, ethyl acetate (20mL) was added, compound 7-9(216mg, 1mmol) was dissolved in ethyl acetate (20mL), and the ethyl acetate solution of compound 7-9 was added dropwise to the reaction system through a dropping funnel under reflux conditions, and after the addition was completed, reflux was continued for 8 h. After the reaction, the solid content in the system was filtered off 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).

Compound 7-10(80mg, 0.271mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (59mg, 0.325mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred into a 100mL flask with methylene chloride, the solvent was distilled off under reduced pressure, and the residue containing compounds 7 to 11 was used in the next reaction without further purification.

The crude compound 7-11 obtained in the previous step was dissolved in a mixed solvent of dichloromethane (6mL) and methanol (2mL), and then a methanol solution of sodium methoxide (4M, 100. mu.L) was added thereto to carry out reaction at room temperature for 1 hour. After completion of the reaction, the reaction was quenched with a saturated ammonium chloride solution (10mL), the aqueous phase (10 mL. times.3) was extracted with ethyl acetate, the organic phases were combined, washed with a saturated saline solution (20 mL. times.1), and dried over anhydrous sodium sulfateThe solvent was evaporated under reduced pressure and the residue was purified by column chromatography (eluent: dichloromethane/ethyl acetate 100:1-70:1) to give compound 7 (brown solid, 15 mg):¹H NMR(300MHz,CDCl₃)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)

Compound 7-10(80mg, 0.27mmol) and 5-methylsulfanyl-1, 3, 4-thiadiazol-2-amine (48mg, 0.325mmol) were weighed into a 15mL pressure-resistant reaction tube, then N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 2 hours at the temperature of 110 ℃. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 2), 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 9:1-7:1) to give compound 8 (brown solid, 31 mg):¹H NMR(300MHz,CDCl₃)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] dioxolo [4,5-g ] benzofuran-7-yl) -2-methoxyimidazo [2,1-b ] [1,3,4] thiadiazole (Compound 9)

Compound 9-1(2.76g, 20mmol) and diiodomethane (8.04g, 30mmol) were weighed out and dissolved in N, N-dimethylformamide (100mL), and then copper oxide (79.5mg, 1mmol) and potassium carbonate (8.28g, 60mmol) were added in that order. The reaction was carried out at 130 ℃ for 4.5h, ethyl acetate (200mL) was added to dilute the reaction mixture, the organic phase was washed with water (100mL × 3) and saturated brine (100mL × 2), 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 7:1-5:1) to give compound 9-2 (yellow oil, 2.6 g).

Compound 9-2(2.6g, 17.3mmol) was weighed and dissolved in dichloromethane (100mL), m-chloroperoxybenzoic acid (3.6g, 20.8mmol) was added in portions under ice bath conditions, then the ice bath was removed, after the system was returned to room temperature, the oil bath was transferred, reaction was performed under reflux conditions for 12 hours, ethyl acetate (200mL) was added to dilute the reaction solution, the organic phase was washed with water (100mL x3) and saturated brine (100mL x1), dried 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 give compound 9-3 (brown solid, 2.9 g).

Compound 9-3(2.8g, 16.9mmol) was dissolved in methanol (10mL), and 10% potassium hydroxide solution (80mL) was added slowly under ice-bath conditions and reacted at room temperature for 6 h. After the reaction was completed, the pH of the system was adjusted to 1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (30mL x3), the organic phases were combined, the organic phase was washed with water (20mL x3) 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 give compound 9-4 (colorless oil, 2.03 g).

Paraformaldehyde (1.33g, 44mmol) and anhydrous magnesium chloride (2.79g, 29mmol) were weighed into a 100mL two-necked flask, a condenser tube was inserted, and the apparatus was treated oxygen-free by exchanging air in the system with argon. Then, a solution of anhydrous tetrahydrofuran (30mL), triethylamine (4.09mL, 29mmol), and compound 9-4(2.03g, 14.7mmol) in anhydrous tetrahydrofuran (5mL) was added sequentially via syringe. The system is reacted for 4h under reflux. After the reaction was completed, the system was adjusted to pH 1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue containing compound 9-5 was used in the next reaction without further purification.

The residue obtained in the above post-reaction treatment containing compound 9-5 was dissolved in acetone (20mL), followed by the addition of potassium carbonate (2.07g, 15mmol), 1-chloropropanone (1.2mL, 15mmol) in that order. The system is reacted for 6h under reflux condition. After the reaction, ethyl acetate (50mL) was added to dilute the reaction solution, the solid content in the system was filtered off 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/dichloromethane: 10:1:1-6:1:1) to obtain compound 9-6 (yellow solid, 600 mg).

Copper bromide (984mg, 4.41mmol) is weighed into a 250mL three-necked flask, ethyl acetate (80mL) is added, compound 9-6(600mg, 2.94mmol) is dissolved in ethyl acetate (100mL), the ethyl acetate solution of compound 9-6 is added dropwise into the reaction system through a dropping funnel under the reflux condition, and after the addition is finished, the reflux is continued for 8 h. After the reaction, solid matters in the system were filtered off 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).

Compound 9-7(180mg, 0.636mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (137mg, 0.763mmol) were weighed into a 15mL pressure-resistant reaction tube, then isopropanol (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred with methylene chloride into a 100mL flask, and the solvent was distilled off under reduced pressure, and the residue containing compound 9-8 was used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the above step containing the compound 9-8 was dissolved in a mixed solvent of dichloromethane (12mL) and methanol (4mL), followed by addition of a methanol solution of sodium methoxide (4M, 239. mu.L) and reaction at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (10mL), the aqueous phase (10mL × 3) was extracted with ethyl acetate, the organic phases were combined, the organic phase was washed with a saturated saline solution (20mL × 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 give a crude product, which was purified by preparative plate chromatography (chromatography: petroleum ether/ethyl acetate/dichloromethane ═ 10:1:1/6:1:1) gave compound 9 (yellow solid, 20 mg):¹H NMR(300MHz,CDCl₃)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] dioxolo [4,5-g ] benzofuran-7-yl) 2- (methylthio) imidazo [2,1-b ] [1,3,4] thiadiazole (Compound 10)

Compound 9-7(150mg, 0.53mmol) and 5-methylthio-1, 3, 4-thiadiazol-2-amine (86mg, 0.583mmol) were weighed into a 15mL pressure-resistant reaction tube, and then anhydrous N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 2 hours at the temperature of 110 ℃. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 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 ═ 7:3:0.2) to give compound 10 (yellow solid, 72 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) -2-methoxyimidazo [2,1-b ] [1,3,4] thiadiazole (compound 11)

Compound 11-1(15g, 98.68mmol), sodium acetate (16.2g, 197.56mmol) and iron powder (450mg, 8.03mmol) were weighed into a 250mL round-bottomed flask, acetic acid (150mL) was added, and then a solution of liquid bromine (5.5mL, 107mmol) in acetic acid (18mL) was added dropwise via a dropping funnel at room temperature, and after the addition, the reaction was carried out at room temperature for 16 hours. After completion of the reaction, most of the acetic acid solution was distilled off under reduced pressure, ethyl acetate (200mL) was added to form a suspension, suction filtration was performed, the solid was filtered off, the filtrate was collected, the filtrate was washed with water (50mL x3) and saturated brine (50mL x1), dried over anhydrous sodium sulfate, the solvent was distilled off again under reduced pressure, and the residue was purified 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 out and dissolved in dichloromethane (15mL), boron tribromide (1M in DCM, 30mL) was added dropwise under ice bath conditions, and after addition, the reaction was carried out overnight at room temperature. After completion of the reaction, the reaction was quenched by slowly adding water (50mL) under ice bath conditions, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phases were combined, the organic phase was washed with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue (2.15g) containing compound 11-3 was used in the next reaction without further purification.

The reaction residue of the previous step containing compound 11-3 was weighed, dissolved in N, N-dimethylformamide (20mL), added with 1, 2-dibromoethane (872 μ L, 10.11mmol) and cesium carbonate (6.52g, 20mmol), reacted at 130 ℃ for 8h, diluted with ethyl acetate (50mL), the organic phase washed with water (20mL x3) and saturated brine (20mL x2), dried over anhydrous sodium sulfate, the solvent evaporated under reduced pressure, and the residue purified by column chromatography (eluent: petroleum ether/ethyl acetate 14:1) to give compound 11-4 (white solid, 1.56 g).

Weighing the compound 11-4(243mg, 1mmol), the pinacol diborate (508mg, 2mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (81.7mg, 0.1mmol) and potassium acetate (300mg, 3mmol) in a 15mL pressure-resistant reaction tube, adding anhydrous 1, 4-dioxane (10mL), bubbling argon for purging for 5min, reacting the system at 100 ℃ for 8h, adding ethyl acetate (30mL) to dilute the reaction solution, filtering off solid matters, distilling off the solvent under reduced pressure, and purifying the residue by column chromatography (eluent: petroleum ether/ethyl acetate ═ 13:1-10:1) to obtain the compound 11-5 (white solid, 163 mg).

Compound 11-5(1125mg, 3.87mmol) was weighed and dissolved in dioxane (20mL), 50% aqueous N-methyl-N-morpholine oxide (885. mu.L) was added, and after 1h at 80 ℃ the reaction was repeated, 50% aqueous N-methyl-N-morpholine oxide (89. mu.L) was added again and the reaction was continued at 80 ℃ for 2 h. After the reaction was completed, a 1N hydrochloric acid solution was added to acidify the system to pH 1, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated brine (10mL × 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 ═ 16:1) to obtain compound 11-6 (pale yellow solid, 524 mg).

Compound 11-6(260mg, 1.44mmol) was weighed out and dissolved in acetone (10mL), followed by the addition of potassium carbonate (260mg, 1.88mmol), 1-chloropropanone (145. mu.L, 1.81mmol) in that order. The system is reacted for 6h under reflux condition. After the reaction, ethyl acetate (30mL) was added to dilute the reaction solution, the solid content in the system was filtered off 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 16:1) to obtain compound 11-7 (yellow solid, 126 mg).

Copper bromide (295mg, 1.32mmol) is weighed into a 100mL three-necked flask, ethyl acetate (20mL) is added, compound 11-7(262mg, 1.20mmol) is dissolved in ethyl acetate (20mL), an ethyl acetate solution of compound 11-7 is added dropwise into the reaction system through a dropping funnel under reflux conditions, and after the addition is finished, the reflux is continued for 8 h. After the reaction, the solid content in the system was filtered off 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).

Compound 11-8(240mg, 0.808mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (174mg, 0.969mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred into a 100mL flask with dichloromethane, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate 4.5:4.5:1) to obtain compound 11-9 (yellow solid, 185 mg).

Compound 11-9(185mg, 0.49mmol) was weighed out and dissolved in a mixed solvent of dichloromethane (6mL) and methanol (2mL), and then a solution of sodium methoxide in methanol (4M, 181. mu.L) was added thereto and reacted at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (10mL), the aqueous phase (10mL × 3) was extracted with ethyl acetate, the organic phases were combined, the organic phase was washed with a saturated saline solution (20mL × 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 ═ 9:1-6:1) to obtain compound 11 (yellow solid, 120 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) -2- (methylthio) imidazo [2,1-b ] [1,3,4] thiadiazole (Compound 12)

Compound 11-8(100mg, 0.34mmol) and 5-methylsulfanyl-1, 3, 4-thiadiazol-2-amine (60mg, 0.4mmol) were weighed into a 15mL pressure-resistant reaction tube, and then anhydrous N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 2 hours at the temperature of 110 ℃. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 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 15:1:1-10:1:1) to give compound 12 (yellow solid, 64 mg):¹H NMR(300MHz,CDCl₃)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] oxaheptino [2,3-g ] benzofuran-9-yl) -2-methoxyimidazo [2,1-b ] [1,3,4] thiadiazole (Compound 13)

Compound 9-1(1.95g,14.1mmol) was weighed, dissolved in anhydrous N, N-dimethylformamide (50mL), added with potassium carbonate (4.09g,29.6mmol) and 1, 3-diiodopropane (5g,16.9mmol), and heated to 110 ℃ for 4h under an argon atmosphere. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (60mL), adjusted to be weakly acidic by adding an appropriate amount of 1N hydrochloric acid, extracted with ethyl acetate (40mL × 3), the organic phases were combined, washed with a saturated saline solution (10mL × 3), 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 oily substance, 1.3 g).

Compound 13-1(1.30g,7.30mmol) was weighed and dissolved in dichloromethane (30mL), m-chloroperoxybenzoic acid (1.51g,8.75mmol) was added, the system was heated under reflux for 12h, TLC detected no increase in reaction progress, the solid content in the reaction solution was removed by filtration, the filtrate was diluted with dichloromethane (20mL), the organic phase was washed with saturated sodium bicarbonate solution (10mL x3) and saturated saline (10mL x1), 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 8:1) to give compound 13-2 (white solid, 1.08 g).

Compound 13-2(1.08g,5.56mmol) was weighed out and dissolved in methanol (20mL), and 10% aqueous potassium hydroxide (20mL) was added and stirred at room temperature for 1 h. After completion of the reaction, the aqueous phase was made acidic by addition of a 1N hydrochloric acid solution, extracted with dichloromethane (20mL × 3), the organic phases were combined, washed with a saturated aqueous salt solution (10mL × 1), 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 ═ 10:1) to give 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) are dissolved in anhydrous tetrahydrofuran (20mL), triethylamine (1.4mL,10.1mmol) is added, stirring is carried out at room temperature for 15min, heating is carried out until reflux heating is carried out, a compound 13-3(0.84g,5.05mmol) anhydrous tetrahydrofuran solution (10mL) is slowly dropped into the reaction system, after dropping is completed, reflux heating is carried out for 5h, TLC detection is carried out until the reaction progress is not increased, the reaction liquid is cooled to room temperature, 1N hydrochloric acid is added to adjust the pH of the aqueous phase to 1, water quenching reaction is added (30mL), ethyl acetate (20mL x3) is carried out, the organic phases are combined, the organic phase is washed by saturated saline solution (10mL x1), anhydrous sodium sulfate is dried, the filtrate is concentrated under reduced pressure, the residue is purified by column chromatography (eluent: petroleum ether/dichloromethane 1:2), compound 13-4 was obtained (pale yellow oil, 0.15 g).

Compound 13-4(0.15g,0.77mmol) was weighed out and dissolved in acetone (10mL), potassium carbonate (0.138g,1mmol) was added, chloroacetone (74. mu.L, 0.92mmol) was slowly added dropwise, after completion of the dropwise addition, the mixture was refluxed for 7h at elevated temperature. After completion of the reaction, the reaction solution was cooled to room temperature, insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane ═ 1:2) to give compound 13-5 (colorless oil, 60 mg).

Weighing copper bromide (70mg,0.312mmol), placing the copper bromide in a 25mL three-necked bottle, adding ethyl acetate (10mL), dissolving the compound 13-5(60mg,0.26mmol) in ethyl acetate (5mL), dropwise adding the ethyl acetate solution of the compound 13-5 into the reaction system through a dropping funnel under the reflux condition, and continuing to reflux for 4 hours after the addition is finished. After the reaction, the solid in the system was filtered off 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 (pale yellow solid, 60 mg).

Compound 13-6(210mg, 0.67mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (144mg, 0.804mmol) were weighed into a 35mL pressure-resistant reaction tube, followed by addition of isopropanol (10mL) and purging of the mixture solution with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred into a 100mL flask with methylene chloride, the solvent was distilled off under reduced pressure, and the residue (containing compound 13-7) was used in the next reaction without further purification.

The residue containing compound 13-7 obtained after the last reaction was dissolved in a mixed solvent of dichloromethane (39mL) and methanol (13mL), followed by addition of a methanol solution of sodium methoxide (4M, 550. mu.L) and reaction at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (60mL), extracted with dichloromethane (20mL × 3), the organic phases were combined, washed with a saturated saline solution (10mL × 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, 20 mg):¹H NMR(300MHz,CDCl₃)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] oxaheptino [2,3-g ] benzofuran-9-yl) -2- (methylthio) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 14)

Compound 13-7(60mg, 0.19mmol) and 5-methylsulfanyl-1, 3, 4-thiadiazol-2-amine (33mg, 0.23mmol) were weighed into a 15mL pressure-resistant reaction tube, then N, N-dimethylformamide (3mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 2 hours at the temperature of 110 ℃. After the reaction was completed, the reaction system was transferred into a 25mL flask with dichloromethane, the solvent was distilled off 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):¹H NMR(300MHz,CDCl₃)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] dioxaoctatriene [2,3-g ] benzofuran-2-yl) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 15)

Compound 11-3(9.4g, 43.11mmol) was weighed and dissolved in N, N-dimethylformamide (125mL), 1, 4-diiodobutane (6.82mL, 51.73mmol) and potassium carbonate (13.68g, 99.15mmol) were added, the system was reacted at 80 ℃ for 8h, ethyl acetate (300mL) was added to dilute the reaction solution, the organic phase was washed with water (100mL x3) and saturated brine (100mL x2), 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 give compound 15-1 (yellow solid, 6.7 g).

Weighing the compound 15-1(3.46g, 12.5mmol), pinacol diboron (6.37g, 25.1mmol), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (1.03g, 1.25mmol) and potassium acetate (3.7g, 37.6mmol) in a 350mL pressure-resistant reaction tube, adding anhydrous 1, 4-dioxane (100mL), bubbling and purging with argon for 5min, reacting the system at 100 ℃ for 8h, adding ethyl acetate (150mL) to dilute the reaction solution, filtering off solid substances, evaporating the solvent under reduced pressure, and purifying the residue by column chromatography (eluent: petroleum ether/ethyl acetate 20:1) to obtain the compound 15-2 (yellow oily liquid, 2.47 g).

Compound 15-2(2.47g, 7.62mmol) was weighed out and dissolved in dioxane (40mL), and 50% aqueous N-methyl-N-morpholine oxide (2.35mL) was added and reacted at 80 ℃ for 4 h. After the reaction was completed, a 1N hydrochloric acid solution was added to acidify the system to pH 1, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phases were combined, washed with saturated brine (30mL × 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 ═ 20:1) to obtain compound 15-3 (yellow oily liquid, 896 mg).

Compound 15-3(208mg, 0.98mmol) was weighed out and dissolved in acetone (10mL), followed by the addition of potassium carbonate (176mg, 1.27mmol), 1-chloropropanone (95. mu.L, 1.2mmol) in that order. The system is reacted for 6h under reflux condition. After the reaction, ethyl acetate (30mL) was added to dilute the reaction solution, the solid content in the system was filtered off 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 20:1) to obtain compound 15-4 (yellow solid, 123 mg).

Copper bromide (216mg, 0.97mmol) was weighed into a 100mL three-necked flask, ethyl acetate (15mL) was added, compound 15-4(187mg, 0.75mmol) was dissolved in ethyl acetate (30mL), and the ethyl acetate solution of compound 15-4 was added dropwise to the reaction system through a dropping funnel under reflux conditions, and after the addition was completed, reflux was continued for 8 h. After the reaction, the solid content in the system was filtered off 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).

Compound 15-5(74mg, 0.22mmol) and 5-methylsulfanyl-1, 3, 4-thiadiazol-2-amine (40mg, 0.27mmol) were weighed into a 35mL pressure-resistant reaction tube, and then anhydrous N, N-dimethylformamide (7mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath and reacts for 4 hours at the temperature of 90 ℃, and then the reaction is continued for 3 hours at the temperature of 120 ℃. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 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 15:1:1-10:1:1) to give compound 15 (yellow solid, 20 mg):¹H NMR(300MHz,CDCl₃)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/z 396.1[M+Na]⁺.

example 16

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

Compound 15-5(101mg, 0.311mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (67mg, 0.373mmol) were weighed into a 35mL pressure-resistant reaction tube, followed by addition of isopropanol (50mL) and purging of the mixture solution with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred with methylene chloride into a 100mL flask, and the solvent was distilled off under reduced pressure, and the residue containing compound 16-1 was used in the next reaction without further purification.

The residue obtained from the above post-reaction treatment containing compound 16-1 was dissolved in a mixed solvent of dichloromethane (15mL) and methanol (5mL), followed by addition of a methanol solution of sodium methoxide (4M, 185. mu.L) and reaction at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (10mL), the aqueous phase was extracted with dichloromethane (15mL × 3), the organic phases were combined, the organic phase was washed with a saturated saline solution (10mL × 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 16 (gray solid, 20 mg):¹H NMR(300MHz,CDCl₃)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] trioxanonatriene [2,3-g ] benzofuran-11-yl) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 17)

Compound 11-3(10.74g, 49.5mmol) was weighed and dissolved in N, N-dimethylformamide (150mL), diethylene glycol bis-p-toluenesulfonate (24.62g, 59.4mmol) and potassium carbonate (15.71g, 114mmol) were added, the system was reacted at 80 ℃ for 8 hours, ethyl acetate (350mL) was added to dilute the reaction solution, the organic phase was washed with water (120mL × 3) and saturated brine (120mL × 2), 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 give compound 17-1 (white solid, 3.55 g).

Compound 17-1(1.9g, 6.6mmol), pinacol diboron ester (3.37g, 13.3mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (542mg, 0.66mmol) and potassium acetate (1.95g, 19.9mmol) were weighed and placed in a 120mL pressure-resistant reaction tube, anhydrous 1, 4-dioxane (30mL) was added, argon gas was bubbled and purged for 5min, the system was reacted at 100 ℃ for 8h, ethyl acetate (60mL) was added to dilute the reaction solution, suction filtration was performed to remove solids, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate 10:1) to give compound 17-2 (yellow oily liquid, 1.33 g).

Compound 17-2(1.34g, 4mmol) was weighed out and dissolved in dioxane (20mL), and 50% aqueous N-methyl-N-morpholine oxide (1.3mL) was added and reacted at 80 ℃ for 4 h. After the reaction was completed, a 1N hydrochloric acid solution was added to acidify the system to pH 1, the aqueous phase was extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with saturated saline (15mL × 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) to obtain compound 17-3 (white solid, 270 mg).

Compound 17-3(153mg, 0.68mmol) was weighed out and dissolved in acetone (6mL), followed by the addition of potassium carbonate (123mg, 0.89mmol), 1-chloropropanone (70. mu.L, 0.82mmol) in that order. The system is reacted for 6h under reflux condition. After the reaction, ethyl acetate (20mL) was added to dilute the reaction solution, the solid content in the system was filtered off 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 20:1) to obtain compound 17-4 (yellow solid, 115 mg).

Copper bromide (127mg, 0.57mmol) was weighed into a 50mL three-necked flask, ethyl acetate (10mL) was added, compound 17-4(115mg, 0.44mmol) was dissolved in ethyl acetate (15mL), and the ethyl acetate solution of compound 17-4 was added dropwise to the reaction system through a dropping funnel under reflux conditions, and after the addition was completed, reflux was continued for 8 h. After the reaction, the solid content in the system was filtered off 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).

Compound 17-5(41mg, 0.12mmol) and 5-methylsulfanyl-1, 3, 4-thiadiazol-2-amine (22mg, 0.15mmol) were weighed into a 15mL pressure-resistant reaction tube, and then anhydrous N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath and reacts for 4 hours at the temperature of 90 ℃, and then the reaction is continued for 3 hours at the temperature of 120 ℃. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 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 15:1:1) to give compound 17 (yellow solid, 10 mg):¹H NMR(300MHz,CDCl₃)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)

Weighing compound 18-1(2g, 14.5mmol) and dissolving in pyridine (2.5mL), adding 3-methyl-2-butenal (2.78mL, 28.8mmol), reacting at 140 ℃ for 10h, after the reaction is finished, evaporating under reduced pressure to remove the solvent, and purifying the residue by column chromatography (eluent: petroleum ether/ethyl acetate 300:5-300:10) to obtain compound 18-2 (brown oily substance, 31 mg).

Compound 18-2(610mg, 3mmol) was weighed out and dissolved in acetone (10mL), followed by the addition of potassium carbonate (621mg, 4.5mmol), 1-chloropropanone (290. mu.L, 1.16mmol) in that order. The system is reacted for 6h under reflux condition. After the reaction, ethyl acetate (30mL) was added to dilute the reaction solution, the solid content in the system was filtered off 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 14:1) to give compound 18-3 (yellow oily substance, 240 mg).

Copper bromide (270mg, 1.2mmol) is weighed into a 100mL three-necked flask, ethyl acetate (20mL) is added, compound 18-3(242mg, 1mmol) is dissolved in ethyl acetate (20mL), an ethyl acetate solution of compound 18-3 is added dropwise into the reaction system through a dropping funnel under reflux conditions, and after the addition is finished, the reflux is continued for 8 h. After the reaction, the solid content in the system was filtered off 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 oily substance, 122 mg).

Compound 18-4(122mg, 0.38mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (82mg, 0.456mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred into a 100mL flask with methylene chloride, the solvent was distilled off under reduced pressure, and the residue containing compound 18-5 was used in the next reaction without further purification.

The crude compound 18-5 obtained in the previous step was dissolved in a mixed solvent of dichloromethane (6mL) and methanol (2mL), and then sodium methoxide solution in methanol (4M, 185. mu.L) was added to react at room temperature for 1 h. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (10mL), the aqueous phase (10mL × 3) was extracted with ethyl acetate, the organic phases were combined, the organic phase was washed with a saturated saline solution (20mL × 1), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (chromatography agent: petroleum ether/ethyl acetate 5:1) to obtain compound 18 (brown solid, 12mg):¹H NMR(300MHz,CDCl₃)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＝8.3Hz,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 ] furan-2-yl) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 19)

Compound 19-1(500mg, 2.9mmol) was weighed out and dissolved in acetone (30mL), followed by the addition of potassium carbonate (522mg, 3.78mmol), 1-chloropropanone (322. mu.L, 3.5mmol) in that order. The system is reacted for 5h under reflux. After the reaction, ethyl acetate (20mL) was added to dilute the reaction solution, the solid content in the system was filtered off 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 20:1-15:1) to obtain compound 19-2 (yellow-white solid, 565 mg).

Copper bromide (780mg, 3.5mmol) was weighed into a 100mL three-necked flask, ethyl acetate (40mL) was added, compound 19-2(565mg, 2.7mmol) was dissolved in ethyl acetate (20mL), and the ethyl acetate solution of compound 19-2 was added dropwise to the reaction system through a dropping funnel under reflux conditions, and after the addition was completed, reflux was continued for 6 h. After the reaction, the solid in the system was filtered off 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 give compound 19-3 (gray solid, 350 mg).

Compound 19-3(83mg, 0.287mmol) and 5-methylthio-1, 3, 4-thiadiazol-2-amine (55mg, 0.373mmol) were weighed into a 15mL pressure-resistant reaction tube, and then anhydrous N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after reaction for 3 hours at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 110 ℃. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 2), 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 ═ 20:1:1-10:1:1) to give compound 19 (yellow solid, 38 mg):¹H NMR(300MHz,DMSO-d₆)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＝7.5Hz,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 ] furan-2-yl) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 20)

Compound 19-3(350mg, 1.21mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (261mg, 1.45mmol) were weighed into a 135mL pressure-resistant reaction tube, followed by addition of isopropanol (20mL) and purging of the mixture solution with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred with methylene chloride into a 100mL flask, and the solvent was distilled off under reduced pressure, and the residue containing compound 20-1 was used in the next reaction without further purification.

The residue obtained in the post-reaction treatment of the above step containing the compound 20-1 was dissolved in a mixed solvent of dichloromethane (27mL) and methanol (9mL), followed by addition of a methanol solution (4M, 765. mu.L) of sodium methoxide and reaction at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (20mL), the aqueous phase (20mL × 3) was extracted with dichloromethane, the organic phases were combined, the organic phase was washed with a saturated saline solution (10mL × 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 ═ 20:1:1-10:1:1) to obtain compound 20 (white solid, 100 mg):¹H NMR(300MHz,CDCl₃)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] dioxino [2,3-g ] benzofuran-8-yl) -2- (methylthio) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 21)

Weighing Compound 12(144mg, 0.42mmol) and dissolving in tetrahydrofuran (20mL), dissolving N-bromosuccinimide (90mg, 0.50mmol) in tetrahydrofuran (5mL), and dissolving N-bromosuccinimide in tetrahydrofuran under ice bath conditions (5mL) was added dropwise to the reaction system, and after the addition was completed, the temperature was raised to room temperature and the mixture was stirred overnight. After the reaction was completed, 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, 150 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) -2- (trifluoromethyl) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 22)

Compound 11-8(100mg, 0.34mmol) and 2-amino-5-trifluoromethyl-1, 3, 4-thiadiazole (74mg, 0.44mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of ethanol (5mL) and purging of the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 80 ℃ for 4 h. After the reaction was completed, 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):¹H NMR(300MHz,CDCl₃)δ8.26(s,1H),7.11(s,1H),7.06(d,J＝8.4Hz,1H),6.84(d,J＝8.5Hz,1H),4.47-4.34(m,4H).ESI-MS:m/z 390.1[M+Na]⁺.

example 23

2- (2, 3-dihydro- [1,4] dioxadieno [2,3-g ] benzofuran-8-yl) -6-methylimidazo [1,2-b ] pyridazine (Compound 23)

Compound 11-8(100mg, 0.34mmol) and 3-amino-6-methylpyridazine (39mg, 0.35mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. Transferring the system into an oil bath at 85 deg.CAnd reacting for 12 hours under the condition. After the reaction was completed, 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, 42 mg):¹H NMR(300MHz,CDCl₃)δ8.29(s,1H),7.81(d,J＝9.3Hz,1H),7.21(s,1H),7.06(d,J＝8.4Hz,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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [1,2-b ] pyridazine (compound 24)

Compound 11-8(100mg, 0.34mmol) and 6-bromo-3-pyrazinamine (70.3mg, 0.404mmol) were weighed into a 15mL pressure-resistant reaction tube, then isopropanol (10mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 5 hours of reaction at 80 ℃, the reaction is continued for 3 hours at 120 ℃. After the reaction was completed, 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):¹H NMR(300MHz,DMSO-d₆)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 C₁₆H₁₁BrN₃O₃[M+H]⁺373.9958,found:373.9961.

example 25

2- (2, 3-dihydro- [1,4] dioxadieno [2,3-g ] benzofuran-8-yl) -6-methoxyimidazo [1,2-b ] pyridazine (Compound 25)

Weighing compound 24(313mg, 0.842mmol) and dissolving in dichloromethane (2mL) and methanol (12mL) to obtain a mixed solutionTo the reagent, a methanol solution of sodium methoxide (4M, 375. mu.L, 1.5mmol) was added, and the mixture was reacted at room temperature for 2 hours, followed by reflux for 2 hours. After completion of the reaction, saturated ammonium chloride (20mL) was added for quenching, ethyl acetate (15mL × 3) was extracted, the organic phases were combined, washed with saturated sodium chloride solution (10mL), 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 ═ 50:150:2-50:150:8) to give compound 25 (pale yellow solid, 120 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [1,2-b ] [1,2,4] triazine (compound 26)

Compound 11-8(100mg, 0.34mmol) and 1,2, 4-triazin-3-amine (48.5mg, 0.51mmol) were weighed into a 15mL pressure-resistant reaction tube, isopropanol (5mL) was then added, and the mixture solution was purged with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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 give compound 26 (orange solid, 40 mg).¹H NMR(300MHz,CDCl₃)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] dioxaoctatriene [2,3-g ] benzofuran-2-yl) imidazo [1,2-b ] pyridazine (Compound 27)

Compound 15-5(97mg, 0.299mmol) and 3-amino-6-methylpyridazine (49mg, 0.448mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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, 60 mg):¹H NMR(300MHz,CDCl₃)δ8.31(s,1H),7.82(d,J＝7.3Hz,1H),7.21(s,1H),7.13(d,J＝9.3Hz,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 C₁₉H₁₈N₃O₃[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)

Compound 19-3(81mg, 0.28mmol) and 3-amino-6-methylpyridazine (37mg, 0.336mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system is moved into an oil bath and reacted for 10 hours at the temperature of 80 ℃. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane/methanol 300:1-100:1) to give compound 28 (yellow solid, 18 mg).¹H NMR(300MHz,CDCl₃)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)

Compound 19-3(83mg, 0.287mmol) and 1,2, 4-triazin-3-amine (41mg, 0.43mmol) were weighed into a 15mL pressure-resistant reaction tube, then isopropanol (5mL) was added, and the mixture solution was purged with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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):¹H NMR(300MHz,DMSO-d₆)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] dioxadieno [2,3-g ] benzofuran-8-yl) -2-methoxyimidazo [1,2-b ] [1,2,4] thiadiazole (compound 30)

Compound 30-1(1.02g, 5.33mmol) was weighed out and dissolved in trifluoroacetic acid (7mL), and urotropin (1.5g, 10.66mmol) was added in portions. The system is reacted for 10 hours under the reflux condition. After the reaction was completed, the pH of the system was adjusted to 1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (15mL × 3), the organic phases were combined, washed with saturated brine (10mL × 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 ═ 100:1-80:1) to obtain compound 30-2 (yellow solid, 739 mg).

A solution of 30-2(350mg, 1.6mmol) in sodium hydroxide (83mg, 2.08mmol) in water (5mL) was weighed out. Then, a solution of hydrogen peroxide (190. mu.L, 6.18mmol) in water (5mL) was slowly added dropwise. The system is reacted for 2h under the condition of room temperature. After the reaction was completed, the pH of the system was adjusted to 1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (20mL × 2), the organic phases were combined, the organic phase was washed with saturated saline (10mL × 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 ═ 10:1-8:1) to obtain compound 30-3 (yellow solid, 258 mg).

30-3(250mg, 1.2mmol) was weighed out and dissolved in N, N-dimethylformamide (8mL), and 1, 2-dibromoethane (156. mu.L, 1.82mmol) and potassium carbonate (358mg, 2.66mmol) were added. The reaction system is carried out at 105 ℃ for 3h, after the reaction is finished, water (10mL) is added, ethyl acetate (10mL x3) is used for extracting an aqueous phase, organic phases are combined, the organic phase is washed by water (10mL x3) and saturated saline (10mL x1), anhydrous sodium sulfate is dried, a solvent is evaporated under reduced pressure, and a residue is purified by column chromatography (an eluent: petroleum ether/ethyl acetate ═ 100:1-80:1) to obtain a compound 30-4 (yellow solid, 225 mg).

Dissolving 30-4(3g, 12.88mmol) in anhydrous tetrahydrofuran (25mL) under the protection of argon, dropwise adding n-butyllithium (5.7mL, 14.16mmol) at 78 ℃, stirring at 78 ℃ for 30min, adding trimethyl borate (1.72mL, 15.5mmol), stirring at 78 ℃ for 60min, heating the solution containing 30-5 to 0 ℃, sequentially adding acetic acid (2.5mL, 14.2mmol) and 48% hydrogen peroxide solution (1.6mL, 51.5mmol), naturally heating for reaction overnight, adding water (10mL), extracting the aqueous phase with ethyl acetate (20mL x3), combining the organic phases, washing the organic phases with water (15mL x3) and saturated saline (10mL x1), drying over anhydrous sodium sulfate, evaporating the solvent under reduced pressure, purifying the residue by column chromatography (eluent: petroleum ether/ethyl acetate ═ 50:1-8:1), compound 30-6 (yellow solid, 1.58g) was obtained.

Under the protection of argon, anhydrous dichloromethane (30mL) and 1, 1-dichloromethyl ether (1.68mL,18.54mmol) are sequentially added, the temperature is reduced to 0 ℃, titanium tetrachloride (2.44mL,22.25mmol) is sequentially and slowly added dropwise, a solution of a compound 30-6(1.58g,9.27mmol) in anhydrous dichloromethane (10mL) is added dropwise, after the dropwise addition is completed, the stirring is continued for 1h while keeping the temperature constant, after the reaction is completed, 1N hydrochloric acid (10mL) is added for dilution, the solution is transferred to a separating funnel, dichloromethane (10mL x3) is used for extraction, organic phases are combined, the organic phases are washed by saturated saline solution (10mL x1), anhydrous sodium sulfate is dried, the solvent is evaporated under reduced pressure, and the residue containing the compound 30-7 is directly used for the next reaction without further purification.

The residue obtained from the post-treatment of the previous step containing compounds 30-7 was dissolved in acetone (40mL), potassium carbonate (1.92g,13.9mmol) was added, 1-chloropropanone (970 μ L,12.05mmol) was slowly added dropwise, after completion of the addition, the temperature was raised under reflux for 3 hours, after completion of the reaction, the reaction liquid was cooled to room temperature, insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane ═ 20:1:1-10:1:1) to give compounds 30-8 (white solid, 442 mg).

Weighing copper bromide (246mg,1.1mmol), placing the copper bromide in a 100mL three-necked bottle, adding ethyl acetate (20mL), dissolving the compound 30-8(200mg,0.85mmol) in ethyl acetate (20mL), dropwise adding the ethyl acetate solution of the compound 30-8 into the reaction system through a dropping funnel under the reflux condition, and continuing to reflux for 8 hours after the addition is finished. After the reaction was completed, the solid content in the system was filtered off by suction filtration, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane ═ 2:1) to obtain 30-9 (yellow solid, 156 mg).

Compound 30-9(90mg, 0.28mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (62mg, 0.34mmol) were weighed into a 35mL pressure-resistant reaction tube, then isopropanol (50mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred into a 100mL flask with methylene chloride, the solvent was distilled off under reduced pressure, and the residue containing compound 30-10 was used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the above step containing the compounds 30 to 10 was dissolved in a mixed solvent of dichloromethane (15mL) and methanol (5mL), followed by addition of a methanol solution of sodium methoxide (4M, 185. mu.L) and reaction at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (10mL), the aqueous phase (15mL × 3) was extracted with dichloromethane, the organic phases were combined, the organic phase was washed with a saturated saline solution (10mL × 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 ═ 8:1:1) to obtain compound 30 (white solid, 28 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) -2-methylsulfanyl imidazo [1,2-b ] [1,2,4] thiadiazole (compound 31)

Compound 30-9(90mg, 0.3mmol) and 5-methylthio-1, 3, 4-thiadiazol-2-amine (50mg, 0.343mmol) were weighed into a 15mL pressure-resistant reaction tube, then N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after reaction for 4 hours at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 110 ℃. After completion of the reaction, water (15mL) was added to dilute the reaction solution, and the reaction solution was extracted with ethyl acetate (10mL × 3), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 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 ═ 20:1:1-8:1:1), whereby compound 31 (orange-yellow solid, 70mg) was obtained:¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) -6-methylimidazo [1,2-b ] pyridazine (Compound 32)

Compound 30-9(90mg, 0.3mmol) and 3-amino-6-methylpyridazine (50mg, 0.343mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction is finished, the solvent is evaporated under reduced pressure, and the residue is purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate: 20:1:1-8:1:1) to obtain a compound 32 (orange)Yellow solid, 70 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [1,2-b ] [1,2,4] triazine (compound 33)

Compound 30-9(62mg, 0.197mmol) and 1,2, 4-triazin-3-amine (28mg, 0.295mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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] dioxadieno [2,3-g ] benzofuran-8-yl) -2-methoxyimidazo [2,1-b ] [1,3,4] thiadiazole (compound 34)

Compound 34-1(10g, 66mmol) was weighed out and dissolved in acetic acid (60mL), and N-chlorosuccinimide (8.8g, 66mmol) was added to react at 105 ℃ for 0.5 h. Then cooled to room temperature and stirred for 2.5 h. After the reaction was completed, the resulting slurry was poured into ice water (200mL), a large amount of yellow solid was immediately precipitated, the aqueous phase was extracted with ethyl acetate (40mL x3), the organic phases were combined, the organic phase was washed with saturated sodium chloride (40mL x3), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and recrystallized from ethanol (15mL) to give compound 34-2 (yellow solid, 6.6 g).

Compound 34-2(6.83g, 36.6mmol) was weighed out and dissolved in dichloromethane (40mL), boron tribromide (2M in DCM, 46mL) was added dropwise through a dropping funnel under ice bath conditions, and after addition, the reaction was allowed to warm to room temperature overnight. After the reaction was completed, the system was slowly poured into ice water (100mL), allowed to stand for separation, the organic phases were collected, the aqueous phase was extracted with ethyl acetate (40mL × 3), the organic phases were combined, the organic phase was washed with saturated sodium chloride (50mL × 2), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the residue containing compound 34-3 was used in the next reaction without further purification.

The residue containing compound 34-3 obtained in the previous reaction was dissolved in N, N-dimethylformamide (60mL), and potassium carbonate (22.5g, 163mmol) and 1, 2-dibromoethane (9.14mL, 106mmol) were added to react at 85 ℃ for 4 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (200mL), the organic phase was washed with water (100mL × 3) and saturated brine (100mL × 3), 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 ═ 20:1-6:1) to give compound 34-4 (yellow solid, 5.46 g).

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

The residue containing compound 34-5 from the previous reaction was dissolved in methanol (30mL), and 10% potassium hydroxide solution (140mL) was slowly added under ice-bath conditions, followed by reaction at room temperature for 3 h. After the reaction was completed, the pH of the system was adjusted to 1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (50mL x3), the organic phases were combined, the organic phase was washed with saturated sodium bicarbonate solution (50mL x3) and saturated brine (50mL 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 20:1-4:1:1) to obtain compound 34-6 (yellow oily substance, 3.7 g).

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

The residue containing compound 34-7 obtained in the previous reaction was dissolved in acetone (40mL), followed by the addition of potassium carbonate (4.3g, 31mmol), 1-chloropropanone (2mL, 25mmol) in that order. The system is reacted for 6h under reflux condition. After the reaction, ethyl acetate (40mL) was added to dilute the reaction solution, the solid content in the system was filtered off 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 ═ 10:1-4:1) to obtain compound 34-8 (yellow solid, 1.93 g).

Weighing copper bromide (2.21g, 9.9mmol), placing the copper bromide in a 250mL three-neck flask, adding ethyl acetate (20mL), dissolving compound 34-8(1.925g, 7.62mmol) in ethyl acetate (80mL), adding the ethyl acetate solution of compound 34-8 dropwise into the reaction system through a dropping funnel under the reflux condition, and continuing to reflux for 5h after the addition is finished. After the reaction, solid matters in the system were filtered off 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).

Compound 34-9(100mg, 0.3mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (65mg, 0.36mmol) were weighed into a 35mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred into a 100mL flask with methylene chloride, the solvent was distilled off under reduced pressure, and the residue containing compound 34-10 was used in the next reaction without further purification.

The crude compound 34-10 obtained in the previous step was dissolved in a mixed solvent of dichloromethane (9mL) and methanol (3mL), and then sodium methoxide solution in methanol (4M, 185. mu.L) was added to react at room temperature for 1 h. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (15mL), the aqueous phase (10mL × 3) was extracted with dichloromethane, the organic phases were combined, the organic phase was washed with a saturated saline solution (20mL × 1), dried over anhydrous sodium sulfate, 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):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) -2-methylsulfanyl imidazo [2,1-b ] [1,3,4] thiadiazole (compound 35)

Compound 34-9(100mg, 0.3mmol) and 5-methylthio-1, 3, 4-thiadiazol-2-amine (53mg, 0.362mmol) were weighed into a 35mL pressure-resistant reaction tube, and then anhydrous N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath and reacts for 4 hours at the temperature of 90 ℃, and then the reaction is continued for 3 hours at the temperature of 120 ℃. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 3), 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 ═ 15:1:1-10:1:1-8:1:1) to give compound 35 (yellow-white solid, 55 mg).¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) -6-methylimidazo [1,2-b ] pyridazine (Compound 36)

Compound 34-9(100mg, 0.3mmol) and 3-amino-6-methylpyridazine (40mg, 0.362mmol) were weighed into a 35mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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 give compound 36 (yellow-white solid, 70 mg).¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [1,2-b ] [1,2,4] triazine (Compound 37)

Compound 34-9(100mg, 0.3mmol) and 1,2, 4-triazin-3-amine (43.5mg, 0.452mmol) were weighed into a 35mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane/petroleum ether/ethyl acetate: 150:50:2-150:50:5-150:50:7) to obtain compound 37 (orange solid, 45 mg):¹H NMR(300MHz,DMSO-d₆)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[M-H]⁺.

example 38

6- (6-bromo-2, 3-dihydro- [1,4] dioxadieno [2,3-g ] benzofuran-8-yl) -2-methoxyimidazo [2,1-b ] [1,3,4] thiadiazole (compound 38)

Compound 34-1(30.1g, 198mmol) was weighed into acetic acid (450mL), sodium acetate (24.6g, 300mmol) was added, and a solution of liquid bromine (10.1mL) in acetic acid (30mL) was slowly added to the system via the addition funnel at room temperature with continued stirring for 1 h. After the reaction was completed, the resulting slurry was poured into ice water (1000mL) to precipitate a large amount of yellow solid immediately, suction filtration was performed, the filter cake was compacted, and the resulting filter cake was vacuum-dried overnight to obtain Compound 38-1 (yellow solid, 43 g).

Compound 38-1(5g, 21.6mmol) was weighed out and dissolved in dichloromethane (50mL), and boron tribromide (1M in DCM, 43.3mL) was added dropwise through a dropping funnel at-50 ℃ and after completion of addition, the reaction was carried out overnight at room temperature. After the reaction was completed, the system was slowly poured into ice water (100mL), allowed to stand for separation, the organic phases were collected, the aqueous phase was extracted with ethyl acetate (50mL × 3), the organic phases were combined, the organic phase was washed with saturated sodium chloride (50mL × 2), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the residue containing compound 38-2 was used in the next reaction without further purification.

The residue containing compound 38-2 obtained in the previous reaction was dissolved in N, N-dimethylformamide (50mL), and potassium carbonate (8.97g, 65mmol) and 1, 2-dibromoethane (2.83mL, 32.5mmol) were added to react at 85 ℃ for 4 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (200mL), the organic phase was washed with water (100mL × 3) and saturated brine (100mL × 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 20:1:1-8:1:1) to give compound 38-3 (yellow solid, 2.26 g).

Weighing the compound 38-3(3.5g, 14.4mmol) and dissolving in dichloromethane (30mL), adding m-chloroperoxybenzoic acid (3.52g, 17.3mmol, 85%) in batches under ice bath condition, removing the ice bath, transferring the system into an oil bath after returning the system to room temperature, reacting for 12h under reflux condition, decompressing and evaporating most of the solvent, wherein the residue containing the compound 38-4 is directly used for the next reaction without further treatment.

The residue containing compound 38-4 from the previous reaction was dissolved in methanol (10mL), and 10% potassium hydroxide solution (80mL) was slowly added under ice-bath conditions to react at room temperature for 6 h. After the reaction was completed, the pH of the system was adjusted to 1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (30mL x3), the organic phases were combined, the organic phase was washed with saturated sodium bicarbonate solution (20mL x3) 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), whereby compound 38-5 (yellow oily substance, 3.2g) was obtained.

Compound 38-5(3.2g, 13.9mmol) was dissolved in anhydrous dichloromethane under an argon atmosphere, dichloromethyl methyl ether (1.88mL, 20.8mmol) was added, a solution of titanium tetrachloride (3.04mL, 27.7mmol) in dichloromethane (4mL) was added dropwise at 0 ℃, and after the addition was completed, the mixture was stirred at room temperature for 48 hours. After completion of the reaction, the reaction was quenched by addition of 1N hydrochloric acid solution (10mL), the aqueous phase was extracted with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with saturated brine (10mL × 1), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue containing compound 38-6 was used in the next reaction without further purification.

The residue containing compound 38-6 obtained in the previous reaction was dissolved in acetone (20mL), followed by the addition of potassium carbonate (2g, 14.5mmol), 1-chloropropanone (553. mu.L, 6.95mmol) in that order. The system is reacted for 6h under reflux condition. After the reaction, ethyl acetate (30mL) was added to dilute the reaction solution, the solid content in the system was filtered off 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/dichloromethane: 20:1:1-8:1:1) to obtain compound 38-7 (yellow solid, 860 mg).

Copper bromide (335mg, 1.5mmol) was weighed into a 100mL three-necked flask, ethyl acetate (20mL) was added, compound 38-7(297mg, 1mmol) was dissolved in ethyl acetate (20mL), and the ethyl acetate solution of compound 38-7 was added dropwise to the reaction system through a dropping funnel under reflux conditions, and after the addition was completed, reflux was continued for 8 h. After the reaction, the solid in the system was filtered off 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).

Compound 38-8(150mg, 0.4mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (86mg, 0.48mmol) were weighed into a 15mL pressure-resistant reaction tube, then isopropanol (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred into a 100mL flask with methylene chloride, the solvent was distilled off under reduced pressure, and the residue containing compound 38-9 was used in the next reaction without further purification.

The crude compound 38-9 obtained in the previous step was dissolved in a mixed solvent of dichloromethane (6mL) and methanol (2mL), and then a methanol solution of sodium methoxide (4M, 100. mu.L) was added thereto, followed by reaction at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (10mL), the aqueous phase was extracted with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with a saturated saline solution (20mL × 1), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane ═ 12:1:1-9:1:1), and the resulting crude product (40mg) was recrystallized in a methanol/dichloromethane system to give compound 38 (white solid, 10 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) -2- (methylthio) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 39)

Compound 38-8(80mg, 0.213mmol) and 5-methylsulfanyl-1, 3, 4-thiadiazol-2-amine (35mg, 0.234mmol) were weighed into a 15mL pressure-resistant reaction tube, and then anhydrous N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. Will be provided withThe system is moved into an oil bath and reacts for 6 hours at the temperature of 80 ℃, and then the reaction is continued for 2 hours at the temperature of 110 ℃. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 2), 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 10:1-8:1) to give compound 39 (yellow solid, 50 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) -6-methylimidazo [1,2-b ] pyridazine (Compound 40)

Compound 38-8(100mg, 0.266mmol) and 3-amino-6-methylpyridazine (32mg, 0.293mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [1,2-b ] [1,2,4] triazine (Compound 41)

Compound 38-8(100mg, 0.266mmol) and 1,2, 4-triazin-3-amine (28mg, 0.293mmol) were weighed into a 15mL pressure-resistant reaction tube, and then addedIsopropanol (5mL) was added and the mixture solution was purged with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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, 52 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [1,2-b ] [1,2,4] thiadiazole (compound 42)

Compound 42-1(200mg, 0.83mmol) was weighed out and dissolved in trifluoroacetic acid (5ml), and urotropin (233mg, 1.66mmol) was added in portions. The system is reacted for 10 hours under the reflux condition. After the reaction was completed, the pH of the system was adjusted to 1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (15mL × 3), the organic phases were combined, the organic phase was washed with saturated saline (10mL × 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 ═ 50:1) to obtain compound 42-2 (white solid, 115 mg).

A solution of 42-2(3.74g, 13.9mmol) in sodium hydroxide (724mg, 18.1mmol) in water (30mL) was weighed out. Then, a solution of hydrogen peroxide (1.7mL, 55.6mmol) in water (10mL) was slowly added dropwise thereto, and the reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, the pH of the system was adjusted to 1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (20mL × 2), the organic phases were combined, the organic phase was washed with saturated saline (10mL × 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 50:1-5:1) to obtain compound 42-3 (colorless oil, 3.18 g).

42-3(2.43g, 9.46mmol) was weighed out and dissolved in N, N-dimethylformamide (20mL), and 1, 2-dibromoethane (1.22mL, 14.19mmol) and potassium carbonate (2.88g, 20.81mmol) were added. The reaction system is carried out at 100 ℃ for 3h, after the reaction is finished, water (50mL) is added, ethyl acetate (20mL x3) is used for extracting an aqueous phase, organic phases are combined, the organic phase is washed by water (15mL x3) and saturated saline (15mL x1), anhydrous sodium sulfate is dried, a solvent is evaporated under reduced pressure, and a residue is purified by column chromatography (an eluent: petroleum ether/ethyl acetate 150:1-100:1) to obtain a compound 42-4 (white solid, 1.87 g).

Under the protection of argon, dissolving 42-4(1.5g,5.3mmol) in anhydrous tetrahydrofuran (15mL), dropwise adding n-butyllithium (2.33mL,5.83mmol) at 78 ℃, stirring at 78 ℃ for 30min, adding trimethyl borate (0.71mL,6.36mmol), stirring at 78 ℃ for 60min, heating the solution containing the compound 42-5 to 0 ℃, sequentially adding acetic acid (1mL,5.83mmol) and hydrogen peroxide solution (0.715mL,23.32mmol), naturally heating for reaction overnight, adding water (10mL), extracting the aqueous phase with ethyl acetate (20mL x3), combining the organic phases, washing the organic phases with water (15mL x3) and saturated saline (10mL x1), drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, purifying the residue by column chromatography (eluent: petroleum ether/ethyl acetate ═ 20:1-5:1), compound 42-6 (brown oil, 888mg) was obtained.

Compound 42-6(99mg, 0.45mmol) was weighed out and dissolved in trifluoroacetic acid (5mL), and urotropin (126mg, 0.9mmol) was added in portions. The system is reacted for 4h under reflux. After the reaction was completed, the pH of the system was adjusted to 1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (8mL × 3), the organic phases were combined, the organic phase was washed with saturated saline (5mL × 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) to obtain compound 42-7 (white solid, 61 mg).

Compound 42-7(60mg, 0.24mmol) was weighed, dissolved in acetone (8mL), potassium carbonate (45mg,0.323mmol) was added, 1-chloropropanone (30 μ L,0.363mmol) was slowly added dropwise, after completion of the dropwise addition, reflux was raised at elevated temperature for 4 hours, after completion of the reaction, the reaction liquid was cooled to room temperature, insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate ═ 10:1-8:1) to give compound 42-8 (white solid, 54 mg).

Copper bromide (69mg,0.308mmol) was weighed into a 50mL three-necked flask, ethyl acetate (8mL) was added, compound 42-8(44mg,0.154mmol) was dissolved in ethyl acetate (5mL), and the ethyl acetate solution of compound 42-8 was added dropwise to the reaction system through a dropping funnel under reflux conditions, and after the addition was completed, reflux was continued for 8 h. After the reaction was completed, the solid content in the system was filtered off by suction filtration, the solvent was distilled off 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).

Compound 42-9(95mg, 0.26mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (56mg, 0.31mmol) were weighed into a 35mL pressure-resistant reaction tube, then isopropanol (6mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred with methylene chloride into a 50mL flask, and the solvent was distilled off under reduced pressure, and the residue containing compound 42-10 was used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the above step containing the compound 42-10 was dissolved in a mixed solvent of dichloromethane (15mL) and methanol (5mL), followed by addition of a methanol solution of sodium methoxide (4M, 170. mu.L) and reaction at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (10mL), the aqueous phase was extracted with dichloromethane (15mL × 3), the organic phases were combined, the organic phase was washed with a saturated saline solution (10mL × 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 ═ 7:1:1) to obtain compound 42 (yellow solid, 25 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [1,2-b ] [1,2,4] thiadiazole (compound 43)

Compound 42-9(100mg, 0.274mmol) and 5-methylsulfanyl-1, 3, 4-thiadiazol-2-amine (48mg, 0.33mmol) were weighed into a 15mL pressure-resistant reaction tube, and then anhydrous N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at 80 ℃, the reaction is continued for 2 hours at 120 ℃. After completion of the reaction, water (15mL) was added to dilute the reaction solution, and the reaction solution was extracted with ethyl acetate (10mL × 3), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 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 15:1:1-12:1:1), whereby compound 43 (yellow solid, 83mg) was obtained:¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [1,2-b ] pyridazine (Compound 44)

Compound 42-9(70mg, 0.2mmol) and 3-amino-6-methylpyridazine (22mg, 0.2mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [1,2-b ] [1,2,4] triazine (Compound 45)

Compound 42-9(95mg, 0.26mmol) and 1,2, 4-triazin-3-amine (37mg, 0.39mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (6mL) and purging of the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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, 25 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl-6-d) -2- (methylthio) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 46)

Weighing the compound 38-3(5.66g, 23.27mmol), pinacol diboron ester (11.82g, 46.54mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (1.9g, 2.33mmol) and potassium acetate (6.85g, 69.8mmol) in a 300mL pressure-resistant reaction tube, adding anhydrous 1, 4-dioxane (80mL), bubbling and purging with argon for 5min, reacting the system at 100 ℃ for 5h, adding ethyl acetate (100mL) to dilute the reaction solution, filtering off solids, evaporating the solvent under reduced pressure, and purifying the residue by column chromatography (eluent: petroleum ether/ethyl acetate 20:1-10:1) to obtain the compound 46-1 (yellow solid, 6.2 g).

Compound 46-1(290mg, 1mmol) was weighed out and dissolved in a mixed solvent of deuterated methanol (3mL) and heavy water (3mL), then triethylamine (138. mu.L, 1mmol) and silver nitrate (170mg, 1mmol) were added in this order, and the mixture was refluxed at 80 ℃ for 2 hours. After the reaction was completed, the system was cooled to room temperature, and suction filtration was performed through celite, the filtrate was collected, ethyl acetate (20mL) was added to dilute the filtrate, the organic phase was washed with saturated sodium chloride (5mL × 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, 85 mg).

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

To the residue containing compound 46-3 obtained in the previous reaction, 10% potassium hydroxide solution (30mL) was slowly added under ice-bath conditions, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the pH of the system was adjusted to 1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (50mL × 3), the organic phases were combined, the organic phase was washed with saturated sodium bicarbonate solution (20mL × 4) and saturated brine (20mL × 2), 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/═ 10:1-5:1) to obtain compound 46-4 (yellow oily substance, 1.72 g).

Paraformaldehyde (785.5mg, 26.18mmol) and anhydrous magnesium chloride (1660mg, 17.34mmol) were weighed into a 50mL two-necked flask, a condenser tube was inserted, the apparatus was anaerobically treated with an argon exchange for the air in the system, and then anhydrous tetrahydrofuran (20mL) was added via syringe. The system was transferred to an oil bath, triethylamine (2.42mL, 17.34mmol) was added slowly under weak reflux at 70 ℃ and a solution of compound 46-4(1.33g, 8.67mmol) in anhydrous tetrahydrofuran (20mL) was added and the reaction was maintained at 70 ℃ for 5h after the addition. After the reaction was completed, the system was cooled to room temperature, a 1N hydrochloric acid solution (20mL) was added, the mixture was stirred for 10min, ethyl acetate (20mL × 3) was extracted, the organic phases were combined, washed with a saturated saline solution (20mL × 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 ═ 20:1-16:1) to obtain compound 46-5 (pale yellow oily substance, 655 mg).

Compound 46-5(655mg, 3.62mmol) was weighed, dissolved in acetone (20mL), potassium carbonate (750mg,5.43mmol) was added, 1-chloropropanone (350 μ L,4.34mmol) was slowly added dropwise, after completion of the dropwise addition, heating under reflux for 3 hours, after completion of the reaction, the reaction liquid was cooled to room temperature, insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane ═ 20:1:1-10:1:1), yielding compound 46-6 (white solid, 470 mg).

Compound 46-6(227mg, 0.74mmol) was weighed out and dissolved in a 50mL two-necked flask, the apparatus was anaerobically treated by exchanging the air in the system with argon, and then anhydrous dichloromethane (7mL) was added via syringe. Under ice-bath conditions, a solution of N, N-diisopropylethylamine (370. mu.L, 2.22mmol) in anhydrous dichloromethane (2mL) was added slowly and the system was allowed to react for 0.5h under ice-bath conditions. A solution of triisopropylsilyl triflate (300. mu.L, 1.11mmol) in anhydrous dichloromethane (2mL) was then added dropwise under ice-bath conditions. After the addition, the mixture was warmed to room temperature and stirred overnight. After the reaction was complete, the system was quenched with saturated sodium bicarbonate solution (15mL), the aqueous phase was extracted with dichloromethane (10mL x3), the organic phases were combined, the organic phase was washed with saturated sodium bicarbonate solution (10mL x1) and saturated brine (10mL x1), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue containing compound 46-7 was used in the next reaction without further purification.

The apparatus was anaerobically treated in a 50mL two-necked flask with air in an argon exchange system, and then a solution of anhydrous tetrahydrofuran (7mL) containing the residue of the compound 46-7 obtained after the last reaction was added via syringe, and a solution of N-bromosuccinimide (145mg, 0.81mmol) in anhydrous tetrahydrofuran (2mL) was added dropwise under ice-bath conditions. After the addition, the temperature is raised to room temperature and the mixture is stirred for 3 hours. After completion of 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 give compound 46-8 (yellow oily liquid, 230 mg).

Weighing the compound 46-8(90mg, 0.3mmol) and 5-methylthio-1, 3, 4-thiadiazole-2-amine (50mg, 0.343mmol) and placing in a 15mL pressure-resistant reactionTo the tube, N-dimethylformamide (5mL) was then added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after reaction for 4 hours at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 120 ℃. After completion of the reaction, the reaction mixture was diluted with water (15mL), extracted with ethyl acetate (10mL × 3), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 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 ═ 20:1:1-8:1:1), whereby compound 46 (white solid, 38mg) was obtained.¹H NMR(300MHz,DMSO-d₆)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 C₁₅H₁₁DN₃O₃S₂[M+H]⁺347.0377,found:347.0375.

Example 47

6- (2, 3-dihydro- [1,4] dioxadieno [2,3-g ] benzofuran-8-yl-6-d) -2- (methoxy) imidazo [2,1-b ] [1,3,4] thiadiazole (Compound 47)

Compound 46(50mg, 0.145mmol) was weighed out and dissolved in tetrahydrofuran (5mL), m-chloroperoxybenzoic acid (85% purity, 147mg, 0.723mmol) was slowly added at room temperature, and after the addition was completed, the reaction was maintained at room temperature for 6 hours. After completion of the reaction, the reaction system was diluted with dichloromethane (20mL), the organic phase was washed with saturated sodium bicarbonate (5 mL. times.3) and saturated brine (5mL), dried over anhydrous sodium sulfate, and the organic phase was evaporated under reduced pressure, and the residue containing compound 47-1 was directly subjected to the next reaction without further purification.

The crude compound 47-1 obtained in the previous step was dissolved in a mixed solvent of dichloromethane (3mL) and methanol (1mL), and a methanol solution of sodium methoxide (4M, 55. mu.L) was added thereto at room temperature to react at room temperature for 1 hour. After completion of the reaction, the reaction was quenched with a saturated ammonium chloride solution (5mL), the aqueous phase (5mL × 3) was extracted with ethyl acetate, the organic phases were combined, the organic phase was washed with a saturated saline solution (5mL), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (washing with column chromatography)Removing the agent: petroleum ether/dichloromethane/ethyl acetate 50:150:1-50:150:6) to give compound 47 (yellow solid, 8 mg):¹H NMR(300MHz,DMSO-d₆)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.for C₁₅H₁₁DN₃O₄S[M+H]⁺347.0606,found:331.0608.

example 48

6- (6- (benzyloxy) -2, 3-dihydro- [1,4] dioxadieno [2,3-g ] benzofuran-8-yl) -2-bromoimidazo [2,1-b ] [1,3,4] thiadiazole (compound 48)

Compound 46-1(6.2g, 21.37mmol) was weighed out and dissolved in dioxane (120mL), 50% aqueous N-methyl-N-morpholine oxide (5.3mL) was added, and after reaction at 80 ℃ for 6h, 50% aqueous N-methyl-N-morpholine oxide (530. mu.L) was added again and reaction continued at 80 ℃ for 2 h. After the reaction was completed, a 1N hydrochloric acid solution was added to acidify the system to pH 1, ethyl acetate (50mL × 3) was extracted, the organic phases were combined, washed with saturated brine (20mL × 2), 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 20:1-10:1) to give compound 48-1 (pale yellow solid, 3.45 g).

Compound 48-1(3.43g, 19.04mmol) was weighed out and dissolved in N, N-dimethylformamide (70mL), and potassium carbonate (3.42g, 24.75mmol) and benzyl bromide (2.94mL, 24.75mmol) were added and the system was stirred at room temperature for 7 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (200mL), the organic phase was washed with water (50mL × 3) and saturated brine (50mL × 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 ═ 20:1-8:1) to give compound 48-2 (pale yellow solid, 4.49 g).

Weighing compound 48-2(4.49g, 16.62mmol) and dissolving in dichloromethane (100mL), adding m-chloroperoxybenzoic acid (4.05g, 19.94mmol, 85%) in batches under ice bath condition, removing the ice bath, transferring the system into an oil bath after returning the system to room temperature, reacting for 12h under reflux condition, decompressing and evaporating most of solvent, and using the residue containing compound 48-3 for next reaction without further treatment.

The residue containing compound 48-3 from the previous reaction was dissolved in methanol (5mL), and 10% potassium hydroxide solution (10mL) was slowly added under ice-bath conditions, followed by reaction at room temperature for 6 h. After the reaction was completed, the pH of the system was adjusted to 1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (50mL × 3), the organic phases were combined, the organic phase was washed with saturated sodium bicarbonate solution (50mL × 2) and saturated brine (50mL × 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 ═ 20:1-15:1) to obtain compound 48-4 (yellow oily substance, 1.82 g).

Paraformaldehyde (2.39g, 79.77mmol) and anhydrous magnesium chloride (5.06g, 53.18mmol) were weighed into a 250mL two-necked flask, a condenser tube was inserted, and the apparatus was anaerobically treated by exchanging air in the system with argon. Then, a solution of anhydrous tetrahydrofuran (100mL), triethylamine (7.39mL, 53.18mmol), compound 48-4(4.9g, 26.59mmol) in anhydrous tetrahydrofuran (10mL) was added sequentially via syringe. The system is reacted for 6h under reflux condition. After the reaction was completed, the pH of the system was adjusted to 1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (50mL × 3), the organic phases were combined, the organic phase was washed with saturated brine (50mL × 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 ═ 10:1-3:1) to obtain compound 48-5 (yellow solid, 4.03 g).

Compound 48-5(4.43g, 15.47mmol) was weighed out and dissolved in acetone (50mL), followed by the addition of potassium carbonate (5.34g, 38.7mmol), 1-chloropropanone (1.48mL, 18.6mmol) in that order. The system is reacted for 6h under reflux condition. After the reaction, ethyl acetate (100mL) was added to dilute the reaction solution, the solid content in the system was filtered off by suction filtration, the filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate 9:1-4:1) to obtain compound 48-6 (yellow solid, 4.52 g).

Copper bromide (4.67g, 20.9mmol) is weighed into a 250mL three-necked flask, ethyl acetate (80mL) is added, compound 48-6(4.52g, 13.94mmol) is dissolved in ethyl acetate (100mL), and the ethyl acetate solution of compound 48-6 is added dropwise into the reaction system through a dropping funnel under reflux conditions, and after the addition is finished, the reflux is continued for 8 h. After the reaction, the solid content in the system was filtered off 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).

Compound 48-7(1008mg, 2.5mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (540mg, 3mmol) were weighed into a 300mL pressure-resistant reaction tube, then isopropanol (50mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After the reaction was completed, the reaction system was transferred into a 250mL flask with dichloromethane, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane ═ 10:1-1:3) to give compound 48 (yellow solid, 700 mg).¹H NMR(300MHz,CDCl₃)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.For C₂₁H₁₅BrN₃O₄S[M+H]⁺485.9941,found:485.9931.

Example 49

6- (6- (benzyloxy) -2, 3-dihydro- [1,4] dioxadieno [2,3-g ] benzofuran-8-yl) -2-methoxyimidazo [2,1-b ] [1,3,4] thiadiazole (compound 49)

Compound 48(80mg, 0.165mmol) was weighed out and dissolved in a mixed solvent of dichloromethane (6mL) and methanol (2mL), and then a solution of sodium methoxide in methanol (4M, 45. mu.L) was added thereto and reacted at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (10mL), the aqueous phase (10 mL. times.3) was extracted with ethyl acetate, the organic phases were combined, the organic phase was washed with a saturated saline solution (20 mL. times.1), 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)After purification of alkane-10: 1:1-7:1:1), compound 49 (white solid, 36mg) was obtained:¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) -2- (methylthio) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 50)

Compound 48-7(201mg, 0.5mmol) and 5-methylsulfanyl-1, 3, 4-thiadiazol-2-amine (81mg, 0.55mmol) were weighed into a 15mL pressure-resistant reaction tube, then N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 2 hours at the temperature of 110 ℃. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane/ethyl acetate 100:1) to give compound 50 (brown solid, 159 mg):¹H NMR(300MHz,CDCl₃)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/z 474.1[M+Na]⁺.

example 51

2- (6- (benzyloxy) -2, 3-dihydro- [1,4] dioxadieno [2,3-g ] benzofuran-8-yl) -6-methylimidazo [1,2-b ] pyridazine (Compound 51)

Compound 48-7(35mg, 0.087mmol) and 3-amino-6-methylpyridazine (10mg, 0.09mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (8mL) and purging of the mixture solution with argon for 5 min. Will be provided withThe system is moved into an oil bath and reacted for 12 hours at the temperature of 65 ℃. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate 10:1-4:1) to give compound 51 (yellow solid, 9 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [1,2-b ] [1,2,4] triazine (compound 52)

Compound 48-7(101mg, 0.25mmol) and 1,2, 4-triazin-3-amine (36mg, 0.36mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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):¹H NMR(300MHz,DMSO-d₆)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] dioxadieno [2,3-g ] benzofuran-8-yl) -2-methoxyimidazo [2,1-b ] [1,3,4] thiadiazole (compound 53)

Compound 48(80mg, 0.165mmol) was weighed out and dissolved in a mixed solvent of dichloromethane (6mL) and methanol (2mL), and then a solution of sodium methoxide in methanol (4M, 45. mu.L) was added thereto and reacted at room temperature for 1 hour. The reaction is finishedThen, the reaction was quenched with a saturated ammonium chloride solution (10mL), the aqueous phase was extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with a saturated saline solution (20mL × 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 ═ 10:1:1-7:1:1), whereby compound 53 (white solid, 36mg) was obtained:¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-6-ol (Compound 54)

Compound 49(204mg, 0.468mmol) and pentamethylbenzene (485mg, 3.276mmol) were dissolved in anhydrous tetrahydrofuran (10mL) under an argon atmosphere, the system was placed at-78 deg.C, boron trichloride (1M in DCM, 1.17mL, 1.17mmol) was added dropwise, and after the addition was completed, the reaction was continued at-78 deg.C for 1.5 h. After completion of the reaction, the reaction was quenched by addition of sodium bicarbonate solution (0.7M in DCM, 10mL) at-78 ℃, warmed to room temperature, stirred for an additional 1h, filtered, the filter cake washed with toluene (5mL) and dried under vacuum to give compound 54 (white solid, 130 mg):¹H NMR(300MHz,DMSO-d₆)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-methoxyimidazo [2,1-b ] [1,3,4] thiadiazole (compound 55)

Weighing the compounds 38-3(486mg, 2mmol), cyclopropylboronic acid (224mg, 2.6mmol), anhydrous potassium phosphate (1484mg, 7mmol), tricyclohexylphosphine (224mg, 0.8mmol) and palladium acetate (90mg, 0.4mmol), placing the mixture in a 15mL pressure-resistant reaction tube, adding toluene (10mL) and water (0.5mL), bubbling and purging with argon for 5min, sealing, and reacting the system at 85 ℃ for 4 h. After the reaction was completed, ethyl acetate (50mL) was added to dilute the reaction system, suction filtration was performed, the solid was filtered off, extraction was performed with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with saturated saline (10mL × 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 15:1:1) to obtain compound 55-1 (yellow solid, 337 mg).

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

The residue containing compound 55-2 from the previous reaction was dissolved in methanol (5mL), and 10% potassium hydroxide solution (20mL) was slowly added under ice bath conditions to react at room temperature for 6 h. After the reaction was completed, the pH of the system was adjusted to 1 with 1N hydrochloric acid solution, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with saturated sodium bicarbonate solution (10mL × 2) and saturated brine (10mL × 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), whereby compound 55-3 (yellow oily substance, 125mg) was obtained.

Compound 55-3(125mg, 0.65mmol) was dissolved in anhydrous dichloromethane under an argon atmosphere, dichloromethyl methyl ether (88. mu.L, 0.98mmol) was added, and a solution of titanium tetrachloride (143. mu.L, 1.3mmol) in dichloromethane (4mL) was added dropwise at 0 ℃ and, after completion of addition, stirred at room temperature for 48 hours. After completion of the reaction, the reaction was quenched by addition of 1N hydrochloric acid solution (10mL), the aqueous phase was extracted with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with saturated brine (10mL × 1), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue containing compound 55-4 was used in the next reaction without further purification.

The residue containing compound 55-4 obtained in the previous reaction was dissolved in acetone (20mL), followed by the addition of potassium carbonate (226mg, 1.64mmol), 1-chloropropanone (85. mu.L, 1.06mmol) in that order. The system is reacted for 6h under reflux condition. After the reaction, ethyl acetate (30mL) was added to dilute the reaction solution, the solid content in the system was filtered off 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/dichloromethane: 20:1:1-10:1:1) to obtain compound 55-5 (pale green solid, 55 mg).

Copper bromide (1082mg, 4.85mmol) is weighed into a 100mL three-necked flask, ethyl acetate (20mL) is added, the compound 55-5(500mg, 1.94mmol) is dissolved in ethyl acetate (20mL), an ethyl acetate solution of the compound 55-5 is added dropwise into the reaction system through a dropping funnel under the reflux condition, and after the addition is finished, the reflux is continued for 8 h. After the reaction, the solid in the system was filtered off 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 give compound 55-6 (yellow solid, 320 mg).

Compound 55-6(92.5mg, 0.274mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (59.4mg, 0.33mmol) were weighed into a 15mL pressure-resistant reaction tube, then isopropanol (5mL) was added and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred into a 100mL flask with methylene chloride, the solvent was distilled off under reduced pressure, and the residue containing compound 55-7 was used in the next reaction without further purification.

The crude compound 55-7 obtained in the previous step was dissolved in a mixed solvent of dichloromethane (15mL) and methanol (5mL), and then sodium methoxide solution in methanol (4M, 163. mu.L) was added to react at room temperature for 1 h. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (10mL), extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with a saturated saline solution (20mL × 1), 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: 1-1)0:1:1) to give compound 55 (yellow solid, 15 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) -2- (methylthio) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 56)

Compound 55-6(75mg, 0.222mmol) and 5-methylsulfanyl-1, 3, 4-thiadiazol-2-amine (40mg, 0.267mmol) were weighed into a 15mL pressure-resistant reaction tube, then N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 2 hours at the temperature of 110 ℃. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 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 15:1:1-10:1:1) to give compound 56 (yellow solid, 80 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) -6-methylimidazo [1,2-b ] pyridazine (Compound 57)

Compound 55-6(75mg, 0.222mmol) and 3-amino-6-methylpyridazine (30mg, 0.267mmol) were weighed into a 15mL pressure-resistant reaction tube, and then isopropyl alcohol was addedAlcohol (5mL), purge the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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):¹H NMR(300MHz,CDCl₃)δ8.27(s,1H),7.80(d,J＝9.3Hz,1H),7.40(s,1H),6.92(d,J＝9.3Hz,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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [1,2-b ] [1,2,4] triazine (Compound 58)

Compound 55-6(80mg, 0.24mmol) and 1,2, 4-triazin-3-amine (34mg, 0.353mmol) were weighed into a 15mL pressure-resistant reaction tube, then isopropanol (5mL) was added, and the mixture solution was purged with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) -2-methoxyimidazo [2,1-b ] [1,3,4] thiadiazole (compound 59)

Weighing the compounds 38-7(1g, 3.4mmol), cyclohexene-1-yl boric acid (933mg, 7.4mmol), palladium acetate (378mg, 1.7mmol), triphenylphosphine (883mg, 3.4mmol) and potassium carbonate (2.8g, 20.2mmol), placing in a 125mL thick-wall pressure-resistant bottle, adding toluene (30mL) and water (3.3mL), purging with argon for 5min, sealing, and placing at 90 ℃ for reaction for 8 h. After the reaction, ethyl acetate (50mL) was added to dilute the reaction system, followed by suction filtration, solid matters in the system were filtered off, and ethyl acetate (30mL × 2) was extracted, followed by washing with saturated saline (20mL × 1), drying over anhydrous sodium sulfate, evaporation under reduced pressure to remove the solvent, 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(577mg, 2mmol) was weighed into a 100mL two-necked flask, the apparatus was anaerobically treated by exchanging the air in the system with argon, and then anhydrous dichloromethane (20mL) was added via syringe. Under ice-bath conditions, a solution of N, N-diisopropylethylamine (748mg, 5.8mmol) in anhydrous dichloromethane (5mL) was added slowly and the system was allowed to react for 0.5h under ice-bath conditions. Then a solution of triisopropylsilyltrifluoromethanesulfonate (888mg, 3mmol) in dry dichloromethane (5mL) was added dropwise under ice-bath conditions. After the addition, the mixture was warmed to room temperature and stirred overnight. After the reaction was complete, the system was quenched with saturated sodium bicarbonate solution (30mL), the aqueous phase was extracted with dichloromethane (15mL x3), the organic phases were combined, washed with saturated sodium bicarbonate solution (20mL x1) and saturated brine (20mL x1), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue containing compound 59-2 was used in the next reaction without further purification.

The apparatus was anaerobically treated in a 100mL two-necked flask with air in an argon exchange system, and then an anhydrous tetrahydrofuran (25mL) solution containing the residue of the compound 59-2 obtained by the post-treatment of the previous reaction was added via syringe, and an anhydrous tetrahydrofuran (10mL) solution of N-bromosuccinimide (534mg, 3mmol) was added dropwise under ice-bath conditions. After the addition, the temperature is raised to room temperature and the mixture is stirred for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane ═ 2:1-1:1) to give compound 59-3 (yellow solid, 250 mg).

Compound 59-3(123mg, 0.33mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (71mg, 0.39mmol) were weighed into a 35mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred into a 100mL flask with methylene chloride, the solvent was distilled off under reduced pressure, and the residue containing compound 59-4 was used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the above step containing the compound 59-4 was dissolved in a mixed solvent of dichloromethane (12mL) and methanol (4mL), followed by addition of a methanol solution (4M, 200. mu.L) of sodium methoxide and reaction at room temperature for 1 hour. After completion of the reaction, the reaction was quenched with a saturated ammonium chloride solution (10mL), the aqueous phase was extracted with dichloromethane (10mL × 3), the organic phases were combined, washed with a saturated saline solution (20mL × 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: 30:1:1-15:1:1) to obtain compound 59 (white solid, 20 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) -2-methylsulfanylimidazo [2,1-b ] [1,3,4] thiadiazole (compound 60)

Compound 59-3(120mg, 0.32mmol) and 5-methylsulfanyl-1, 3, 4-thiadiazol-2-amine (56mg, 0.38mmol) were weighed into a 35mL pressure-resistant reaction tube, and then anhydrous N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath and reacts for 4 hours at the temperature of 90 ℃, and then the reaction is continued for 3 hours at the temperature of 120 ℃. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), and the organic phase was washed with water (10 mL. times.3) and saturated brine (10 mL. times.2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressureThe residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate 10:1:1-8:1:1) to give compound 60 (white solid, 30 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) -6-methylimidazo [1,2-b ] pyridazine (Compound 61)

Compound 59-3(30mg, 0.08mmol) and 3-amino-6-methylpyridazine (11mg, 0.095mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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 61 (yellow solid, 12mg):¹H NMR(300MHz,CDCl₃)δ8.31(s,1H),7.83(d,J＝9.3Hz,1H),7.45(s,1H),6.95(d,J＝9.3Hz,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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [1,2-b ] [1,2,4] triazine (compound 62)

Compound 41(25mg, 0.07mmol), cyclohexen-1-ylboronic acid (20mg, 0.15mmol), palladium acetate (8mg, 0.03mmol), triphenylphosphine (18mg,0.07 mmol) and potassium carbonate (56mg, 0.40mmol) were weighed out and placed in a containerA15 mL thick-walled pressure bottle was charged with toluene (3mL) and water (300. mu.L), purged with argon for 5min, sealed, and allowed to react at 90 ℃ for 8 h. After completion of the reaction, ethyl acetate (20mL) was added to dilute the reaction system, the solid content in the system was removed by suction filtration, extracted with ethyl acetate (10mL × 2), washed with saturated saline (10mL × 1), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate: 50:150:1-50:150:5) to give compound 62 (orange-yellow solid, 15 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [1,2-b ] pyridazine (Compound 63)

Weighing the compound 40(66mg, 0.2mmol), phenylboronic acid (46mg, 0.4mmol), palladium acetate (20mg, 0.1mmol), triphenylphosphine (45mg, 0.2mmol) and potassium carbonate (142mg, 1.0mmol), placing in a 35mL thick-wall pressure-resistant bottle, adding toluene (5mL) and water (555 mu L), purging with argon for 5min, sealing, and placing at 90 ℃ for reacting for 8 h. After completion of the reaction, ethyl acetate (20mL) was added to dilute the reaction system, the solid content in the system was removed by suction filtration, extracted with ethyl acetate (10mL × 2), washed with saturated brine (10mL × 1), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate 20:1:1-5:1:1) to give compound 63 (yellow solid, 50 mg).¹H NMR(300MHz,DMSO-d₆)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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 64)

Weighing the compounds 38-7(267mg, 0.9mmol), 4-methylphenylboronic acid (269mg, 2.0mmol), palladium acetate (100mg, 0.45mmol), triphenylphosphine (236mg, 0.9mmol) and potassium carbonate (745mg, 5.4mmol), placing in a 35mL thick-wall pressure-resistant bottle, adding toluene (5mL) and water (555 μ L), purging with argon for 5min, sealing, and placing at 90 ℃ for reaction for 8 h. After the reaction, ethyl acetate (20mL) was added to dilute the reaction system, followed by suction filtration, solid matters in the system were filtered off, and extracted with ethyl acetate (10mL × 2), washed with saturated saline (10mL × 1), 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 20:1-10:1) to obtain compound 64-1 (yellow-green solid, 203 mg).

Copper bromide (191mg, 0.86mmol) was weighed into a 100mL three-necked flask, ethyl acetate (15mL) was added, compound 64-1(203mg, 0.66mmol) was dissolved in ethyl acetate (30mL), and the ethyl acetate solution of compound 64-1 was added dropwise to the reaction system through a dropping funnel under reflux conditions, and after the addition was completed, reflux was continued for 8 h. After the reaction, the solid content in the system was filtered off by suction filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane ═ 4:1-3:1-2:1-1:1) to give compound 64-2 (yellow-white solid, 187 mg).

Compound 64-2(92.5mg, 0.239mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (52mg, 0.287mmol) were weighed into a 15mL pressure-resistant reaction tube, then isopropanol (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred with methylene chloride into a 100mL flask, and the solvent was distilled off under reduced pressure, whereby the residue containing compound 64-3 was used in the next reaction without further purification.

The compound 64-3 is obtained by the last reaction post-treatmentThe residue was dissolved in a mixed solvent of dichloromethane (15mL) and methanol (5mL), followed by addition of a methanol solution of sodium methoxide (4M, 155. mu.L) and reaction at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (10mL), the aqueous phase was extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with a saturated saline solution (20mL × 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 ═ 20:1:1-15:1:1-10:1:1-8:1:1) to obtain compound 64 (yellow solid, 40 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 65)

Compound 64-2(72mg, 0.2mmol) and 5-methylsulfanyl-1, 3, 4-thiadiazol-2-amine (35mg, 0.24mmol) were weighed into a 15mL pressure-resistant reaction tube, and then anhydrous N, N-dimethylformamide (3mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath and reacts for 4 hours at the temperature of 90 ℃, and then the reaction is continued for 3 hours at the temperature of 120 ℃. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 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 20:1:1-10:1:1-8:1:1) to obtain compound 65 (yellow solid, 54 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [1,2-b ] pyridazine (Compound 66)

Weighing the compound 40(70mg, 0.2mmol), 4-methylphenylboronic acid (55mg, 0.4mmol), palladium acetate (21mg, 0.1mmol), triphenylphosphine (48mg, 0.2mmol) and potassium carbonate (151mg, 1.1mmol), placing in a 35mL thick-wall pressure-resistant bottle, adding toluene (5mL) and water (555 mu L), purging with argon for 5min, sealing, and placing at 90 ℃ for reaction for 8 h. After completion of the reaction, ethyl acetate (20mL) was added to dilute the reaction system, suction filtration was performed, the solid content in the system was filtered, extraction was performed with ethyl acetate (10mL × 2), washing was performed with saturated saline (10mL × 1), drying was performed with 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), whereby compound 66 (yellow solid, 40mg) was obtained:¹H NMR(300MHz,DMSO-d₆)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 C₂₄H₁₉N₃O₃[M+Na]⁺420.1319,found:420.1319.

example 67

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

Weighing the compound 41(80mg, 0.214mmol), 4-methylbenzeneboronic acid (64mg, 0.471mmol), palladium acetate (24mg, 0.107mmol), triphenylphosphine (56mg, 0.214mmol) and potassium carbonate (177mg, 1.284mmol), placing in a 15mL thick-walled pressure-resistant bottle, adding toluene (3mL) and water (300 mu L), purging with argon for 5min, sealing, and placing at 100 ℃ for reacting for 8 h. After the reaction is finished, adding ethyl acetate (20mL) to dilute the reaction system, filtering by suction, filtering solid matters in the system, extracting by using ethyl acetate (10mL x2),saturated brine (10mL × 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: 20:50:1-6:20:1) to give compound 67 (orange solid, 67 mg):¹H NMR(300MHz,DMSO-d₆)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 C₂₂H₁₇N₄O₃[M+H]⁺385.1295,found:385.1300.

example 68

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

Weighing the compound 40(66mg, 0.17mmol), 4-methoxyphenylboronic acid (57mg, 0.38mmol), palladium acetate (20mg, 0.1mmol), triphenylphosphine (45mg, 0.2mmol) and potassium carbonate (142mg, 1.0mmol), placing in a 35mL thick-walled pressure-resistant bottle, adding toluene (5mL) and water (555 mu L), purging with argon for 5min, sealing, and placing at 90 ℃ for reacting for 8 h. After completion of the reaction, ethyl acetate (20mL) was added to dilute the reaction system, followed by suction filtration, solid matters in the system were filtered off, and extracted with ethyl acetate (10mL × 2), washed with saturated saline (10mL × 1), dried over anhydrous sodium sulfate, the solvent was distilled off 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, 40 mg).¹H NMR(300MHz,DMSO-d₆)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] dioxadieno [2,3-g ] benzofuran-8-yl) -6-methylimidazo [1,2-b ] pyridazine (Compound 69)

Weighing the compound 40(80mg, 0.21mmol), 4-fluorobenzeneboronic acid (64mg, 0.456mmol), palladium acetate (24mg, 0.104mmol), triphenylphosphine (55mg, 0.21mmol) and potassium carbonate (172mg, 1.243mmol), placing in a 35mL thick-wall pressure-resistant bottle, adding toluene (5mL) and water (555 mu L), purging with argon for 5min, sealing, and placing at 90 ℃ for reacting for 8 h. After completion of the reaction, ethyl acetate (20mL) was added to dilute the reaction system, suction filtration was performed, the solid content in the system was filtered, extraction was performed with ethyl acetate (10mL × 2), washing was performed with saturated saline (10mL × 1), drying was performed with 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), whereby compound 69 (yellow solid, 38mg) was obtained:¹H NMR(300MHz,CDCl₃)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 C₂₃H₁₇FN₃O₃[M+H]⁺402.1248,found:402.1249.

example 70

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

Weighing the compound 41(79mg, 0.212mmol), 4-fluorobenzeneboronic acid (65mg, 0.466mmol), palladium acetate (24mg, 0.107mmol), triphenylphosphine (56mg, 0.214mmol) and potassium carbonate (177mg, 1.284mmol), placing in a 15mL thick-walled pressure-resistant bottle, adding toluene (3mL) and water (300 mu L), purging with argon for 5min, sealing, and placing at 100 ℃ for reacting for 8 h. After the reaction, ethyl acetate (20mL) was added to dilute the reaction system, followed by suction filtration, filtration of the solid content in the system, extraction with ethyl acetate (10 mL. times.2), washing with saturated brine (10 mL. times.1), drying over anhydrous sodium sulfate, and evaporation under reduced pressureThe solvent was removed and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate 20:50:1-6:20:1) to give compound 70 (orange solid, 75 mg):¹H NMR(300MHz,DMSO-d₆)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 C₂₁H₁₄FN₄O₃[M+H]⁺389.1044,found:389.1047.

example 71

6-methyl-2- (6- (4- (trifluoromethyl) phenyl) -2, 3-dihydro- [1,4] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [1,2-b ] pyridazine (Compound 71)

Weighing the compound 40(80mg, 0.207mmol), 4-trifluoromethylphenylboronic acid (43mg, 0.228mmol), palladium acetate (12mg, 0.052mmol), triphenylphosphine (27mg,0.104mmol) and potassium carbonate (86mg, 0.621mmol), placing in a 15mL thick-wall pressure-resistant bottle, adding toluene (5mL) and water (250 μ L), purging with argon for 5min, sealing, and placing at 100 ℃ for reacting for 8 h. After completion of the reaction, ethyl acetate (20mL) was added to dilute the reaction system, suction filtration was performed, the solid content in the system was filtered, extraction was performed with ethyl acetate (10mL × 2), washing was performed with saturated saline (10mL × 1), drying was performed with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate 20:1:1-10:1:1) to obtain compound 71 (yellow-green solid, 20 mg):¹H NMR(300MHz,CDCl₃)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 C₂₄H₁₇F₃N₃O₃[M+H]⁺402.1217,found:402.1218.

example 72

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

Weighing the compound 41(48mg, 0.129mmol), 4-trifluoromethylphenylboronic acid (54mg, 0.283mmol), palladium acetate (14mg, 0.064mmol), triphenylphosphine (34mg, 0.128mmol) and potassium carbonate (106g, 0.772mmol), placing in a 15mL thick-wall pressure-resistant bottle, adding toluene (3mL) and water (300 mu L), purging with argon for 5min, sealing, and placing at 100 ℃ for reacting for 8 h. After completion of the reaction, ethyl acetate (20mL) was added to dilute the reaction system, suction filtration was performed, the solid content in the system was filtered, extraction was performed with ethyl acetate (10mL × 2), washing was performed with saturated saline (10mL × 1), drying was performed with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate ═ 20:50:1-6:20:1) to obtain compound 72 (orange-yellow solid, 34 mg):¹H NMR(300MHz,CDCl₃)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 C₂₂H₁₄F₃N₄O₃[M+H]⁺439.1013,found:439.1012.

example 73

2- (methylthio) -6- (6- (pyrrolidin-1-yl) -2, 3-dihydro [1,4] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 73)

Weighing the compound 38-7(1.91g, 6.43mmol) and dissolving in toluene (25mL), adding p-toluenesulfonic acid (245mg, 1.29mmol), connecting a water separator, and reacting the system for 8h under reflux. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), the organic phase was washed with water (20mL × 2) and saturated brine (20mL × 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 20:1:1-15:1:1) to give compound 73-1 (white solid, 1.624 g).

Compound 73-1(233mg, 0.683mmol), tetrahydropyrrole (67. mu.L, 0.82mmol), tris (dibenzylideneacetone) dipalladium (62mg, 0.07mmol), 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl (82mg, 0.17mmol), sodium tert-butoxide (79mg, 0.82mmol) were weighed in a 35mL thick-walled flask, anhydrous toluene (5mL) was added, and the mixture was frozen and extracted 3 times, and reacted at 90 ℃ for 6 hours. After completion of the reaction, ethyl acetate (20mL) was added to dilute the reaction system, followed by suction filtration, solid matters in the system were filtered off, and extracted with ethyl acetate (10mL × 2), washed with saturated saline (10mL × 1), dried over anhydrous sodium sulfate, 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) to obtain compound 73-2 (red solid, 149 mg).

Compound 73-2(149mg, 0.45mmol) was weighed out and dissolved in acetone (10mL), and 2N hydrochloric acid solution (5mL) was added to react at room temperature for 1 hour. After the reaction was completed, the system was made alkaline with a saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10 mL. times.2), the organic phases were combined, the organic phase was washed with a saturated brine (10 mL. times.1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue containing compound 73-3 was used in the next reaction without further treatment.

The residue containing compound 73-3 from the previous reaction was taken up in a 25mL two-necked flask, the apparatus was anaerobically treated with an argon exchange system for air, and then anhydrous dichloromethane (5mL) was added via syringe. Under ice-bath conditions, a solution of N, N-diisopropylethylamine (230. mu.L, 1.39mmol) in anhydrous dichloromethane (1mL) was added slowly and the system was allowed to react for 0.5h under ice-bath conditions. A solution of triisopropylsilyltriflate (186. mu.L, 0.69mmol) in anhydrous dichloromethane (1mL) was then added dropwise under ice-bath conditions. After the addition, the mixture was warmed to room temperature and stirred overnight. After the reaction was complete, the system was quenched with saturated sodium bicarbonate solution (10mL), the aqueous phase was extracted with dichloromethane (8mL x3), the organic phases were combined, the organic phase was washed with saturated sodium bicarbonate solution (10mL x1) and saturated brine (10mL x1), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue containing compound 73-4 was used in the next reaction without further purification.

The apparatus was anaerobically treated in a 25mL two-necked flask with air in an argon exchange system, and then a solution of anhydrous tetrahydrofuran (5mL) containing the residue of compound 73-4 obtained from the last post-reaction treatment was added via syringe, and a solution of N-bromosuccinimide (90mg, 0.51mmol) in anhydrous tetrahydrofuran (1mL) was added dropwise under ice-bath conditions. After the addition, the temperature is raised to room temperature and the mixture is stirred for 3 hours. After completion of 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 give compound 73-5 (red solid, 60 mg).

Compound 73-5(60mg, 0.164mmol) and 5-methylsulfanyl-1, 3, 4-thiadiazol-2-amine (29mg, 0.197mmol) were weighed into a 35mL pressure-resistant reaction tube, and then anhydrous N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath and reacts for 4 hours at the temperature of 90 ℃, and then the reaction is continued for 3 hours at the temperature of 120 ℃. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 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 4:1:1) to give 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/z 437.1[M+Na]⁺.

Example 74

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

Compound 73-1(200mg, 0.586mmol), piperidine (64. mu.L, 0.703mmol), tris (dibenzylideneacetone) dipalladium (54mg, 0.06mmol), 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl (70mg, 0.147mmol), sodium tert-butoxide (68mg, 0.703mmol) were weighed out in a 35mL thick-walled pressure-resistant bottle, anhydrous toluene (5mL) was added, and the mixture was frozen and extracted 3 times, and reacted at 90 ℃ for 6 hours. After completion of the reaction, ethyl acetate (20mL) was added to dilute the reaction system, followed by suction filtration, solid matters in the system were filtered off, followed by extraction with ethyl acetate (10mL × 2), washing with saturated brine (10mL × 1), drying over anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, and purification of the residue by column chromatography (eluent: petroleum ether/dichloromethane/ethyl acetate 10:1:1) to obtain compound 74-1 (red solid, 152 mg).

Compound 74-1(152mg, 0.44mmol) was weighed out and dissolved in acetone (8mL), and 2N hydrochloric acid solution (6mL) was added and reacted at room temperature for 1 h. After the reaction was completed, the system was made alkaline with a saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with a saturated brine (10mL × 1), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the residue containing compound 74-2 was used in the next reaction without further treatment.

The residue containing compound 74-2 from the previous reaction was taken up in a 25mL two-necked flask, the apparatus was anaerobically treated with an argon exchange system for air, and then anhydrous dichloromethane (8mL) was added via syringe. Under ice-bath conditions, a solution of N, N-diisopropylethylamine (218. mu.L, 1.32mmol) in anhydrous dichloromethane (2mL) was added slowly and the system was allowed to react for 0.5h under ice-bath conditions. A solution of triisopropylsilyl triflate (177. mu.L, 0.66mmol) in anhydrous dichloromethane (2mL) was then added dropwise under ice-bath conditions. After the addition, the mixture was warmed to room temperature and stirred overnight. After the reaction was complete, the system was quenched with saturated sodium bicarbonate solution (10mL), the aqueous phase was extracted with dichloromethane (10mL x3), the organic phases were combined, washed with saturated sodium bicarbonate solution (10mL x1) and saturated brine (10mL x1), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue containing compound 74-3 was used in the next reaction without further purification.

The apparatus was anaerobically treated in a 25mL two-necked flask with air in an argon exchange system, and then a solution of anhydrous tetrahydrofuran (6mL) containing the residue of the compound 74-3 obtained from the last post-reaction treatment was added via syringe, and a solution of N-bromosuccinimide (86mg, 0.483mmol) in anhydrous tetrahydrofuran (2mL) was added dropwise under ice-bath conditions. After the addition, the temperature is raised to room temperature and the mixture is stirred for 3 hours. After completion of 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 give compound 74-4 (red solid, 58 mg).

Compound 74-4(100mg, 0.264mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (57mg, 0.32mmol) were weighed into a 35mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system is moved into an oil bath, and after 5 hours of reaction at 80 ℃, the reaction is continued for 3 hours at 130 ℃. After completion of 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 give compound 74 (yellow solid, 23 mg):¹H NMR(300MHz,CDCl₃)δ8.15(s,1H),7.12(s,1H),6.31(s,1H),4.39(d,J＝5.0Hz,2H),4.35(d,J＝5.2Hz,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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 75)

Compound 74(122mg, 0.264mmol) was weighed out and dissolved in a mixed solvent of dichloromethane (15mL) and methanol (5mL), and then a methanol solution of sodium methoxide (4M, 160. mu.L) was added thereto and reacted at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (15mL), the aqueous phase was extracted with dichloromethane (10mL × 3), the organic phases were combined, washed with a saturated saline solution (20mL × 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-yellow solid, 24 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 76)

Compound 74-4(55mg, 0.145mmol) and 5-methylthio-1, 3, 4-thiadiazol-2-amine (26mg, 0.174mmol) were weighed into a 35mL pressure-resistant reaction tube, and then anhydrous N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath and reacts for 4 hours at the temperature of 90 ℃, and then the reaction is continued for 3 hours at the temperature of 120 ℃. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 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 10:1:1-4:1:1) to give compound 76 (red solid, 27 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [1,2-b ] pyridazine (Compound 77)

Compound 74-4(84mg, 0.222mmol) and 3-amino-6-methylpyridazine (29mg, 0.266mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, the solvent was evaporated 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):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [1,2-b ] [1,2,4] triazine (Compound 78)

Compound 74-4(125mg, 0.33mmol) and 1,2, 4-triazin-3-amine (48mg, 0.5mmol) were weighed into a 35mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-6-yl) morpholine (Compound 79)

Compound 73-1(402mg, 1.178mmol), morpholine (122. mu.L, 1.41mmol), tris (dibenzylideneacetone) dipalladium (108mg, 0.118mmol), 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl (140mg, 0.295mmol), sodium tert-butoxide (135mg, 1.41mmol) were weighed out in a 35mL thick-walled pressure-resistant bottle, anhydrous toluene (5mL) was added, and the mixture was frozen and extracted 3 times, and reacted at 90 ℃ for 6 hours. After completion of the reaction, ethyl acetate (20mL) was added to dilute the reaction system, followed by suction filtration, solid matters in the system were filtered off, and extracted with ethyl acetate (10mL × 2), washed with saturated brine (10mL × 1), dried over anhydrous sodium sulfate, the solvent was distilled off 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).

Compound 79-1(312mg, 0.90mmol) was weighed out and dissolved in acetone (10mL), and 2N hydrochloric acid solution (8mL) was added to react at room temperature for 1 hour. After the reaction was completed, the system was made alkaline with a saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with a saturated brine (10mL × 1), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the residue containing compound 79-2 was used in the next reaction without further treatment.

The residue containing compound 79-2 from the previous reaction was taken up in a 50mL two-necked flask, the apparatus was anaerobically treated with an argon exchange system for air, and then anhydrous dichloromethane (15mL) was added via syringe. Under ice-bath conditions, a solution of N, N-diisopropylethylamine (490. mu.L, 2.967mmol) in anhydrous dichloromethane (2mL) was added slowly and the system was allowed to react for 0.5h under ice-bath conditions. A solution of triisopropylsilyl triflate (397. mu.L, 1.48mmol) in anhydrous dichloromethane (2mL) was then added dropwise under ice-bath conditions. After the addition, the mixture was warmed to room temperature and stirred overnight. After the reaction was complete, the system was quenched with saturated sodium bicarbonate solution (15mL), the aqueous phase was extracted with dichloromethane (10mL x3), the organic phases were combined, washed with saturated sodium bicarbonate solution (10mL x1) and saturated brine (10mL x1), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue containing compound 79-3 was used in the next reaction without further purification.

The apparatus was anaerobically treated in a 50mL two-necked flask with air in an argon exchange system, and then a solution of anhydrous tetrahydrofuran (10mL) containing the residue of the compound 79-3 obtained by the post-treatment of the previous reaction was added via syringe, and a solution of N-bromosuccinimide (194mg, 1.1mmol) in anhydrous tetrahydrofuran (5mL) was added dropwise under ice-bath conditions. After the addition, the temperature is raised to room temperature and the mixture is stirred for 3 hours. After the reaction was completed, 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 give compound 79-4 (orange solid, 180 mg).

Compound 79-4(82mg, 0.2mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (46mg, 0.26mmol) were weighed into a 35mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred into a 100mL flask with methylene chloride, the solvent was distilled off under reduced pressure, and the residue containing the compound 79-5 was used in the next reaction without further purification.

The crude compound 79-5 obtained in the previous step was dissolved in a mixed solvent of dichloromethane (9mL) and methanol (3mL), and then a methanol solution of sodium methoxide (4M, 150. mu.L) was added thereto to carry out reaction at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (15mL), the aqueous phase was extracted with dichloromethane (10mL × 3), the organic phases were combined, washed with a saturated saline solution (20mL × 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: 5:1:1-1:1:1) to obtain compound 79 (orange solid, 34 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-6-yl) morpholine (Compound 80)

Compound 79-4(100mg, 0.262mmol) and 5-methylsulfanyl-1, 3, 4-thiadiazol-2-amine (46mg, 0.314mmol) were weighed into a 35mL pressure-resistant reaction tube, and then anhydrous N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath and reacts for 4 hours at the temperature of 90 ℃, and then the reaction is continued for 3 hours at the temperature of 120 ℃. After completion of the reaction, ethyl acetate (20mL) was added to dilute the reaction solution inThe organic phase was washed with water (10mL x3) and saturated brine (10mL x2), 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 4:1:1) to give compound 80 (red solid, 28 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-6-yl) morpholine (Compound 81)

Compound 79-4(51mg, 0.133mmol) and 3-amino-6-methylpyridazine (17mg, 0.16mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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 give compound 81 (yellow solid, 28 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-6-yl) morpholine (Compound 82)

Compound 79-4(70mg, 0.183mmol) and 1,2, 4-triazin-3-amine (26mg, 0.275mmol) were weighed into a 35mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL), and mixed by purging with argonThe mixture solution was for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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):¹H NMR(300MHz,CDCl₃)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] dioxine [2,3-g ] benzofuran-6-yl) thiomorpholine 1, 1-dioxide (Compound 83)

The 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 weighed out in a 35mL thick-walled pressure-resistant bottle, added with anhydrous toluene (5mL), freeze-extracted 3 times, and reacted at 90 ℃ for 6 hours. After completion of the reaction, ethyl acetate (20mL) was added to dilute the reaction system, followed by suction filtration, solid matters in the system were filtered off, and extracted with ethyl acetate (10mL × 2), washed with saturated saline (10mL × 1), dried over anhydrous sodium sulfate, 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 83-1 (yellow solid, 90 mg).

Compound 83-1(85mg, 0.215mmol) was weighed out and dissolved in acetone (5mL), and 2N hydrochloric acid solution (2.5mL) was added to react at room temperature for 1 hour. After the reaction was completed, the system was made alkaline with a saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with a saturated brine (10mL × 1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue containing compound 83-2 was used in the next reaction without further treatment.

The residue containing 83-2 obtained in the previous reaction was taken up in a 25mL two-necked flask, the apparatus was anaerobically treated with an argon gas exchange system for air, and then anhydrous dichloromethane (5mL) was added via syringe. Under ice-bath conditions, a solution of N, N-diisopropylethylamine (110. mu.L, 0.65mmol) in anhydrous dichloromethane (1mL) was added slowly and the system was allowed to react for 0.5h under ice-bath conditions. A solution of triisopropylsilyl triflate (90. mu.L, 0.32mmol) in anhydrous dichloromethane (1mL) was then added dropwise under ice-bath conditions. After the addition, the mixture was warmed to room temperature and stirred overnight. After the reaction was complete, the system was quenched with saturated sodium bicarbonate solution (10mL), the aqueous phase was extracted with dichloromethane (8mL x3), the organic phases were combined, washed with saturated sodium bicarbonate solution (10mL x1) and saturated brine (10mL x1), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue containing compound 83-3 was used in the next reaction without further purification.

The apparatus was anaerobically treated in a 25mL two-necked flask with air in an argon exchange system, and then a solution of anhydrous tetrahydrofuran (7mL) containing the residue of compound 83-3 obtained from the last post-reaction treatment was added via syringe, and a solution of N-bromosuccinimide (42mg, 0.24mmol) in anhydrous tetrahydrofuran (2mL) was added dropwise under ice-bath conditions. After the addition, the temperature is raised to room temperature and the mixture is stirred for 3 hours. After the reaction was completed, 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 give compound 83-4 (orange solid, 36 mg).

Compound 83-4(36mg, 0.084mmol) and 3-amino-6-methylpyridazine (11mg, 0.1mmol) were weighed into a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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):¹H NMR(300MHz,DMSO-d₆)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[M-H]⁺.

example 84

2-methoxy-6- (6- (3-methoxypropoxy) -2, 3-dihydro- [1,4] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 84)

Compound 48-6(1.4g, 4.32mmol) was weighed out and dissolved in a mixed solvent of methanol (10mL) and tetrahydrofuran (10mL), followed by the addition of 10% palladium on carbon (1.8g, 17.14mmol) and cyclohexene (18mL) in that order. The system is reacted for 5h under reflux. After the reaction, the solid in the system was filtered off 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 84-1 (yellow solid, 809 mg).

Compound 84-1(100mg, 0.43mmol) was weighed out and dissolved in N, N-dimethylformamide (15mL), and potassium carbonate (177mg, 1.3mmol) and 1-bromo-3-methoxypropane (145. mu.L, 1.3mmol) were added and reacted at 50 ℃ for 3 h. After the reaction was completed, the reaction mixture was diluted with water (20mL), the aqueous phase was extracted with dichloromethane (10mL × 3), the organic phases were combined, washed with water (10mL × 3) and saturated brine (10mL × 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 ═ 15:1:1-10:1:1) to give compound 84-2 (yellow solid, 118 mg).

Compound 84-2(227mg, 0.74mmol) was weighed out and dissolved in a 50mL two-necked flask, the apparatus was anaerobically treated by exchanging the air in the system with argon, and then anhydrous dichloromethane (7mL) was added via syringe. Under ice-bath conditions, a solution of N, N-diisopropylethylamine (370. mu.L, 2.22mmol) in anhydrous dichloromethane (2mL) was added slowly and the system was allowed to react for 0.5h under ice-bath conditions. A solution of triisopropylsilyl triflate (300. mu.L, 1.11mmol) in anhydrous dichloromethane (2mL) was then added dropwise under ice-bath conditions. After the addition, the mixture was warmed to room temperature and stirred overnight. After the reaction was complete, the system was quenched with saturated sodium bicarbonate solution (15mL), the aqueous phase was extracted with dichloromethane (10mL x3), the organic phases were combined, washed with saturated sodium bicarbonate solution (10mL x1) and saturated brine (10mL x1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue containing compound 84-3 was used in the next reaction without further purification.

The apparatus was anaerobically treated in a 50mL two-necked flask with air in an argon exchange system, and then a solution of anhydrous tetrahydrofuran (7mL) containing the residue of the compound 84-3 obtained by the post-treatment of the previous reaction was added via syringe, and a solution of N-bromosuccinimide (145mg, 0.81mmol) in anhydrous tetrahydrofuran (2mL) was added dropwise under ice-bath conditions. After the addition, the temperature is raised to room temperature and the mixture is stirred for 3 hours. After the completion of 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 give compound 84-4 (yellow oily liquid, 230 mg).

Compound 84-4(114mg, 0.3mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (64mg, 0.355mmol) were weighed into a 35mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred into a 100mL flask with methylene chloride, the solvent was distilled off under reduced pressure, and the residue containing compound 84-5 was used in the next reaction without further purification.

The residue obtained from the above post-reaction treatment containing compound 84-5 was dissolved in a mixed solvent of dichloromethane (15mL) and methanol (5mL), followed by addition of a methanol solution of sodium methoxide (4M, 180. mu.L) and reaction at room temperature for 1 hour. After completion of the reaction, the reaction was quenched with a saturated ammonium chloride solution (10mL), the aqueous phase was extracted with dichloromethane (15mL × 3), the organic phases were combined, washed with a saturated saline solution (10mL × 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: 8:1:1-4:1:1) to obtain compound 84 (yellow solid, 28 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 85)

Compound 84-4(80mg, 0.269mmol) and 5-methylsulfanyl-1, 3, 4-thiadiazol-2-amine (48mg, 0.323mmol) were weighed into a 15mL pressure-resistant reaction tube, then N, N-dimethylformamide (5mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 2 hours at the temperature of 110 ℃. After completion of the reaction, water (15mL) was added to dilute the reaction solution, and the reaction solution was extracted with ethyl acetate (10mL × 3), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 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: 10:1:1-3:1:1) to obtain compound 85 (yellow solid, 20 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-6-yl) oxy) ethyl) morpholine (Compound 86)

Under argon atmosphere, compound 54(50mg,0.145mmol) was dissolved in anhydrous N, N-dimethylformamide (7mL), sodium tert-butoxide (42mg,0.434mmol) was added, and 4- (2-bromoethyl) morpholine hydrobromide (48mg,0.174mmol) was dissolved in anhydrous N, N-dimethylformamide (1mL), and added dropwise to the above system, followed by stirring at room temperature for 1.5 hours. After completion of the reaction, water (15mL) was added to the system, the aqueous phase was extracted with ethyl acetate (10mL x2), the organic phases were combined and the organic phase was washed with water (10mL x2)x3) and saturated brine (10mL x1), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: purification of petroleum ether/ethyl acetate/dichloromethane ═ 2:1:1-1:2:2) gave compound 86 (yellow solid, 28 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-6-yl) oxy) ethyl) morpholine (Compound 87)

Compound 50(204mg, 0.468mmol) and pentamethylbenzene (485mg, 3.276mmol) were dissolved in anhydrous tetrahydrofuran (10mL) under an argon atmosphere, the system was placed at-78 deg.C, boron trichloride (1M in DCM, 1.17mL, 1.17mmol) was added dropwise, and after the addition was completed, the reaction was continued at-78 deg.C for 1.5 h. After completion of the reaction, sodium bicarbonate solution (0.7M in DCM, 10mL) was added at-78 deg.C to quench the reaction, warmed to room temperature, stirred for 1h, filtered, the filter cake was washed with toluene (5mL) and dried under vacuum to give compound 87-1 (white solid, 130mg)

Under argon atmosphere, compound 87-1(55mg,0.152mmol) was dissolved in anhydrous N, N-dimethylformamide (6mL), sodium tert-butoxide (44mg,0.457mmol) was added, 4- (2-bromoethyl) morpholine hydrobromide (51mg,0.183mmol) was dissolved in anhydrous N, N-dimethylformamide (1mL), and the mixture was added dropwise to the system, followed by stirring at room temperature for 1.5 hours. After completion of the reaction, water (15mL) was added to the system, the aqueous phase was extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 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 ═ 2:1:1-1:2:2) to give compound 87 (yellow solid, 50 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,13-g ] benzofuran-6-yl) oxy) methyl) -5-methylthiazol-2-yl) morpholine (Compound 88)

Copper bromide (5.76g,25.8mmol) was weighed into ethyl acetate (20mL), heated to reflux, compound 88-1(1.5g,12.9mmol) was dissolved in chloroform (4mL) and added dropwise to the system, and heating at reflux was continued for 1 hour, with a large amount of white solid being produced during the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, the insoluble matter was removed by filtration through celite, and the filtrate was concentrated under reduced pressure to give a crude product (dark green oil, 8g) containing compound 88-2.

To a solution of compound 88-3(3.32mL,38.1mmol) in chloroform (20mL) at room temperature was added trimethylsilyl isothiocyanate (2.68mL,19.1mmol) dropwise, yielding a large amount of white solid immediately, and stirring was continued for 1 hour. After completion of the reaction, filtration, washing of the filter cake with chloroform (2mL x3) and drying of the filter cake under vacuum overnight gave compound 88-4 (white solid, 2.5 g).

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

Compound 88-5(0.41g,1.69mmol) was dissolved in anhydrous tetrahydrofuran (10mL) under argon, and a 2M solution of lithium borohydride in tetrahydrofuran (1.69mL,3.38mmol) was added slowly dropwise to the above system at 0 deg.C, after completion of the addition, the mixture was allowed to warm to room temperature and stirred overnight. After completion of the reaction, methanol (2mL) was added dropwise to the reaction solution to stop the reaction until no air bubbles were generated in the reaction solution, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate 1:2) to obtain compound 88-6 (white solid, 217 mg).

Dissolving compound 88-6(0.25g,1.16mmol) in anhydrous dichloromethane (5mL), dissolving phosphorus tribromide (60 μ L,0.580mmol) in dichloromethane (1mL) under ice-bath condition, dropwise adding into the system, and reacting at room temperature for 4 hours after dropwise addition. After completion of the reaction, the reaction was quenched by addition of saturated sodium bicarbonate solution (10mL), extracted with dichloromethane (5mL × 3), the organic phases were combined, washed with saturated brine (5mL × 3), 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) to give compound 88-7 (white crystal, 145 mg).

Under argon atmosphere, compound 54(80mg,0.25mmol) was dissolved in anhydrous N, N-dimethylformamide (5mL), sodium tert-butoxide (26mg,0.28mmol) was added, and compound 88-7(76mg,0.28mmol) was dissolved in anhydrous N, N-dimethylformamide (1mL), and the mixture was added dropwise to the above system and stirred at room temperature for 2.5 hours. After completion of the reaction, the system was diluted with ethyl acetate (20mL), the organic phase was washed with water (5mL × 3) and saturated brine (5mL × 3) in this order, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: dichloromethane: ethyl acetate ═ 6:4:1) to give compound 88 (white solid, 49 mg):¹H NMR(300MHz,CDCl₃)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-thiomorpholinthiazol-4-yl) methoxy) -2, 3-dihydro [1,4] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 89)

Compound 89 was prepared according to the procedure of example 88:¹H NMR(300MHz,CDCl₃)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.for C₂₃H₂₁N₅O₅S₃[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] dioxadieno [2,3-g ] benzofuran-8-yl) imidazo [2,1-b ] [1,3,4] thiadiazole (compound 90)

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

The crude compound 90-2 (2.45g,8.53mmol) from the previous step was dissolved in anhydrous tetrahydrofuran (30mL) under argon, and 2M solution of lithium borohydride in tetrahydrofuran (17mL,34mmol) was added dropwise slowly to the system at 0 deg.C, after completion of addition, the mixture was warmed to room temperature and stirred overnight. After completion of the reaction, methanol (20mL) was added dropwise to the reaction solution to stop the reaction until no bubble was formed in the reaction solution, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate: 8:1-3:1) to obtain compound 90-3 (white solid, 1.44 g).

Dissolving compound 90-3(519mg,2mmol) in anhydrous dichloromethane (10mL), dissolving phosphorus tribromide (188 uL, 2mmol) in dichloromethane (2mL) under ice-bath condition, dropwise adding into the system, and reacting at room temperature for 4 hours after dropwise adding. After completion of the reaction, the reaction was quenched by addition of saturated sodium bicarbonate solution (10mL), extracted with dichloromethane (5mL × 3), the organic phases were combined, washed with saturated brine (5mL × 3), 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 ═ 20:1-10:1) to give compound 90-4 (white solid, 200 mg).

Under argon atmosphere, compound 54(70mg,0.20mmol) was dissolved in anhydrous N, N-dimethylformamide (5mL), sodium tert-butoxide (23mg,0.244mmol) was added, and compound 90-4(85mg,0.26mmol) was dissolved in anhydrous N, N-dimethylformamide (1mL), and the mixture was added dropwise to the above system and stirred at room temperature for 2.5 hours. After completion of the reaction, the system was diluted with ethyl acetate (20mL), the organic phase was washed with water (5mL × 3) and saturated brine (5mL × 3) in this order, 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 ═ 15:1:1-5:1:1), and re-purified by recrystallization (ethyl acetate/tetrahydrofuran/methanol/dichloromethane), to give compound 90 (white solid, 15 mg):¹H NMR(300MHz,CDCl₃)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 C₂₆H₁₇F₃N₄O₅S₂[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] dioxadieno [2,3-g ] benzofuran-6-yl) oxy) methyl) thiazol-2-yl) -N, N-dimethylbenzamide (Compound 91)

91-1 (100. mu.L, 0.98mmol) was weighed into a 50mL bottle, the apparatus was subjected to anaerobic treatment by exchanging air in an argon gas system, and anhydrous N, N-dimethylformamide (5mL) was added, followed by dropwise addition of an anhydrous N, N-dimethylformamide (1mL) solution of imidazole (133mg, 1.96mmol) and an anhydrous N, N-dimethylformamide (1mL) solution of t-butyldimethylchlorosilane (221mg, 1.47mmol) in this order at 0 ℃. The system is reacted for 6h under the condition of room temperature. After the reaction was completed, water (10mL) was added to the system, the aqueous phase was extracted with ethyl acetate (8mL × 3), the organic phases were combined, the organic phase was washed with water (8mL × 3) and saturated brine (8mL × 1), 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 100:1) to give compound 91-2 (colorless oily liquid, 272 mg).

Weighing the compound 91-2(105mg, 0.341mmol), 4- (N, N-dimethylcarbamoyl) phenylboronic acid (99mg, 0.512mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (28mg, 0.034mmol), and sodium carbonate (44mg, 0.42mmol) in a 35mL thick-wall pressure-resistant bottle, adding toluene (3mL), water (200. mu.L) and ethanol (1mL), purging with argon for 5min, sealing, and reacting at 95 ℃ for 4 h. After completion of the reaction, saturated sodium bicarbonate (10mL) was added, extraction was performed with ethyl acetate (6mL × 3), the mixture was washed with saturated brine (5mL × 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 4:1-2:1) to obtain compound 91-3 (yellow oily liquid, 116 mg).

Compound 91-3(116mg, 0.31mmol) was weighed out and dissolved in tetrahydrofuran (5mL), tetrabutylammonium fluoride (770. mu.L, 0.77mmol) was slowly added thereto at room temperature, and the reaction was allowed to proceed overnight at room temperature. After completion of the reaction, saturated sodium chloride (10mL), ethyl acetate (10mL × 3) was added and extracted, and the mixture was washed with saturated brine (10mL × 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 ═ 2:1-1:1) to give compound 91-4 (white solid, 63 mg).

Dissolving compound 91-4(60g,0.28mmol) in anhydrous dichloromethane (4mL), dissolving phosphorus tribromide (21 uL, 0.224mmol) in dichloromethane (0.5mL) under ice-bath condition, dropwise adding into the system, and reacting at room temperature for 4 hours after dropwise adding. After completion of the reaction, the reaction was quenched by addition of saturated sodium bicarbonate solution (10mL), extracted with dichloromethane (6mL × 3), the organic phases were combined, washed with saturated brine (5mL × 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 ═ 2:1) to give compound 91-5 (yellow oily liquid, 51 mg).

Compound 54(48mg,0.139mmol) was dissolved in dry N, N-dimethylformamide (4mL) under argon, sodium tert-butoxide (20mg,0.208mmol) was added, and compound 91-5(54mg,0.167 mmol) was addedmmol) was dissolved in anhydrous N, N-dimethylformamide (1mL), and the mixture was added dropwise to the above system and stirred at room temperature for 1.5 hours. After completion of the reaction, water (10mL) was added to the system, the aqueous phase was extracted with ethyl acetate (8mL × 3), the organic phases were combined, the organic phase was washed with water (5mL × 3) and saturated brine (5mL × 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 ═ 2:1:1-1:5:5) to give compound 91 (white solid, 45 mg):¹H NMR(300MHz,CDCl₃)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/z 612.2[M+Na]⁺.

example 92

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

Under argon protection, 87-1(22mg,0.061mmol) was dissolved in anhydrous N, N-dimethylformamide (3mL), sodium tert-butoxide (9mg,0.09mmol) was added, and 91-5(24mg,0.073mmol) was dissolved in anhydrous N, N-dimethylformamide (1mL), and the mixture was added dropwise to the above system and stirred at room temperature for 1.5 hours. After completion of the reaction, water (15mL) was added to the system, the aqueous phase was extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 1), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane/methanol ═ 100:1-50:1) to give compound 92 (yellow-white solid, 10 mg):¹H NMR(300MHz,CDCl₃)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/z 628.2[M+Na]⁺.

example 93

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

Compound 84-1(234.6mg, 1.002mmol) was weighed out and dissolved in N, N-dimethylformamide (20mL), and 1-bromo-4- [ [4- (bromomethyl) phenoxy ] methyl ] -benzene (461.1mg, 1.303mmol) and potassium carbonate (180.1mg, 1.303mmol) were added, and the system was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50mL), the organic phase was washed with water (20mL × 3) and saturated brine (20mL × 2), 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 give compound 93-1 (yellow solid, 458 mg).

Under the protection of argon, weighing compound 93-1(175mg, 0.34mmol) and dissolving in anhydrous tetrahydrofuran (20mL), slowly adding dropwise benzyltrimethyl ammonium dichloroiodate (144mg,0.41mmol) solution in anhydrous tetrahydrofuran (10mL) at room temperature, after completing dropwise addition, transferring the system into an oil bath, and reacting at 45 ℃ overnight. After completion of the reaction, the reaction solution was diluted with ether (10mL) and ethyl acetate (10mL), and the organic phase was washed with dilute sodium bicarbonate (20mL x2), saturated sodium thiosulfate (20mL x2), and saturated brine (20mL x2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue containing compound 93-2 was used in the next reaction without further purification.

The residue obtained in the last post-reaction treatment of the compound 93-2 and 1,2, 4-triazin-3-amine (53.2mg, 0.55mmol) were placed in a 15mL pressure-resistant reaction tube, followed by addition of isopropanol (5mL) and purging of the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction was completed, 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 give compound 93 (orange solid, 10 mg).¹H NMR(300MHz,CDCl₃)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 C₂₉H₂₁BrN₄O₅[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] dioxadieno [2,3-g ] benzofuran-6-yl) oxy) -1- (pyrrolidin-1-yl) ethan-1-one (Compound 94)

Pyrrolidine (130. mu.L, 1.58mmol) was dissolved in anhydrous dichloromethane (2mL) under argon protection, and a solution of triethylamine (264. mu.L, 1.89mmol) and bromoacetyl chloride (145. mu.L, 1.74mmol) in anhydrous dichloromethane (2mL) was added dropwise in this order at 0 ℃ and stirred at room temperature overnight. After completion of the reaction, water (15mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10mL × 2), washed with saturated sodium bicarbonate (8mL × 2) and saturated sodium chloride (5mL × 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 give compound 94-1 (yellow oily liquid, 112 mg).

Under argon atmosphere, compound 54(22mg,0.062mmol) was dissolved in anhydrous N, N-dimethylformamide (3mL), sodium tert-butoxide (9mg,0.09mmol) was added, compound 94-1(14mg,0.075mmol) was dissolved in anhydrous N, N-dimethylformamide (1mL), and the mixture was added dropwise to the above system and stirred at room temperature for 1.5 hours. After completion of the reaction, water (15mL) was added to the system, the aqueous phase was extracted with ethyl acetate (10mL × 2), the organic phases were combined, the organic phase was washed with water (8mL × 3) and saturated brine (5mL × 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 ═ 2:1:1-1:3:3) to give compound 94 (yellow solid, 14 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-6-yl) oxy) -1- (piperidin-1-yl) ethan-1-one (Compound 95)

Piperidine (100. mu.L, 1.58mmol) was dissolved in anhydrous dichloromethane (2mL) under argon protection, and a solution of triethylamine (263. mu.L, 1.89mmol) and bromoacetyl chloride (131. mu.L, 1.58mmol) in anhydrous dichloromethane (2mL) was added dropwise in this order at 0 ℃ and stirred at room temperature overnight. After completion of the reaction, water (15mL) was added to the reaction solution, extracted with dichloromethane (10mL × 2), washed with saturated sodium bicarbonate (8mL × 2) and saturated sodium chloride (5mL × 1), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the residue containing compound 95-1 was used in the next reaction without further purification.

Under argon protection, compound 54(25mg,0.072mmol) was dissolved in anhydrous N, N-dimethylformamide (3mL), sodium tert-butoxide (10mg,0.11mmol) was added, compound 95-1(18mg,0.083mmol) was dissolved in anhydrous N, N-dimethylformamide (1mL), and the mixture was added dropwise to the system and stirred at room temperature for 1.5 hours. After completion of the reaction, water (10mL) was added to the system, the aqueous phase was extracted with ethyl acetate (8mL × 2), the organic phases were combined, the organic phase was washed with water (6mL × 3) and saturated brine (6mL × 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 ═ 5:1:1-1:1:1), to give compound 95 (yellow-white solid, 30 mg):¹H NMR(300MHz,CDCl₃)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] thiadiazol-6-yl) -2, 3-dihydro- [1,4] dioxadieno [2,3-g ] benzofuran-6-yl) oxy) ethan-1-one (Compound 96)

Under the protection of argon, 4-difluoropiperidine hydrochloride (207mg, 1.3mmol) was dissolved in anhydrous dichloromethane (3mL), and a solution of triethylamine (548. mu.L, 3.94mmol) and bromoacetyl chloride (120. mu.L, 1.45mmol) in anhydrous dichloromethane (2mL) was added dropwise in this order at 0 ℃ and stirred at room temperature overnight. After completion of the reaction, water (15mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10mL × 2), washed with saturated sodium bicarbonate (8mL × 2) and saturated sodium chloride (5mL × 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), whereby compound 96-1 (yellow oily liquid, 119mg) was obtained.

Under argon atmosphere, compound 54(22mg,0.062mmol) was dissolved in anhydrous N, N-dimethylformamide (2mL), sodium tert-butoxide (9mg,0.093mmol) was added, compound 96-1(18mg,0.075mmol) was dissolved in anhydrous N, N-dimethylformamide (1mL), and the mixture was added dropwise to the above system and stirred at room temperature for 1.5 hours. After completion of the reaction, water (10mL) was added to the system, the aqueous phase was extracted with ethyl acetate (8mL × 2), the organic phases were combined, the organic phase was washed with water (6mL × 2) and saturated brine (5mL × 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 ═ 3:1:1-1:1:1) to give compound 96 (white solid, 20 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-6-yl) oxy) -1-morpholinoethan-1-one (Compound 97)

Morpholine (600. mu.L, 6.9mmol) was dissolved in anhydrous dichloromethane (8mL) under argon protection, and a solution of triethylamine (960. mu.L, 6.9mmol) and bromoacetyl chloride (580. mu.L, 6.9mmol) in anhydrous dichloromethane (4mL) was added dropwise in this order at 0 ℃ and stirred at room temperature overnight. After completion of the reaction, water (15mL) was added to the reaction solution, extracted with dichloromethane (15mL × 2), washed with saturated sodium bicarbonate (8mL × 2) and saturated sodium chloride (10mL × 1), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the residue containing compound 97-1 was used in the next reaction without further purification.

Under argon protection, compound 54(25mg,0.072mmol) was dissolved in anhydrous N, N-dimethylformamide (3mL), sodium tert-butoxide (10mg,0.11mmol) was added, compound 97-1(20mg,0.087mmol) was dissolved in anhydrous N, N-dimethylformamide (1mL), and the mixture was added dropwise to the system and stirred at room temperature for 1.5 hours. After completion of the reaction, water (10mL) was added to the system, the aqueous phase was extracted with ethyl acetate (8mL × 2), the organic phases were combined, the organic phase was washed with water (6mL × 3) and saturated brine (6mL × 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 ═ 5:1:1-1:1:1), to give compound 97 (yellow-white solid, 24 mg):¹H NMR(300MHz,CDCl₃)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-Methylsulfanylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) -2, 3-dihydro- [1,4] dioxadieno [2,3-g ] benzofuran-6-yl) oxy) -1-morpholinoethan-1-one (Compound 98)

Compound 87-1(53mg,0.147mmol) was dissolved in anhydrous N, N-dimethylformamide (5mL) under argon protection, sodium tert-butoxide (21mg,0.22mmol), compound 97-1(37mg,0.176mmol) was dissolved in anhydrous N, N-dimethylformamide (1mL), and added dropwise to the above system, followed by stirring at room temperature for 1.5 hours. After completion of the reaction, water (10mL) was added to the system, the aqueous phase was extracted with ethyl acetate (8mL × 2), the organic phases were combined, the organic phase was washed with water (6mL × 3) and saturated brine (6mL × 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 ═ 3:1:1-1:2:2) to give compound 98 (yellow-white solid, 20 mg):¹H NMR(300MHz,CDCl₃)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-Disulfido) -2- ((8- (2-methoxyimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) -2, 3-dihydro- [1,4] dioxadieno [2,3-g ] benzofuran-6-yl) oxy) ethan-1-one (Compound 99)

Thiomorpholine-1, 1-dioxide (300mg, 2.22mmol) was weighed out and dissolved in anhydrous dichloromethane (2mL) under argon protection, and a solution of triethylamine (370. mu.L, 2.66mmol) and bromoacetyl chloride (185. mu.L, 2.22mmol) in anhydrous dichloromethane (2mL) was added dropwise in this order at 0 ℃ and stirred at room temperature overnight. After completion of the reaction, water (15mL) was added to the reaction solution, extracted with dichloromethane (10mL × 5), washed with saturated sodium bicarbonate (5mL × 2) and saturated sodium chloride (5mL × 1), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the residue containing the compound 99-1 was used in the next reaction without further purification.

Under argon atmosphere, 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), and the mixture was 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 (8 mL. times.2), and the organic phases were combinedThe organic phase was washed with water (6mL x3) and saturated brine (6mL 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 ═ 1:1:1-1:2:2) to give 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] dioxadieno [2,3-g ] benzofuran-3-yl) methanol (Compound 100)

Sodium hydride (147mg, 3.67mmol) was dissolved in dimethyl sulfoxide (8mL) under argon protection, a solution of compound 9-1(203mg, 1.47mmol) in dimethyl sulfoxide (2mL) was added dropwise at 0 ℃, the system was stirred at room temperature for 1 hour, benzyl bromide (175 μ L, 0.98mmol) was added dropwise at 0 ℃, the system was stirred at room temperature overnight, after completion of the reaction, ice water (10mL) was added to quench the reaction, an appropriate amount of 1N hydrochloric acid was added to adjust the pH of the aqueous phase to 1, extraction was performed with dichloromethane (10mL x3), the organic phases were combined, washed with saturated brine (10mL x1), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by eluent (petroleum ether/ethyl acetate column chromatography ═ 20:1) to give compound 100-1 (yellow solid, 140 mg).

Compound 100-1(135mg, 0.59mmol) was weighed out and dissolved in N, N-dimethylformamide (6mL), and potassium carbonate (106mg, 0.77mmol) and bromopropylene oxide (63. mu.l, 0.77mmol) were added, and the mixture was heated to 50 ℃ for 6 hours. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (15mL), extracted with ethyl acetate (8mL × 3), the organic phases were combined, washed with water (6mL × 3) and saturated brine (6mL × 1), 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 ═ 20:1-6:1) to give compound 100-2 (colorless oil, 148 mg).

Weighing compound 100-2(202mg, 0.71mmol) and dissolving in dichloromethane (8mL), adding m-chloroperoxybenzoic acid (202mg, 0.995mmol, 85%) in portions under ice bath condition, then removing the ice bath, reacting at room temperature for 12h, filtering to remove insoluble substances, washing filtrate with saturated sodium bicarbonate (10mL x2) and saturated saline (8mL x1), drying over anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and using the residue containing compound 100-3 in the next reaction without further treatment.

The residue containing compound 100-3 from the previous reaction was dissolved in methanol (7mL), and anhydrous potassium carbonate (294mg, 2.13mmol) was slowly added under ice-bath conditions, followed by reaction at room temperature for 3 h. After the reaction was completed, the reaction system was adjusted to pH 1 with 1N hydrochloric acid solution, extracted with dichloromethane (10mL × 2), the organic phases were combined, washed with saturated brine (8mL × 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 give compound 100-4 (colorless oily substance, 111 mg).

Compound 100-4(110mg, 0.404mmol) was dissolved in anhydrous tetrahydrofuran under an argon atmosphere, triethylamine (140. mu.L, 1.01mmol) was added at 0 ℃, a solution of acetyl chloride (36. mu.L, 0.505mmol) in anhydrous tetrahydrofuran (1mL) was added dropwise, and after the addition was completed, the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched by addition of water (6mL), the aqueous phase was extracted with ethyl acetate (6mL × 2), the organic phases were combined, washed with saturated brine (5mL × 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 6:1) to give compound 100-5 (colorless oil, 113 mg).

Compound 100-5(110mg, 0.35mmol) was weighed out and dissolved in ethyl acetate (6mL), 10% palladium on carbon (24mg, 0.23mmol) was added and the apparatus was treated oxygen-free with exchange of air in the system with hydrogen. The reaction was carried out at room temperature overnight, ethyl acetate (10mL) was added to dilute the reaction mixture, the solid content in the reaction mixture was filtered off by suction filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate 2:1) to give 100-6 (colorless oil, 73 mg).

Under the protection of argon, anhydrous dichloromethane (14mL) and 1, 1-dichloromethyl ether (525 μ L,5.8 mmol) are sequentially added, the temperature is reduced to 0 ℃, titanium tetrachloride (763 μ L, 6.96mmol) is sequentially and slowly added dropwise, a solution of a compound 100-6(650mg, 2.9mmol) in anhydrous dichloromethane (8mL) is added dropwise, after the dropwise addition is completed, the temperature is kept unchanged, stirring is continued for 1h, after the reaction is completed, 1N hydrochloric acid (10mL) is added for dilution, the solution is transferred to a separating funnel, extraction is carried out by dichloromethane (10mL x3), organic phases are combined, the organic phases are washed by saturated saline (10mL x1), anhydrous sodium sulfate is dried, the solvent is evaporated under reduced pressure, and the residue containing the compound 100-7 is directly used for the next reaction without further purification.

The residue obtained from the post-reaction treatment of the above step containing the compound 100-7 was dissolved in acetone (20mL), potassium carbonate (520mg, 3.77mmol) was added, 1-chloropropanone (302 μ L, 3.77mmol) was slowly added dropwise, after completion of the dropwise addition, the mixture was refluxed at elevated temperature for 3 hours, after completion of the reaction, the reaction liquid was cooled to room temperature, insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate ═ 8:1-5:1) to obtain the compound 100-8 (yellow oily liquid, 314 mg).

Copper bromide (116mg, 0.52mmol) was weighed into a 50mL three-necked flask, ethyl acetate (15mL) was added, compound 100-8(105mg, 0.4mmol) was dissolved in ethyl acetate (8mL), and the ethyl acetate solution of compound 100-8 was added dropwise to the reaction system through a dropping funnel under reflux conditions, and after the addition was completed, reflux was continued for 4 h. After the reaction was completed, the solid content in the system was filtered off by suction filtration, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/dichloromethane ═ 2:1-1:9) to obtain 100-9 (yellow oily liquid, 72 mg).

Compound 100-9(100mg, 0.271mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (58mg, 0.325mmol) were weighed into a 35mL pressure-resistant reaction tube, followed by addition of isopropanol (6mL) and purging of the mixture solution with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 3 hours at the temperature of 130 ℃. After completion of the reaction, the reaction system was transferred into a 100mL flask with methylene chloride, and the solvent was distilled off under reduced pressure, and the residue containing compound 100-10 was used in the next reaction without further purification.

The residue obtained from the post-reaction treatment of the above step containing the compound 100-10 was dissolved in a mixed solvent of dichloromethane (15mL) and methanol (5mL), followed by addition of a methanol solution of sodium methoxide (4M, 170. mu.L) and reaction at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (10mL), the aqueous phase was extracted with dichloromethane (15mL × 3), the organic phases were combined, the organic phase was washed with a saturated saline solution (10mL × 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 ═ 8:1:1) to obtain compound 100 (white solid, 18 mg):¹H NMR(300MHz,DMSO-d₆)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] dioxadieno [2,3-g ] benzofuran-3-yl) acetic acid methyl ester (Compound 101)

Compound 100-9(67mg, 0.181mmol) and 5-methylsulfanyl-1, 3, 4-thiadiazol-2-amine (32mg, 0.22mmol) were weighed into a 15mL pressure-resistant reaction tube, then N, N-dimethylformamide (4mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath, and after 6 hours of reaction at the temperature of 80 ℃, the reaction is continued for 2 hours at the temperature of 110 ℃. After completion of the reaction, water (15mL) was added to dilute the reaction solution, and the reaction solution was extracted with ethyl acetate (10mL × 3), the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 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: 8:1:1-4:1:1) to obtain compound 101 (white solid, 42 mg):¹H NMR(300MHz,CDCl₃)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 C₁₈H₁₅N₃O₅S₂[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] dioxadieno [2,3-g ] benzofuran-3-yl) methanol (Compound 102)

Weighing compound 101(34mg, 0.0815mmol) and dissolving in methanol (2mL) and tetrahydrofuran (2mL) under the protection of argon, dropping a solution of lithium hydroxide monohydrate (4.5mg, 0.106mmol) in water (0.2mL) at 0 ℃, stirring the system at room temperature for 1 hour, filtering off solids in the system by suction filtration, washing the filter cake with water and ethanol, and drying under reduced pressure to remove the solvent to obtain compound 102 (white solid, 24 mg):¹H NMR(300MHz,DMSO-d₆)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 C₁₆H₁₃N₃O₄S₂[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] dioxadieno [2,3-g ] benzofuran-3-yl) methyl 4-methylbenzenesulfonate (Compound 103)

Weighing compound 102(104mg, 0.277mmol), dissolving in pyridine (13mL), adding 4-tosyl chloride (106mg, 0.554mmol) in portions at 0 ℃, reacting the system at room temperature overnight, adding saturated common salt water (5mL), diluting, extracting with dichloromethane (10mL x3), combining organic phases, washing the organic phases with 2N hydrochloric acid (10mL x3) and saturated common salt water (10mL x1), drying over anhydrous sodium sulfate, concentrating under reduced pressure, filteringThe residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane ═ 8:1:1-4:1:1) to give compound 103 (yellow solid, 85 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-8-yl) -2- (methylthio) imidazo [1,2-b ] [1,2,4] thiadiazole (compound 104)

Compound 100-8(511mg, 1.76mmol) was weighed out and dissolved in methanol (8mL), and a solution of sodium hydroxide (84mg, 2.11mmol) in water (2mL) was added dropwise at 0 ℃ and stirred at room temperature overnight. After completion of the reaction, 1N hydrochloric acid was added to adjust the solution pH to 1, the aqueous phase was extracted with dichloromethane (6mL × 3), the organic phases were combined, the organic phase was washed with saturated brine (5mL × 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 give compound 104-1 (yellow solid, 300 mg).

Compound 104-1(81mg, 0.297mmol) was dissolved in anhydrous dichloromethane (8mL) under an argon atmosphere, triethylamine (103. mu.L, 0.744mmol) was added at 0 ℃, a solution of 4-toluenesulfonyl chloride (85mg, 0.446mmol) in anhydrous dichloromethane (2mL) was added dropwise, and after the addition was completed, the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched by addition of water (6mL), the aqueous phase was extracted with dichloromethane (6mL × 3), the organic phases were combined, washed with saturated brine (5mL × 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 ═ 5:1) to give compound 104-2 (white solid, 104 mg).

Copper bromide (40mg, 0.175mmol) was weighed into a 50mL three-necked flask, ethyl acetate (8mL) was added, compound 104-2(50mg, 0.134mmol) was dissolved in ethyl acetate (10mL), and the ethyl acetate solution of compound 104-2 was added dropwise to the reaction system through a dropping funnel under reflux conditions, and after the addition was completed, reflux was continued for 4 h. After the reaction, the solid content in the system was filtered off by suction filtration, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane 8:1:1-6:1:1) to obtain compound 104-3 (white solid, 35 mg).

Compound 104-3(55mg, 0.114mmol) and 5-methylsulfanyl-1, 3, 4-thiadiazol-2-amine (20mg, 0.137mmol) were weighed into a 15mL pressure-resistant reaction tube, then N, N-dimethylformamide (4mL) was added, and the mixture solution was purged with argon for 5 min. The system is moved into an oil bath and reacts for 5 hours at the temperature of 90 ℃, and then the reaction is continued for 3 hours at the temperature of 120 ℃. After completion of the reaction, water (15mL) was added to dilute the reaction solution, and the reaction solution was extracted with ethyl acetate (8mL × 3), the organic phase was washed with water (5mL × 3) and saturated brine (5mL × 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 8:1:1-7:1:1) to give compound 104 (yellow solid, 22 mg):¹H NMR(300MHz,CDCl₃)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.for C₁₆H₁₂BrN₃O₃S₂[M+H]⁺437.9503,found:437.9576

example 105

(8- (6-methylimidazo [1,2-b ] pyridazin-2-yl) -2, 3-dihydro- [1,4] dioxino [2,3-g ] benzofuran-3-yl) methyl 4-methylbenzenesulfonate (Compound 105)

Compound 104-3(102mg, 0.212mmol) and 3-amino-6-methylpyridazine (35mg, 0.318mmol) were weighed into a 35mL pressure-resistant reaction tube, followed by addition of isopropanol (10mL) and purging of the mixture solution with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ℃ for 12 h. After the reaction is finished, the solvent is distilled off under reduced pressure, and the residue is subjected to column chromatography (elution)Preparation: purification of petroleum ether/ethyl acetate/dichloromethane ═ 8:1:1-2:1:1) gave compound 105 (yellow solid, 58 mg):¹H NMR(300MHz,CDCl₃)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 C₂₅H₂₁N₃O₃S[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] dioxadieno [2,3-g ] benzofuran-3-yl) methylthiomorpholine-4-carboxylate 1, 1-dioxide (Compound 106)

Compound 102(48mg, 0.128mmol) was weighed out and dissolved in dry tetrahydrofuran (5mL), triethylamine (500. mu.L, 0.32mmol) was added at 0 ℃, a solution of p-nitrophenyl chloroformate (52mg, 0.256mmol) in dry tetrahydrofuran (1mL) was added dropwise, and after completion, the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched by addition of water (15mL), the pH of the aqueous phase was adjusted to 1 with 1N hydrochloric acid, the aqueous phase was extracted with dichloromethane (10mL × 3), the organic phases were combined, washed with saturated saline (10mL × 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 ═ 8:1:1-4:1:1) to give compound 106-1 (yellow solid, 17 mg).

Compound 106-1(30mg, 0.056mmol) was weighed out and dissolved in anhydrous N, N-dimethylformamide (5mL), N-diisopropylethylamine (14. mu.L, 0.083mmol), thiomorpholine-1, 1-dioxide (9mg, 0.067mmol) were added successively at room temperature, and after the addition, stirring was carried out at room temperature overnight. After completion of the reaction, water (15mL) was added for dilution, the aqueous phase was extracted with ethyl acetate (8mL x3), the organic phases were combined, the organic phase was washed with water (8mL x3) and saturated brine (8mL x1), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum oil: eluent: solvent)Purification of ether/ethyl acetate/dichloromethane ═ 8:1:1-1:1:1) gave compound 106 (white solid, 12mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-3-yl) methyl (2- (4-methylpiperazin-1-yl) ethyl) carbamate (Compound 107)

Compound 106-1(25mg, 0.046mmol) was weighed and dissolved in anhydrous N, N-dimethylformamide (4mL), and N, N-diisopropylethylamine (11. mu.L, 0.07mmol) and 4-methyl-1-piperazineethylamine (9. mu.L, 0.056mmol) were added sequentially at room temperature, and after the addition was completed, the mixture was stirred at room temperature overnight. After completion of the reaction, water (10mL) was added for dilution, the aqueous phase was extracted with ethyl acetate (10mL × 3), the organic phases were combined, the organic phase was washed with water (10mL × 3) and saturated brine (10mL × 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 ═ 1:1:1-1:3:3) to give compound 107 (yellow solid, 25 mg):¹H NMR(300MHz,CDCl₃)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] dioxadieno [2,3-g ] benzofuran-3-yl) methyl (2- (4-methylpiperazin-1-yl) ethyl) carbamate (Compound 108)

Compound 106-1(24mg, 0.045mmol) was weighed and dissolved in anhydrous N, N-dimethylformamide (4mL), and N, N-diisopropylethylamine (11. mu.L, 0.067mmol) and morpholine (5. mu.L, 0.0533mmol) were added sequentially at room temperature, and after the addition, the mixture was stirred at room temperature overnight. After completion of the reaction, water (15mL) was added for dilution, the aqueous phase was extracted with ethyl acetate (8mL × 2), the organic phases were combined, the organic phase was washed with water (8mL × 3) and saturated brine (8mL × 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 ═ 6:1:1-1:1:1), to give compound 108 (white solid, 18 mg):¹H NMR(300MHz,CDCl₃)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 anti-platelet aggregation Activity in vitro

The test principle is as follows: AYP is a specific agonist peptide of PAR4, and has sequence of AYPGKF-NH₂Can selectively activate PAR4 to cause platelet aggregation, and the compound can antagonize platelet PAR4 to inhibit platelet aggregation. The platelet aggregation inhibition rate may reflect the activity of the compound. The test used filtered platelets taken from mouse arterial plasma.

Platelet aggregation assay: sucking 300. mu.L of Tyrode's buffer, placing the buffer in a test area of a platelet aggregation instrument, adjusting to zero, sucking 270. mu.L of filtered platelets, placing the filtered platelets in a preheating tank, adding 20. mu.L of each test sample (the concentration of the compound is 20nM), preheating at 37 ℃ for 5min, placing the filtered platelets in the test area, adding test beads and 10. mu.L of AYP, and measuring the maximum aggregation rate of the platelets within 5 min. Wherein the negative control group was normal saline. The aggregation inhibition rate of platelets was calculated by the following formula. Calculating the formula: the platelet aggregation inhibition rate is [ (X-Y)/X ] 100%, wherein X is the maximum platelet aggregation rate in the saline group, and Y is the maximum platelet aggregation rate of the compound. The results of the experiments for some of the compounds are shown in table 2.

TABLE 2 inhibition of AYP-induced platelet aggregation by Compounds

The experimental results (table 2) show that when the concentration of the inducer AYP is 100 μ M and the concentration of the compound is 20nM, the inhibition rate of the 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 and 98 on the in vitro filtered platelet aggregation exceeds that of BMS-986120, and the compounds of the present invention have excellent anti-platelet aggregation activity. For example, the test patterns of the inhibition rates of compound 11 and compound 88 on in vitro filtered platelet aggregation are shown in fig. 1 and fig. 2, respectively.

Example 110

Study on metabolic stability of compound to human liver microsome

The evaluation of the metabolic stability of human liver microsome is an important means for evaluating the pharmacokinetic properties of candidate compounds in the preclinical process of drug development.

An experimental incubation system (volume 250 μ L, n ═ 3) was prepared by incubating liver microsomes, a sample working solution and a phosphate buffer solution at 37 ℃ for one hour, adding an NADPH solution, and then timing, and terminating the reaction at each time point by adding a stop solution, wherein the sampling time points were 0, 5, 15, 30 and 60min, and the total time points were 5. Negative control without NADPH,

sampling time point

0, 60 min. Analysis by LC-MS/MS, slope was determined by plotting the natural logarithm of the percentage of the remaining test substance against timeThe absolute value k of the ratio is calculated according to the following formula: t is_1/2(half-life) ═ ln2/k ═ 0.693/k. The results of the experiment are shown in table 3.

TABLE 3 Metabolic stability Studies of some Compounds in human liver microsomes

The results of the experiments (Table 3) show that the compounds 9, 11, 13, 30, 31, 38, 47, 86 and 88 of the invention have improved hepatic microsome metabolic stability compared with BMS-986120, and T is higher than that of BMS-986120_1/2There was an increase and the stability of compounds 30, 38, 86 was significantly improved. This shows that some compounds of the present invention have better metabolic stability in the organism, which may reduce the liver first-pass effect of the drug, and show that the compounds of the present invention have better pharmacokinetic properties.

Example 111

Tablet formulation

Compound 11(50g) obtained in example 11, hydroxypropylmethylcellulose E (150g), starch (200g), povidone K30, and magnesium stearate (1g) were mixed, granulated, and tabletted.

Claims

1. A compound shown below, or a pharmaceutically acceptable salt thereof:

2. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

3. a pharmaceutical composition comprising as an active ingredient a compound according to any one of claims 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

4. Use of a compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis or treatment of a thromboembolic disorder.

5. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, oral liquid, inhalant, ointment, suppository, or patch.