Enyne compound and use thereof

Abstract

Provided are an enyne compound and a use thereof. Specifically, provided are a compound represented by Formula I, or a pharmaceutically acceptable salt thereof, functional groups being as defined in the text. Also provided are a method for preparing the compound of Formula I, a pharmaceutical composition containing the compound, a use thereof as a therapeutic, in particular a use thereof as an SMARCA2 inhibitor, and a use thereof in the preparation of a medicament for preventing and / or treating cancer.

Description

Enyne compound and application thereof TECHNICAL FIELD

[0001] The present disclosure belongs to the field of medicine and relates to an enyne compound and application thereof. BACKGROUND

[0002] Gene regulation is essential for the proper execution of all biological processes. Over 3.2 billion DNA base pairs in each human cell are compressed into higher-order chromatin structures, the dynamic regulation of which is essential to ensure the correct timing, location, and order of events.

[0003] SWI / SNF (S Witch / Sucrose Nonfermentable) is a chromatin remodeling complex (CRC) that utilizes the energy of ATP hydrolysis to reposition nucleosomes, thereby regulating access to DNA and modulating transcription and DNA replication / repair, which has two SWI2-like ATPases, BRG1 (Brahma-Related Gene 1) and BRM (Brahma). BRG1, also known as ATP-dependent chromatin-remodeling agent SMARCA4, is overexpressed in some cancer tumors and is essential for cancer cell proliferation. BRM is also known as global transcriptional activator SNF2L2 and / or ATP-dependent chromatin-remodeling factor SMARCA2. One of SMARCA2 and SMARCA4 must be present in the BAF complex to enable chromatin reorganization processes, and when one of SMARCA2 and SMARCA4 is damaged or lost, SMARCA2 and SMARCA4 can compensate for each other's functions. Functional gene screening shows that there is a synthetic lethal relationship between SMARCA2 and SMARCA4 (Cancer Cell. 2014; 26, 309-317). Since SMARCA4 is a common mutation in various tumor cells, accounting for about 10% in non-small cell lung cancer (J. Med. Chem. 2018; 61, 10155-10172). Therefore, selective inhibition of SMARCA2 for tumor cells characterized by SMARCA4 functional mutations or deletions can significantly slow down the growth of tumor cells.

[0004] Papillon, J.P.N. et al. reported a series of dual ATPase inhibitors of SMARCA2 and SMARCA4. These compounds can effectively inhibit the growth of SMARCA4 mutant cancer cell lines (J. Med. Chem. 2018; 61, 10155-10172).

[0005] In addition, other selective SMARCA2 inhibitors have also been reported one after another, such as WO2022103899, WO2023220219 and WO2024088351, and no SMARCA2 / 4 inhibitor has been marketed so far, and the compounds of the present disclosure have not been disclosed in any literature, and such compounds exhibit good selective inhibitory effect on SMARCA2 / 4. SUMMARY

[0006] The present disclosure provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof

[0007] wherein R 1 is selected from hydrogen, halogen, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each independently optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each independently optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy;

[0008] R 2 is selected from hydrogen, halogen, amino, C 1-6 alkyl and C 1-6 alkoxy, each independently optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy; 1-6 1-

[0009] X 1 is selected from N or CR 1a , R 1a is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each independently optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each independently optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy;

[0010] X 2 ​​Selected from -S-, -SO-, -SO2- and -S(O)(=NH)-;

[0011] R 3 It is hydrogen or C 1-6 Alkyl, the C 1-6 Alkyl groups may be selected from one or more groups chosen from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 The alkoxy group is replaced;

[0012] Each R 4 and R 5 Each is independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally selected from one or more groups chosen from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 The alkoxy group is replaced.

[0013] Or, R 4 R 5 Together with the attached carbon atom, they form C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 3-6 The cycloalkyl group and the 3- to 6-membered heterocycloalkyl group are each independently and optionally selected from one or more halogen, oxo, hydroxy, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 The alkoxy group is replaced;

[0014] L 1 It is a 5-10-membered heterocyclic alkyl or a 5-10-membered heteroaryl, wherein each of the 5-10-membered heterocyclic alkyl and 5-10-membered heteroaryl groups is independently and optionally selected from one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 The group substituted in the alkoxy group, the C 1-6 Alkyl and C 1-6 Each alkoxy group may be independently and optionally replaced by one or more groups selected from halogen, hydroxyl, cyano, nitro, and amino groups;

[0015] Ring A is a C6 aromatic ring or a 5- to 6-membered heteroaromatic ring;

[0016] R 6 Selected from C 2-6 alkenyl, C 2-6 acetylinyl and -OC 2-6 alkenyl, the C 2-6 alkenyl, C 2-6 acetylinyl and -OC2-6 each alkenyl group is independently optionally substituted with one or more R 2a substituents;

[0017] R 2a each R is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkenyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 alkenyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl, each independently optionally substituted with one or more groups selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, and C 1-6 alkoxy groups, or two R 2a groups attached to the same carbon atom form a C 3-8 cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, said C 3-8 cycloalkyl, and 3- to 8-membered heterocycloalkyl, each independently optionally substituted with one or more groups selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, and C 1-6 alkoxy groups;

[0018] R 7 each R is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2- alkynyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 3-10 cycloalkoxy, 3- to 10-membered heterocycloalkoxy, and -O-C 2-6 alkenyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3- 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 3-10 cycloalkoxy, 3- to 10-membered heterocycloalkoxy, and -O-C 2-6 each alkenyl group is independently optionally substituted with one or more R 3a substituents;

[0019] R 3a each R is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl, said C1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl or 3- to 10-membered heterocyclic alkyl group is independently selected from one or more groups chosen from halogen, oxo, hydroxy, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 The alkoxy group is replaced;

[0020] R 8 Selected from hydrogen, halogen, hydroxyl, amino, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally selected from one or more groups chosen from halogen, oxo, hydroxyl, cyano, nitro, amino, C. 1-6 Alkyl and C 1-6 The alkoxy group is replaced;

[0021] R 9 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally selected from one or more groups chosen from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 The group that replaces the alkoxy group, or two R atoms attached to the same atom. 9 Formation = O;

[0022] X 3 Selected from O, NR 4a and C(R) 4b )2, Z 1 and Z 2 Each is independently selected from the bond, O, and -C(R) 5a )2-, and the condition is that X 3 When Z is 0, then 1 and Z 2 Independently for the key or -C(R) 5a )2-;

[0023] R 4a It is hydrogen or C 1-6 Alkyl, the C 1-6 Alkyl groups may be selected from one or more groups chosen from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 The alkoxy group is replaced;

[0024] R 4b Each is independently selected from hydrogen, halogen, nitro, cyano, amino, C1-6 alkyl, C 1-6 alkoxy, C 3- 6cycloalkyl and 3- to 6-membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are each independently optionally substituted with one or more halogen, oxo, hydroxy, cyano, nitro, amino, C 1- 6alkyl and C 1-6 alkoxy, or two R 4b together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl, said C 3-8 cycloalkyl and 3- to 8-membered heterocycloalkyl are each independently optionally substituted with one or more halogen, oxo, hydroxy, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy;

[0025] R 5a each independently selected from the group consisting of hydrogen, halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3- 6cycloalkyl and 3- to 6-membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are each independently optionally substituted with one or more halogen, oxo, hydroxy, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy, or two R 5a together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl, said C 3-8 cycloalkyl and 3- to 8-membered heterocycloalkyl are each independently optionally substituted with one or more halogen, oxo, hydroxy, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy;

[0026] m is 0, 1, 2 or 3;

[0027] n is 0, 1 or 2;

[0028] o is 0, 1, 2, 3 or 4.

[0029] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is a compound of Formula la, or a pharmaceutically acceptable salt thereof

[0030] In some embodiments, X in the compound of formula I or a pharmaceutically acceptable salt thereof 1 For CR 1a R 1a As defined above.

[0031] On the other hand, in some embodiments, L in the compound of formula I or its pharmaceutically acceptable salt 1 for Where X 4 X 5 X 6 X 7 X 8 X 9 Each is independently N or CR 6a R 6a Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group and the 3- to 6-membered heterocycloalkyl group are each independently and optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 The alkoxy group is replaced;

[0032] A 1 End and Connected, A 2 End and Connected.

[0033] In some implementation schemes, X 5 For N. In some implementations, X 5 Let N, X 4 For CR 6a .

[0034] In some embodiments, L in the compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from Where A 1 and A 2 As defined above.

[0035] In some embodiments, L in the compound of formula I or a pharmaceutically acceptable salt thereof 1 for Where A 1 and A 2 As defined above.

[0036] In some embodiments, X in the compound of formula I or a pharmaceutically acceptable salt thereof3 is O.

[0037] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is a compound of Formula II, or a pharmaceutically acceptable salt thereof 1 is a bond or C(R 5a )2, R 5a is as previously defined.

[0038] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is a compound of Formula II, or a pharmaceutically acceptable salt thereof 1 is a bond.

[0039] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is a compound of Formula II, or a pharmaceutically acceptable salt thereof 3 is selected from hydrogen, methyl, ethyl, and propyl.

[0040] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is a compound of Formula II, or a pharmaceutically acceptable salt thereof 3 is hydrogen.

[0041] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is a compound of Formula II, or a pharmaceutically acceptable salt thereof 2 is -S- or -SO2-.

[0042] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is a compound of Formula II, or a pharmaceutically acceptable salt thereof 2 is -S(O)(=NH)-.

[0043] Some embodiments provide a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein is selected from

[0044] Some embodiments provide a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein is

[0045] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is a compound of Formula IIa, or a pharmaceutically acceptable salt thereof wherein R 1 , R 2 , R 4 , R 9 , R 5a , X 1 , ring A, m, n, and o are as defined in the compound of Formula I; p is 0, 1, 2, 3, or 4; and each R 7a is independently selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-6The cycloalkyl group and the 3- to 6-membered heterocycloalkyl group are each independently and optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 The group in the alkoxy group is replaced.

[0046] In some embodiments, R in the compound of formula IIa or its pharmaceutically acceptable salt 7a Each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally selected from one or more groups chosen from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 The alkoxy group is substituted. In some embodiments, R in the compound of formula IIa or its pharmaceutically acceptable salt is... 7a Each can be a halogen, such as fluorine or chlorine.

[0047] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is the compound of formula IIa-1 or a pharmaceutically acceptable salt thereof. Where R 1 ~R 2 R 4 ~R 9 R 5a X 1 The rings A, m, n, and o are defined in the compound shown in Formula I.

[0048] On the other hand, L in the compound shown in Formula I or its pharmaceutically acceptable salt 1 for Where X 4 X 5 X 6 and X 10 Each is independently N or CR 6a R 6a Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3 to 6-membered heterocyclic alkyl groups, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclic alkyl groups is independently and optionally selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1- 6-alkyl and C 1-6 The alkoxy group is replaced;

[0049] A 1 End and The connected key, A 2 End and Connected.

[0050] In some embodiments, X 4 is N. 5 In some embodiments, X 6 is N. 10 In some embodiments, at least one of X

[0051] In some embodiments, X 5 is N. In some embodiments, X 5 is N, X 4 is CR 6a In some embodiments, X 5 is N, X 4 , X 6 , and X 10 are each CR 6a In some embodiments, X 5 is N, X 6 , and X 10 are each CH, X 4 is CR 6a In some embodiments, X 5 is N, X 4 , X 6 , and X 10 are each CH. In some embodiments, X 5 , and X 6 are each N.

[0052] In some embodiments, X 4 is CR 6a , each R 6a is independently selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, each of said alkyl, alkoxy, cycloalkyl, and heterocycloalkyl being independently optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, and C 1-6 alkoxy.

[0053] In some embodiments, X 4 is CR 6a , each R 6a is independently selected from the group consisting of halogen (such as fluorine), C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, each of said alkyl, alkoxy, cycloalkyl, and heterocycloalkyl being independently optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, and C 1-6 alkoxy.

[0054] In some implementation schemes, X 4 For CR 6a R 6a Each is an independent halogen (such as fluorine).

[0055] In some implementation schemes, X 4 For CR 6a R 6a Each independently is C 1-6 Alkyl or C 1-6 Alkoxy groups, such as methyl, ethyl, methoxy, or ethoxy.

[0056] In some implementations, L1 is selected from R 6a Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group and the 3- to 6-membered heterocycloalkyl group are each independently and optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 The group in the alkoxy group is replaced; A 1 End and Connected, A 2 End and Connected.

[0057] In some implementations, L1 is selected from A 1 End and Connected, A 2 End and Connected.

[0058] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is the compound of formula IIb or a pharmaceutically acceptable salt thereof. Where R 1 ~R 2 R 4 ~R 9 R 5a X 1 Rings A, m, n, and o are defined as in compounds of formula I; p is 0, 1, 2, 3, or 4; R 7a Each is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6cycloalkyl and 3- to 6-membered heterocycloalkyl, each independently optionally substituted with one or more radicals selected from the group consisting of halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each independently optionally substituted with one or more radicals selected from the group consisting of halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy, said C

[0059] In some embodiments, the compound of Formula IIb, or pharmaceutically acceptable salt thereof, is 7a each independently selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 alkoxy, said C 1-6 alkyl and C 1-6 alkoxy, each independently optionally substituted with one or more radicals selected from the group consisting of halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy. In some embodiments, the compound of Formula IIb, or pharmaceutically acceptable salt thereof, is 7a each independently halogen, such as fluorine or chlorine.

[0060] In some embodiments, the compound of Formula I, or pharmaceutically acceptable salt thereof, is a compound of Formula IIb-1, or pharmaceutically acceptable salt thereof wherein R 1 ~R 2 , R 4 ~R 9 , R 5a , X 1 , ring A, m, n and o are as defined in the compound of Formula I.

[0061] In some embodiments, the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1, or pharmaceutically acceptable salt thereof, is a compound of Formula IIb-2, or pharmaceutically acceptable salt thereof 4 and R 5 each independently selected from the group consisting of hydrogen, halogen and C 1-6 alkyl (e.g., methyl, ethyl).

[0062] In some embodiments, the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1, or pharmaceutically acceptable salt thereof, is a compound of Formula IIb-2, or pharmaceutically acceptable salt thereof 4 and R 5 each independently hydrogen.

[0063] In other embodiments, the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1, or pharmaceutically acceptable salt thereof, is a compound of Formula IIb-2, or pharmaceutically acceptable salt thereof

[0064] In other embodiments, the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: wherein R 6 , R 7 and o are as previously defined.

[0065] In some embodiments, the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1, or a pharmaceutically acceptable salt thereof, is In some embodiments, the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1, or a pharmaceutically acceptable salt thereof, is

[0066] In some embodiments, the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1, or a pharmaceutically acceptable salt thereof, is

[0067] In some embodiments, the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1, or a pharmaceutically acceptable salt thereof, is

[0068] In another aspect, the present disclosure provides a compound of Formula I selected from the group consisting of:

[0069] wherein R 1 , R 2 , R 4 , R 9 , R 5a , X 1 , R 6a , m, n and o are as previously defined.

[0070] In other embodiments, the compound of Formula I is selected from the group consisting of:

[0071] wherein R 1 , R 2 , R 4 , R 9 , R 5a , X 1 , R 6a , m, n and o are as previously defined.

[0072] ​​​​In some embodiments, the compound represented by Formula III-12 is the same as the compound represented by Formula III-7.

[0073] Where R 1 ~R 2 R 4 ~R 9 R 5a X 1 m, n and o are as defined above.

[0074] In some embodiments, the compound represented by formula III-12 is the compound represented by formula III-12a.

[0075] Where R 1 ~R 2 R 4 ~R 9 R 5a X 1 m, n and o are as defined above.

[0076] In some embodiments, R in the compound of formula I or IIa or IIb or IIa-1 or IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12 or a pharmaceutically acceptable salt thereof 6 C 2-6 alkenyl or C 2-6 alkynyl group, the C 2-6 alkenyl and C 2-6 Each alkynyl group is independently and optionally influenced by one or more R groups. 2a What it replaced.

[0077] In some embodiments, R in the compound of formula I or IIa or IIb or IIa-1 or IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12 or a pharmaceutically acceptable salt thereof 6 Selected from one or more R 2a The replaced vinyl, ethynyl, propynyl and propynyl groups.

[0078] In other embodiments, R in the compound of formula I or IIa or IIb or IIa-1 or IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12 or a pharmaceutically acceptable salt thereof 6-O-C 2-6 alkenyl, said -O-C 2-6 alkenyl is optionally substituted with one or more R 2a substituents.

[0079] In some embodiments, the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, is 6 -O-vinyl or -O-propenyl optionally substituted with one or more R 2a substituents.

[0080] In some embodiments, the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, is 2a halo, hydroxyl, C 1-6 alkyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl, each independently optionally substituted with one or more R 1-6 halo, hydroxyl, C 3-10 alkyl, C 1-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, each independently optionally substituted with one or more R 1-6 alkoxy.

[0081] In some embodiments, the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, is 2a halo, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, each independently optionally substituted with one or more R 1-6 halo, hydroxyl, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, each independently optionally substituted with one or more R

[0082] In some embodiments, in the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12 or a pharmaceutically acceptable salt thereof, R 2a each independently is amino.

[0083] In some embodiments, in the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12 or a pharmaceutically acceptable salt thereof, R 2a is selected from halo, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, and cyclopentyl.

[0084] In some embodiments, in the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12 or a pharmaceutically acceptable salt thereof, R 2a each independently is amino or hydroxyl.

[0085] In some embodiments, in the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12 or a pharmaceutically acceptable salt thereof, R 2a is 3- to 6-membered heterocycloalkyl optionally substituted with one or more groups selected from halo, oxo, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, and C 1-6 alkoxy, for example tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, or morpholinyl.

[0086] In some embodiments, in the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12 or a pharmaceutically acceptable salt thereof, R 2a is selected from halo, oxo, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, and C 1-6 alkoxy, for example tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, or morpholinyl.

[0087] In some embodiments, the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12 or a pharmaceutically acceptable salt thereof, R 2a is cyclopropyl or cyclobutyl optionally substituted with one or more groups selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, and C 1-6 alkoxy.

[0088] In some embodiments, the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12 or a pharmaceutically acceptable salt thereof, R 2a is C 3-10 cycloalkyl (including spiro, fused, or bridged rings, for example or ).

[0089] In some embodiments, the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12 or a pharmaceutically acceptable salt thereof, R 2a is cyclopropyl or cyclobutyl optionally substituted with one or more groups selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, and C 1-6 alkoxy.

[0090] In some embodiments, the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12 or a pharmaceutically acceptable salt thereof, R 2a each independently selected from halogen, amino (-N(R a )2), hydroxyl, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, or morpholinyl, R a each independently selected from hydrogen, C 1-6 alkyl, C 3-6cycloalkyl and 3- to 6-membered heterocycloalkyl, or two R 2a form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

[0091] In some embodiments, the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, is 2a each independently selected from halogen, amino (-N(R a )2), hydroxyl, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, or morpholinyl, R a each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, or two R 2a form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

[0092] In some embodiments, the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, is 2a is and two R 2a form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

[0093] In some embodiments, the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, is a each independently selected from hydrogen, methyl, ethyl, and propyl.

[0094] In another aspect, in some embodiments, the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, is 7 each independently selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy and C 3-10 cycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy and C 3-10 cycloalkyl are each independently optionally substituted with one or more R3a substituted.

[0095] In some embodiments, in the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, R 7 each independently selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy and C 3-6 cycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy and C 3-6 cycloalkyl each independently optionally substituted with one or more R 3a substituted.

[0096] In some embodiments, in the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, R 7 each independently selected from C 2-6 alkenyl, C 2-6 alkynyl and -O-C 2-6 alkenyl, said C 2- 6alkenyl, C 2-6 alkynyl or -O-C 2-6 alkenyl each independently optionally substituted with one or more R 3a substituted.

[0097] In some embodiments, in the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, R 7 each independently selected from fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy and ethoxy.

[0098] In some embodiments, in the compound of Formula I or Ha or lib or Ha-I or lib-I or III-I or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, R 7each independently selected from difluoromethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.

[0099] In some embodiments, in the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, R 7 each independently selected from fluorine, chlorine, cyclopropylmethyloxy, cyclopropyloxy, and cyclobutyloxy.

[0100] In some embodiments, in the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, R 1 is selected from hydrogen, halogen, and C 1-6 alkyl, said alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, and C 1-6 alkoxy.

[0101] In some embodiments, in the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, R 1 is selected from hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl, and propyl.

[0102] In some embodiments, in the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, R 2 is selected from hydrogen, halogen, and C 1-6 alkyl, said alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, and C 1-6 alkoxy.

[0103] In some embodiments, in the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, R 2 is selected from hydrogen, fluorine, chlorine, bromine, methyl, difluoromethyl, trifluoromethyl, ethyl, and propyl.

[0104] In some embodiments, in the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, R 1a is selected from hydrogen, halogen, and C 1-6 alkyl, said alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, and C 1-6 alkoxy.

[0105] In some embodiments, in the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, R 1a is selected from hydrogen, fluorine, chlorine, bromine, methyl, difluoromethyl, trifluoromethyl, ethyl, and propyl.

[0106] In some embodiments, in the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, R 8 is selected from hydrogen, halogen, and C 1-6 alkyl, said alkyl being optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, and C 1-6 alkoxy.

[0107] In some embodiments, in the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, R 8 is selected from hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl, and propyl.

[0108] In some embodiments, in the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, n is 0 or 1.

[0109] In some embodiments, in the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, m is 0, 1, or 2.

[0110] In some embodiments, in the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, o is 0 or 1.

[0111] In some embodiments, in the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, X 3 is N.

[0112] In some embodiments, in the compound of Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, R 5a are each independently selected from hydrogen, halogen, and C 1-6alkyl, said alkyl is optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy, said alkyl and C

[0113] In some embodiments, the compound of Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, is 5a each independently selected from the group consisting of hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl and propyl.

[0114] In some embodiments, the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, is 2a forms a C 3-8 cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0115] In some embodiments, the compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12, or a pharmaceutically acceptable salt thereof, is 2a forms a 3- to 8-membered heterocycloalkyl, for example oxetanyl, oxetanyl or oxetanyl.

[0116] In other embodiments, the compound of Formula IIa or IIb or Formula IIa-1 or Formula IIb-1, or a pharmaceutically acceptable salt thereof, is is

[0117] The compounds of the present disclosure include, but are not limited to

[0118] In another aspect, the compounds of the present disclosure include, but are not limited to

[0119] In some embodiments, the compound of Formula I is selected from:

[0120] In other embodiments, the compound of Formula I is selected from:

[0121] In other embodiments, the compound of Formula I is selected from:

[0122] The present disclosure also provides isotopically-substituted versions of the foregoing compounds or pharmaceutically acceptable salts thereof. In some embodiments, the isotopically-substituted versions are deuterated versions.

[0123] The present disclosure also provides nitroxides of the foregoing compounds or pharmaceutically acceptable salts thereof.

[0124] In assays that measure the ATPase catalytic activity of BRM or BRG-1, in some embodiments, the compounds of the present disclosure have an IC50 value for SMARCA2 inhibitory activity of 0.01 to 50 nM. In some embodiments, the compounds of the present disclosure have an IC50 value for SMARCA2 inhibitory activity of 0.1 to 20 nM. In some embodiments, the compounds of the present disclosure have an IC50 value for SMARCA2 inhibitory activity of 1 to 20 nM. Also, in some embodiments, the compounds of the present disclosure exhibit selective inhibitory activity for SMARCA2.

[0125] Also provided in the present disclosure is a pharmaceutical composition comprising at least one therapeutically effective amount of the foregoing compound of Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12 or a pharmaceutically acceptable salt thereof, or an isotopically-substituted version thereof, and a pharmaceutically acceptable excipient.

[0126] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the foregoing compound or a pharmaceutically acceptable salt thereof or an isotopically-substituted version thereof, based on the total weight of the composition.

[0127] In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-substituted version thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-substituted version thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-substituted version thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-substituted version thereof.

[0128] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.

[0129] Also provided in the present disclosure is a combination comprising the aforementioned pharmaceutical composition, and instructions for using the pharmaceutical composition.

[0130] The present disclosure also provides a method for preventing and / or treating cancer by administering to the individual a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition.

[0131] The present disclosure also provides use of a compound as shown in the aforementioned Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12 or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the manufacture of a medicament for preventing and / or treating cancer.

[0132] The present disclosure also provides a compound as shown in the aforementioned Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12 or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition, which acts as a medicament.

[0133] The present disclosure also provides a compound as shown in the aforementioned Formula I or Formula IIa or IIb or Formula IIa-1 or Formula IIb-1 or III-1 or III-2 or III-3 or III-4 or III-5 or III-6 or III-7 or III-8 or III-9 or III-10 or III-11 or III-12 or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition for use in the prevention and / or treatment of cancer.

[0134] In some embodiments, the aforementioned cancer is selected from lung cancer, intestinal cancer, breast cancer, melanoma, skin cancer, lymphoma, prostate cancer.

[0135] The pharmaceutically acceptable salt of the compound described in the present disclosure can be selected from inorganic salts or organic salts.

[0136] The salt of the compound described in the present disclosure is selected from inorganic salts or organic salts.

[0137] In another aspect, the present disclosure also provides a method for preparing a compound as shown in Formula I or a pharmaceutically acceptable salt thereof

[0138] which comprises a step of reacting a compound as shown in Formula A with a compound as shown in Formula B to form a compound as shown in Formula I,

[0139] wherein R 1 ~R 9 , X 1 , X 2 , X 3 , Z 1 , Z 2 , L 1 , ring A, m, n and o are defined as in the compound of Formula I, and PG1 is selected from hydroxyl or a leaving group (such as halogen or an ester group, including methyl or ethyl ester).

[0140] The present disclosure also provides a compound as shown in Formula B or a salt thereof wherein R 3 ~R 7 , L 1 , ring A, n and o are defined as in the compound of Formula I. In some embodiments, R 3 in the compound of Formula B is hydrogen.

[0141] In some embodiments, L 1 in the compound of Formula B is selected from wherein X 4 , X 5 , X 6 and X 10 are each independently N or CR 6a , and X 4 , X 5 , X6 and X 10 at least one of N, R 6a each independently selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each independently optionally substituted with one or more groups selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy;

[0142] A 1 terminus is connected to A 2 terminus is connected to A

[0143] In some embodiments, the compound of Formula B is selected from: wherein R 6 , R 7 and o are as defined in the compound of Formula I.

[0144] In some embodiments, the compound of Formula B or salt thereof is selected from:

[0145] wherein R 4 , R 5 , R 6 , R 7 and n, o are as defined in the compound of Formula I; R 6a is as previously defined.

[0146] In some embodiments, wherein R 4 , R 5 , R 6 , R 7 , n and o are as defined in the compound of Formula I.

[0147] Another aspect of the present disclosure also provides a method of preparing a compound of Formula B or salt thereof, comprising the step of reacting a compound of Formula C,

[0148] wherein R 3 to R 7 , L 1 , ring A, n and o are as defined in the compound of Formula I; PG2 is a protecting group, for example -Boc.​​

[0149] The present disclosure also provides a compound of Formula C wherein R 3 ~R 7 , L 1 , ring A, n and o are defined as in Formula I; PG2is a protecting group, for example -Boc.

[0150] The compounds of the present disclosure can exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-forms, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as racemic mixtures and other mixtures thereof, e.g., mixtures of enantiomers or diastereomers, all of which are intended to be within the scope of the present disclosure. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are included within the scope of the present disclosure. Compounds of the present disclosure containing unsaturated carbon-carbon bonds can exist in (E)- and (Z)- forms. The present disclosure contemplates both (E)- and (Z)- forms.

[0151] Optically active (R)- and (S)-isomers, and D and L isomers, can be prepared by chiral synthesis or by chiral reagents or other conventional techniques. If desired, one enantiomer of a compound of the present disclosure can be obtained by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl) is present in the molecule, diastereomeric salts can be formed with an appropriate optically active acid or base, and the diastereomeric salt separated by conventional means, and the pure enantiomer recovered by treating with base or acid, as the case can be. In addition, separation of the enantiomers and diastereomers is typically accomplished by chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).

[0152] In the chemical structures of the compounds of the present disclosure, the bond indicates that the configuration is not specified, i.e., if chiral isomers are present in the chemical structure, the bond may be or both configurations.

[0153] For example if chiral isomers are present, both and configurations are included, e.g. ​

[0154] In the chemical structure of the compounds of the present disclosure, the bond is not specified as to configuration, i.e., the configuration of the bond may be E or Z, or both E and Z. For example, the double bond in

[0155] The compounds and intermediates of the present disclosure can also exist in different tautomeric forms and all such forms are embraced within the scope of the present disclosure. The term "tautomer" or "tautomeric forms" refers to different energy structures that are interconvertible via a low energy barrier. For example, prototropic tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. An example of a lactam-lactim equilibrium is between A and B as shown below.

[0156] All compounds in the present disclosure can be drawn as either A or B. All tautomeric forms are within the scope of the present disclosure. The naming of the compounds does not exclude any tautomers.

[0157] The present disclosure also includes some isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, and the like.

[0158] Unless otherwise indicated, when a position is designated specifically as deuterium (D), the position is to be understood as having deuterium in an abundance of at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 10% deuterium incorporation). The compound of the example can have deuterium in an abundance of at least 1000 times greater than the natural abundance of deuterium, at least 2000 times greater than the natural abundance of deuterium, at least 3000 times greater than the natural abundance of deuterium, at least 4000 times greater than the natural abundance of deuterium, at least 5000 times greater than the natural abundance of deuterium, at least 6000 times greater than the natural abundance of deuterium, or greater. The present disclosure also includes various deuterated forms of the compounds of Formula (I). Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. Those skilled in the art are able to synthesize deuterated forms of the compounds of Formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of the compounds of Formula (I), or they can be synthesized using conventional techniques employing deuterated reagents, including but not limited to deuterated borane, trideuteroborane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane, among others.

[0159] "Optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted with halo or cyano" means that the alkyl group can or can not be substituted with halo or cyano, and that the description includes instances where the alkyl group is substituted with halo or cyano and instances where the alkyl group is not substituted with halo or cyano. 1- 6"Alkyl" means that halo or cyano can or can not be present, and that the description includes instances where the alkyl group is substituted with halo or cyano and instances where the alkyl group is not substituted with halo or cyano.

[0160] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically acceptable salt or prodrug thereof, with other chemical components, such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to an organism and to facilitate absorption of the active ingredient to thereby elicit a biological activity.

[0161] "Pharmaceutically acceptable excipient" includes, but is not limited to, any of the agents, carriers, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surface-active agents, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifying agents, which have been approved by the Federal Food and Drug Administration (FDA) as being acceptable for use in humans or domestic animals.

[0162] An "effective amount" or "therapeutically effective amount" in the present disclosure includes an amount sufficient to ameliorate or prevent symptoms or conditions of a medical disorder. An effective amount also means an amount that is sufficient to allow or promote diagnosis. The effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the overall health status of the patient, the method route and dose of administration, and the severity of side effects. The effective amount can be the maximum dose or administration regimen that avoids significant side effects or toxic effects.

[0163] "Alkyl" refers to saturated aliphatic hydrocarbon radicals, including straight-chain and branched-chain groups of 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and various branched isomers thereof, and the like. Alkyl groups can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available attachment point, preferably one or more of the following groups, independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 Alkoxy.

[0164] "Alkenyl" refers to unsaturated aliphatic straight-chain or branched-chain hydrocarbon radicals, and contain one or more carbon-carbon double bonds. Exemplary alkenyl groups include C2-C6, C2-C4, and C3 alkenyl groups. These include, but are not limited to, ethenyl (i.e., vinyl), 1-propenyl, 2-propenyl (i.e., allyl), 2-methyl-l- propenyl, 1-butenyl, 2-butenyl (i.e., crotyl), and the like. Alkenyl groups used in any context herein are optionally substituted in the same manner as alkyl groups.

[0165] "Akynyl" refers to unsaturated aliphatic straight-chain or branched-chain hydrocarbon radicals, and contain one or more carbon-carbon triple bonds. Exemplary akynyl groups include C2-C6, C2-C4, and C3 akynyl groups. These include, but are not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-4-ynyl, and pent-1,4-diynyl. Akynyl groups used in any context herein are optionally substituted in the same manner as alkyl groups.

[0166] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, the cycloalkyl ring comprising 3 to 10 carbon atoms, such as 4 carbon atoms or 5 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused ring, and bridged ring cycloalkyl groups. Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, independently selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 Alkoxy.

[0167] The term "heterocycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, comprising 3 to 10 ring atoms, such as 4 ring atoms or 5 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) mheteroatoms, but not including -0-0-, -0-S-, or -S-S-, the remaining ring atoms being carbon. Non-limiting examples of "heterocycloalkyl" groups include: and the like.

[0168] Heterocycloalkyl groups can be optionally substituted or unsubstituted, and when substituted, the substituent groups are preferably one or more groups independently selected from halogen, oxo, hydroxy, cyano, nitro, amino, C 1-6 alkyl and C 1- 6alkoxy.

[0169] In some embodiments, the heterocycloalkyl group can be fused to an aryl or heteroaryl ring, wherein the ring that is attached to the parent structure along with the ring of the heterocycloalkyl group is an aryl ring. Non-limiting examples of aryl groups include:

[0170] In some embodiments, the heterocycloalkyl group exists in a polycyclic ring, including a "spiro", "fused", or "bridged" ring.

[0171] The term "spiro" refers to a compound in which two rings share one atom. Non-limiting examples of spirocycloalkyl groups include:

[0172] The term "fused" refers to a compound in which two or more rings are joined by sharing two adjacent atoms. Non-limiting examples of fused cycloalkyl groups include:

[0173] The term "bridged" refers to a structure in which two or more ring structures share two non-adjacent ring atoms with each other. Depending on the number of rings that make up the structure, the bridged cycloalkyl group can be a bicyclic, tricyclic, tetracyclic, or polycyclic ring, preferably a bicyclic, tricyclic, or tetracyclic ring, more preferably a bicyclic or tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include:

[0174] The term "alkoxy" refers to -0-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propyloxy, butyloxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent groups are preferably one or more groups independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy.

[0175] The term "aryl" or "aromatic ring" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (that is, rings which share pairs of adjacent carbon atoms) ring having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring can be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure along with the ring of the aryl group is an aryl ring. Non-limiting examples of aryl groups include:

[0176] Aryl can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 Alkoxy.

[0177] The term "heteroaryl" or "heteroaromatic" refers to a heteroaromatic system comprising from 1 to 4 heteroatoms, and from 5 to 10 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably from 5 to 10 members, such as 7, 8, or 9 members, and more preferably 5 or 6 members. Non-limiting examples include:

[0178] The heteroaryl group can be fused to an aryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl, non-limiting examples of which include:

[0179] Heteroaryl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 Alkoxy.

[0180] A "monovalent group" refers to a compound that has "formally" lost a single valence atom or group. A "divalent group" refers to a compound that has "formally" lost two single valence atoms or one double valence atom or group, such as "methylene" which represents the portion of an alkane molecule remaining after removal of two hydrogen atoms.

[0181] In some embodiments, alkyl, heteroaryl can be monovalent, divalent, or polyvalent, and one skilled in the art will recognize from the context the number of valences available.

[0182] The term "amino" refers to -N(R a )2, wherein R a are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, and 3- to 6-membered heterocycloalkyl, each of said alkyl, cycloalkyl, and heterocycloalkyl being independently optionally substituted with one or more groups selected from halogen, hydroxy, cyano, nitro, C 1-6 Alkyl and C 1-6 Alkoxy. In some embodiments, "amino" can be unsubstituted amino (i.e., -NH2) or substituted amino (-N(R a )2, R a is not both hydrogen).

[0183] The term "hydroxy" refers to an -OH group.

[0184] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0185] The term "cyano" refers to -CN.

[0186] The term "nitro" refers to -NO2.

[0187] The term "oxo" refers to =O.

[0188] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of a group are independently of each other replaced with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can be determined (experimentally or theoretically) by the person skilled in the art without undue effort, as possible or impossible. DETAILED DESCRIPTION

[0189] The following examples are intended to further describe the present disclosure, but are not intended to limit the scope of the present disclosure.

[0190] The structure of the compounds is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR is measured by a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0191] The MS is measured by Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatograph-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS). Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector). THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO QExactive).

[0192] The high performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200 DAD, Agilent HPLC 1200 VWD and Waters HPLC e2695-2489 high performance liquid chromatograph.

[0193] Chiral HPLC analysis was determined using Agilent 1260 DAD high performance liquid chromatograph.

[0194] High performance liquid preparation used Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.

[0195] Chiral preparation used Shimadzu LC-20AP preparative chromatograph.

[0196] CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

[0197] Thin layer chromatography silica gel plate used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specification of silica gel plate used in thin layer chromatography was 0.15mm-0.2mm, and the specification of product purified by thin layer chromatography was 0.4mm-0.5mm.

[0198] Silica gel column chromatography generally used Yantai Huanghai silica gel 200-300 mesh silica gel as carrier.

[0199] Determination of average inhibition rate and IC 50 values of kinases used NovoStar microplate reader (Germany BMG company).

[0200] Known starting materials of the present disclosure can be synthesized according to methods known in the art or purchased from ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio INc, Darui Chemicals and the like.

[0201] Unless otherwise specified in the examples, the reactions were carried out under argon or nitrogen atmosphere.

[0202] Argon or nitrogen atmosphere refers to that the reaction bottle is connected with an argon or nitrogen balloon with a volume of about 1L.

[0203] Hydrogen atmosphere refers to that the reaction bottle is connected with a hydrogen balloon with a volume of about 1L.

[0204] Pressurized hydrogenation reaction used Parr 3916EKX type hydrogenation instrument and Qinglan QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument.

[0205] Hydrogenation reaction was usually vacuumed, filled with hydrogen, and repeated for 3 times.

[0206] Microwave reaction uses CEM Discover-S 908860 type microwave reactor.

[0207] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0208] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20-30°C.

[0209] The monitoring of the reaction progress in the examples uses thin layer chromatography (TLC), and the developing agent used in the reaction, the eluent system used in column chromatography for purifying compounds, and the developing agent system of thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, the volume ratio of the solvents is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0210] Example 1

[0211] (R,E)-N-((2-(2-(2-cyclopropylethenyl)-6-(difluoromethyl)pyridin-3-yl)-1,6- naphthyridin-7-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7- carboxamide 5,5-dioxide 1

[0212] First step

[0213] tert-Butyl ((2-(2-(cyclopropylmethoxy)-6-(difluoromethyl)pyridin-3-yl)-1,6- naphthyridin-7-yl)methyl)carbamate 1c

[0214] tert-Butyl ((2-chloro-1,6-naphthyridin-7-yl)methyl)carbamate 1a (200 mg, 0.68 mmol, prepared by the method disclosed in patent application “WO2021155264A1 specification page 73 example 32”) and 2-(cyclopropylmethoxy)-6-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 1b (266 mg, 0.82 mmol, prepared by the method disclosed in patent application “WO2023220219A1 specification page 272 compound 332”) were taken in a 100 mL single necked flask, 8 mL of 1,4-dioxane and 2 mL of water were added, potassium phosphate (433 mg, 2.04 mmol) and 1,1-bis(tert-butylphosphine)palladium chloropalladium (45 mg, 0.07 mmol) were added, nitrogen was purged for three times, the reaction mixture was warmed to 80 °C and stirred for 16 h. The reaction mixture was cooled to room temperature, 10 mL of water was added, the organic layer was extracted with ethyl acetate (10 mL x 3), the combined organic layer was washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography using eluent system B to give the title compound 1c (260 mg, yield: 84%).

[0215] MS m / z (ESI): 457.2 [M+1].

[0216] Second step

[0217] 3-(7-(aminomethyl)-1,6-naphthyridin-2-yl)-6-(difluoromethyl)pyridin-2-ol trifluoroacetate 1d

[0218] The compound 1c (140 mg, 0.31 mmol) was taken in a 50 mL single necked flask, 2 mL of dichloromethane was added, 0.3 mL of trifluoroacetic acid was added dropwise under ice bath, the reaction was carried out for 16 h. The reaction mixture was concentrated to give the crude product of the title compound 1d (162 mg, yield: 100%), which was used directly in the next step without purification.

[0219] MS m / z (ESI): 303.3 [M+1].

[0220] Third step

[0221] ((2-(6-(difluoromethyl)-2-hydroxypyridin-3-yl)-1,6-naphthyridin-7-yl)methyl)carbamate tert-butyl 1e

[0222] Compound 1d (160 mg, 0.31 mmol), di-tert-butyl dicarbonate (208 mg, 0.95 mmol, Adamas Reagent), triethylamine (267 mg, 2.64 mmol) were dissolved in 10 mL of dichloromethane, and the reaction was allowed to proceed for 1.5 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 1e (100 mg, yield: 80%). Step 4

[0223] Step 5MS m / z (ESI): 403.0 [M+1]. Step 6

[0224] Step 7Fourth step Step 8

[0225] Step 93-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthyridin-2-yl)-6- (difluoromethyl)pyridin-2-yl trifluoromethanesulfonate 1f Step 10

[0226] Step 11Compound 1e (100 mg, 0.25 mmol), N-phenylbis(trifluoromethane)sulfonimide (111 mg, 0.31 mmol), N,N-diisopropylethylamine (96 mg, 0.75 mmol), and 4- dimethylaminopyridine (3.0 mg, 0.03 mmol) were weighed into a 50 mL vial, 4 mL of dichloromethane was added, and the reaction was allowed to proceed for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 1f (130 mg, yield: 98%). Step 12

[0227] Step 13MS m / z (ESI): 535.0 [M+1]. Step 14

[0228] Step 15Fifth step Step 16

[0229] Step 17(E)-((2-(2-(2-cyclopropylethenyl)-6-(difluoromethyl)pyridin-3-yl)-1,6- naphthyridin-7-yl)methyl)carbamic acid tert-butyl ester 1h Step 18

[0230] Step 19Compound 1f (100 mg, 0.19 mmol), (E)-(2-cyclopropylethenyl)boronic acid 1g (31 mg, 0.29 mmol, Bide Pharma) were weighed into a 50 mL vial, 3 mL of 1,4- dioxane and 0.7 mL of water were added, potassium carbonate (78 mg, 0.56 mmol), 1,1'- bis(diphenylphosphino)ferrocene palladium dichloride (27 mg, 0.04 mmol) were added, nitrogen was replaced for three times, and the reaction was allowed to proceed for 16 hours while being stirred at 90°C. The reaction solution was cooled to room temperature, 10 mL of water was added, and the organic phase was extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 1h (32 mg, yield: 38%).

[0231] MS m / z (ESI): 453.5 [M+1].

[0232] Sixth step

[0233] (E)-(2-(2-(2-cyclopropylethenyl)-6-(difluoromethyl)pyridin-3-yl)-1,6- naphthyridin-7-yl)methanamine trifluoroacetic acid salt 1i

[0234] Compound 1h (32 mg, 0.07 mmol) was weighed into a 50 mL single necked flask, 1.2 mL of dichloromethane was added, 0.2 mL of trifluoroacetic acid was added, and the reaction was allowed to proceed for 1 hour. The reaction was concentrated to obtain crude title compound 1i (40 mg, yield: 100%) which was used as such for the next step without purification.

[0235] MS m / z (ESI): 353.2 [M+1].

[0236] Seventh step

[0237] (R,E)-N-((2-(2-(2-cyclopropylethenyl)-6-(difluoromethyl)pyridin-3-yl)-1,6- naphthyridin-7-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7- carboxamide 5,5-dioxide 1

[0238] Compound 1i (40 mg, 0.07 mmol), (R)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxylic acid 5,5-dioxide 1j (22 mg, 0.08 mmol, prepared using the method disclosed in the specification of patent application “WO2023220219A1, page 176, intermediate 2”) were weighed into a 25 mL single necked flask, 3 mL of N,N-dimethylformamide was added, N,N-diisopropylethylamine (60 mg, 0.46 mmol) was added, 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (44 mg, 0.12 mmol) was added, and the reaction was allowed to proceed for 1 hour. Purification was carried out by high performance liquid chromatography preparative chromatography (Waters-2545, eluent system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 35-65%, flow rate: 30 mL / min) to obtain title compound 1 (15 mg, yield: 35%).

[0239] MS m / z (ESI): 613.0 [M+1].

[0240] 1H NMR (500 MHz, DMSO-d6) δ 9.68 (t, 1H), 9.48 (s, 1H), 8.74 (d, 1H), 8.34 (s, 1H), 8.31 (dd, 1H), 8.09 (d, 1H), 7.88-7.86 (m, 2H), 7.63 (d, 1H), 7.00 (t, 1H), 6.66 (d, 1H), 6.51 (dd, 1H), 6.27 (ddd, 1H), 4.84 (d, 2H), 4.61 (dt, 1H), 4.16 (t, 1H), 2.85-2.74 (m, 1H), 2.65-2.56 (m, 1H), 1.58-1.51 (m, 1H), 0.84-0.80 (m, 2H), 0.59-0.56 (m, 2H).

[0241] Example 2

[0242] (R,E)-9-chloro-N-((2-(2-(2-cyclopropylethenyl)-6-(difluoromethyl)pyridin-3-yl)-1,6- naphthyridin-7-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 2

[0243] Using the method of Example 1, the starting material compound 1j in the seventh step was replaced by (R)-9-chloro-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxylic acid 5,5-dioxide (prepared using the method disclosed in the specification of patent application “WO2023220219A1, page 200, intermediate 3”), purified by high performance liquid preparative chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 35%-65%, flow rate: 30 mL / min) to obtain the title compound 2 (4 mg, yield: 37%).

[0244] MS m / z (ESI): 629.0 [M+1].

[0245] 1H NMR (500 MHz, DMSO-d6) δ 9.69 (t, 1H), 9.49 (s, 1H), 8.74 (d, 1H), 8.53 (d, 1H), 8.44 (d, 1H), 8.10 (d, 1H), 7.89-7.85 (m, 2H), 7.63 (d, 1H), 7.00 (t, 1H), 6.66 (d, 1H), 6.51 (dd, 1H), 6.24 (ddd, 1H), 4.83 (d, 2H), 4.61 (dt, 1H), 4.10 (t, 1H), 2.89-2.76 (m, 1H), 2.61-2.57 (m, 1H), 1.57-1.52 (m, 1H), 0.84-0.80 (m, 2H), 0.59-0.56 (m, 2H).

[0246] Example 3

[0247] (R,E)-N-((2-(2-(2-cyclopentylethenyl)-6-(difluoromethyl)pyridin-3-yl)-1,6- naphthyridin-7-yl)methyl)-N-methylmethanamine

[0248] 4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 3

[0249] The method of Example 1 was used, replacing the fifth step starting material compound 1g with (E)-(2-cyclopentylethenyl)boronic acid (Bide Pharm) and purifying by high performance liquid preparative chromatography (Waters-2545, elution system: 10 mmol / L aqueous ammonium bicarbonate and acetonitrile, gradient of acetonitrile: 35%-65%, flow rate: 30 mL / min) to obtain the title compound 3 (5 mg, yield: 23%).

[0250] MS m / z (ESI): 641.2 [M+1].

[0251] 1H NMR (500 MHz, DMSO-d6) δ 9.69 (t, 1H), 9.48 (s, 1H), 8.73 (dd, 1H), 8.35 (s, 1H), 8.31 (dd, 1H), 8.14 (d, 1H), 7.87 (d, 1H), 7.84 (s, 1H), 7.68 (d, 1H), 7.04 (t, 1H), 6.96-6.92 (m, 1H), 6.60 (dd, 1H), 6.24 (ddd, 1H), 4.83 (d, 2H), 4.61 (dt, 1H), 4.15 (t, 1H), 2.88-2.74 (m, 2H), 2.62-2.58 (m, 1H), 1.74-1.68 (m, 2H), 1.60-1.55 (m, 2H), 1.52-1.47 (m, 2H), 1.34-1.27 (m, 2H).

[0252] Example 4

[0253] (R)-N-((2-(2-(cyclopropylethynyl)-6-(difluoromethyl)pyridin-3-yl)-1,6- naphthyridin-7-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathi epine-7- carboxamide 5,5-dioxide 4

[0254] First step

[0255] tert-Butyl ((2-(2-(cyclopropylethynyl)-6-(difluoromethyl)pyridin-3-yl)-1,6- naphthyridin-7-yl)methyl)carbamate 4b

[0256] Compound 1f (35 mg, 0.07 mmol), cyclopropylacetylene 4a (13 mg, 0.19 mmol, Alfa Aesar), copper iodide (1.5 mg, 0.008 mmol), dichlorobis(triphenylphosphine)palladium (5 mg, 0.007 mmol), triethylamine (20 mg, 0.19 mmol) were weighed into a 25 mL single-necked flask, and 3 mL of N,N-dimethylformamide was added. The mixture was stirred at 70 °C for 16 h. The reaction solution was cooled to room temperature, 10 mL of water was added, and the mixture was extracted with 10 mL of ethyl acetate three times. The combined organic phase was washed with 15 mL of saturated sodium chloride solution three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 4b (13 mg, yield: 44%).

[0257] MS m / z (ESI): 451.2 [M+1].

[0258] Second step

[0259] (2-(2-(cyclopropylethynyl)-6-(difluoromethyl)pyridin-3-yl)-1,6-naphthyridin-7-yl)methanamine trifluoroacetate salt 4c

[0260] Compound 4b (13 mg, 0.03 mmol) was weighed into a 25 mL vial, 2 mL of dichloromethane was added, 0.2 mL of trifluoroacetic acid was added, and the reaction was allowed to proceed for 1 h. The reaction was concentrated to give the crude product of title compound 4c (17 mg, yield: 100%), which was used in the next step without purification.

[0261] MS m / z (ESI): 351.4 [M+1].

[0262] Third Step

[0263] (R)-N-((2-(2-(cyclopropylethynyl)-6-(difluoromethyl)pyridin-3-yl)-1,6-naphthyridin-7-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 4

[0264] Compound 4c (17 mg, 0.03 mmol) and compound 1j (9 mg, 0.03 mmol) were weighed into a 25 mL vial, 2 mL of N,N-dimethylformamide was added, N,N- diisopropylethylamine (23 mg, 0.18 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (17 mg, 0.04 mmol) was added, and the reaction was allowed to proceed for 1 h. Purification was performed by high performance liquid chromatography (Waters-2545, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 50-95%, flow rate: 30 mL / min) to give title compound 4 (3.6 mg, yield: 20%).

[0265] MS m / z (ESI): 611.5 [M+1].

[0266] 1 H NMR (500 MHz, DMSO-d6) δ 9.69 (t, 1H), 9.49 (s, 1H), 8.73 (dd, 1H), 8.37-8.33 (m, 2H), 8.31 (dd, 1H), 8.18 (d, 1H), 7.86 (s, 1H), 7.80 (d, 1H), 7.03 (t, 1H), 6.26 (ddd, 1H), 4.83 (d, 2H), 4.61 (dt, 1H), 4.16 (t, 1H), 2.90-2.74 (m, 2H), 1.30-1.27 (m, 1H), 0.86-0.81 (m, 2H), 0.62-0.59 (m, 2H).

[0267] Example 5

[0268] (R)-N-((2-(3-ethynylphenyl)-1,6-naphthyridin-7-yl)methyl)-4,9-difluoro-3,4- dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 5

[0269] First Step

[0270] tert-Butyl ((2-(3-ethynylphenyl)-1,6-naphthyridin-7-yl)methyl)carbamate 5b

[0271] Compound 1a (200 mg, 0.68 mmol), (3-ethynylphenyl)boronic acid 5a (109 mg, 0.75 mmol, Bide Pharma), 3 mL of toluene and 0.5 mL of water were weighed into a 50 mL single neck flask. Sodium carbonate (216 mg, 2.04 mmol) and dichlorobis(triphenylphosphine)palladium (45 mg, 0.07 mmol) were added. The flask was flushed with nitrogen three times and the reaction was heated to 80 °C for 16 h. The reaction was cooled to room temperature and water (10 mL) was added. The organic layer was extracted with ethyl acetate (10 mL x 3), washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 5b (82 mg, yield: 34%).

[0272] MS m / z (ESI): 360.2 [M+1].

[0273] Second Step

[0274] (2-(3-ethynylphenyl)-1,6-naphthyridin-7-yl)methanamine trifluoroacetate salt 5c

[0275] Compound 5b (53 mg, 0.15 mmol) was weighed into a 50 mL single neck flask. 1 mL of dichloromethane and 0.1 mL of trifluoroacetic acid were added dropwise. The reaction was carried out for 30 min. The reaction was concentrated under reduced pressure to obtain the crude title compound 5c (83 mg, yield: 100%). The crude product was used directly for the next reaction without purification.

[0276] MS m / z (ESI): 260.3 [M+1].

[0277] Third Step

[0278] (R)-N-((2-(3-ethynylphenyl)-1,6-naphthyridin-7-yl)methyl)-4,9-difluoro-3,4-dihydro-2H- benzo [b] [1,4] oxathiepin-7-carboxamide 5,5-dioxide 5

[0279] Compound 5c (50 mg, 0.09 mmol) and compound 1j (25 mg, 0.09 mmol) were weighed into a 25 mL single neck flask, 1 mL of N,N-dimethylformamide was added, N,N- diisopropylethylamine (69 mg, 0.54 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (51 mg, 0.13 mmol) was added, and the reaction was allowed to proceed for 30 minutes. The reaction was filtered and purified by high performance liquid preparative chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 35%-65%, flow rate: 30 mL / min) to give the title compound 5 (13 mg, yield: 28%).

[0280] MS m / z (ESI): 520.2 [M+1].

[0281] 1 H NMR (500 MHz, DMSO-d6) 9.66 (t, 1H), 9.41 (s, 1H), 8.69 (d, 1H), 8.40 (s, 1H), 8.37-8.32 (m, 4H), 7.87 (s, 1H), 7.67 (dt, 1H), 7.60 (t, 1H), 6.27 (ddd, 1H), 4.82 (d, 2H), 4.61 (dt, 1H), 4.32 (s, 1H), 4.18 (t, 1H), 2.85-2.75 (m, 1H), 2.64-2.58 (m, 1H).

[0282] Example 6

[0283] (R)-9-chloro-N-((2-(3-ethynylphenyl)-1,6-naphthyridin-7-yl)methyl)-4-fluoro-3,4-dihydro-2H- benzo [b] [1,4] oxathiepin-7-carboxamide 5,5-dioxide 6

[0284] The method of Example 5 was adopted, and the raw material compound 1j of the third step was replaced by (R)-9-chloro-4-fluoro-3,4-dihydro-2H- benzo[b][1,4]oxathiepine-7-carboxylic acid 5,5-dioxide (prepared by the method disclosed in the specification of “WO2023220219A1, page 200, intermediate 3”), and purified by high performance liquid preparative chromatography (Waters-2545, elution system: 10 mmol / L aqueous ammonium bicarbonate and acetonitrile, gradient of acetonitrile: 35%-65%, flow rate: 30 mL / min) to obtain the title compound 6 (8 mg, yield: 29%).

[0285] MS m / z (ESI): 536.0 [M+1].

[0286] 1 H NMR (500 MHz, DMSO-d6) 9.68 (t, 1H), 9.41 (s, 1H), 8.69 (dd, 1H), 8.55 (d, 1H), 8.46 (d, 1H), 8.41 (t, 1H), 8.36-8.34 (m, 2H), 7.88 (s, 1H), 7.67 (dt, 1H), 7.60 (t, 1H), 6.26 (ddd, 1H), 4.82 (d, 2H), 4.62 (dt, 1H), 4.32 (s, 1H), 4.12 (t, 1H), 2.90-2.77 (m, 1H), 2.62-2.58 (m, 1H).

[0287] Example 7

[0288] (R,E)-N-((2-(6-difluoromethyl)-2-(2-(1-fluorocyclopropyl)vinyl)pyridin-3-yl)-1,6- naphthyridin-7-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7- carboxamide 5,5-dioxide 7

[0289] First step

[0290] (E)-2-(2-(1-fluorocyclopropyl)vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7b

[0291] Into a 25 mL single necked flask, 2,2,6,6-tetramethylpiperidine (197 mg, 1.39 mmol) was weighed, and 4 mL of tetrahydrofuran was added. The temperature of the system was reduced to 0 °C, and n-butyllithium n-hexane solution (2.5 M, 1.76 mmol, 0.71 mL) was slowly added dropwise. After the dropwise addition was completed, the reaction was continued at 0 °C for 1 hour, then bis[(pinacolato)boron]methyl (372 mg, 1.39 mmol) was added, and the reaction was continued for 15 minutes, and the temperature was reduced to -78 °C, and a 0.3 mL tetrahydrofuran solution of 1-fluorocyclopropane-1-carbaldehyde 7a (170 mg, 1.16 mmol, prepared by the method disclosed in the specification of patent application “WO2020146194A1, page 21, Scheme 8”) was added dropwise. After the dropwise addition was completed, the reaction was continued at this temperature for 4 hours. The temperature was naturally increased to 0 °C, and 20 mL of saturated ammonium chloride solution was added dropwise to quench the reaction, and the reaction liquid was extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution (25 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 7b (50 mg, yield: 20%).

[0292] 1 H NMR (500 MHz, CDCl3) δ 6.34 (dd, 1H), 5.72 (d, 1H), 1.27 (s, 12H), 0.92-0.87 (m, 4H).

[0293] Second step

[0294] (E)-((2-(6-(di fluoromethyl)-2-(2-(1-fluorocyclopropyl)vinyl)pyridin-3-yl)-1,6- naphthyridin-7-yl)methyl)carbamic acid tert-butyl ester 7c

[0295] Into a 50 mL single necked flask, compound 1f (50 mg, 0.09 mmol), 7b (45 mg, 0.15 mmol) was weighed, 6 mL of 1,4-dioxane and 1 mL of water was added, potassium phosphate (60 mg, 0.28 mmol) was added, [1,1'-bis(di-tert-butylphosphine)ferrocene] dichloropalladium (6 mg, 0.01 mmol) was added, and nitrogen was replaced for three times, and the temperature was increased to 85 °C for 16 hours. The reaction liquid was cooled to room temperature, 10 mL of water was added, and extracted with ethyl acetate (10 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 7c (60 mg, yield: 76%).

[0296] MS m / z (ESI): 470.9 [M+1].

[0297] Step 3

[0298] (E)-(2-(6-difluoromethyl)-2-(2-(1-fluorocyclopropyl)vinyl)pyridin-3-yl)-1,6- naphthyridin-7-yl)methanamine trifluoroacetate salt 7d

[0299] Compound 7c (60 mg, 0.13 mmol) was weighed into a 25 mL vial, 2 mL of dichloromethane was added, 0.3 mL of trifluoroacetic acid was added dropwise, and the reaction was allowed to proceed for 1 h. The reaction was concentrated under reduced pressure to give the crude product of title compound 7d (76 mg, yield: 100%), which was used directly in the next step without purification.

[0300] MS m / z (ESI): 371.4 [M+1].

[0301] Step 4

[0302] (R,E)-N-((2-(6-difluoromethyl)-2-(2-(1-fluorocyclopropyl)vinyl)pyridin-3-yl)-1,6- naphthyridin-7-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7- carboxamide 5,5-dioxide 7

[0303] Compound 7d (76 mg, 0.13 mmol), compound 1j (35 mg, 0.13 mmol) was weighed into a 25 mL vial, 2.5 mL of N,N-dimethylformamide was added, N,N- diisopropylethylamine (99 mg, 0.77 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (77 mg, 0.20 mmol) was added, and the reaction was allowed to proceed for 1 h. The reaction was filtered and purified by high performance liquid chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 45%-95%, flow rate: 30 mL / min) to give title compound 7 (35 mg, yield: 44%).

[0304] MS m / z (ESI): 631.4 [M+1].

[0305] 1H NMR (500 MHz, DMSO-d6) δ 9.68 (t, 1H), 9.49 (s, 1H), 8.76 (d, 1H), 8.34 (s, 1H), 8.30 (dd, 1H), 8.19 (d, 1H), 7.92 (d, 1H), 7.86 (s, 1H), 7.72 (d, 1H), 7.04 (t, 1H), 6.90-6.80 (m, 2H), 6.27 (ddd, 1H), 4.83 (d, 2H), 4.61 (dt, 1H), 4.16 (t, 1H), 2.87-2.74 (m, 1H), 2.62-2.57 (m, 1H), 1.37-1.31 (m, 2H), 1.12-1.08 (td, 2H).

[0306] Example 8

[0307] (R)-N-((2-(4-(difluoromethoxy)-3-ethynylphenyl)-1,6-naphthyridin-7-yl)methyl)-4,9- difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 8

[0308] First step

[0309] 4-bromo-1-(difluoromethoxy)-2-iodobenzene 8c

[0310] Into a 100 mL single-necked flask, 4-bromo-2-iodophenol 8a (1.0 g, 3.34 mmol, Leyan Reagent), sodium difluorochloroacetate 8b (765 mg, 5.02 mmol, Shaoyuan Technology (Shanghai)), cesium carbonate (2.18 g, 6.69 mmol) were weighed, 8 mL of N,N-dimethylformamide and 2 mL of water were added, and the temperature was raised to 120 °C for 16 hours of reaction. The reaction liquid was cooled to room temperature, 30 mL of water was added, extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (45 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 8c (851 mg, yield: 73%).

[0311] 1 H NMR (500 MHz, DMSO-d6) δ 8.01 (d, 1H), 7.49 (dd, 1H), 7.07 (d, 1H), 6.53 (t, 1H).

[0312] Second step

[0313] ((5-bromo-2-(difluoromethoxy)phenyl)ethynyl)trimethylsilane 8e

[0314] Into a 50-mL single-necked flask, compound 8c (200 mg, 0.57 mmol), cuprous iodide (11 mg, 0.06 mmol), bis(triphenylphosphine)palladium dichloride (19 mg, 0.03 mmol) were taken, 3 mL of triethylamine and 3 mL of tetrahydrofuran were added, replaced with nitrogen for three times, ethynyltrimethylsilane 8d (70 mg, 0.72 mmol, Bid pharmaceutical) was added, and the temperature was raised to 85°C for 6 hours of reaction. The reaction solution was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 8e (601 mg, yield: 78%).

[0315] tert-Butyl (2-(4-(difluoromethoxy)-3-((trimethylsilyl)ethynyl)phenyl)-1,6- naphthyridin-7-yl)methyl)carbamate 8f

[0316] Into a 50-mL single-necked flask, compound 1a (100 mg, 0.34 mmol), hexamethylditin (133 mg, 0.41 mmol, Shaoyuan Technology (Shanghai)), tetrakis(triphenylphosphine)palladium (39 mg, 0.03 mmol) were taken, 2 mL of 1,4-dioxane was added, replaced with nitrogen for three times, and the temperature was raised to 100°C for 2 hours of reaction. The reaction solution was cooled to room temperature, compound 8e (105 mg, 0.33 mmol) and bis(triphenylphosphine)palladium dichloride (35 mg, 0.05 mmol) were added, replaced with nitrogen for three times, and the temperature was raised to 100°C for 16 hours of reaction. The reaction solution was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 8f (68 mg, yield: 41%).

[0317] MS m / z (ESI): 497.9 [M+1].

[0318] Fourth step

[0319] (2-(4-(difluoromethoxy)-3-((trimethylsilyl)ethynyl)phenyl)-1,6-naphthyridin-7- yl)methanamine trifluoroacetate 8g

[0320] Into a 50-mL single-necked flask, compound 8f (35 mg, 0.07 mmol) was taken, 1 mL of dichloromethane was added, 0.1 mL of trifluoroacetic acid was added dropwise, and the reaction was carried out for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product of the title compound 8g (40 mg, yield: 100%), which was directly used in the next step reaction without purification.

[0321] MS m / z (ESI): 398.4 [M+1].

[0322] Fifth step

[0323] (2-(4-(difluoromethoxy)-3-ethynylphenyl)-1,6-naphthyridin-7-yl)methanamine 8h

[0324] Compound 8g (40 mg, 0.07 mmol), potassium carbonate (32 mg, 0.23 mmol) were weighed into a 50 mL single neck flask, 1.5 mL of methanol was added, and the reaction was allowed to proceed for 1 h. The reaction was concentrated under reduced pressure, 10 mL of water was added, and the reaction was extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 8h (23 mg, yield: 100%).

[0325] MS m / z (ESI): 326.4 [M+1].

[0326] Sixth step

[0327] (R)-N-((2-(4-(difluoromethoxy)-3-ethynylphenyl)-1,6-naphthyridin-7-yl)methyl)-4,9- difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 8

[0328] Compound 8h (18 mg, 0.06 mmol) and 1j (15 mg, 0.05 mmol) were weighed into a 25 mL single neck flask, 1 mL of N,N-dimethylformamide was added, N,N- diisopropylethylamine (35 mg, 0.23 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (31 mg, 0.08 mmol) was added, and the reaction was allowed to proceed for 1 h. The reaction was filtered, and purified by high performance liquid chromatography (Waters-2545, eluent: 10 mmol / L aqueous ammonium bicarbonate and acetonitrile, gradient of acetonitrile: 35%-95%, flow rate: 30 mL / min) to obtain the title compound 8 (4 mg, yield: 12%).

[0329] MS m / z (ESI): 586.8 [M+1].

[0330] 1H NMR (500 MHz, DMSO-d6) δ 9.66 (t, 1H), 9.40 (s, 1H), 8.69 (d, 1H), 8.51 (d, 1H), 8.42 (dd, 1H), 8.36 - 8.32 (m, 3H), 7.86 (s, 1H), 7.47 (d, 1H), 7.43 (s, 1H), 6.28 (ddd, 1H), 4.82 (d, 2H), 4.61 (dt, 1H), 4.56 (s, 1H), 4.18 (t, 1H), 2.86 - 2.78 (m, 1H), 2.63 - 2.58 (m, 1H).

[0331] Example 9

[0332] (R)-N-((2-(3-ethynyl-4-(2,2,2-trifluoroethoxy)phenyl)-1,6-naphthyridin-7-yl)methyl)- 4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 9

[0333] First step

[0334] 4-bromo-2-iodo-1-(2,2,2-trifluoroethoxy)benzene 9b

[0335] Compound 8a (1 g, 3.34 mmol) was weighed into a 100 mL single-necked flask, 10 mL of N,N-dimethylformamide was added, the temperature of the system was reduced to 0 °C, cesium carbonate (3.27 g, 10.03 mmol) was added in portions, 2,2,2-trifluoroethyl trifluoromethanesulfonate 9a (1.55 g, 6.69 mmol, Shanyuan Technology (Shanghai)) was added dropwise, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, 30 mL of water was added, it was extracted with ethyl acetate (30 mL x 3), the combined organic phases were washed with saturated sodium chloride solution (45 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 9b (1.19 g, yield: 93%).

[0336] 1 H NMR (500 MHz, DMSO-d6) δ 7.95 (d, 1H), 7.46 (dd, 1H), 6.74 (d, 1H), 4.39 (q, 2H).

[0337] Second step

[0338] ((5-bromo-2-(2,2,2-trifluoroethoxy)phenyl)ethynyl)trimethylsilane 9c

[0339] Into a 50-mL single-necked flask, compound 9b (300 mg, 0.79 mmol), cuprous iodide (15 mg, 0.08 mmol), bis(triphenylphosphine)palladium dichloride (26 mg, 0.04 mmol) were taken, 3 mL of triethylamine and 3 mL of tetrahydrofuran were added, replaced with nitrogen for three times, compound 8d (97 mg, 0.98 mmol) was added, and the temperature was raised to 85°C for 6 hours of reaction. The reaction solution was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 9c (270 mg, yield: 96%).

[0340] Third step

[0341] ((2-(4-(2,2,2-trifluoroethoxy)-3-((trimethylsilyl)ethynyl)phenyl)-1,6-naphthyridin-7-yl)methyl)carbamic acid tert-butyl ester 9d

[0342] Into a 50-mL single-necked flask, compound 1a (100 mg, 0.34 mmol), hexamethylditin (133 mg, 0.41 mmol), bis(triphenylphosphine)palladium dichloride (39 mg, 0.03 mmol) were taken, 2 mL of 1,4-dioxane was added, replaced with nitrogen for three times, and the temperature was raised to 100°C for 2 hours of reaction. The reaction solution was cooled to room temperature, compound 9c (105 mg, 0.33 mmol) and bis(triphenylphosphine)palladium dichloride (35 mg, 0.05 mmol) were added, replaced with nitrogen for three times, and the temperature was raised to 100°C for 16 hours of reaction. The reaction solution was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 9d (125 mg, yield: 71%).

[0343] MS m / z (ESI): 530.2 [M+1].

[0344] Fourth step

[0345] (2-(4-(2,2,2-trifluoroethoxy)-3-((trimethylsilyl)ethynyl)phenyl)-1,6-naphthyridin-7-yl)methanamine trifluoroacetate 9e

[0346] Take compound 9d (60 mg, 0.11 mmol) into a 50 mL single necked flask, add 1 mL of dichloromethane, drop 0.1 mL of trifluoroacetic acid, react for 1 hour. Concentrate the reaction solution under reduced pressure to obtain the crude product of title compound 9e (61 mg, yield: 100%), which is directly used in the next step without purification.

[0347] MS m / z (ESI): 430.4 [M+1].

[0348] Fifth step

[0349] (2-(3-ethynyl-4-(2,2,2-trifluoroethoxy)phenyl)-1,6-naphthyridin-7-yl)methanamine 9f

[0350] Take compound 9e (61 mg, 0.11 mmol) and potassium carbonate (46 mg, 0.34 mmol) into a 50 mL single necked flask, add 1.5 mL of methanol, react for 1 hour. Concentrate the reaction solution under reduced pressure, add 10 mL of water, extract with ethyl acetate (10 mL x 3), combine the organic phase, wash with saturated sodium chloride solution (15 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain title compound 9f (38 mg, yield: 95%).

[0351] MS m / z (ESI): 358.3 [M+1].

[0352] Sixth step

[0353] (R)-N-((2-(3-ethynyl-4-(2,2,2-trifluoroethoxy)phenyl)-1,6-naphthyridin-7-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 9

[0354] Take compound 9f (19 mg, 0.05 mmol) and 1j (15 mg, 0.05 mmol) into a 25 mL single necked flask, add 1 mL of N,N-dimethylformamide, add N,N-diisopropylethylamine (35 mg, 0.23 mmol), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (31 mg, 0.08 mmol), and react for 1 hour. Filter the reaction solution and purify by high performance liquid preparative chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 40%-95%, flow rate: 30 mL / min) to obtain title compound 9 (7 mg, yield: 21%).

[0355] MS m / z (ESI): 618.1 [M+1].

[0356] 1 H NMR (500 MHz, DMSO-d6) δ 9.66 (t, 1H), 9.37 (s, 1H), 8.64 (d, 1H), 8.44 (d, 1H), 8.39-8.36 (m, 2H), 8.34 (s, 1H), 8.32 (s, 1H), 7.84 (s, 1H), 7.38 (d, 1H), 6.28 (ddd, 1H), 4.97 (q, 2H), 4.81 (d, 2H), 4.62 (dt, 1H), 4.43 (s, 1H), 4.18 (t, 1H), 2.85-2.75 (m, 1H), 2.63-2.58 (m, 1H).

[0357] Example 10

[0358] (R)-4,9-difluoro-N-((2-(3-(prop-1-yn-1-yl)phenyl)-1,6-naphthyridin-7-yl)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 10

[0359] First step

[0360] 1-bromo-3-(prop-1-yn-1-yl)benzene 10c

[0361] To a 100 mL single necked flask was charged with 1-bromo-3-iodobenzene 10a (2.0 g, 7.07 mmol), cuprous iodide (404 mg, 2.12 mmol), tetrakis(triphenylphosphine)palladium (408 mg, 0.35 mmol), 10 mL of toluene, nitrogen was purged for three times, trimethyl(prop-1-ynyl)silane 10b (794 mg, 7.07 mmol), triethylamine (2.36 g, 23.33 mmol) and tetrabutylammonium fluoride solution (1 M, 7.1 mL, 7.10 mmol) was added, the reaction was stirred for 16 hours. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (100 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to give the title compound 10c (1.18 g, yield: 85%).

[0362] Second step

[0363] tert-butyl ((2-(3-(prop-1-yn-1-yl)phenyl)-1,6-naphthyridin-7-yl)methyl)carbamate 10d

[0364] Compound 1a (100 mg, 0.34 mmol), hexamethylditin (133 mg, 0.41 mmol), tetrakis(triphenylphosphine)palladium (39 mg, 0.03 mmol) were taken in a 50 mL single necked flask, 2 mL of 1,4-dioxane was added, flushed with nitrogen for three times, warmed to 100 °C for 2 h. The reaction was cooled to room temperature, compound 10c (80 mg, 0.41 mmol) and dichlorobis(triphenylphosphine)palladium (35 mg, 0.05 mmol) were added, flushed with nitrogen for three times, warmed to 100 °C for 16 h. The reaction was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to afford the title compound 10d (64 mg, yield: 50%).

[0365] MS m / z (ESI): 374.0 [M+1].

[0366] Third Step

[0367] (2-(3-(prop-1-yn-1-yl)phenyl)-1,6-naphthyridin-7-yl)methanamine trifluoroacetate salt 10e

[0368] Compound 10d (30 mg, 0.08 mmol) was taken in a 25 mL single necked flask, 1 mL of dichloromethane was added, 0.25 mL of trifluoroacetic acid was added dropwise, the reaction was carried out for 30 min. The reaction was concentrated under reduced pressure to afford the crude product of the title compound 10e (31 mg, yield: 100%), which was used directly for the next step without purification.

[0369] MS m / z (ESI): 274.1 [M+1].

[0370] Fourth Step

[0371] (R)-4,9-difluoro-N-((2-(3-(prop-1-yn-1-yl)phenyl)-1,6-naphthyridin-7-yl)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 10

[0372] Compound 10e (31 mg, 0.08 mmol) and 1j (45 mg, 0.16 mmol) were weighed into a 25 mL single neck flask, 1 mL of N,N-dimethylformamide was added, N,N-diisopropylethylamine (42 mg, 0.32 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (92 mg, 0.24 mmol) was added, and the reaction was allowed to proceed for 30 minutes. Purification was performed by high performance liquid chromatography (Waters-2545, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 35%-95%, flow rate: 80 mL / min) to obtain the title compound 10 (6 mg, yield: 14%).

[0373] MS m / z (ESI): 533.8 [M+1].

[0374] 1 H NMR (500 MHz, DMSO) δ 9.67 (t, 1H), 9.40 (s, 1H), 8.67 (d, 1H), 8.38-8.33 (m, 2H), 8.32 (s, 2H), 8.26 (dt, 1H), 7.86 (s, 1H), 7.57-7.53 (m, 2H), 6.28 (ddd, 1H), 4.82 (d, 2H), 4.62 (dt, 1H), 4.18 (t, 1H), 2.88-2.75 (m, 1H), 2.64-2.58 (m, 1H), 2.09 (s, 3H).

[0375] Example 11

[0376] (R)-N-((2-(4-difluoromethoxy)-3-(prop-1-yn-1-yl)phenyl)-1,6-naphthyridin-7-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 11

[0377] First step

[0378] 4-bromo-1-(difluoromethoxy)-2-(prop-1-yn-1-yl)benzene 11a

[0379] Into a 25 mL vial, compound 8c (100 mg, 0.29 mmol), copper iodide (16 mg, 0.09 mmol), tetrakis(triphenylphosphine)palladium (17 mg, 0.014 mmol) were weighed, 1 mL of toluene was added, nitrogen was bubbled for three times, compound 10b (32 mg, 0.29 mmol), triethylamine (96 mg, 0.95 mmol) and tetrabutylammonium fluoride solution (1 M, 0.29 mL, 0.29 mmol) were added, the reaction was carried out for 16 h. The reaction was quenched by water (10 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to give the title compound 11a (62 mg, yield: 83%).

[0380] Second step

[0381] ((2-(4-(difluoromethoxy)-3-(prop-1-yn-1-yl)phenyl)-1,6-naphthyridin-7-yl)methyl)carbamic acid tert-butyl ester 11b

[0382] Into a 25 mL vial, compound 1a (105 mg, 0.36 mmol), hexamethylditin (140 mg, 0.43 mmol), tetrakis(triphenylphosphine)palladium (41 mg, 0.036 mmol) were weighed, 2 mL of 1,4-dioxane was added, nitrogen was bubbled for three times, the reaction was carried out for 2 h at 100 °C. The reaction was cooled to room temperature, compound 11a (62 mg, 0.24 mmol) and dichlorobispalladium(II)triphenylphosphine (25 mg, 0.036 mmol) were added, nitrogen was bubbled for three times, the reaction was carried out for 16 h at 100 °C. The reaction was cooled to room temperature, water 10 mL was added, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to give the title compound 11b (12 mg, yield: 11%).

[0383] MS m / z (ESI): 440.2 [M+1].

[0384] Third step

[0385] (2-(4-difluoromethoxy)-3-(prop-1-yn-1-yl)phenyl)-1,6-naphthyridin-7-yl)methanamine trifluoroacetic acid salt 11c

[0386] Compound 11b (12 mg, 0.027 mmol) was weighed into a 25 mL vial, 1 mL of dichloromethane was added, 0.25 mL of trifluoroacetic acid was added dropwise, and the reaction was allowed to proceed for 30 minutes. The reaction was concentrated under reduced pressure to obtain the crude product of title compound 11c (12 mg, yield: 100%), which was used directly in the next step without purification.

[0387] MS m / z (ESI): 340.2 [M+1].

[0388] Fourth step

[0389] (R)-N-((2-(4-difluoromethoxy)-3-(prop-1-yn-1-yl)phenyl)-1,6-naphthyridin-7-yl)methyl)- 4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 11

[0390] Compound 11c (12 mg, 0.027 mmol) and 1j (15 mg, 0.055 mmol) were weighed into a 25 mL vial, 1 mL of N,N-dimethylformamide was added, N,N-diisopropylethylamine (14 mg, 0.11 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (31 mg, 0.082 mmol) was added, and the reaction was allowed to proceed for 30 minutes. Purification was performed by high-performance liquid chromatography (GILSON-306, eluent: 10 mmol / L aqueous ammonium bicarbonate and acetonitrile, gradient of acetonitrile: 40%-95%, flow rate: 30 mL / min) to obtain title compound 11 (2.5 mg, yield: 15%).

[0391] MS m / z (ESI): 600.1 [M+1].

[0392] 1 H NMR (500 MHz, DMSO) δ 9.66 (t, 1H), 9.40 (s, 1H), 8.67 (d, 1H), 8.43 (d, 1H), 8.37-8.32 (m, 3H), 7.85 (s, 1H), 7.54-7.25 (m, 3H), 6.33-6.24 (m, 1H), 4.82 (d, 2H), 4.62 (dt, 1H), 4.18 (t, 1H), 2.82 (dt, 2H), 2.13 (s, 3H).

[0393] Example 12

[0394] (R)-4,9-difluoro-N-((2-(3-(prop-1-yn-1-yl)-4-(2,2,2-trifluoroethoxy)phenyl)-1,6- naphthyridin-7-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5- dioxide 12

[0395] First step

[0396] 4-bromo-2-(prop-1-yn-1-yl)-1-(2,2,2-trifluoroethoxy)benzene 12a

[0397] Compound 9b (100 mg, 0.26 mmol), cuprous iodide (15 mg, 0.078 mmol), tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol) were weighed into a 25 mL vial, 1 mL of toluene was added, nitrogen was bubbled through three times, compound 10b (29 mg, 0.26 mmol), triethylamine (88 mg, 0.87 mmol) and tetrabutylammonium fluoride solution (1 M, 0.26 mL, 0.26 mmol) were added, and the reaction was allowed to proceed for 16 hours. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL x 3), the organic layers were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 12a (36 mg, yield: 47%).

[0398] Second step

[0399] ((2-(3-(prop-1-yn-1-yl)-4-(2,2,2-trifluoroethoxy)phenyl)-1,6-naphthyridin-7-yl)methyl)carbamic acid tert-butyl ester 12b

[0400] Compound 1a (54 mg, 0.18 mmol), hexamethylditin (72 mg, 0.22 mmol), tetrakis(triphenylphosphine)palladium (21 mg, 0.018 mmol) were weighed into a 25 mL vial, 1 mL of 1,4-dioxane was added, nitrogen was bubbled through three times, and the reaction was allowed to proceed at 100 °C for 2 hours. The reaction was cooled to room temperature, compound 12a (36 mg, 0.12 mmol) and dichlorobispalladium(II)triphenylphosphine (13 mg, 0.018 mmol) were added, nitrogen was bubbled through three times, and the reaction was allowed to proceed at 100 °C for 16 hours. The reaction was cooled to room temperature, water (10 mL) was added, and the reaction was extracted with ethyl acetate (10 mL x 3). The organic layers were combined, washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 12b (30 mg, yield: 52%).

[0401] MS m / z (ESI): 472.2 [M+1].

[0402] Third step

[0403] (2-(3-(prop-1-yn-1-yl)-4-(2,2,2-trifluoroethoxy)phenyl)-1,6-naphthyridin-7-yl)methanamine trifluoroacetate salt 12c

[0404] Compound 12b (30 mg, 0.064 mmol) was weighed into a 25 mL single neck flask, 1 mL of dichloromethane was added, 0.25 mL of trifluoroacetic acid was added dropwise, and the reaction was allowed to proceed for 30 minutes. The reaction was concentrated under reduced pressure to obtain the crude product of the title compound 12c (30 mg, yield: 100%), which was used directly in the next step without purification.

[0405] MS m / z (ESI): 472.2 [M+1].

[0406] Fourth step

[0407] (R)-4,9-difluoro-N-((2-(3-(prop-1-yn-1-yl)-4-(2,2,2-trifluoroethoxy)phenyl)-1,6-naphthyridin-7-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 12

[0408] Compound 12c (30 mg, 0.064 mmol) and 1j (35 mg, 0.13 mmol) were weighed into a 25 mL single neck flask, 1 mL of N,N-dimethylformamide was added, N,N-diisopropylethylamine (33 mg, 0.25 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (73 mg, 0.19 mmol) was added, and the reaction was allowed to proceed for 30 minutes. Purification was carried out by high performance liquid chromatography (GILSON-306, eluent: 10 mmol / L aqueous ammonium bicarbonate and acetonitrile, gradient of acetonitrile: 40%-95%, flow rate: 30 mL / min) to obtain the title compound 12 (3 mg, yield: 7%).

[0409] MS m / z (ESI): 472.2 [M+1].

[0410] 1H NMR (500 MHz, DMSO) δ 9.66 (t, 1H), 9.36 (s, 1H), 8.62 (d, 1H), 8.36 (d, 2H), 8.35 8.27 (m, 3H), 7.83 (s, 1H), 7.35 (d, 1H), 6.33-6.24 (m, 1H), 4.95 (q, 2H), 4.81 (d, 2H), 4.62 (dt, 1H), 4.18 (t, 1H), 2.82 (dt, 2H), 2.11 (s, 3H).

[0411] Example 13

[0412] (R)-N-((2-(6-(cyclopropylethynyl)-5-(difluoromethoxy)pyridin-2-yl)-1,6- naphthyridin-7-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7- carboxamide 5,5-dioxide 13

[0413] First step

[0414] 6-bromo-3-(difluoromethoxy)-2-iodopyridine 13b

[0415] Into a 100 mL single-necked flask, 6-bromo-2-iodo-3-hydroxypyridine 13a (2.4 g, 8.00 mmol), compound 8b (1.8 g, 12.00 mmol), cesium carbonate (3.9 g, 12.00 mmol) were weighed, 10 mL of N,N-dimethylformamide was added, and the reaction was heated to 80 °C for 16 hours. The reaction was cooled to room temperature, 30 mL of water was added, and the organic phase was extracted with ethyl acetate (30 mL x 3), washed with saturated sodium chloride solution (45 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 13b (1.9 g, yield: 68%).

[0416] MS m / z (ESI): 349.8 [M+1].

[0417] Second step

[0418] 6-bromo-2-(cyclopropylethynyl)-3-(difluoromethoxy)pyridine 13c

[0419] Into a 50 mL flask, compound 13b (1.1 g, 3.14 mmol), cuprous iodide (60 mg, 0.31 mmol), bis(triphenylphosphine)palladium dichloride (105 mg, 0.16 mmol) were taken, 6 mL of triethylamine and 6 mL of tetrahydrofuran were added, replaced with nitrogen for three times, compound 4a (228 mg, 3.46 mmol) was added, and the temperature was raised to 80 °C for 8 hours of reaction. The reaction solution was cooled to room temperature, 30 mL of water was added, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (45 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 13c (750 mg, yield: 83%).

[0420] MS m / z (ESI): 288.0 [M+1].

[0421] Third step

[0422] ((2-(6-(cyclopropylethynyl)-5-(difluoromethoxy)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)carbamic acid tert-butyl ester 13d

[0423] Into a 50 mL flask, compound 1a (750 mg, 2.55 mmol), hexamethylditin (1.0 g, 3.06 mmol), bis(triphenylphosphine)palladium dichloride (147 mg, 0.13 mmol) were taken, 2 mL of 1,4-dioxane was added, replaced with nitrogen for three times, and the temperature was raised to 100 °C for 3 hours of reaction. The reaction solution was cooled to room temperature, compound 13c (700 mg, 2.43 mmol) and bis(triphenylphosphine)palladium dichloride (170 mg, 0.24 mmol) were added, replaced with nitrogen for three times, and the temperature was raised to 100 °C for 16 hours of reaction. The reaction solution was cooled to room temperature, 30 mL of water was added, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (45 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 13d (632 mg, yield: 56%).

[0424] MS m / z (ESI): 467.2 [M+1].

[0425] Fourth step

[0426] (2-(6-(cyclopropylethynyl)-5-(difluoromethoxy)pyridin-2-yl)-1,6-naphthyridin-7-yl)methanamine trifluoroacetate salt 13e

[0427] Compound 13d (100 mg, 0.21 mmol) was taken in a 50 mL single necked flask, 1.5 mL of dichloromethane was added, 0.2 mL of trifluoroacetic acid was added drop wise and the reaction was carried out for 3 h. The reaction mass was concentrated under reduced pressure to get the crude product of title compound 13e (102 mg, yield: 100%) which was used as such for the next step without purification.

[0428] MS m / z (ESI): 367.4 [M+1].

[0429] Fifth step

[0430] (R)-N-((2-(6-(cyclopropylethynyl)-5-(difluoromethoxy)pyridin-2-yl)-1,6- naphthyridin-7-yl)methyl)-N-methylmethanamine

[0431] 4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 13

[0432] Compound 13e (102 mg, 0.21 mmol) and 1j (50 mg, 0.18 mmol) were taken in a 25 mL single necked flask, 1.5 mL of N,N-dimethylformamide was added, N,N- diisopropylethylamine (161 mg, 1.25 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) was added and the reaction was carried out for 1 h. The reaction mass was filtered and purified by high performance liquid preparative chromatography (Waters-2545, eluent system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 40-95%, flow rate: 30 mL / min) to get the title compound 13 (33 mg, yield: 25%).

[0433] MS m / z (ESI): 627.0 [M+1].

[0434] 1 H NMR (500 MHz, DMSO-d6) δ 9.68 (t, 1H), 9.45 (s, 1H), 8.74-8.70 (m, 1H), 8.60-8.56 (m, 2H), 8.36 (s, 1H), 8.33 (dd, 1H), 7.90 (d, 1H), 7.88 (s, 1H), 7.42 (t, 1H), 6.29 (m, 1H), 4.83 (d, 2H), 4.62 (dt, 1H), 4.17 (t, 1H), 2.85-2.76 (m, 1H), 2.63-2.57 (m, 1H), 1.73-1.68 (m, 1H), 1.05-0.99 (m, 2H), 0.89-0.84 (m, 2H).

[0435] Example 14

[0436] (R)-N-((4-(3-(cyclopropylethynyl)phenyl)pyridin-2-yl)methyl)-4,9-difluoro-3,4- dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 14

[0437] First step

[0438] 1-bromo-3-(cyclopropylethynyl)benzene 14a

[0439] Compound 10a (200 mg, 0.71 mmol), cuprous iodide (13 mg, 0.07 mmol), dichlorobis(triphenylphosphine)palladium (24 mg, 0.03 mmol) were weighed into a 50 mL two-necked flask, 3 mL of triethylamine and 3 mL of tetrahydrofuran were added, replaced with nitrogen for three times, compound 4a (56 mg, 0.85 mmol) was added, and the temperature was raised to 75 °C for reaction for 4 hours. The reaction solution was cooled to room temperature, 15 mL of water was added, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 14a (142 mg, yield: 91%).

[0440] Second step

[0441] tert-butyl ((4-(3-(cyclopropylethynyl)phenyl)pyridin-2-yl)methyl)carbamate 14c

[0442] Compound 14a (80 mg, 0.36 mmol), (2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4- yl)boronic acid 14b (109 mg, 0.43 mmol, prepared by the method disclosed in the specification of patent application “WO2021105474A1, page 74, intermediate 23-2”), [1,1'- bis(ditert-butylphosphino)ferrocene]dichloropalladium (25 mg, 0.04 mmol), anhydrous potassium carbonate (150 mg, 1.08 mmol) were weighed into a 25 mL single-necked flask, 2 mL of 1,4-dioxane and 0.5 mL of water were added, replaced with nitrogen for three times, and the temperature was raised to 95 °C for reaction for 16 hours. The reaction solution was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 14c (82 mg, yield: 68%).

[0443] MS m / z (ESI): 349.2 [M+1].

[0444] Third Step

[0445] (4-(3-(Cyclopropylethynyl)phenyl)pyridin-2-yl)methanamine trifluoroacetate salt 14d

[0446] Compound 14c (40 mg, 0.11 mmol) was weighed into a 25 mL vial, 1 mL of dichloromethane was added, 0.1 mL of trifluoroacetic acid was added dropwise, and the reaction was allowed to proceed for 1 hour. The reaction was concentrated under reduced pressure to give the crude product of title compound 14d (42 mg, yield: 100%), which was used directly in the next step without purification.

[0447] MS m / z (ESI): 249.4 [M+1].

[0448] Fourth Step

[0449] (R)-N-((4-(3-(Cyclopropylethynyl)phenyl)pyridin-2-yl)methyl)-4,9-difluoro-3,4- dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 14

[0450] Compound 14d (42 mg, 0.11 mmol) and 1j (22 mg, 0.28 mmol) were weighed into a 25 mL vial, 1 mL of N,N-dimethylformamide was added, N,N-diisopropylethylamine (69 mg, 0.53 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (50 mg, 0.13 mmol) was added, and the reaction was allowed to proceed for 1 hour. The reaction was filtered and purified by high performance liquid chromatography (Waters-2545, elution system: 10 mmol / L aqueous ammonium bicarbonate and acetonitrile, gradient of acetonitrile: 40%-95%, flow rate: 30 mL / min) to give title compound 14 (13 mg, yield: 23%).

[0451] MS m / z (ESI): 509.1 [M+1].

[0452] 1H NMR (500 MHz, DMSO-d6) δ 9.49 (t, 1H), 8.58 (d, 1H), 8.30 (s, 1H), 8.27 (dd, 1H), 7.75-7.70 (m, 3H), 7.63 (dd, 1H), 7.50-7.45 (m, 2H), 6.27 (ddd, 1H), 4.67 (d, 2H), 4.60 (dt, 1H), 4.15 (t, 1H), 2.84-2.74 (m, 1H), 2.62-2.57 (m, 1H), 1.60-1.55 (m, 1H), 0.93-0.89 (m, 2H), 0.78-0.75 (m, 2H).

[0453] Example 15

[0454] (R)-N-((2'-(cyclopropylethynyl)-[4,4'-bipyridin]-2-yl)methyl)-4,9-difluoro-3,4- dihydro-2H-benzo[b][l,4]oxathiepine-7-carboxamide 5,5-dioxide 15

[0455] The method of Example 14 was used, replacing the first step starting material compound 10a with 2-bromo-4-chloropyridine (Bide Pharm), and the final product was purified by high performance liquid preparative chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 25%-95%, flow rate: 30 mL / min) to give the title compound 15 (60 mg, yield: 38%).

[0456] MS m / z (ESI): 510.1 [M+1].

[0457] 1 H NMR (500 MHz, DMSO-d6) δ 9.50 (t, 1H), 8.65 (dd, 2H), 8.30 (s, 1H), 8.27 (dd, 1H), 7.83 (d, 2H), 7.75-7.72 (m, 2H), 6.27 (ddd, 1H), 4.69 (d, 2H), 4.61 (dt, 1H), 4.14 (t, 1H), 2.85-2.74 (m, 1H), 2.62-2.57 (m, 1H), 1.65-1.59 (m, 1H), 0.98-0.94 (m, 2H), 0.83-0.80 (m, 2H).

[0458] Example 16

[0459] (R)-N-((4-(3-(cyclopropylethynyl)-4-fluorophenyl)pyridin-2-yl)methyl)-4,9- difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 16

[0460] The procedure of Example 14 was followed using 2-iodo-4-bromo-fluorobenzene (Bide Pharm) instead of compound 10a as the first step starting material. The final product was purified by preparative HPLC (Waters-2545, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 40-65%, flow rate: 30 mL / min) to give the title compound 16 (6 mg, yield: 12%).

[0461] MS m / z (ESI): 527.2 [M+1].

[0462] 1 H NMR (500 MHz, DMSO-d6) δ 9.48 (t, 1H), 8.57 (d, 1H), 8.30 (s, 1H), 8.27 (dd, 1H), 7.86 (dd, 1H), 7.80-7.77 (m, 1H), 7.70 (s, 1H), 7.63 (dd, 1H), 7.41 (t, 1H), 6.27 (ddd, 1H), 4.66 (d, 2H), 4.61 (dt, 1H), 4.14 (t, 1H), 2.84-2.74 (m, 1H), 2.63-2.57 (m, 1H), 1.65-1.60 (m, 1H), 0.97-0.93 (m, 2H), 0.81-0.77 (m, 2H).

[0463] Example 17

[0464] (R)-4,9-difluoro-N-((4-(3-(oxetan-3-ylethynyl)phenyl)pyridin-2-yl)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 17

[0465] The procedure of Example 14 was followed using 3-ethynyloxetane (Bide Pharm) instead of compound 4a as the first step starting material. The final product was purified by preparative HPLC (GILSON 306, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 35-95%, flow rate: 30 mL / min) to give the title compound 17 (18 mg, yield: 30%).

[0466] MS m / z (ESI): 525.0 [M+1].

[0467] 1 H NMR (500 MHz, DMSO-d6) δ 9.50 (t, 1H), 8.60 (d, 1H), 8.30 (s, 1H), 8.27 (dd, 1H), 7.84 (s, 1H), 7.79-7.77 (m, 1H), 7.73 (s, 1H), 7.65 (d, 1H), 7.56-7.52 (m, 2H), 6.27 (ddd, 1H), 4.84-4.81 (m, 2H), 4.68-4.58 (m, 5H), 4.21-4.12 (m, 2H), 2.85-2.78 (m, 1H), 2.60-2.57 (m, 1H).

[0468] Example 18

[0469] (R)-4,9-difluoro-N-((4-(3-((tetrahydro-2H-pyran-4-yl)ethynyl)phenyl)pyridin-2-yl)methyl)- 3,4-dihydro-2H-benzo[b][l,4]oxathiepine-7-carboxamide 5,5-dioxide 18

[0470] The method of Example 14 was used, replacing the first step starting compound 4a with 2-ethynyltetrahydro-2H-pyran (Bide Pharm), and the final product was purified by high performance liquid preparative chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 40%-70%, flow rate: 30 mL / min) to obtain the title compound 18 (18 mg, yield: 30%).

[0471] MS m / z (ESI): 553.1 [M+1].

[0472] 1 H NMR (500 MHz, DMSO-d6) δ 9.50 (t, 1H), 8.60 (d, 1H), 8.30 (s, 1H), 8.27 (dd, 1H), 7.84 (s, 1H), 7.79-7.77 (m, 1H), 7.73 (s, 1H), 7.65 (d, 1H), 7.56-7.52 (m, 2H), 6.27 (ddd, 1H), 4.84-4.81 (m, 2H), 4.68-4.58 (m, 5H), 4.21-4.12 (m, 2H), 2.85-2.78 (m, 1H), 2.60-2.57 (m, 1H).

[0473] Example 19

[0474] (R)-4,9-difluoro-N-((4-(3-(3-morpholinoprop-1-yn-1-yl)phenyl)pyridin-2-yl)methyl)- 3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 19

[0475] The procedure of Example 14 was used, replacing the first step starting material compound 4a with 4-(prop-2-yn-1-yl)morpholine (Bide Pharmachem), and the final product was purified by preparative HPLC (LC-20AP, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 30%-95%, flow rate: 30 mL / min) to give the title compound 19 (25 mg, yield: 34%).

[0476] MS m / z (ESI): 568.0 [M+1].

[0477] 1 H NMR (500 MHz, DMSO-d6) δ 9.50 (t, 1H), 8.60 (d, 1H), 8.30 (d, 1H), 8.27 (dd, 1H), 7.82 (s, 1H), 7.78 (dt, 1H), 7.72 (s, 1H), 7.65 (dd, 1H), 7.56-7.51 (m, 2H), 6.27 (ddd, 1H), 4.67 (d, 2H), 4.61 (dt, 1H), 4.15 (t, 1H), 3.62 (t, 4H), 3.54 (s, 2H), 3.31 (s, 4H), 2.84-2.76 (m, 1H), 2.62-2.59 (m, 1H).

[0478] Example 20

[0479] (R)-4,9-difluoro-N-((4-(3-((1-morpholinocyclopropyl)ethynyl)phenyl)pyridin-2-yl)methyl)- 3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 20

[0480] First step

[0481] tert-Butyl (1-((3-bromophenyl)ethynyl)cyclopropyl)carbamate 20b

[0482] Into a 50 mL two-necked flask, compound 10a (400 mg, 1.41 mmol), cuprous iodide (27 mg, 0.14 mmol), dichlorobis(triphenylphosphine)palladium (47 mg, 0.07 mmol) were weighed, 3 mL of triethylamine and 3 mL of tetrahydrofuran were added, replaced with nitrogen for three times, (1-ethynylcyclopropyl)carbamic acid tert-butyl ester 20a (281 mg, 1.55 mmol) was added, and the reaction was carried out for 16 hours. 15 mL of water was added to the reaction solution, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 20b (472 mg, yield: 99%).

[0483] MS m / z (ESI): 336.0 [M+1].

[0484] Second step

[0485] 1-((3-bromophenyl)ethynyl)cyclopropylamine trifluoroacetate salt 20c

[0486] Into a 25 mL single-necked flask, compound 20b (150 mg, 0.45 mmol) was weighed, 1 mL of dichloromethane was added, and 0.2 mL of trifluoroacetic acid was added dropwise. The reaction was carried out for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product of the title compound 20c (158 mg, yield: 100%), which was directly used in the next step without purification.

[0487] MS m / z (ESI): 236.0 [M+1].

[0488] Third step

[0489] 4-(1-((3-bromophenyl)ethynyl)cyclopropyl)morpholine 20d

[0490] Into a 15 mL sealed tube, compound 20c (156 mg, 0.45 mmol), 2,2'-dibromo-diethyl ether (207 mg, 0.89 mmol, Bide Pharmaceutical), N,N-diisopropyl ethylamine (288 mg, 2.23 mmol) were weighed, 2 mL of acetonitrile was added, and the reaction was carried out in a sealed tube at 100°C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 20d (79 mg, yield: 58%).

[0491] MS m / z (ESI): 306.0 [M+1].

[0492] Fourth step

[0493] tert-Butyl ((4-(3-((1-morpholinocyclopropyl)ethynyl)phenyl)pyridin-2- yl)methyl)carbamate 20e

[0494] Compound 20d (79 mg, 0.26 mmol), compound 14b (70 mg, 0.28 mmol), [1,1'- bis(ditert-butylphosphino)ferrocene]dichloropalladium (17 mg, 0.03 mmol), anhydrous potassium carbonate (107 mg, 0.77 mmol) were weighed into a 25 mL single neck flask, 1.5 mL 1,4-dioxane and 0.3 mL water were added, replaced with nitrogen for three times, and then the reaction was heated to 95 °C for 16 hours. The reaction was cooled to room temperature, 10 mL water was added, and then the reaction was extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 20e (48 mg, yield: 43%).

[0495] MS m / z (ESI): 434.2 [M+1].

[0496] Fifth step

[0497] (R)-4,9-difluoro-N-((4-(3-((1-morpholinocyclopropyl)ethynyl)phenyl)pyridin-2- yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 20

[0498] Compound 20e (48 mg, 0.11 mmol) was weighed into a 25 mL single neck flask, 1 mL dichloromethane was added, and then 0.1 mL trifluoroacetic acid was added dropwise. The reaction was carried out for 2 hours. The reaction was concentrated under reduced pressure to obtain the crude product of the title compound 20f (61 mg, yield: 99%), which was used directly in the next step without purification.

[0499] MS m / z (ESI): 334.2 [M+1].

[0500] Sixth step

[0501] (R)-4,9-difluoro-N-((4-(3-((1-morpholinocyclopropyl)ethynyl)phenyl)pyridin-2- yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 20

[0502] Compound 20f (61 mg, 0.11 mmol) and 1j (30 mg, 0.11 mmol) were weighed into a 25 mL single neck flask, 1 mL of N,N-dimethylformamide was added, N,N-diisopropylethylamine (85 mg, 0.66 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (62 mg, 0.16 mmol) was added, and the reaction was allowed to proceed for 1 h. The reaction was filtered and purified by high performance liquid chromatography (GILSON-281, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 40-95%, flow rate: 30 mL / min) to give the title compound 20 (17 mg, yield: 26%).

[0503] MS m / z (ESI): 594.2 [M+1].

[0504] 1 H NMR (500 MHz, DMSO-d6) δ 9.50 (t, 1H), 8.59 (d, 1H), 8.30 (s, 1H), 8.27 (dd, 1H), 7.78 (s, 1H), 7.77-7.75 (m, 1H), 7.72 (s, 1H), 7.65 (dd, 1H), 7.52 (d, 2H), 6.27 (ddd, 1H), 4.67 (d, 2H), 4.60 (dt, 1H), 4.14 (t, 1H), 3.57 (t, 4H), 2.84-2.76 (m, 1H), 2.68 (t, 4H), 2.62-2.57 (m, 1H), 1.02-1.00 (m, 2H), 0.98-0.95 (t, 2H).

[0505] Example 21

[0506] (R)-N-((4-(3-((1-(dimethylamino)cyclopropyl)ethynyl)phenyl)pyridin-2-yl)methyl)- 4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 21

[0507] First step

[0508] 1-((3-bromophenyl)ethynyl)-N,N-dimethylcyclopropan-1-amine 21a

[0509] Take compound 20c (156 mg, 0.45 mmol), 30% aqueous formaldehyde solution (506 mg, 4.46 mmol), sodium triacetylborohydride (283 mg, 1.34 mmol) into a 25 mL single neck flask, add 2 mL acetonitrile, react for 2 hours. Add 10 mL water to the reaction solution, extract with ethyl acetate (15 mL x 3), combine the organic phase, wash with saturated sodium chloride solution (15 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, purify the obtained residue with silica gel column chromatography with eluent system B to obtain the title compound 21a (86 mg, yield: 73%).

[0510] MS m / z (ESI): 264.0 [M+1].

[0511] Second step

[0512] tert-Butyl ((4-(3-((1-(dimethylamino)cyclopropyl)ethynyl)phenyl)pyridin-2- yl)methyl)carbamate 21b

[0513] Take compound 21a (86 mg, 0.33 mmol), compound 14b (90 mg, 0.36 mmol), [1,1'- bis(ditert-butylphosphino)ferrocene]dichloropalladium (22 mg, 0.03 mmol), anhydrous potassium carbonate (135 mg, 0.98 mmol) into a 25 mL single neck flask, add 1.5 mL 1,4-dioxane and 0.3 mL water, replace with nitrogen for three times, warm up to 95 °C and react for 16 hours. Cool the reaction solution to room temperature, add 10 mL water, extract with ethyl acetate (30 mL x 3), combine the organic phase, wash with saturated sodium chloride solution (15 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, purify the obtained residue with silica gel column chromatography with eluent system B to obtain the title compound 21b (46 mg, yield: 36%).

[0514] MS m / z (ESI): 392.2 [M+1].

[0515] Third step

[0516] 1-((3-(2-(Aminomethyl)pyridin-4-yl)phenyl)ethynyl)-N,N-dimethylcyclopropan-1-amine trifluoroacetate 21c

[0517] Take compound 21b (46 mg, 0.12 mmol) into a 25 mL single neck flask, add 1 mL dichloromethane, drop 0.1 mL trifluoroacetic acid, react for 2 hours. Concentrate the reaction solution under reduced pressure to obtain the crude product of the title compound 21c (62 mg, yield: 99%), which is directly used in the next step reaction without purification.

[0518] MS m / z (ESI): 292.2 [M+1].

[0519] Fourth step

[0520] (R)-N-((4-(3-((1-(dimethylamino)cyclopropyl)ethynyl)phenyl)pyridin-2-yl)methyl)- 4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 21

[0521] Compound 21c (62 mg, 0.11 mmol) and 1j (30 mg, 0.11 mmol) were weighed into a 25 mL single neck flask, 1 mL of N,N-dimethylformamide was added, N,N- diisopropylethylamine (90 mg, 0.69 mmol) was added, 2-(7-azabenzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate (66 mg, 0.17 mmol) was added, and the reaction was allowed to proceed for 1 h. The reaction was filtered and purified by high performance liquid preparative chromatography (Waters-2545, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 40-60%, flow rate: 30 mL / min) to give the title compound 21 (18 mg, yield: 28%).

[0522] MS m / z (ESI): 552.2 [M+1].

[0523] 1 H NMR (500 MHz, DMSO-d6) δ 9.50 (t, 1H), 8.59 (d, 1H), 8.30 (s, 1H), 8.27 (dd, 1H), 7.77-7.74 (m, 2H), 7.71 (s, 1H), 7.65 (dd, 1H), 7.54-7.51 (m, 2H), 6.27 (ddd, 1H), 4.67 (d, 2H), 4.61 (dt, 1H), 4.14 (t, 1H), 2.82-2.74 (m, 1H), 2.62-2.57 (m, 1H), 2.31 (s, 6H), 1.00-0.98 (m, 2H), 0.92-0.90 (m, 2H).

[0524] Example 22

[0525] (R)-N-((6-(cyclopropylethynyl)-5-(difluoromethoxy)-[2,4'-bipyridin]-2'-yl)methyl)-4,9- difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 22

[0526] First step

[0527] ((6-(cyclopropylethynyl)-5-(difluoromethoxy)-[2,4'-bipyridinyl]-2'- yl)methyl)aminoformic acid tert-butyl ester 22a

[0528] Compound 13c (123 mg, 0.43 mmol), compound 14b (110 mg, 0.44 mmol), [1,1'- bis(ditert-butylphosphino)ferrocene]dichloropalladium (29 mg, 0.04 mmol), anhydrous potassium carbonate (177 mg, 1.28 mmol) were weighed into a 25 mL single neck flask, 2 mL 1,4-dioxane and 0.5 mL water were added, replaced with nitrogen for three times, and then the reaction was heated to 95 °C for 16 hours. The reaction was cooled to room temperature, 10 mL water was added, and the mixture was extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 22a (78 mg, yield: 44%).

[0529] MS m / z (ESI): 416.2 [M+1].

[0530] Second step

[0531] (6-(cyclopropylethynyl)-5-(difluoromethoxy)-[2,4'-bipyridinyl]-2'- yl)methanamine trifluoroacetate 22b

[0532] Compound 22a (35 mg, 0.08 mmol) was weighed into a 25 mL single neck flask, 1 mL dichloromethane was added, and 0.1 mL trifluoroacetic acid was added dropwise. The reaction was carried out for 2 hours. The reaction was concentrated under reduced pressure to obtain the crude product of the title compound 22b (36 mg, yield: 99%), which was used directly in the next step without purification.

[0533] MS m / z (ESI): 316.4 [M+1].

[0534] Third step

[0535] (R)-N-((6-(cyclopropylethynyl)-5-(difluoromethoxy)-[2,4'-bipyridinyl]-2'- yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5- dioxide 22

[0536] Compound 22b (36 mg, 0.08 mmol) and 1j (22 mg, 0.08 mmol) were weighed into a 25 mL single neck flask, 1 mL of N,N-dimethylformamide was added, N,N-diisopropylethylamine (65 mg, 0.50 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (48 mg, 0.13 mmol) was added, and the reaction was allowed to proceed for 1 h. The reaction was filtered and purified by high performance liquid chromatography (GILSON-281, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 30%-95%, flow rate: 30 mL / min) to give the title compound 22 (12 mg, yield: 25%).

[0537] MS m / z (ESI): 576.0 [M+1].

[0538] 1 H NMR (500 MHz, DMSO-d6) δ 9.58 (t, 1H), 8.65 (d, 1H), 8.32 (s, 1H), 8.28 (dd, 1H), 8.11 (d, 1H), 7.98 (s, 1H), 7.89 (d, 1H), 7.84 (d, 1H), 7.36 (t, 1H), 6.28 (ddd, 1H), 4.69 (d, 2H), 4.61 (dt, 1H), 4.15 (t, 1H), 2.88-2.75 (m, 1H), 2.64-2.55 (m, 1H), 1.69-1.64 (m, 1H), 1.01-0.97 (m, 2H), 0.83-0.80 (m, 2H).

[0539] Example 23

[0540] (R)-N-((4-(3-(cyclopropylethynyl)-4-(difluoromethoxy)phenyl)pyridin-2-yl)methyl)- 4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 23

[0541] First Step

[0542] 4-bromo-2-(cyclopropylethynyl)-1-(difluoromethoxy)benzene 23a

[0543] Into a 50 mL flask, compound 8c (500 mg, 1.43 mmol), cuprous iodide (27 mg, 0.14 mmol), dichlorobis(triphenylphosphine)palladium (48 mg, 0.07 mmol) were weighed, 2 mL of triethylamine and 2 mL of tetrahydrofuran were added, replaced with nitrogen for three times, compound 4a (104 mg, 1.57 mmol) was added, and the reaction was carried out for 16 hours. 15 mL of water was added to the reaction solution, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 23a (408 mg, yield: 99%).

[0544] Second step

[0545] tert-Butyl ((4-(3-(cyclopropylethynyl)-4-(difluoromethoxy)phenyl)pyridin-2- yl)methyl)carbamate 23b

[0546] Into a 25 mL flask, compound 23a (200 mg, 0.70 mmol), compound 14b (170 mg, 0.67 mmol), [1,1'-bis(ditert-butylphosphino)ferrocene]dichloropalladium (47 mg, 0.07 mmol), anhydrous potassium carbonate (288 mg, 2.09 mmol) were weighed, 2 mL of 1,4-dioxane and 0.5 mL of water were added, replaced with nitrogen for three times, and the reaction was carried out at 95°C for 16 hours. The reaction solution was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 23b (165 mg, yield: 57%).

[0547] MS m / z (ESI): 415.2 [M+1].

[0548] Third step

[0549] (4-(3-(cyclopropylethynyl)-4-(difluoromethoxy)phenyl)pyridin-2-yl)methanamine trifluoroacetate 23c

[0550] Into a 25 mL flask, compound 23b (50 mg, 0.12 mmol) was weighed, 1 mL of dichloromethane was added, and 0.1 mL of trifluoroacetic acid was added dropwise, and the reaction was carried out for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product of the title compound 23c (51 mg, yield: 99%), which was directly used in the next step without purification.

[0551] MS m / z (ESI): 315.4 [M+1].

[0552] Fourth step

[0553] (R)-N-((4-(3-(cyclopropylethynyl)-4-(difluoromethoxy)phenyl)pyridin-2-yl)methyl)- 4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 23

[0554] Compound 23c (51 mg, 0.12 mmol) and 1j (25 mg, 0.09 mmol) were weighed into a 25 mL single neck flask, 1 mL of N,N-dimethylformamide was added, N,N- diisopropylethylamine (70 mg, 0.56 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (53 mg, 0.14 mmol) was added, and the reaction was allowed to proceed for 1 h. The reaction was filtered and purified by high performance liquid preparative chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 45%-95%, flow rate: 30 mL / min) to give the title compound 23 (13 mg, yield: 24%).

[0555] MS m / z (ESI): 575.1 [M+1].

[0556] 1 H NMR (500 MHz, DMSO-d6) δ 9.49 (t, 1H), 8.58 (d, 1H), 8.31 (s, 1H), 8.27 (dd, 1H), 7.87 (d, 1H), 7.79 (dd, 1H), 7.71 (s, 1H), 7.63 (dd, 1H), 7.36 (d, 1H), 7.29 (t, 1H), 6.27 (ddd, 1H), 4.67 (d, 2H), 4.61 (dt, 1H), 4.15 (t, 1H), 2.86-2.74 (m, 1H), 2.63-2.56 (m, 1H), 1.64-1.58 (m, 1H), 0.97-0.93 (m, 2H), 0.79-0.76 (m, 2H).

[0557] Example 24

[0558] (R)-9-chloro-N-((4-(3-(cyclopropylethynyl)-4-(difluoromethoxy)phenyl)pyridin-2- yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 24

[0559] To a 25 mL single necked flask was added compound 23c (165 mg, 0.38 mmol) and (R)-9-chloro-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxylic acid 5,5-dioxide 24a (prepared using the method disclosed in the patent application “WO2023220219A1 specification page 204, intermediate 3”, 130 mg, 0.44 mmol), 2 mL of N,N-dimethylformamide, N,N-diisopropylethylamine (299 mg, 2.31 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (220 mg, 0.58 mmol), and the reaction was stirred for 1 h. The reaction was filtered and purified by high performance liquid chromatography (GILSON-281, elution system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 40-95%, flow rate: 30 mL / min) to give the title compound 24 (38 mg, yield: 17%).

[0560] MS m / z (ESI): 591.2 [M+1].

[0561] 1 H NMR (500 MHz, DMSO-d6) δ 9.50 (t, 1H), 8.58 (d, 1H), 8.49 (d, 1H), 8.40 (d, 1H), 7.87 (d, 1H), 7.79 (dd, 1H), 7.71 (s, 1H), 7.63 (dd, 1H), 7.36 (d, 1H), 7.29 (t, 1H), 6.25 (ddd, 1H), 4.66 (d, 2H), 4.61 (dt, 1H), 4.08 (t, 1H), 2.86-2.76 (m, 1H), 2.62-2.58 (m, 1H), 1.64-1.58 (m, 1H), 0.96-0.93 (m, 2H), 0.79-0.76 (m, 2H).

[0562] Example 25

[0563] (R)-N-((4-(4-(di fluoromethoxy)-3-(oxetan-3-ylethynyl)phenyl)pyridin-2-yl)methyl)-4,9- di fluor o-3, 4-dihydro-2H-benzo [b] [1,4] oxathi epine-7-carboxamide 5, 5-dioxide 25

[0564] The method of Example 23 was used, replacing the first step starting material compound 4a with 3-ethynyloxetane (Bide Pharm), and the final product was purified by high performance liquid preparative chromatography (Waters-2545, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 35%-95%, flow rate: 30 mL / min) to give the title compound 25 (30 mg, yield: 20%).

[0565] MS m / z (ESI): 591.1 [M+1].

[0566] 1 H NMR (500 MHz, DMSO-d6) δ 9.50 (t, 1H), 8.60 (d, 1H), 8.30 (s, 1H), 8.27 (dd, 1H), 7.97 (d, 1H), 7.85 (dd, 1H), 7.73 (s, 1H), 7.66 (dd, 1H), 7.41 (d, 1H), 7.36 (t, 1H), 6.27 (ddd, 1H), 4.86-4.83 (m, 2H), 4.67-4.59 (m, 5H), 4.25-4.19 (m, 1H), 4.14 (t, 1H), 2.87-2.74 (m, 1H), 2.61-2.57 (m, 1H).

[0567] Example 26

[0568] (R)-N-((4-(4-(diifluoromethoxy)-3-((tetrahydro-2H-pyran-4-yl)ethynyl)phenyl)pyridin-2- yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 26

[0569] The method of Example 23 was used, replacing the first step starting material compound 4a with 2-ethynyltetrahydro-2H-pyran (Bide Pharm), and the final product was purified by high performance liquid preparative chromatography (Waters-2545, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 40%-60%, flow rate: 30 mL / min) to give the title compound 26 (45 mg, yield: 22%).

[0570] MS m / z (ESI): 619.0 [M+1].

[0571] 1H NMR (500 MHz, DMSO-d6) δ 9.49 (t, 1H), 8.59 (d, 1H), 8.30 (s, 1H), 8.27 (dd, 1H), 7.89 (d, 1H), 7.83 (dd, 1H), 7.72 (s, 1H), 7.65 (dd, 1H), 7.39 (d, 1H), 7.32 (t, 1H), 6.27 (ddd, 1H), 4.67 (d, 2H), 4.61 (dt, 1H), 4.14 (t, 1H), 3.85-3.81 (m, 2H), 3.52-3.47 (m, 2H), 3.01-2.96 (m, 1H), 2.87-2.74 (m, 1H), 2.61-2.57 (m, 1H), 1.89-1.84 (m, 2H), 1.66-1.59 (m, 2H).

[0572] Example 27

[0573] (R)-N-((4-(4-(diifluoromethoxy)-3-((1-morpholino cyclopropyl)ethynyl)phenyl)pyridin-2-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathi epine-7-carboxamide 5,5-dioxide 27

[0574] The method of Example 20 was used, replacing the first step starting material compound 10a with compound 8c, and the final product was purified by high performance liquid preparative chromatography (Shimadzu LC-20AP, elution system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 40%-60%, flow rate: 30 mL / min) to give the title compound 27 (56 mg, yield: 39%).

[0575] MS m / z (ESI): 660.2 [M+1].

[0576] 1 H NMR (500 MHz, DMSO-d6) δ 9.49 (t, 1H), 8.59 (d, 1H), 8.30 (s, 1H), 8.27 (dd, 1H), 7.89 (d, 1H), 7.83 (dd, 1H), 7.72 (s, 1H), 7.65 (dd, 1H), 7.40 (d, 1H), 7.33 (t, 1H), 6.27 (ddd, 1H), 4.67 (d, 2H), 4.61 (dt, 1H), 4.14 (t, 1H), 3.57 (t, 4H), 2.84-2.77 (m, 1H), 2.69 (t, 4H), 2.62-2.57 (m, 1H), 1.03-0.97 (m, 4H).

[0577] Example 28

[0578] (R)-9-chloro-N-((4-(4-(difluoromethoxy)-3-((1- morpholylcyclopropyl)ethynyl)phenyl)pyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H- benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 28

[0579] The method of Example 20 was used, replacing the first step starting material compound 10a with compound 8c, and replacing the sixth step starting material compound 1j with compound 24a. The final product was purified by high performance liquid preparative chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 40%-65%, flow rate: 30 mL / min) to give the title compound 28 (56 mg, yield: 32%).

[0580] MS m / z (ESI): 676.0 [M+1].

[0581] 1 H NMR (500 MHz, DMSO-d6) δ 9.51 (t, 1H), 8.59 (d, 1H), 8.49 (d, 1H), 8.40 (d, 1H), 7.89 (d, 1H), 7.83 (dd, 1H), 7.73 (s, 1H), 7.65 (dd, 1H), 7.40 (d, 1H), 7.33 (t, 1H), 6.25 (ddd, 1H), 4.67 (d, 2H), 4.61 (dt, 1H), 4.08 (t, 1H), 3.57 (t, 4H), 2.86-2.76 (m, 1H), 2.69 (t, 4H), 2.61-2.55 (m, 1H), 1.03-0.97 (m, 4H).

[0582] Example 29

[0583] (R)-N-((4-(4-(difluoromethoxy)-3-((1-(dimethylamino)cyclopropyl)ethynyl)phenyl)pyridin-2- yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 29

[0584] First step

[0585] (1-((5-bromo-2-(difluoromethoxy)phenyl)ethynyl)cyclopropyl)carbamic acid tert-butyl ester 29a

[0586] Into a 50 mL flask, compound 8c (600 mg, 1.72 mmol), cuprous iodide (33 mg, 0.17 mmol), dichlorobis(triphenylphosphine)palladium (58 mg, 0.08 mmol) were weighed, 3 mL of triethylamine and 3 mL of tetrahydrofuran were added, replaced with nitrogen for 3 times, compound 20a (343 mg, 1.89 mmol) was added, and the reaction was carried out for 16 hours. 15 mL of water was added to the reaction solution, extracted with 30 mL of ethyl acetate for 3 times, the organic phases were combined, washed with 30 mL of saturated sodium chloride solution for 3 times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 29a (557 mg, yield: 81%).

[0587] MS m / z (ESI): 402.1 [M+1].

[0588] Second step

[0589] 1-((5-bromo-2-(difluoromethoxy)phenyl)ethynyl)cycloprop-1-amine trifluoroacetate salt 29b

[0590] Into a 25 mL flask, compound 29a (380 mg, 0.94 mmol) was weighed, 1 mL of dichloromethane was added, and 0.3 mL of trifluoroacetic acid was added dropwise, and the reaction was carried out for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product of the title compound 29b (392 mg, yield: 100%), which was directly used in the next step without purification.

[0591] MS m / z (ESI): 302.0 [M+1].

[0592] Third step

[0593] 1-((5-bromo-2-(difluoromethoxy)phenyl)ethynyl)-N,N-dimethylcycloprop-1-amine 29c

[0594] Into a 25 mL flask, compound 29b (196 mg, 0.47 mmol), 30% aqueous formaldehyde solution (535 mg, 4.71 mmol), sodium triacetylborohydride (300 mg, 1.41 mmol) were weighed, 2 mL of acetonitrile was added, and the reaction was carried out for 2 hours. 10 mL of water was added to the reaction solution, extracted with 15 mL of ethyl acetate for 3 times, the organic phases were combined, washed with 15 mL of saturated sodium chloride solution for 3 times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 29c (70 mg, yield: 45%).

[0595] MS m / z (ESI): 330.0 [M+1].

[0596] Fourth step

[0597] tert-Butyl ((4-(4-(difluoromethoxy)-3-(1-((dimethylamino)cyclopropyl)ethynyl)phenyl)pyridin-2- yl)methyl)carbamate 29d

[0598] Compound 29c (70 mg, 0.21 mmol), compound 14b (60 mg, 0.24 mmol), [1,1'- bis(ditert-butylphosphino)ferrocene]dichloropalladium (14 mg, 0.02 mmol), anhydrous potassium carbonate (88 mg, 0.64 mmol) were weighed into a 25 mL single neck flask, 1.5 mL 1,4-dioxane and 0.3 mL water were added, replaced with nitrogen for three times, and then the reaction was heated to 95 °C for 16 hours. The reaction was cooled to room temperature, 10 mL water was added, and then the mixture was extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 29d (63 mg, yield: 65%).

[0599] MS m / z (ESI): 458.2 [M+1].

[0600] Fifth step

[0601] 1-((5-(2-(Aminomethyl)pyridin-4-yl)-2-(difluoromethoxy)phenyl)ethynyl)-N,N- dimethylcyclopropane

[0602] -1-amine trifluoroacetate 29e

[0603] Compound 29d (63 mg, 0.14 mmol) was weighed into a 25 mL single neck flask, 1 mL dichloromethane was added, and then 0.1 mL trifluoroacetic acid was added dropwise. The reaction was carried out for 2 hours. The reaction was concentrated under reduced pressure to give the crude product of the title compound 29e (82 mg, yield: 99%), which was used directly in the next step without purification.

[0604] MS m / z (ESI): 358.2 [M+1].

[0605] Sixth step

[0606] (R)-N-((4-(4-(difluoromethoxy)-3-((1-(dimethylamino)cyclopropyl)ethynyl)phenyl)pyridin-2- yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 29

[0607] Compound 29e (82 mg, 0.14 mmol) and 1j (37 mg, 0.13 mmol) were weighed into a 25 mL single neck flask, 1 mL of N,N-dimethylformamide was added, N,N-diisopropylethylamine (105 mg, 0.81 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (77 mg, 0.20 mmol) was added, and the reaction was allowed to proceed for 1 h. The reaction was filtered and purified by high performance liquid chromatography (Shimadzu LC-20AP, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 40-60%, flow rate: 30 mL / min) to give the title compound 29 (33 mg, yield: 39%).

[0608] MS m / z (ESI): 618.2 [M+1].

[0609] 1 H NMR (500 MHz, DMSO-d6) δ 9.49 (t, 1H), 8.59 (d, 1H), 8.30 (s, 1H), 8.27 (dd, 1H), 7.87 (d, 1H), 7.82 (dd, 1H), 7.71 (s, 1H), 7.65 (d, 1H), 7.39 (d, 1H), 7.33 (t, 1H), 6.27 (ddd, 1H), 4.67 (d, 2H), 4.61 (dt, 1H), 4.14 (t, 1H), 2.84-2.74 (m, 1H), 2.61-2.57 (m, 1H), 2.32 (s, 6H), 1.01-0.97 (m, 2H), 0.96-0.92 (m, 2H).

[0610] Example 30

[0611] (R)-9-chloro-N-((4-(4-(difluoromethoxy)-3-((1-(dimethylamino)cyclopropyl)ethynyl)phenyl)pyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 30

[0612] The method of Example 29 was used, replacing the starting material compound 1j in the sixth step with compound 24a, and the final product was purified by high performance liquid chromatography (GILSON-281, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 35-65%, flow rate: 30 mL / min) to give the title compound 30 (48 mg, yield: 40%).

[0613] MS m / z (ESI): 634.1 [M+1].

[0614] 1 H NMR (500 MHz, DMSO-d6) δ 9.51 (t, 1H), 8.58 (d, 1H), 8.48 (d, 1H), 8.40 (d, 1H), 7.86 (d, 1H), 7.81 (dd, 1H), 7.71 (s, 1H), 7.64 (dd, 1H), 7.40 (d, 1H), 7.33 (t, 1H), 6.24 (ddd, 1H), 4.67 (d, 2H), 4.61 (dt, 1H), 4.08 (t, 1H), 2.89-2.74 (m, 1H), 2.63-2.54 (m, 1H), 2.31 (s, 6H), 1.00-0.96 (m, 2H), 0.95-0.90 (m, 2H).

[0615] Example 31

[0616] (R)-N-((4-(3-((1-aminocyclopropyl)ethynyl)-4-(difluoromethoxy)phenyl)pyridin-2- yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 31

[0617] First Step

[0618] (2-(aminomethyl)pyridin-4-yl)trifluoroacetate 31a

[0619] Compound 14b (1.07 g, 4.24 mmol) was weighed into a 100 mL single neck flask, 15 mL of dichloromethane was added, 5 mL of trifluoroacetic acid was added dropwise and the reaction was allowed to proceed for 1 hour. The reaction was concentrated under reduced pressure to obtain the crude product of the title compound 31a (1.12 g, yield: 99%) which was used as such for the next step without purification.

[0620] MS m / z (ESI): 153.1 [M+1].

[0621] Second Step

[0622] (2-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-4-yl)boronic acid 31b

[0623] Into a 100 mL flask, compound 31a (1.12 g, 4.25 mmol), phthalic anhydride (630 mg, 4.25 mmol) were weighed, 20 mL of toluene was added, triethylamine (2.15 g, 21.25 mmol) was added, and the temperature was raised to 120 °C for 16 hours. The reaction was cooled to room temperature, and the reaction was concentrated under reduced pressure to obtain the crude product of the title compound 31b (1.19 g, yield: 100%), which was used directly in the next step without purification.

[0624] MS m / z (ESI): 283.1 [M+1].

[0625] Third step

[0626] tert-Butyl (1-((2-(difluoromethoxy)-5-(2-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-4-yl)phenyl)ethynyl)cyclopropyl)carbamate 31c

[0627] Into a 25 mL flask, compound 31b (252 mg, 0.89 mmol), compound 29a (120 mg, 0.30 mmol), [1,1'-bis(ditert-butylphosphino)ferrocene]dichloropalladium (20 mg, 0.03 mmol), potassium phosphate (190 mg, 0.89 mmol) were weighed, 2 mL of 1,4-dioxane and 0.5 mL of water were added, replaced with nitrogen three times, and the temperature was raised to 90 °C for 16 hours. The reaction was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 31c (92 mg, yield: 55%).

[0628] MS m / z (ESI): 560.0 [M+1].

[0629] Fourth step

[0630] tert-Butyl (1-((5-(2-(aminomethyl)pyridin-4-yl)-2-(difluoromethoxy)phenyl)ethynyl)cyclopropyl)carbamate 31d

[0631] Into a 25 mL flask, compound 31c (92 mg, 0.16 mmol) was weighed, 2 mL of ethanol was added, 80% hydrazine hydrate (484 mg, 8.22 mmol) was added, and the temperature was raised to 70 °C for 1 hour. The reaction was cooled to room temperature, and the reaction was concentrated under reduced pressure to obtain the crude product of the title compound 31d (70 mg, yield: 99%), which was used directly in the next step without purification.

[0632] MS m / z (ESI): 430.3 [M+1].

[0633] Fifth step

[0634] (R)-(1-((5-(2-((4,9-difluoro-5,5-dioxide-3,4-dihydro-2H- benzo[b][1,4]oxathiepine-7-carbonyl)amino)methyl)pyridin-4-yl)-2- (difluoromethoxy)phenyl)ethynyl)cyclopropyl)carbamic acid tert-butyl ester 31e

[0635] Compound 31d (70 mg, 0.16 mmol) and 1j (45 mg, 0.16 mmol) were weighed into a 25 mL single neck flask, 1 mL of N,N-dimethylformamide was added, N,N-diisopropylethylamine (126 mg, 0.98 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (93 mg, 0.24 mmol) was added, and the reaction was allowed to proceed for 1 hour. Water (10 mL) was added to the reaction, and the product was extracted with ethyl acetate (15 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound 31e (101 mg, yield: 90%), which was used directly in the next step without purification.

[0636] MS m / z (ESI): 690.1 [M+1].

[0637] Sixth step

[0638] (R)-N-((4-(3-((1-amino cyclopropyl)ethynyl)-4-(difluoromethoxy)phenyl)pyridin-2-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 31

[0639] Compound 31e (101 mg, 0.15 mmol) was weighed into a 25 mL single neck flask, 1 mL of dichloromethane was added, and 0.2 mL of trifluoroacetic acid was added dropwise, and the reaction was allowed to proceed for 4 hours. The reaction was filtered, and purified by high performance liquid chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 30%-55%, flow rate: 30 mL / min) to obtain the title compound 31 (4 mg, yield: 5%).

[0640] MS m / z (ESI): 590.0 [M+1].

[0641] 1H NMR (500 MHz, DMSO-d6) δ 9.49 (t, 1H), 8.59 (d, 1H), 8.30 (s, 1H), 8.27 (dd, 1H), 7.84 (d, 1H), 7.80 (dd, 1H), 7.70 (s, 1H), 7.63 (dd, 1H), 7.37 (d, 1H), 7.29 (t, 1H), 6.27 (ddd, 1H), 4.66 (d, 2H), 4.61 (dt, 1H), 4.14 (t, 1H), 2.84-2.74 (m, 1H), 2.62-2.59 (m, 1H), 1.25 (s, 2H), 0.98-0.95 (m, 2H), 0.91-0.89 (m, 2H).

[0642] Example 32

[0643] (R)-N-((4-(4-(difluoromethoxy)-3-((1-hydroxycyclobutyl)ethynyl)phenyl)pyridin-2- yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 32

[0644] First step

[0645] 2-bromo-1-(difluoromethoxy)-4-iodobenzene 32b

[0646] Potassium hydroxide (5.63 g, 100.35 mmol) was dissolved in water (10 mL), and a solution of 2-bromo-4-iodo-phenol 32a (3 g, 10.04 mmol, Bide Pharma) in acetonitrile (50 mL) was added dropwise under ice bath. After the addition was completed, the mixture was stirred under ice bath for 20 minutes, and then diethyl bromofluoromethylphosphonate (5.36 g, 20.07 mmol, Adamas Reagent) was added dropwise. After the addition was completed, the mixture was stirred under ice bath for 1.5 hours. Ice water (20 mL) was added to the reaction mixture, and dichloromethane (20 mL x 2) was added for extraction. The combined organic phase was washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 32b (3 g, yield: 86%).

[0647] Second step

[0648] tert-Butyl ((4-(3-bromo-4-(difluoromethoxy)phenyl)pyridin-2-yl)methyl)carbamate 32c

[0649] Into a 100 mL flask, compound 14b (2.39 g, 9.48 mmol) and 32b (3 g, 8.60 mmol) were weighed, followed by the addition of tetrakis(triphenylphosphine)palladium (993 mg, 0.86 mmol), anhydrous potassium carbonate (3.57 g, 25.83 mmol), 21 mL of toluene, 7 mL of ethanol and 7 mL of water, nitrogen replacement for three times, and then the temperature was raised to 100 °C for 4 hours. The reaction was cooled to room temperature, 30 mL of water was added, and the organic phase was extracted with ethyl acetate (30 mL x 3), washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 32c (1.70 g, yield: 46%).

[0650] MS m / z (ESI): 429.1 [M+1].

[0651] Third step

[0652] tert-Butyl ((4-(4-(difluoromethoxy)-3-((1-hydroxycyclobutyl)ethynyl)phenyl)pyridin-2- yl)methyl)carbamate 32e

[0653] Into a 50 mL flask, compound 32c (200 mg, 0.46 mmol), cuprous iodide (10 mg, 0.05 mmol), dichlorobis(triphenylphosphine)palladium (16 mg, 0.02 mmol) and triethylamine (238 mg, 2.35 mmol), 1-ethynylcyclobutanol 32d (448 mg, 4.66 mmol, prepared by the method disclosed in the specification of patent application “WO2019143994A1, page 277, intermediate R1”) were weighed, followed by the addition of 5 mL of N,N-dimethylformamide, nitrogen replacement for three times, and then the temperature was raised to 80 °C for 16 hours. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 32e (170 mg, yield: 82%).

[0654] MS m / z (ESI): 445.2 [M+1].

[0655] Fourth step

[0656] 1-((5-(2-Aminomethyl)pyridin-4-yl)-2-(difluoromethoxy)phenyl)ethynyl)cyclobutan-1-ol trifluoroacetate 32f

[0657] Compound 32e (170 mg, 0.23 mmol) was taken in a 50 mL single necked flask, 6 mL of dichloromethane was added, 2 mL of trifluoroacetic acid was added drop wise and the reaction was carried out for 1 h. The reaction mixture was concentrated under reduced pressure to get the crude product of title compound 32f (105 mg, yield: 99%) which was used as such for the next step without further purification.

[0658] MS m / z (ESI): 345.2 [M+1].

[0659] Fifth step

[0660] (R)-N-((4-(4-(difluoromethoxy)-3-((1-hydroxycyclobutyl)ethynyl)phenyl)pyridin-2- yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5- dioxide 32

[0661] Compound 32f (50 mg, 0.11 mmol) and 1j (30 mg, 0.11 mmol) were taken in a 25 mL single necked flask, 2 mL of N,N-dimethylformamide was added, N,N- diisopropylethylamine (71 mg, 0.55 mmol) was added, 2-(7-azabenzotriazol-1- yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (50 mg, 0.13 mmol) was added and the reaction was carried out for 1 h. The reaction mixture was filtered and purified by high pressure liquid chromatography (Waters-2545, eluent system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 35-60%, flow rate: 30 mL / min) to get the title compound 32 (9 mg, yield: 14%).

[0662] MS m / z (ESI): 605.1 [M+1].

[0663] 1 H NMR (500 MHz, DMSO-d6) δ 9.50 (t, 1H), 8.60 (d, 1H), 8.30 (d, 1H), 8.27 (dd, 1H), 7.91 (d, 1H), 7.85 (dd, 1H), 7.73 (d, 1H), 7.65 (d, 1H), 7.41 (d, 1H), 7.34 (t, 1H), 6.27 (ddd, 1H), 5.95 (s, 1H), 4.68 (d, 2H), 4.60 (dt, 1H), 4.14 (t, 1H), 2.87-2.74 (m, 1H), 2.61-2.57 (m, 1H), 2.43-2.38 (m, 2H), 2.28-2.22 (m, 2H), 1.83-1.77 (m, 2H).

[0664] Example 33

[0665] (R)-N-((4-(4-(difluoromethoxy)-3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)pyridin-2- yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 33

[0666] First step

[0667] ((4-(5-bromo-2-(difluoromethoxy)phenyl)-2-methylbut-3-yn-2-yl)oxy)trimethylsilane 33b

[0668] Compound 8c (150 mg, 0.43 mmol), cuprous iodide (8 mg, 0.04 mmol), bis(triphenylphosphine)palladium dichloride (14 mg, 0.02 mmol) were weighed into a 50 mL two-necked flask, 1.5 mL of triethylamine and 1.5 mL of tetrahydrofuran were added, replaced with nitrogen for three times, [(1,1-dimethyl-2-propynyl)oxy]trimethylsilane 33a (74 mg, 0.47 mmol) was added, and the temperature was raised to 75 °C for reaction for 4 hours. The reaction solution was cooled to room temperature, 15 mL of water was added, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 33b (159 mg, yield: 98%).

[0669] Second step

[0670] ((4-(4-(difluoromethoxy)-3-(3-methyl-3-((trimethylsilyl)oxy)but-1-yn-1-yl)phenyl)pyridin-2- yl)methyl)carbamic acid tert-butyl ester 33c

[0671] Compound 33b (100 mg, 0.27 mmol), compound 14b (80 mg, 0.32 mmol), [1,1'- bis(ditert-butylphosphino)ferrocene]dichloropalladium (18 mg, 0.03 mmol), anhydrous potassium carbonate (73 mg, 0.53 mmol) were weighed into a 25 mL single-necked flask, 1.6 mL of 1,4-dioxane and 0.4 mL of water were added, replaced with nitrogen for three times, and the temperature was raised to 95 °C for reaction for 16 hours. The reaction solution was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 33c (95 mg, yield: 71%).

[0672] MS m / z (ESI): 505.2 [M+1].

[0673] Third Step

[0674] tert-Butyl ((4-(4-(difluoromethoxy)-3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)pyridin-2- yl)methyl)carbamate 33d

[0675] Compound 33c (40 mg, 0.08 mmol), p-toluenesulfonic acid monohydrate (30 mg, 0.16 mmol) were weighed into a 25 ml single necked flask, 1.5 mL of dichloromethane was added, and the reaction was allowed to proceed for 30 minutes. To the reaction mixture, 10 mL of water was added, and the reaction mixture was extracted with dichloromethane (10 mL x 3), the organic layers were combined, washed with saturated sodium bicarbonate solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 33d (34 mg, yield: 100%). The crude product was used as such in the next step without further purification.

[0676] MS m / z (ESI): 433.2 [M+1].

[0677] Fourth Step

[0678] 4-(5-(2-(Aminomethyl)pyridin-4-yl)-2-(difluoromethoxy)phenyl)-2-methylbut-3-yn-2-ol 33e

[0679] Compound 33d (34 mg, 0.08 mmol) was weighed into a 10 mL microwave reaction tube, 4 mL of hexafluoroisopropanol was added, and the reaction was allowed to proceed at 120 °C for 6 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude title compound 33e (26 mg, yield: 100%). The crude product was used as such in the next step without further purification.

[0680] MS m / z (ESI): 333.0 [M+1].

[0681] Fifth Step

[0682] (R)-N-((4-(4-(Difluoromethoxy)-3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)pyridin-2- yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 33

[0683] Compound 33e (26 mg, 0.08 mmol) and 1j (22 mg, 0.08 mmol) were weighed into a 25 mL single neck flask, 1 mL of N,N-dimethylformamide was added, N,N-diisopropylethylamine (40 mg, 0.31 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (89 mg, 0.23 mmol) was added, and the reaction was allowed to proceed for 1 h. The reaction was filtered and purified by high performance liquid chromatography (Waters-2545, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 35%-95%, flow rate: 30 mL / min) to give the title compound 33 (20 mg, yield: 43%).

[0684] MS m / z (ESI): 593.1 [M+1].

[0685] 1 H NMR (500 MHz, DMSO-d6) δ 9.49 (t, 1H), 8.59 (d, 1H), 8.31-8.25 (m, 2H), 7.88-7.82 (m, 2H), 7.72 (s, 1H), 7.65 (dd, 1H), 7.40 (d, 1H), 7.32 (t, 1H), 6.27 (ddd, 1H), 5.52 (s, 1H), 4.67 (d, 2H), 4.60 (dt, 1H), 4.15 (t, 1H), 2.87-2.74 (m, 1H), 2.61-2.58 (m, 1H), 1.49 (s, 6H).

[0686] Example 34

[0687] (R)-N-((6-(cyclopropylethynyl)-[2,4'-bipyridine]-2'-yl)methyl)-4,9-difluoro-3,4- dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 34

[0688] The method of Example 14 was used, replacing the starting material compound 10a in the first step with 2-bromo-6-chloropyridine (Bide Pharm), and the final product was purified by high performance liquid chromatography (Waters-2545, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 30%-70%, flow rate: 30 mL / min) to give the title compound 34 (21 mg, yield: 33%).

[0689] MS m / z (ESI): 510.2 [M+1].

[0690] 1H NMR (500 MHz, DMSO-d6) δ 9.57 (t, 1H), 8.65 (d, 1H), 8.32 (s, 1H), 8.28 (d, 1H), 8.03-8.00 (m, 2H), 7.94-7.90 (m, 2H), 7.50 (d, 1H), 6.27 (ddd, 1H), 4.69 (d, 2H), 4.61 (dt, 1H), 4.15 (t, 1H), 2.85-2.74 (m, 1H), 2.61-2.57 (m, 1H), 1.64-1.59 (m, 1H), 0.97-0.93 (m, 2H), 0.82-0.79 (m, 2H).

[0691] Example 35

[0692] (R)-N-((4-(4-(diifluoromethoxy)-3-((1-(hydroxymethyl)cyclopropyl)ethynyl)phenyl)pyridin-2-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 35

[0693] First step

[0694] (1-ethynylcyclopropyl)methanol 35b

[0695] Compound 35a (500 mg, 4.54 mmol) was weighed into a 100 mL two-necked flask, 8 mL of tetrahydrofuran was added, replaced with nitrogen for three times, lithium aluminum hydride (2.5 M, 2.7 mL, 6.80 mmol) was added dropwise at 0 °C, slowly raised to room temperature for 6 hours. 2.7 mL of water, 2.7 mL of 15% NaOH aqueous solution, 8.1 mL of water were added to quench the reaction, 15 mL of water was added, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 35b (275 mg, yield: 63%).

[0696] Second step

[0697] (1-((5-bromo-2-(difluoromethoxy)phenyl)ethynyl)cyclopropyl)methanol 35c

[0698] Into a 50 mL two-necked flask, compound 8c (200 mg, 0.57 mmol), cuprous iodide (11 mg, 0.06 mmol), dichlorobis(triphenylphosphine)palladium (19 mg, 0.03 mmol) were taken, 1.5 mL of triethylamine and 1.5 mL of tetrahydrofuran were added, replaced with nitrogen for three times, compound 35b (61 mg, 0.63 mmol) was added, and the reaction was heated to 75 °C for 4 hours. The reaction was cooled to room temperature, 15 mL of water was added, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 35c (185 mg, yield: 100%).

[0699] Third step

[0700] tert-Butyl ((4-(4-(difluoromethoxy)-3-((1-(hydroxymethyl)cyclopropyl)ethynyl)phenyl)pyridin-2- yl)methyl)carbamate 35d

[0701] Into a 25 mL single-necked flask, compound 35c (90 mg, 0.28 mmol), compound 14b (86 mg, 0.34 mmol), [1,1'-bis(ditert-butylphosphino)ferrocene]dichloropalladium (19 mg, 0.03 mmol), anhydrous potassium carbonate (118 mg, 0.85 mmol) were taken, 1.6 mL of 1,4-dioxane and 0.4 mL of water were added, replaced with nitrogen for three times, and the reaction was heated to 95 °C for 16 hours. The reaction was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 35d (36 mg, yield: 29%).

[0702] MS m / z (ESI): 445.2 [M+1].

[0703] Fourth step

[0704] (1-((5-(2-(Aminomethyl)pyridin-4-yl)-2-(difluoromethoxy)phenyl)ethynyl)cyclopropyl)methanol trifluoroacetate 35e

[0705] Into a 25 mL single-necked flask, compound 35d (36 mg, 0.08 mmol) was taken, 1 mL of dichloromethane was added, and 0.25 mL of trifluoroacetic acid was added dropwise. The reaction was carried out for 1 hour. The reaction was concentrated under reduced pressure to obtain the crude product of the title compound 35e (36 mg, yield: 97%), which was used directly in the next step without purification.

[0706] MS m / z (ESI): 345.2 [M+1].

[0707] Fifth step

[0708] (R)-N-((4-(4-(difluoromethoxy)-3-((1-(hydroxymethyl)cyclopropyl)ethynyl)phenyl)pyridin-2- yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 35

[0709] Compound 35e (36 mg, 0.08 mmol) and 1j (22 mg, 0.08 mmol) were weighed into a 25 mL single neck flask, 1 mL of N,N-dimethylformamide was added, N,N- diisopropylethylamine (41 mg, 0.31 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (89 mg, 0.24 mmol) was added, and the reaction was allowed to proceed for 1 h. The reaction was filtered and purified by high performance liquid preparative chromatography (Waters-2545, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 35-95%, flow rate: 30 mL / min) to give the title compound 35 (10 mg, yield: 21%).

[0710] MS m / z (ESI): 605.0 [M+1].

[0711] 1 H NMR (500 MHz, DMSO-d6) δ 9.49 (t, 1H), 8.59 (d, 1H), 8.31-8.25 (m, 2H), 7.87 (d, 1H), 7.79 (dd, 1H), 7.72 (s, 1H), 7.64 (dd, 1H), 7.36 (d, 1H), 7.29 (t, 1H), 6.27 (d, 1H), 4.94 (t, 1H), 4.67 (d, 2H), 4.60 (dt, 1H), 4.16 (t, 1H), 3.48 (d, 2H), 2.84-2.76 (m, 1H), 2.60-2.57 (m, 1H), 0.95-0.85 (m, 4H).

[0712] Example 36

[0713] (R)-9-chloro-N-((4-(4-(difluoromethoxy)-3-((1-(hydroxymethyl)cyclopropyl)ethynyl)phenyl)pyridin- 2-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 36

[0714] The method of Example 35 was used, replacing the starting material compound 1j of the fifth step with compound 24a, and the end product was purified by high performance liquid preparative chromatography (GILSON-281, elution system: 10 mmol / L aqueous ammonium bicarbonate and acetonitrile, gradient of acetonitrile: 40%-95%, flow rate: 30 mL / min) to obtain the title compound 36 (40 mg, yield: 38%).

[0715] MS m / z (ESI): 621.0 [M+1].

[0716] 1 H NMR (500 MHz, DMSO-d6) δ 9.51 (t, 1H), 8.58 (d, 1H), 8.49 (d, 1H), 8.40 (d, 1H), 7.87 (d, 1H), 7.80 (dd, 1H), 7.72 (s, 1H), 7.64 (dd, 1H), 7.36 (d, 1H), 7.28 (t, 1H), 6.25 (ddd, 1H), 4.94 (t, 1H), 4.67 (d, 2H), 4.61 (dt, 1H), 4.08 (t, 1H), 3.48 (d, 2H), 2.87-2.76 (m, 1H), 2.62-2.55 (m, 1H), 0.95-0.89 (m, 4H).

[0717] Example 37

[0718] (R)-9-chloro-N-((4-(3-(cyclopropylethynyl)-4-(difluoromethoxy)phenyl)-3- fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7- carboxamide 5,5-dioxide 37

[0719] First step

[0720] 2-(3-(cyclopropylethynyl)-4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane 37a

[0721] Into a 100 mL single-necked flask, weighed compound 23a (333 mg, 1.16 mmol), bis(pinacolato)diboron (300 mg, 1.18 mmol, Shanghai Heowin Biotech Co., Ltd.), [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium (85 mg, 0.12 mmol), potassium acetate (344 mg, 3.50 mmol), added 7 mL of 1,4-dioxane, replaced with nitrogen for three times, and warmed to 90 °C for 16 hours. The reaction solution was cooled to room temperature, added 50 mL of water, extracted with ethyl acetate (30 mL x 3), combined the organic phase, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 37a (100 mg, yield: 26%).

[0722] MS m / z (ESI): 335.2 [M+1].

[0723] Second step

[0724] ((4-(3-(cyclopropylethynyl)-4-(difluoromethoxy)phenyl)-3-fluoropyridin-2-yl)methyl)carbamic acid tert-butyl ester 37c

[0725] Into a 100 mL single-necked flask, weighed ((4-chloro-3-fluoropyridin-2-yl)methyl)carbamic acid tert-butyl ester 37b (325 mg, 1.25 mmol, prepared by the method disclosed in the specification of patent application “WO2021072156A1, page 184, intermediate 36b”), compound 37a (332 mg, 0.99 mmol), [1,1’-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (65 mg, 0.10 mmol), anhydrous potassium carbonate (275 mg, 1.99 mmol), added 7 mL of 1,4-dioxane and 1.5 mL of water, replaced with nitrogen for three times, and warmed to 90 °C for 16 hours. The reaction solution was cooled to room temperature, added 50 mL of water, extracted with ethyl acetate (30 mL x 3), combined the organic phase, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 37c (400 mg, yield: 93%).

[0726] MS m / z (ESI): 433.2 [M+1].

[0727] Third step

[0728] (4-(3-(cyclopropylethynyl)-4-(difluoromethoxy)phenyl)-3-fluoropyridin-2-yl)methanamine 37d

[0729] Take compound 37c (400 mg, 0.92 mmol), p-toluenesulfonic acid monohydrate (420 mg, 2.21 mmol) into a 100 mL single-neck flask, add 10 mL of acetonitrile, and warm to 60°C for 2 hours. Cool the reaction solution to room temperature, add 50 mL of water to the reaction solution, extract with ethyl acetate (30 mL x 3), combine the organic phase, wash with saturated sodium bicarbonate solution (15 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product of title compound 37d (307 mg, yield: 100%). The crude product is directly used in the next step without purification.

[0730] MS m / z (ESI): 333.4 [M+1].

[0731] Fourth step

[0732] (R)-9-chloro-N-((4-(3-(cyclopropylethynyl)-4-(difluoromethoxy)phenyl)-3- fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7- carboxamide 5,5-dioxide 37

[0733] Take compound 37d (84 mg, 0.25 mmol) and 24a (75 mg, 0.25 mmol) into a 25 mL single-neck flask, add 3 mL of N,N-dimethylformamide, add N,N- diisopropylethylamine (100 mg, 0.77 mmol), 2-(7-azabenzotriazol)-N,N,N',N'- tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol), and react for 1 hour. Filter the reaction solution and purify by high performance liquid chromatography (GILSON-281, elution system: 10 mmol / L aqueous ammonium bicarbonate and acetonitrile, gradient of acetonitrile: 50%-95%, flow rate: 30 mL / min) to obtain title compound 37 (30 mg, yield: 19%).

[0734] MS m / z (ESI): 609.1 [M+1].

[0735] 1H NMR (500 MHz, DMSO-d6) δ 9.47 (t, 1H), 8.46 (d, 1H), 8.43 (d, 1H), 8.39 (d, 1H), 7.75 (d, 1H), 7.69 (d, 1H), 7.58 (t, 1H), 7.39 (d, 1H), 7.33 (t, 1H), 6.25 (ddd, 1H), 4.73 (dd, 2H), 4.61 (dt, 1H), 4.09 (t, 1H), 2.89-2.75 (m, 1H), 2.62-2.55 (m, 1H), 1.64-1.59 (m, 1H), 1.00-0.93 (m, 2H), 0.79-0.73 (m, 2H).

[0736] Example 38

[0737] (R)-N-((4-(3-(cyclopropylethynyl)-4-(difluoromethoxy)phenyl)-3-fluoropyridin-2-yl)methyl)- 4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 38

[0738] The title compound 38 (11 mg, yield: 10%) was obtained by replacing the fourth step raw material compound 24a with compound 1j in the method of Example 37, and purifying the final product by high performance liquid preparative chromatography (Waters-2545, elution system: 10 mmol / L aqueous ammonium bicarbonate and acetonitrile, gradient of acetonitrile: 45%-67%, flow rate: 30 mL / min).

[0739] MS m / z (ESI): 593.1 [M+1].

[0740] 1 H NMR (500 MHz, DMSO-d6) δ 9.45 (t, 1H), 8.43 (d, 1H), 8.29 (s, 1H), 8.24 (dd, 1H), 7.75 (s, 1H), 7.69 (d, 1H), 7.58 (t, 1H), 7.39 (d, 1H), 7.32 (t, 1H), 6.27 (ddd, 1H), 4.73 (d, 2H), 4.61 (dt, 1H), 4.15 (t, 1H), 2.88-2.73 (m, 1H), 2.63-2.56 (m, 1H), 1.64-1.59 (m, 1H), 0.97-0.93 (m, 2H), 0.79-0.76 (m, 2H).

[0741] Example 39

[0742] (R)-9-chloro-N-((4-(4-(difluoromethoxy)-3-((1-methylcyclopropyl)ethynyl)phenyl)-3- fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7- carboxamide 5,5-dioxide 39

[0743] First step

[0744] 4-bromo-1-(difluoromethoxy)-2-((1-methylcyclopropyl)ethynyl)benzene 39b

[0745] Compound 8c (5.0 g, 14.33 mmol) was weighed into a 100 mL two-necked flask, 25 mL of N,N-dimethylformamide was added, cuprous iodide (545 mg, 2.87 mmol), bis(triphenylphosphine)palladium dichloride (962 mg, 1.43 mmol) were added, nitrogen was replaced for three times, trimethyl((1-methylcyclopropyl)ethynyl)silane 39a (4.0 g, 26.26 mmol, prepared by the method disclosed in the specification of patent application "WO2011059784A1", page 113, intermediate 4A) was added, 5 mL of methanol solution of cesium fluoride (6.53 g, 42.99 mmol) was added, and the reaction was carried out for 16 hours. 50 mL of water was added to the reaction solution, extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 39b (4.13 g, yield: 96%).

[0746] Second step

[0747] 2-(4-(difluoromethoxy)-3-((1-methylcyclopropyl)ethynyl)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane 39c

[0748] Into a 100 mL single-necked flask, compound 39b (500 mg, 1.66 mmol), bis(pinacolato)diboron (600 mg, 2.36 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (130 mg, 0.18 mmol), potassium acetate (560 mg, 5.71 mmol) were taken, 10 mL of 1,4-dioxane was added, replaced with nitrogen for three times, and then the temperature was raised to 90 °C for 16 hours. The reaction solution was cooled to room temperature, 50 mL of water was added, and then extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 39c (120 mg, yield: 21%).

[0749] MS m / z (ESI): 349.2 [M+1].

[0750] Third step

[0751] ((4-(4-(Difluoromethoxy)-3-((1-methylcyclopropyl)ethynyl)phenyl)-3-fluoropyridin-2-yl)methyl)carbamic acid tert-butyl ester 39d

[0752] Into a 100 mL single-necked flask, compound 37b (100 mg, 0.38 mmol), compound 39c (120 mg, 0.34 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (24 mg, 0.04 mmol), anhydrous potassium carbonate (100 mg, 0.72 mmol) were taken, 5 mL of 1,4-dioxane and 1 mL of water were added, replaced with nitrogen for three times, and then the temperature was raised to 90 °C for 16 hours. The reaction solution was cooled to room temperature, 20 mL of water was added, and then extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 39d (34 mg, yield: 22%).

[0753] MS m / z (ESI): 447.2 [M+1].

[0754] Fourth step

[0755] (4-(4-(Difluoromethoxy)-3-((1-methylcyclopropyl)ethynyl)phenyl)-3-fluoropyridin-2-yl)methanamine 39e

[0756] Compound 39d (34 mg, 0.08 mmol), p-toluenesulfonic acid monohydrate (36 mg, 0.19 mmol) were weighed into a 50 mL vial, 5 mL of acetonitrile was added, and the reaction was heated to 60 °C for 2 h. The reaction was cooled to room temperature, 15 mL of water was added to the reaction, and the reaction was extracted with 15 mL of dichloromethane (3x). The organic layers were combined, washed with 10 mL of saturated sodium bicarbonate solution (3x), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product of title compound 39e (26 mg, yield: 99%). The crude product was used directly in the next step without purification.

[0757] MS m / z (ESI): 347.3 [M+1].

[0758] Fifth step

[0759] (R)-9-chloro-N-((4-(4-(difluoromethoxy)-3-((1-methylcyclopropyl)ethynyl)phenyl)-3- fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 39

[0760] Compound 39e (26 mg, 0.08 mmol) and 24a (39 mg, 0.13 mmol) were weighed into a 25 mL vial, 2 mL of N,N-dimethylformamide was added, N,N-diisopropylethylamine (45 mg, 0.35 mmol) was added, and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (50 mg, 0.13 mmol) was added. The reaction was stirred for 1 h. The reaction was filtered and purified by high performance liquid chromatography (Waters-2555, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 55-80%, flow rate: 80 mL / min) to give title compound 39 (9 mg, yield: 12%).

[0761] MS m / z (ESI): 623.1 [M+1].

[0762] 1H NMR (500 MHz, DMSO-d6) 9.47 (s, 1H), 8.46-8.39 (m, 3H), 7.74 (s, 1H), 7.69 (d, 1H), 7.59 (s, 1H), 7.39 (d, 1H), 7.31 (t, 1H), 6.26 (d, 1H), 4.74 (s, 2H), 4.61 (d, 1H), 4.09 (t, 1H), 2.86-2.76 (m, 1H), 2.61-2.57 (m, 1H), 1.34 (s, 3H), 1.02-0.93 (m, 2H), 0.85-0.74 (s, 2H).

[0763] Example 40

[0764] (R)-9-chloro-N-((4-(3-((1-cyanocyclopropyl)ethynyl)-4- (difluoromethoxy)phenyl)pyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H- benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 40

[0765] First step

[0766] 1-((5-bromo-2-(difluoromethoxy)phenyl)ethynyl)cyclopropane-1-carboxylic acid 40b

[0767] Compound 8c (2 g, 5.73 mmol), cuprous iodide (218 mg, 1.15 mmol), tetrakis(triphenylphosphine)palladium (662 mg, 0.57 mmol) were weighed into a 250 mL two-necked flask, diethylamine (1.26 g, 17.23 mmol) and 50 mL of tetrahydrofuran were added, replaced with nitrogen for three times, 1-ethynylcyclopropane-1-carboxylic acid 40a (632 mg, 5.74 mmol, Bide Pharmaceutical) was added, the temperature was raised to 70°C and reacted for 16 hours. The reaction liquid was cooled to room temperature, 15 mL of water was added to the reaction liquid, and the pH of the reaction liquid was adjusted to 3-4 by dropwise adding saturated potassium bisulfate solution under ice bath cooling. The reaction liquid was extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 40b (1.50 g, yield: 79%).

[0768] MS m / z (ESI): 330.0 [M-1].

[0769] Second step

[0770] 1-((5-bromo-2-(difluoromethoxy)phenyl)ethynyl)cyclopropane-1-carboxylic acid 40b

[0771] Compound 40b (1.30 g, 3.93 mmol) was dissolved in acetonitrile (50 mL), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.98 g, 7.85 mmol) was added, and the reaction was allowed to proceed for 2 hours. Ammonia (11.78 mmol, 30 mL, 0.4 M in dioxane) was further added, and the reaction was allowed to proceed for 16 hours. Water (10 mL) was added to the reaction mixture, and extraction was performed with dichloromethane (30 mL x 3), and the combined organic phase was washed with saturated sodium bicarbonate solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound 40c (1.0 g, yield: 77%), which was used in the next reaction without purification.

[0772] MS m / z (ESI): 331.1 [M+1].

[0773] Third step

[0774] 1-((5-bromo-2-(difluoromethoxy)phenyl)ethynyl)cyclopropane-1-carbonitrile 40d

[0775] Compound 40c (1.0 g, 3.03 mmol) was dissolved in pyridine (40 mL), and 2,2,2-trifluoroacetyl-2,2,2-trifluoroacetate (2.54 g, 12.12 mmol) was added dropwise while cooling in an ice bath, and the reaction was allowed to proceed for 30 minutes. Ethyl acetate (50 mL) was added to the reaction mixture, and washing was performed with saturated sodium chloride solution (30 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 40d (945 mg, yield: 99%).

[0776] Fourth step

[0777] ((4-(3-((1-cyanocyclopropyl)ethynyl)-4-(difluoromethoxy)phenyl)pyridin-2-yl)methyl)carbamic acid tert-butyl ester 40e

[0778] Into a 100 mL single-necked flask, compound 40d (945 mg, 3.03 mmol), compound 14b (807 mg, 3.20 mmol), [1,1'-bis (di-tert-butylphosphino) ferrocene] dichloropalladium (417 mg, 0.64 mmol), potassium phosphate (2 g, 9.61 mmol) were taken, 50 mL of 1,4-dioxane and 5 mL of water were added, replaced with nitrogen for three times, and warmed to 95 °C for 16 h. The reaction was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (35 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 40e (420 mg, yield: 30%).

[0779] MS m / z (ESI): 440.5 [M+1].

[0780] Fifth step

[0781] 1-((5-(2-(Aminomethyl)pyridin-4-yl)-2-(difluoromethoxy)phenyl)ethynyl)cyclopropane-1- carboxylic acid 40g

[0782] Into a 100 mL single-necked flask, compound 40e (380 mg, 0.86 mmol), p-toluenesulfonic acid monohydrate (493 mg, 2.59 mmol) were taken, 10 mL of acetonitrile was added, and warmed to 60 °C for 2 h. The reaction was cooled to room temperature, 50 mL of water was added to the reaction, extracted with dichloromethane (30 mL x 3), the organic phases were combined, washed with saturated sodium bicarbonate solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product of the title compound 40f (200 mg, yield: 68%), which was used directly in the next step without purification.

[0783] MS m / z (ESI): 340.3 [M+1].

[0784] Sixth step

[0785] (R)-9-chloro-N-((4-(3-((1-cyanocyclopropyl)ethynyl)-4-(difluoromethoxy)phenyl)pyridin-2- yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 40

[0786] Compound 40f (85 mg, 0.25 mmol) and 24a (74 mg, 0.25 mmol) were weighed into a 25 mL single neck flask, 3 mL of N,N-dimethylformamide was added, N,N-diisopropylethylamine (100 mg, 0.77 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (190 mg, 0.50 mmol) was added, and the reaction was allowed to proceed for 1 h. The reaction was filtered and purified by high performance liquid chromatography (Waters-2545, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 45%-65%, flow rate: 30 mL / min) to give the title compound 40 (30 mg, yield: 19%).

[0787] MS m / z (ESI): 616.1 [M+1].

[0788] 1 H NMR (500 MHz, DMSO-d6) δ 9.51 (t, 1H), 8.60 (d, 1H), 8.49 (s, 1H), 8.40 (s, 1H), 8.01 (s, 1H), 7.90 (d, 1H), 7.74 (s, 1H), 7.66 (d, 1H), 7.42 (d, 1H), 7.35 (t, 1H), 6.25 (dd, 1H), 4.67 (d, 2H), 4.61 (d, 1H), 4.08 (t, 1H), 2.86-2.76 (m, 1H), 2.61-2.56 (m, 1H), 1.89-1.87 (m, 2H), 1.64-1.61 (m, 2H).

[0789] Example 41

[0790] (R)-9-chloro-N-((4-(3-((1-cyanocyclopropyl)ethynyl)-4- (difluoromethoxy)phenyl)-3-fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H- benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 41

[0791] First step

[0792] (2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)boronic acid 41a

[0793] Into a 100 mL single necked flask, was placed compound 37b (1.0 g, 3.83 mmol), bis(pinacolato)diboron (1.46 g, 5.75 mmol), palladium acetate (51 mg, 0.23 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (219 mg, 0.46 mmol), potassium acetate (1.13 g, 11.51 mmol), 30 mL of 1,4-dioxane, and the reaction mixture was purged with nitrogen for 3 times, then heated to 100 °C for 3 h. The reaction mixture was cooled to room temperature, added 50 mL of water, extracted with ethyl acetate (50 mL x 3), combined organic phase, washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product of title compound 41a (1.0 g, yield: 96 %), which was used directly in the next step without further purification.

[0794] MS m / z (ESI): 271.1 [M+1].

[0795] Second step

[0796] ((4-(3-((1-cyanocyclopropyl)ethynyl)-4-(difluoromethoxy)phenyl)-3-fluoropyridin-2-yl)methyl)carbamic acid tert-butyl ester 41b

[0797] Into a 100 mL single necked flask, was placed compound 41a (130 mg, 0.48 mmol), compound 40d (150 mg, 0.48 mmol), [1,1'-bis(ditert-butylphosphino)ferrocene]dichloropalladium (33 mg, 0.05 mmol), potassium phosphate (256 mg, 0.96 mmol), 6 mL of 1,4-dioxane, and the reaction mixture was purged with nitrogen for 3 times, then heated to 85 °C for 10 h. The reaction mixture was cooled to room temperature, added 50 mL of water, extracted with ethyl acetate (30 mL x 3), combined organic phase, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to give title compound 41b (100 mg, yield: 45 %)

[0798] MS m / z (ESI): 458.2 [M+1].

[0799] Third step

[0800] 1-((5-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(difluoromethoxy)phenyl)ethynyl)cyclopropane-1-carbonitrile 41c

[0801] Compound 41b (10 mg, 0.02 mmol), p-toluenesulfonic acid monohydrate (12.47 mg, 0.06 mmol) were weighed into a 100 mL single-necked flask, 5 mL of acetonitrile was added, and the temperature was raised to 60 °C for 2 hours of reaction. The reaction solution was cooled to room temperature, 50 mL of water was added, extracted with dichloromethane (30 mL x 3), the combined organic phase was washed with saturated sodium bicarbonate solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound 41c (7 mg, yield: 90%). The crude product was directly used in the next step without purification.

[0802] MS m / z (ESI): 358.3 [M+1].

[0803] Fourth step

[0804] (R)-9-chloro-N-((4-(3-((1-cyanocyclopropyl)ethynyl)-4- (difluoromethoxy)phenyl)-3-fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H- benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 41

[0805] Compound 41c (7 mg, 0.02 mmol) and 24a (6 mg, 0.02 mmol) were weighed into a 25 mL single-necked flask, 3 mL of N,N-dimethylformamide was added, N,N- diisopropylethylamine (10 mg, 0.08 mmol) was added, 2-(7-azabenzotriazol)-N,N,N',N'- tetramethyluronium hexafluorophosphate (15 mg, 0.04 mmol) was added, and the reaction was allowed to proceed for 1 hour. The reaction solution was filtered and purified by high performance liquid chromatography (Waters-2545, elution system: 10 mmol / L aqueous ammonium bicarbonate and acetonitrile, gradient of acetonitrile: 40%-70%, flow rate: 30 mL / min) to obtain the title compound 41 (3 mg, yield: 20%).

[0806] MS m / z (ESI): 634.3 [M+1].

[0807] 1H NMR (500 MHz, DMSO-d6) δ 9.48 (t, 1H), 8.46-8.44 (m, 2H), 8.39 (s, 1H), 7.88 (s, 1H), 7.79 (d, 1H), 7.60 (t, 1H), 7.46 (d, 1H), 7.38 (t, 1H), 6.25 (dd, 1H), 4.73 (d, 2H), 4.61 (d, 1H), 4.09 (t, 1H), 2.86-2.78 (m, 1H), 2.60-2.58 (m, 1H), 1.89-1.86 (m, 2H), 1.65-1.62 (m, 2H).

[0808] Example 42

[0809] (R)-N-((4-(4-(difluoromethoxy)-3-(3,3-dimethylbut-1-yn-1-yl)phenyl)pyridin-2- yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5- dioxide 42

[0810] First step

[0811] tert-Butyl ((4-(4-(difluoromethoxy)-3-(3,3-dimethylbut-1-yn-1-yl)phenyl)pyridin-2- yl)methyl)carbamate 42b

[0812] Compound 32c (200 mg, 0.46 mmol), cuprous iodide (13 mg, 0.07 mmol), bis(triphenylphosphine)palladium dichloride (31 mg, 0.05 mmol) and 3,3-dimethylbut-1- yne 42a (76 mg, 0.9 mmol, Bide Pharmatech) were weighed into a 50 mL single neck flask, 1.5 mL of triethylamine and 2 mL of tetrahydrofuran were added, replaced with nitrogen for three times, and then the temperature was raised to 75 °C for 16 hours. The reaction was cooled to room temperature, the reaction was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 42b (119 mg, yield: 59%).

[0813] MS m / z (ESI): 431.4 [M+1].

[0814] Second step

[0815] (4-(4-(difluoromethoxy)-3-(3,3-dimethylbut-1-yn-1-yl)phenyl)pyridin-2-yl)methanamine trifluoroacetate 42c

[0816] Compound 42b (30 mg, 0.07 mmol) was taken in a 50 mL single necked flask, 1 mL of dichloromethane was added, 0.25 mL of trifluoroacetic acid was added drop wise and the reaction was carried out for 1 h. The reaction mass was concentrated under reduced pressure to get the crude product of title compound 42c (31 mg, yield: 99%) which was used as such for the next step without purification.

[0817] MS m / z (ESI): 331.3 [M+1].

[0818] Third Step

[0819] (R)-N-((4-(4-(difluoromethoxy)-3-(3,3-dimethylbut-1-yn-1-yl)phenyl)pyridin-2- yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5- dioxide 42

[0820] Compound 42c (31 mg, 0.07 mmol) and 1j (19 mg, 0.07 mmol) were taken in a 25 mL single necked flask, 1 mL of N,N-dimethylformamide was added, N,N- diisopropylethylamine (36 mg, 0.28 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (79 mg, 0.21 mmol) was added and the reaction was carried out for 1 h. The reaction mass was filtered and purified by high performance liquid preparative chromatography (Waters-2545, eluent system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 45-75%, flow rate: 30 mL / min) to get the title compound 42 (28 mg, yield: 68%).

[0821] MS m / z (ESI): 591.2 [M+1].

[0822] 1 H NMR (500 MHz, DMSO-d6) δ 9.49 (t, 1H), 8.58 (d, 1H), 8.30 (s, 1H), 8.27 (dd, 1H), 7.85-7.79 (m, 2H), 7.72 (d, 1H), 7.65 (dd, 1H), 7.37 (d, 1H), 7.27 (t, 1H), 6.27 (ddd, 1H), 4.67 (d, 2H), 4.61 (dt, 1H), 4.13 (t, 1H), 2.84-2.77 (m, 1H), 2.61-2.57 (m, 1H), 1.32 (s, 9H).

[0823] Example 43

[0824] (R)-N-((4-(4-(difluoromethoxy)-3-(3,3-dimethylbut-1-yn-1-yl)phenyl)-3- fluoropyridin-2-yl)methyl)-4,9-difluoro-3,4-dihydro-2H- benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 43

[0825] First step

[0826] 4-bromo-1-(difluoromethoxy)-2-(3,3-dimethylbut-1-yn-1-yl)benzene 43a

[0827] Compound 8c (6.0 g, 17.20 mmol), cuprous iodide (655 mg, 3.44 mmol), bis(triphenylphosphine)palladium dichloride (577 mg, 0.86 mmol) were weighed into a 250 mL flask with two necks, 40 mL of triethylamine and 40 mL of tetrahydrofuran were added, replaced with nitrogen for three times, compound 42a (1.55 g, 18.87 mmol) was added, and the reaction was carried out for 16 hours. 50 mL of water was added to the reaction solution, extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 43a (4.0 g, yield: 77%).

[0828] Second step

[0829] 2-(4-(difluoromethoxy)-3-(3,3-dimethylbut-1-yn-1-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 43b

[0830] Compound 43a (3.0 g, 9.89 mmol), pinacol diboronic acid (3.0 g, 11.88 mmol), [1,1’-bis(diphenylphosphino)ferrocene]palladium dichloride (724 mg, 0.99 mmol), potassium acetate (2.91 g, 29.69 mmol) were weighed into a 250 mL flask with a single neck, 100 mL of 1,4-dioxane was added, replaced with nitrogen for three times, and the reaction was carried out at 100°C for 4 hours. The reaction solution was cooled to room temperature, 50 mL of water was added, extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound 43b (3.40 g, yield: 98%). The crude product was directly used in the next step reaction without purification.

[0831] MS m / z (ESI): 351.2 [M+1].

[0832] Third step

[0833] ((4-(4-(diifluoromethoxy)-3-(3,3-dimethylbut-1-yn-1-yl)phenyl)-3- fluoropyridin-2-yl)methyl)carbamic acid tert-butyl ester 43c

[0834] Compound 37b (3.04 g, 11.65 mmol), compound 43b (3.40 g, 9.70 mmol), [1,1'- bis(ditert-butylphosphino)ferrocene]dichloropalladium (632 mg, 0.97 mmol), anhydrous potassium carbonate (4.02 g, 29.12 mmol) were weighed into a 250 mL single-necked flask, 150 mL of 1,4-dioxane and 20 mL of water were added, replaced with nitrogen for three times, and the temperature was raised to 90 °C for 16 hours of reaction. The reaction solution was cooled to room temperature, 20 mL of water was added, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 43c (3.80 g, yield: 87%).

[0835] MS m / z (ESI): 449.2 [M+1].

[0836] Fourth step

[0837] (4-(4-(diifluoromethoxy)-3-(3,3-dimethylbut-1-yn-1-yl)phenyl)-3- fluoropyridin-2-yl)methyl)carbamic acid tert-butyl ester 43c

[0838] Compound 43c (300 mg, 0.67 mmol), p-toluenesulfonic acid monohydrate (381 mg, 2.00 mmol) were weighed into a 50 mL single-necked flask, 5 mL of acetonitrile was added, and the temperature was raised to 60 °C for 2 hours of reaction. The reaction solution was cooled to room temperature, 15 mL of water was added to the reaction solution, extracted with dichloromethane (15 mL x 3), the organic phases were combined, washed with saturated sodium bicarbonate solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound 43d (233 mg, yield: 99%). The crude product was directly used in the next step reaction without purification.

[0839] MS m / z (ESI): 449.2 [M+1].

[0840] Fifth step

[0841] (R)-N-((4-(4-(diifluoromethoxy)-3-(3,3-dimethylbut-1-yn-1-yl)phenyl)-3- fluoropyridin-2-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathi epine-7-carboxamide 5,5-dioxide 43

[0842] Compound 43d (100 mg, 0.29 mmol) and 1j (80 mg, 0.29 mmol) were weighed into a 25 mL single neck flask, 2 mL of N,N-dimethylformamide was added, N,N-diisopropylethylamine (75 mg, 0.58 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (164 mg, 0.43 mmol) was added, and the reaction was allowed to proceed for 1 h. The reaction was filtered and purified by high performance liquid preparative chromatography (GILSON-281, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 40%-95%, flow rate: 80 mL / min) to give the title compound 43 (40 mg, yield: 23%).

[0843] MS m / z (ESI): 609.1 [M+1].

[0844] 1 H NMR (500 MHz, DMSO-d6) δ 9.45 (t, 1H), 8.43 (d, 1H), 8.29 (s, 1H), 8.24 (d, 1H), 7.73 (s, 1H), 7.70 (d, 1H), 7.60 (t, 1H), 7.41 (d, 1H), 7.31 (t, 1H), 6.27 (dd, 1H), 4.73 (d, 2H), 4.60 (dt, 1H), 4.15 (t, 1H), 2.86-2.74 (m, 1H), 2.61-2.57 (m, 1H), 1.32 (s, 9H).

[0845] Example 44

[0846] (R)-9-chloro-N-((4-(4-(difluoromethoxy)-3-(3,3-dimethylbut-1-yn-1-yl)phenyl)-3- fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7- carboxamide 5,5-dioxide 44

[0847] The method of Example 43 was used, replacing the starting material compound 1j in the fifth step with 24a, and the final product was purified by high performance liquid preparative chromatography (Waters-2545, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 50%-85%, flow rate: 30 mL / min) to give the title compound 44 (120 mg, yield: 29%).

[0848] MS m / z (ESI): 625.1 [M+1].

[0849] 1 H NMR (500 MHz, DMSO-d6) δ 9.48 (t, 1H), 8.46 (s, 1H), 8.43 (d, 1H), 8.39 (s, 1H), 7.73 (s, 1H), 7.70 (d, 1H), 7.60 (t, 1H), 7.41 (d, 1H), 7.31 (t, 1H), 6.25 (dd, 1H), 4.74 (d, 2H), 4.61 (dt, 1H), 4.09 (t, 1H), 2.86-2.76 (m, 1H), 2.60-2.56 (m, 1H), 1.32 (s, 9H).

[0850] Example 45

[0851] (R)-9-chloro-N-((4-(4-(difluoromethoxy)-3-((1-fluorocyclopropyl)ethynyl)phenyl)-3- fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7- carboxamide 5,5-dioxide 45

[0852] First step

[0853] 1-ethynyl-1-fluorocyclopropane 45a

[0854] Compound 7a (2.7 g, 30.65 mmol) was weighed into a 100 mL two necked flask, 15 mL of methanol was added, anhydrous potassium carbonate (8.47 g, 61.30 mmol) was added, (1-diazo-2-oxopropyl) dimethyl phosphonate (8.83 g, 45.97 mmol) was added and the reaction was allowed to proceed for 16 hours. To the reaction mixture, 50 mL of water was added, extracted with xylene (50 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was distilled at 120-130 °C to obtain the crude title compound 45a (260 mg, yield: 10%) which was used as such for the next step without purification.

[0855] Second step

[0856] 4-bromo-1-(difluoromethoxy)-2-((1-fluorocyclopropyl)ethynyl)benzene 45b

[0857] Into a 25 mL single-necked flask, compound 8c (600 mg, 1.72 mmol), compound 45a (180 mg, 2.14 mmol), dichlorobispalladium(II)triphenylphosphine (61 mg, 0.09 mmol), cuprous iodide (33 mg, 0.17 mmol) were taken, 4 mL of tetrahydrofuran and 2 mL of triethylamine were added, replaced with nitrogen for three times, and the reaction was carried out for 16 hours. 20 mL of water was added to the reaction solution, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (15 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 45b (300 mg, yield: 57%).

[0858] 1 H NMR (500 MHz, CDCl3) δ 7.62 (s, 1H), 7.45 (d, 1H), 7.06 (d, 1H), 6.53 (t, 1H), 1.47-1.41 (m, 2H), 1.18-1.13 (m, 2H).

[0859] Third step

[0860] ((4-(4-(Difluoromethoxy)-3-((1-fluorocyclopropyl)ethynyl)phenyl)-3-fluoropyridin-2-yl)methyl)carbamic acid tert-butyl ester 45c

[0861] Into a 100 mL single-necked flask, compound 41a (283 mg, 1.05 mmol), compound 45b (280 mg, 0.92 mmol), [1,1'-bis(ditert-butylphosphine)ferrocene]dichloropalladium (60 mg, 0.09 mmol), anhydrous potassium carbonate (254 mg, 1.84 mmol) were taken, 6 mL of 1,4-dioxane and 0.5 mL of water were added, replaced with nitrogen for three times, and the reaction was carried out at 90°C for 3.5 hours. The reaction solution was cooled to room temperature, 50 mL of water was added, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 45c (400 mg, yield: 97%).

[0862] MS m / z (ESI): 451.1 [M+1].

[0863] Fourth step

[0864] (4-(4-(Difluoromethoxy)-3-((1-fluorocyclopropyl)ethynyl)phenyl)-3-fluoropyridin-2-yl)methanamine 45d

[0865] Take compound 45c (400 mg, 0.89 mmol), p-toluenesulfonic acid monohydrate (423 mg, 2.23 mmol) into a 25 mL single-neck flask, add 12 mL of acetonitrile, and warm to 60°C for 2 hours. Cool the reaction to room temperature, add 20 mL of water to the reaction, extract with dichloromethane (50 mL x 3), combine the organic phases, wash with saturated sodium bicarbonate solution (30 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product of title compound 45d (311 mg, yield: 99%). The crude product is used directly in the next step without purification.

[0866] MS m / z (ESI): 351.1 [M+1].

[0867] Fifth step

[0868] (R)-9-chloro-N-((4-(4-(difluoromethoxy)-3-((1-fluorocyclopropyl)ethynyl)phenyl)-3- fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 45

[0869] Take compound 45d (311 mg, 0.89 mmol) and 24a (275 mg, 0.93 mmol) into a 25 mL single-neck flask, add 4 mL of N,N-dimethylformamide, add N,N-diisopropylethylamine (287 mg, 2.22 mmol), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (406 mg, 1.07 mmol), and react for 0.5 hours. Filter the reaction and purify by high-performance liquid chromatography (GILSON-281, elution system: 10 mmol / L aqueous ammonium bicarbonate and acetonitrile, gradient of acetonitrile: 50%-80%, flow rate: 30 mL / min) to obtain title compound 45 (190 mg, yield: 34%).

[0870] MS m / z (ESI): 627.0 [M+1].

[0871] 1H NMR (500 MHz, DMSO-d6) δ 9.48 (t, 1H), 8.47-8.44 (m, 2H), 8.39 (d, 1H), 7.89 (s, 1H), 7.81 (d, 1H), 7.61 (t, 1H), 7.48 (d, 1H), 7.40 (t, 1H), 6.26 (dd, 1H), 4.74 (d, 2H), 4.61 (dt, 1H), 4.09 (t, 1H), 2.86-2.76 (m, 1H), 2.61-2.57 (m, 1H), 1.56-1.49 (m, 2H), 1.25-1.21 (m, 2H).

[0872] Example 46

[0873] (R)-N-((4-(4-(difluoromethoxy)-3-((1-fluorocyclopropyl)ethynyl)phenyl)-3- fluoropyridin-2-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathi epine-7- carboxamide 5,5-dioxide 46

[0874] The method of Example 45 was used, replacing the starting material compound 24a in the fifth step with compound 1j, and the final product was purified by high performance liquid preparative chromatography (Shimadzu LC-20AP, elution system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 45%-70%, flow rate: 30 mL / min) to obtain the title compound 46 (18 mg, yield: 15%).

[0875] MS m / z (ESI): 611.0 [M+1].

[0876] 1 H NMR (500 MHz, DMSO-d6) δ 9.46 (t, 1H), 8.45 (d, 1H), 8.29 (s, 1H), 8.25 (d, 1H), 7.90 (s, 1H), 7.81 (d, 1H), 7.61 (t, 1H), 7.48 (d, 1H), 7.40 (t, 1H), 6.27 (dd, 1H), 4.74 (d, 2H), 4.61 (d, 1H), 4.15 (t, 1H), 2.84-2.76 (m, 1H), 2.62-2.59 (m, 1H), 1.56-1.49 (m, 2H), 1.25-1.21 (m, 2H).

[0877] Example 47

[0878] (R)-9-chloro-N-((4-(4-(difluoromethoxy)-3-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-3- fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 47

[0879] First step

[0880] 4-bromo-1-(difluoromethoxy)-2-((1-(trifluoromethyl)cyclopropyl)ethynyl)benzene 47b

[0881] Compound 8c (1.50 g, 3.87 mmol), 1-ethynyl-1-trifluoromethylcyclopropane 47a (560 mg, 4.18 mmol, prepared by the method disclosed in the specification of patent application “WO2025051110A1, page 94, intermediate 4”), dichlorobispalladium(triphenylphosphine) (130 mg, 0.19 mmol), cuprous iodide (74 mg, 0.39 mmol) were weighed into a 50 mL single neck flask, 7 mL tetrahydrofuran and 5 mL triethylamine were added, replaced with nitrogen for three times, and the reaction was carried out for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 47b (1.0 g, yield: 73%).

[0882] Second step

[0883] tert-butyl ((4-(4-(difluoromethoxy)-3-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-3- fluoropyridin-2-yl)methyl)carbamate 47c

[0884] Compound 41a (297 mg, 1.10 mmol), compound 47b (350 mg, 0.96 mmol), [1,1'- bis(ditert-butylphosphino)ferrocene]dichloropalladium (67 mg, 0.10 mmol), potassium phosphate (787 mg, 2.96 mmol) were weighed into a 50 mL single neck flask, 5 mL 1,4-dioxane and 1 mL water were added, replaced with nitrogen for three times, and the reaction was carried out at 90 °C for 3 hours. The reaction solution was cooled to room temperature, 50 mL water was added, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 47c (400 mg, yield: 81%).

[0885] MS m / z (ESI): 501.0 [M+1].

[0886] Third step

[0887] (4-(4-(diifluoromethoxy)-3-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-3- fluoropyridin-2-yl)methanamine 47d

[0888] Compound 47c (400 mg, 0.80 mmol), p-toluenesulfonic acid monohydrate (304 mg, 1.60 mmol) were weighed into a 25 mL single neck flask, 8 mL of acetonitrile was added, and the reaction was warmed to 60 °C for 2 hours. The reaction was cooled to room temperature, 15 mL of water was added to the reaction, and the reaction was extracted with dichloromethane (15 mL x 3), the organic layers were combined, washed with saturated sodium bicarbonate solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product of title compound 47d (213 mg, yield: 67%), which was used directly in the next step without purification.

[0889] MS m / z (ESI): 401.3 [M+1].

[0890] Fourth Step

[0891] (R)-9-chloro-N-((4-(4-(diifluoromethoxy)-3-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-3- fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 47

[0892] Compound 47d (213 mg, 0.53 mmol) and 24a (157 mg, 0.53 mmol) were weighed into a 25 mL single neck flask, 2.5 mL of N,N-dimethylformamide was added, N,N- diisopropylethylamine (172 mg, 1.33 mmol) was added, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (242 mg, 0.64 mmol) was added, and the reaction was allowed to proceed for 1 hour. The reaction was filtered and purified by high performance liquid chromatography (GILSON-281, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 45% to 75%, flow rate: 30 mL / min) to give title compound 47 (153 mg, yield: 42%).

[0893] MS m / z (ESI): 677.1 [M+1].

[0894] 1H NMR (500 MHz, DMSO-d6) δ 9.48 (t, 1H), 8.46 (s, 1H), 8.44 (d, 1H), 8.39 (s, 1H), 7.84 (s, 1H), 7.78 (d, 1H), 7.60 (t, 1H), 7.46 (d, 1H), 7.36 (t, 1H), 6.26 (dd, 1H), 4.74 (d, 2H), 4.61 (dt, 1H), 4.09 (t, 1H), 2.86-2.78 (m, 1H), 2.59-2.57 (m, 1H), 1.51-1.49 (m, 2H), 1.42-1.39 (m, 2H).

[0895] Example 48

[0896] (R)-N-((4-(4-(diifluoromethoxy)-3-((1-(trifluoromethyl)cyclopropyl)ethynyl)phenyl)-3- fluoropyridin-2-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathi epine-7- carboxamide 5,5-dioxide 48

[0897] The title compound 48 (25 mg, yield: 30%) was obtained by using the method of Example 47, replacing the raw material compound 24a in the fourth step with compound 1j, and purifying the final product by high performance liquid preparative chromatography (GILSON-281, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 45%-70%, flow rate: 30 mL / min).

[0898] MS m / z (ESI): 661.1 [M+1].

[0899] 1 H NMR (500 MHz, DMSO-d6) δ 9.46 (t, 1H), 8.44 (d, 1H), 8.29 (s, 1H), 8.24 (d, 1H), 7.84 (s, 1H), 7.78 (d, 1H), 7.60 (t, 1H), 7.46 (d, 1H), 7.36 (t, 1H), 6.27 (dd, 1H), 4.74 (d, 2H), 4.61 (d, 1H), 4.15 (t, 1H), 2.84-2.76 (m, 1H), 2.61-2.57 (m, 1H), 1.52-1.49 (m, 2H), 1.42-1.39 (m, 2H).

[0900] Example 49

[0901] (R)-9-chloro-N-((4-(4-(difluoromethoxy)-3-(3-methylbut-1-yn-1-yl)phenyl)-3- fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7- carboxamide 5,5-dioxide 49

[0902] The method of Example 43 was used, replacing the starting compound 42a in the first step with 3-methyl-1-butyne (Aldrich), and replacing the starting compound 1j in the fifth step with compound 24a. The final product was purified by preparative HPLC (GILSON-281, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 55-85%, flow rate: 30 mL / min) to give the title compound 49 (35 mg, yield: 27%).

[0903] MS m / z (ESI): 611.0 [M+1].

[0904] 1 H NMR (500 MHz, DMSO-d6) δ 9.47 (t, 1H), 8.46 (s, 1H), 8.44 (d, 1H), 8.39 (s, 1H), 7.76 (s, 1H), 7.71 (d, 1H), 7.60 (t, 1H), 7.41 (d, 1H), 7.33 (t, 1H), 6.26 (dd, 1H), 4.74 (d, 2H), 4.61 (d, 1H), 4.09 (t, 1H), 2.90-2.84 (m, 1H), 2.81-2.76 (m, 1H), 2.61-2.56 (m, 1H), 1.24 (d, 6H).

[0905] Example 50

[0906] (R)-9-chloro-N-((4-(3-(cyclobutylethynyl)-4-(difluoromethoxy)phenyl)-3- fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7- carboxamide 5,5-dioxide 50

[0907] The method of Example 47 was used, replacing the starting compound 47a in the first step with ethynylcyclobutane (Bide Pharm). The final product was purified by preparative HPLC (Waters-2545, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 50-80%, flow rate: 30 mL / min) to give the title compound 50 (7 mg, yield: 8%).

[0908] MS m / z (ESI): 623.1 [M+1].

[0909] 1 H NMR (500 MHz, DMSO-d6) δ 9.47 (t, 1H), 8.46 (s, 1H), 8.44 (d, 1H), 8.39 (s, 1H), 7.78 (s, 1H), 7.71 (d, 1H), 7.60 (t, 1H), 7.41 (d, 1H), 7.35 (t, 1H), 6.25 (dd, 1H), 4.73 (d, 2H), 4.61 (d, 1H), 4.09 (t, 1H), 2.86-2.78 (m, 1H), 2.60-2.57 (m, 1H), 2.38-2.32 (m, 2H), 2.20-2.13 (m, 2H), 2.03-1.94 (m, 2H), 1.93-1.90 (m, 1H).

[0910] Example 51

[0911] (R)-N-((4-(3-(dicyclo[1.1.1]pentan-1-ylethynyl)-4- (difluoromethoxy)phenyl)-3-fluoropyridin-2-yl)methyl)-9-chloro-4-fluoro-3,4-dihydro- 2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 51

[0912] First Step

[0913] Dicyclo[1.1.1]pentan-1-ylmethanol 51b

[0914] Dicyclo[1.1.1]pentane-1-carboxylic acid 51a (2 g, 17.84 mmol, Bedrock Medicines) was weighed into a 100 mL single necked flask, 20 mL tetrahydrofuran was added, lithium aluminium hydride (2.5 M, 8.6 mL, 21.42 mmol) was added drop wise at 0 °C, slowly raised to room temperature for 3 hours. To the reaction was added 0.8 mL water, 0.8 mL 15% sodium hydroxide solution, 2.4 mL water to quench the reaction, filtered, the filtrate was concentrated under reduced pressure to get the crude product title compound 51b (1.63 g, yield: 91%) which was used as such for the next step without purification.

[0915] Second Step

[0916] Dicyclo[1.1.1]pentan-1-carbaldehyde 51c

[0917] Into a 100 mL flask, was placed compound 51b (1.63 g, 16.61 mmol), 35 mL of dichloromethane, and pyridinium chlorochromate (4.3 g, 19.95 mmol). The reaction was stirred for 16 hours. Additional pyridinium chlorochromate (1.8 g, 8.35 mmol) was added and the reaction was stirred for 4 hours. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound 51c (1.59 g, yield: 99%) which was used in the next step without further purification.

[0918] Third Step

[0919] 1-ethynylbicyclo[1.1.1]pentane 51d

[0920] Into a 100 mL flask, was placed compound 51c (1.59 g, 16.54 mmol), 20 mL of methanol, and anhydrous potassium carbonate (4.66 g, 33.72 mmol). The reaction was stirred for 16 hours. To the reaction was added 50 mL of water and the mixture was extracted with 10 mL of diethyl ether three times. The organic layers were combined and washed with 30 mL of saturated sodium chloride solution three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a solution of the crude title compound 51d (800 mg, yield: 51%) which was used in the next step without further purification.

[0921] Fourth Step

[0922] 1-((5-bromo-2-(difluoromethoxy)phenyl)ethynyl)bicyclo[1.1.1]pentane 51e

[0923] Into a 100 mL flask, was placed compound 8c (2 g, 5.73 mmol), the solution of compound 51d from the previous step (800 mg, 8.68 mmol), dichlorobis(triphenylphosphine)palladium (193 mg, 0.29 mmol), and cuprous iodide (110 mg, 0.58 mmol). The reaction was stirred for 16 hours under nitrogen. To the reaction was added 20 mL of water and the mixture was extracted with 30 mL of ethyl acetate three times. The organic layers were combined and washed with 15 mL of saturated sodium chloride solution two times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using eluent system B to give the title compound 51e (830 mg, yield: 46%).

[0924] Fifth Step

[0925] ((4-(3-(bicyclo[1.1.1]pent-1-ylethynyl)-4-(difluoromethoxy)phenyl)-3- fluoropyridin-2-yl)methyl)carbamic acid tert-butyl ester 51f

[0926] Compound 41a (227 mg, 0.84 mmol), compound 51e (250 mg, 0.80 mmol), [1,1'- bis(ditert-butylphosphino)ferrocene]dichloropalladium (52 mg, 0.08 mmol), anhydrous potassium carbonate (508 mg, 2.39 mmol) were weighed into a 100 mL single-necked flask, 5 mL of 1,4-dioxane and 1 mL of water were added, replaced with nitrogen for three times, and then the temperature was raised to 90 °C for 3.5 hours of reaction. The reaction solution was cooled to room temperature, 50 mL of water was added, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 51f (260 mg, yield: 71%).

[0927] MS m / z (ESI): 459.2 [M+1].

[0928] Sixth step

[0929] (4-(3-(Bicyclo[1.1.1]pentan-1-ylethynyl)-4-(difluoromethoxy)phenyl)-3-fluoropyridin-2- yl)methanamine 51g

[0930] Compound 51f (260 mg, 0.57 mmol), p-toluenesulfonic acid monohydrate (270 mg, 1.42 mmol) were weighed into a 50 mL single-necked flask, 10 mL of acetonitrile was added, and the temperature was raised to 60 °C for 1.5 hours of reaction. The reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, extracted with dichloromethane (50 mL x 3), the organic phase was combined, washed with saturated sodium bicarbonate solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound 51g (200 mg, yield: 98%). The crude product was directly used in the next step reaction without purification.

[0931] MS m / z (ESI): 359.0 [M+1].

[0932] Seventh step

[0933] (R)-N-((4-(3-(Bicyclo[1.1.1]pentan-1-ylethynyl)-4-(difluoromethoxy)phenyl)-3-fluoropyridin-2- yl)methyl)-9-chloro-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5- dioxide 51

[0934] Compound 51g (63 mg, 0.18 mmol) and 24a (50 mg, 0.17 mmol) were weighed into a 25 mL single neck flask, 2 mL of N,N-dimethylformamide was added, N,N- diisopropylethylamine (55 mg, 0.43 mmol) was added, 2-(7-azabenzotriazol-1- yl)-1,1,3,3-hexafluoro-phosphonic hexafluorophosphate (78 mg, 0.21 mmol) was added, and the reaction was allowed to proceed for 1 h. The reaction was filtered and purified by high performance liquid preparative chromatography (GILSON-281, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 60-85%, flow rate: 30 mL / min) to give the title compound 51 (43 mg, yield: 40%).

[0935] MS m / z (ESI): 635.0 [M+1].

[0936] 1 H NMR (500 MHz, DMSO-d6) δ 9.47 (t, 1H), 8.46 (s, 1H), 8.43 (d, 1H), 8.39 (s, 1H), 7.79 (s, 1H), 7.73 (d, 1H), 7.60 (t, 1H), 7.41 (d, 1H), 7.35 (t, 1H), 6.25 (dd, 1H), 4.73 (d, 2H), 4.61 (d, 1H), 4.09 (t, 1H), 2.86-2.76 (m, 1H), 2.60-2.57 (m, 1H), 2.37 (s, 1H), 2.17 (s, 6H).

[0937] Example 52

[0938] (R)-N-((4-(3-(dicyclo[1.1.1]pentan-1-ylethynyl)-4-(difluoromethoxy)phenyl)-3- fluoropyridin-2-yl)methyl)-4,9-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxathi epine-7- carboxamide 5,5-dioxide 52

[0939] The method of Example 51 was used, replacing the starting material compound 24a in the seventh step with compound 1j, and the final product was purified by high performance liquid preparative chromatography (Waters-2545, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 45-85%, flow rate: 30 mL / min) to give the title compound 52 (5 mg, yield: 7%).

[0940] MS m / z (ESI): 619.0 [M+1].

[0941] 1H NMR (500 MHz, DMSO-d6) δ 9.45 (t, 1H), 8.43 (d, 1H), 8.29 (s, 1H), 8.24 (d, 1H), 7.79 (s, 1H), 7.73 (d, 1H), 7.60 (t, 1H), 7.41 (d, 1H), 7.35 (t, 1H), 6.27 (dd, 1H), 4.73 (d, 2H), 4.60 (d, 1H), 4.15 (t, 1H), 2.84-2.77 (m, 1H), 2.59-2.57 (m, 1H), 2.38 (s, 1H), 2.18 (s, 6H).

[0942] Example 53

[0943] (4R)-9-chloro-N-((4-(4-(difluoromethoxy)-3-((2,2-dimethylcyclopropyl)ethynyl)phenyl)-3- fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 53

[0944] The method of Example 51 was used, replacing the starting compound 51a in the first step with 2,2-dimethylcyclopropane-1-carboxylic acid (“Bedminster”), and the final product was purified by high performance liquid preparative chromatography (Shimadzu LC-20AP, elution system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 55%-80%, flow rate: 30 mL / min) to give the title compound 53 (60 mg, yield: 37%).

[0945] MS m / z (ESI): 637.0 [M+1].

[0946] 1 H NMR (500 MHz, DMSO-d6) δ 9.47 (t, 1H), 8.46 (s, 1H), 8.44 (d, 1H), 8.39 (s, 1H), 7.76 (s, 1H), 7.68 (d, 1H), 7.58 (t, 1H), 7.39 (d, 1H), 7.33 (t, 1H), 6.26 (dd, 1H), 4.73 (d, 2H), 4.61 (d, 1H), 4.09 (t, 1H), 2.86-2.78 (m, 1H), 2.60-2.57 (m, 1H), 1.50 (dd, 1H), 1.26 (s, 3H), 1.14 (s, 3H), 0.96 (dd, 1H), 0.64 (t, 1H).

[0947] Example 54

[0948] (R)-9-chloro-N-((4-(4-(difluoromethoxy)-3-(((S)-2,2-dimethylcyclopropyl)ethynyl)phenyl)-3- fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H- benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 54

[0949] The procedure of Example 51 was followed, replacing the starting compound 51a in the first step with (S)-2,2-dimethylcyclopropane-1-carboxylic acid (Biotage) and purifying the final product by preparative high-performance liquid chromatography (Shimadzu LC-20AP, eluent: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 55-80%, flow rate: 30 mL / min) to give the title compound 54 (13 mg, yield: 7%).

[0950] MS m / z (ESI): 637.0 [M+1].

[0951] 1 H NMR (500 MHz, DMSO-d6) δ 9.47 (t, 1H), 8.46 (s, 1H), 8.44 (d, 1H), 8.39 (s, 1H), 7.76 (s, 1H), 7.68 (d, 1H), 7.58 (t, 1H), 7.39 (d, 1H), 7.33 (t, 1H), 6.26 (dd, 1H), 4.73 (d, 2H), 4.61 (d, 1H), 4.09 (t, 1H), 2.86-2.78 (m, 1H), 2.59-2.57 (m, 1H), 1.50 (dd, 1H), 1.26 (s, 3H), 1.14 (s, 3H), 0.96 (dd, 1H), 0.64 (t, 1H).

[0952] Example 55

[0953] (4R)-9-chloro-N-((4-(3-((2,2-difluorocyclopropyl)ethynyl)-4- (difluoromethoxy)phenyl)-3-fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H- benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 55

[0954] The method of Example 51 was used, replacing the starting compound 51a in the first step with 2,2-difluorocyclopropane-1-carboxylic acid (Bide Pharmatech). The final product was purified by high performance liquid preparative chromatography (Waters-2545, eluent: 10 mmol / L aqueous ammonium bicarbonate and acetonitrile, gradient of acetonitrile: 50%-85%, flow rate: 30 mL / min) to give the title compound 55 (50 mg, yield: 32%).

[0955] MS m / z (ESI): 645.0 [M+1].

[0956] 1 H NMR (500 MHz, DMSO-d6) δ 9.48 (t, 1H), 8.46 (s, 1H), 8.44 (d, 1H), 8.39 (s, 1H), 7.82 (s, 1H), 7.76 (d, 1H), 7.60 (t, 1H), 7.44 (d, 1H), 7.37 (t, 1H), 6.26 (dd, 1H), 4.74 (d, 2H), 4.61 (d, 1H), 4.09 (t, 1H), 2.94-2.86 (m, 1H), 2.84-2.75 (m, 1H), 2.61-2.57 (m, 1H), 2.16-2.09 (m, 1H), 1.86-1.79 (m, 1H).

[0957] Example 56

[0958] (4R)-9-chloro-N-((4-(4-(difluoromethoxy)-3-(spiro[2.2]pentan-1-ylethynyl)phenyl)-3- fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7- carboxamide 5,5-dioxide 56

[0959] The method of Example 51 was used, replacing the starting compound 51a in the first step with spiro[2.2]pentane-2-carboxylic acid (Bide Pharmatech). The final product was purified by high performance liquid preparative chromatography (GILSON-281, eluent: 10 mmol / L aqueous ammonium bicarbonate and acetonitrile, gradient of acetonitrile: 55%-80%, flow rate: 30 mL / min) to give the title compound 56 (30 mg, yield: 24%).

[0960] MS m / z (ESI): 635.0 [M+1].

[0961] 1H NMR (500 MHz, DMSO-d6) δ 9.47 (t, 1H), 8.46 (s, 1H), 8.44 (d, 1H), 8.39 (s, 1H), 7.76 (s, 1H), 7.69 (d, 1H), 7.59 (t, 1H), 7.40 (d, 1H), 7.33 (t, 1H), 6.25 (dd, 1H), 4.73 (d, 2H), 4.61 (d, 1H), 4.09 (t, 1H), 2.86-2.78 (m, 1H), 2.61-2.59 (m, 1H), 2.02 (dd, 1H), 1.48 (dd, 1H), 1.23 (d, 1H), 1.04-1.00 (m, 1H), 0.97-0.92 (m, 2H), 0.91-0.88 (m, 1H).

[0962] Example 57

[0963] (R)-9-chloro-N-((4-(4-(difluoromethoxy)-3-(((1S,2S)-2-methylcyclopropyl)ethynyl)phenyl)-3- fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 57

[0964] The method of Example 51 was used, replacing the starting compound 51a in the first step with (1S,2S)-2-methylcyclopropane-1-carboxylic acid (Bide Pharm), and the final product was purified by high performance liquid preparative chromatography (GILSON-281, elution system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 50%-80%, flow rate: 30 mL / min) to give the title compound 57 (20 mg, yield: 18%).

[0965] MS m / z (ESI): 623.0 [M+1].

[0966] 1H NMR (500 MHz, DMSO-d6) δ 9.47 (t, 1H), 8.46 (s, 1H), 8.43 (d, 1H), 8.39 (s, 1H), 7.74 (s, 1H), 7.67 (d, 1H), 7.58 (t, 1H), 7.38 (d, 1H), 7.32 (t, 1H), 6.25 (dd, 1H), 4.73 (d, 2H), 4.61 (d, 1H), 4.09 (t, 1H), 2.86-2.78 (m, 1H), 2.60-2.57 (m, 1H), 1.25 (s, 2H), 1.10 (d, 6H), 1.01 (t, 1H).

[0967] Example 58

[0968] (R)-9-chloro-N-((4-(4-(difluoromethoxy)-3-(((1r,2R,3S)-2,3-dimethylcyclopropyl)ethynyl)phenyl)-3-fluoropyridin-2-yl)methyl)-4-fluoro-3,4-dihydro-2H- benzo[b][1,4]oxathiepine-7-carboxamide 5,5-dioxide 58

[0969] The method of Example 51 was used, replacing the starting compound 51a in the first step with (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (Bide Pharm), and the end product was purified by high performance liquid preparative chromatography (Shimadzu LC-20AP, elution system: 10 mmol / L ammonium bicarbonate in water and acetonitrile, gradient of acetonitrile: 55%-80%, flow rate: 30 mL / min), to obtain the title compound 58 (30 mg, yield: 35%).

[0970] MS m / z (ESI): 637.1 [M+1].

[0971] 1 H NMR (500 MHz, DMSO-d6) δ 9.47 (t, 1H), 8.46 (s, 1H), 8.43 (d, 1H), 8.39 (s, 1H), 7.74 (s, 1H), 7.67 (d, 1H), 7.58 (t, 1H), 7.38 (d, 1H), 7.32 (t, 1H), 6.25 (dd, 1H), 4.73 (d, 2H), 4.61 (d, 1H), 4.09 (t, 1H), 2.86-2.78 (m, 1H), 2.60-2.57 (m, 1H), 1.25 (s, 2H), 1.10 (d, 6H), 1.01 (t, 1H).

[0972] Biological evaluation

[0973] The present disclosure is further described and explained with the following test examples, which are not meant to limit the scope of the present disclosure.

[0974] Test Example 1 Cell proliferation inhibition experiment

[0975] The in vitro cell experiment described below can be used to determine the inhibitory activity of the test compound on the proliferation of human lung cancer cells A549 and NCI-H520, and the activity can be represented by IC 50 Values. On the first day of the experiment, A549 (ATCC) cells and NCI-H520 (ATCC) cells were seeded in 96-well cell culture plates (Corning, 3903) at a density of 400 cells / well and 2000 cells / well, respectively, using Ham's F-12K (Gibco, 21127-030) medium containing 10% FBS (Corning, 35-081-CV) and RPMI1640 (Meilunbio, PWL047) medium containing 10% FBS, respectively, 200 μL of cell suspension per well, and incubated overnight in a 37°C, 5% CO2 cell incubator. On the second day, compounds were added to the cell plates using a Tecan D300e, with a final concentration of 9 concentration points starting from 10 μM with 4-fold gradient dilution, and DMSO-only cell wells were set as vehicle control wells, and medium and DMSO-only wells were set as blank control wells, with a DMSO content of 0.5% in all wells. The well plates were placed in a 37°C, 5% CO2 cell incubator for five days. On the seventh day, the cell culture plates were removed, and the cells were passaged to new 96-well cell culture plates at a certain ratio. The cell culture plates were placed in a 37°C, 5% CO2 cell incubator for 4 hours, and then the cells were treated with compounds again, and the well plates were placed in a 37°C, 5% CO2 cell incubator for continued culture for five days. On the twelfth day, the 96-well cell culture plates were removed, 100 μL of medium supernatant was aspirated from each well and discarded, and 50 μL of luminescent cell viability assay reagent (Promega, G7573) was added, shaken in the dark for 5 minutes, and then placed at room temperature for 10 minutes. The luminescent signal value (RLU) was read using an enzyme-labeled instrument (PerkinElmer, EnVision2105). The inhibition rate of each concentration of the compound was calculated by the following formula, where the maximum value is the maximum inhibition rate of the compound on cell proliferation. GraphPad Prism was used to perform curve fitting and calculate the IC 50 value according to the logarithmic concentration of the compound and the inhibition rate.

[0976] Inhibition rate (%) = (RLU 溶媒对照 -RLU 化合物RLU 溶媒对照 RLU 空白对照 RLU

[0977] The activity of the compounds of the present disclosure was obtained from the above analysis, and the calculated IC 50 values are as follows:

[0978] Table 1 Inhibition activity of the compounds of the present disclosure on the proliferation of A549 cells Note: " / " not detected

[0979] Conclusion: The compounds of the present disclosure have obvious proliferation inhibition activity on A549 cells, and weak inhibition activity on the proliferation of NCI-H520, and have obvious selectivity.

[0980] Test Example 2 SMARCA2 and SMARCA4 enzyme activity inhibition experiment

[0981] The in vitro biochemical experiment described below can be used to determine the inhibition activity of the test compound on the SMARCA2 and SMARCA4 enzyme activity, and the activity can be represented by the IC 50 value. The experimental buffer containing 20 mM HEPES (PH 8.0), 1 mM MgCl2, 20 mM KCl, 1 mM DTT, 0.005% Tween20 and 0.01% BSA was prepared. UltraPure TM Salmon Sperm DNA Solution (Invitrogen, 15632-011), SMARCA2 (VIA Biologies) or SMARCA4 (VIA Biologies) protein were diluted with the experimental buffer to prepare DNA and enzyme working solutions, and 2 μL of DNA working solution and 2 μL of SMARCA2 or SMARCA4 enzyme working solution or experimental buffer were added to each well of a 384-well plate (Corning, 4513). Then, using a Tecan D300e, compounds were added to the wells, with a final concentration of 9 concentration points starting from 10 μM (SMARCA2 protein) or 30 μM (SMARCA4 protein) for 4-fold gradient dilution, while setting the DMSO-containing wells as the vehicle control wells, the wells containing no enzyme but only DNA, ATP and DMSO as the blank control wells, and the DMSO content of all wells being 0.5%. The well plate was placed in a 25°C biochemical incubator for pre-incubation for 10 minutes. ADP-Glo TMATP working solution was prepared from ATP in the Kinase Assay kit (Promega, V9102). 1 μL ATP working solution was added to each well of a 384-well plate. Thus, in a 5 μL enzyme reaction system, the final concentrations of enzyme, DNA and ATP were 10 nM, 20 nM and 400 μM, respectively. The plate was incubated in a 25°C biochemical incubator for 1 hour. After 1 hour, 5 μL ADP-Glo in the kit was added to each well of the 384-well plate, and the plate was incubated in a 25°C biochemical incubator for 40 minutes. After 40 minutes, the 384-well plate was removed, 10 μL Kinase Detection Reagent in the kit was added to each well, and the plate was incubated in a 25°C biochemical incubator in the dark for 40 minutes. The luminescence signal value (RLU) was read using an enzyme marker (BMG LABTECH, PHERAstar FSX). The inhibition rate of each concentration of the compound was calculated by the following formula, where the maximum value is the maximum inhibition rate of the compound on enzyme activity. The log concentration of the compound and the inhibition rate were fitted and the IC 50 value was calculated using GraphPad Prism. 溶媒对照 Inhibition rate (%) = (RLU 化合物 -RLU 溶媒对照 ) / (RLU 空白对照 -RLU

[0982] The activity of the compounds of the present disclosure was obtained from the above analysis, and the calculated IC 50 values are as follows:

[0983] Table 2 Inhibition activity of the compounds of the present disclosure on SMARCA2 and SMARCA4 enzyme activity Note: " / " not detected

[0984] Conclusion: The compounds of the present disclosure have obvious inhibitory activity on SMARCA2 enzyme activity, and weak inhibition on SMARCA4 enzyme activity, and have selectivity.

[0985] Test Example 3 Reporter gene experiment

[0986] The in vitro cell experiments described below can be used to determine the inhibitory effect of the test compound on the reporter gene activity of human lung cancer cells A549-MMTV-luc and human breast cancer cells MDA-SMARCA2-KO, and the IC 50A549-MMTV-luc cells were obtained by transfecting MMTV-luc reporter gene into A549 cells (ATCC), and MDA-SMARCA2-KO cells were obtained by knocking out SMARCA2 in MDA cells (ATCC). On the first day of the experiment, A549-MMTV-luc cells and MDA-SMARCA2-KO cells were seeded in 96-well cell culture plates (Corning, 3903) at a density of 15000 cells / well and 25000 cells / well, respectively, using Ham's F-12K (Gibco, 21127-030) medium containing 5% charcoal-stripped fetal bovine serum (CS-FBS) (Biosun, BS-0004-500) and Leibovitz's L-15 (Gibco, 11415064) medium containing 5% CS-FBS, respectively, 200 μL of cell suspension per well, and the A549-MMTV-luc cells were placed in a 37°C, 5% CO2 cell incubator (same below), and the MDA-SMARCA2-KO cells were placed in a 37°C, CO2-free cell incubator (same below), and both were incubated overnight. On the second day, the Tecan D300e was used to add compounds to the cell plates, and the final concentration of the compounds was 9 concentration points starting from 10 μM with 4-fold gradient dilution, and dexamethasone was also added. The cell wells containing only DMSO and dexamethasone were set as the solvent control wells, and the cell wells containing only DMSO were set as the blank control wells, and the DMSO concentration in all wells was 0.5%. The cell plates were placed in a 37°C, 5% CO2 or CO2-free cell incubator, respectively, for 6 hours. After 6 hours, the 96-well cell culture plates were removed, 100 μL of culture medium supernatant was aspirated from each well and discarded, and 50 μL of detection reagent ONE-Glo Luciferase Assay System (Promega, E6120) was added, shaken in the dark for 5 minutes, and then placed at room temperature for 10 minutes. The luminescence signal value (RLU) was read using an enzyme-labeled instrument (BMG LABTECH, PHERAstar FSX). The inhibition rate of each concentration of the compound was calculated by the following formula, where the maximum value is the maximum inhibition rate of the compound on the transcriptional activity of the cells. The log concentration of the compound and the inhibition rate were fitted and the IC 50 value was calculated using GraphPad Prism. 溶媒对照 Inhibition rate (%) = (RLU 化合物 -RLU 溶媒对照 ) / (RLU 空白对照 -RLU

[0987] The activity of the compounds of the present disclosure was obtained from the above analysis, and the calculated IC 50 values are as follows:

[0988] Table 3 Inhibitory activity of the compounds of the present disclosure on the transcription level of A549-MMTV-luc and MDA-SMARCA2-KO cells Note: “ / ” not detected

[0989] Conclusion: The compounds of the present disclosure have obvious inhibitory activity on the transcription level of A549-MMTV-luc cells, and weaker inhibitory activity on the transcription level of MDA-SMARCA2-KO cells, and have obvious selectivity.

[0990] Test Example 4: Inhibitory activity of different compounds on hERG channel

[0991] 1. Experimental method

[0992] 1.1) Cell culture

[0993] CHO hERG cells (provided by B’SYS) were grown in culture dishes containing culture medium (Ham’s F12 medium, 10% fetal bovine serum, 100 μg / mL hygromycin B, 100 μg / mL Geneticin) and incubated in a 37°C incubator with 5% CO2. Twenty-four to forty-eight hours before electrophysiological experiments, CHO hERG cells were transferred to circular glass slides placed in culture dishes and grown under the same culture medium and culture conditions. The density of CHO hERG cells on each circular glass slide needed to meet the requirement that most cells were independent and single.

[0994] 1.2) Whole-cell recording

[0995] The hERG inhibitory activity of the test sample was tested at different concentrations (30, 10, 3, 1, 0.3 and 0.1 μM). Before the experiment, the test sample was diluted with DMSO in a gradient to 10, 3, 1, 0.3 and 0.1 mM stock solutions, and then diluted with extracellular solution (2 mM CaCl2, 1 mM MgCl2, 4 mM KCl, 145 mM NaCl, 10 mM Glucose, 10 mM HEPES, pH 7.4, osmotic pressure ~ 305 mOsm) to the final concentration.

[0996] The patch-clamp experiment adopts a manual patch-clamp system (HEKA EPC-10 signal amplifier and digital conversion system, purchased from HEKA Electronics, Germany) to record the whole-cell current. The round glass slide with CHO hERG cells grown on the surface is placed in the electrophysiological recording tank under the inverted microscope, and the extracellular fluid is continuously perfused in the recording tank (about 1 ml per minute). The conventional whole-cell patch-clamp current recording technique is used during the experiment. The cell is clamped at a voltage of -80 mV, then depolarized to +20 mV to activate the hERG potassium channel, and then clamped to -50 mV after 5 seconds to eliminate inactivation and generate a tail current. The peak value of the tail current is used as the numerical value of the hERG current size. After the hERG current recorded by the above steps reaches a stable state under the continuous extracellular perfusion in the recording tank, the compound to be tested can be superimposed and perfused until the inhibitory effect of the compound on the hERG current reaches a stable state. Multiple concentrations of the same compound are tested on one cell, and the extracellular fluid needs to be washed after reaching a steady state between different concentrations until the hERG current returns to the size before the compound is added.

[0997] 1.3) Result analysis

[0998] The experimental data is analyzed by the data analysis software provided by HEKA Patchmaster (V2x73.2), Microsoft Excel and Graphpad Prism 10.0.

[0999] Comparative Example 1: Synthesized according to the method reported in WO2023220219A1 Example 332.

[1000] The IC 50 values of the compounds of the present disclosure obtained by experiments are as follows:

[1001] Table 4 Inhibitory activity of the compounds of the present disclosure on hERG channel

[1002] Conclusion: The compounds of the present disclosure have weak inhibitory activity on hERG channel, which has certain advantages.

[1003] Test Example 5 Pharmacokinetic evaluation

[1004] 1. Overview

[1005] The drug concentrations in the plasma of mice at different time points after oral administration of the compounds of Examples 37, 45, 46 and 47 to the mice were determined by LC / MS / MS method. The pharmacokinetic behavior of the compounds of the present disclosure in mice was studied, and the pharmacokinetic characteristics were evaluated.

[1006] 2. Test scheme

[1007] 2.1 Test drugs

[1008] Example compounds 37, 45, 46, 47.

[1009] 2.2 Test animals

[1010] A total of 45 C57 mice were used this time. Among them, for the pharmacokinetic study of compound 37 and control example 1, 18 mice were used in this institution. They were female and purchased from Vetoliva Laboratory Animal Co., Ltd. The animal production license number is: SCXK(Beijing)2021-0006. For compounds 45, 46, and 47, the tests were entrusted to a third-party testing unit. 27 mice were used. They were female and the animal use license number is: SYXK(Jiangsu)2025-0022.

[1011] 2.3 Drug preparation​​​​​​​​​​​​​​​​​​​​​​​​​​​

[1021] Table 5 Pharmacokinetic parameters of the compounds of the present disclosure

[1022] Conclusion: The compounds of the present disclosure have good pharmacokinetic absorption and pharmacokinetic advantages.

Claims

1. A compound of formula I ###0001### or a pharmaceutically acceptable salt thereof wherein R 1 Selected from hydrogen, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group and the 3- to 6-membered heterocycloalkyl group are each independently and optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 The alkoxy group is replaced; R 2 selected from hydrogen, halogen, amino, C 1-6 alkyl and C 1-6 alkoxy, said C 1-6 alkyl and C 1-6 alkoxy are each independently optionally substituted with one or more radicals selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl and C 1- 6alkoxy; X 1 N or CR 1a R 1a is selected from hydrogen, halogen, C 1-6 1-6 alkyl, C 1-6 1-6 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each independently optionally substituted with one or more halogen, oxo, hydroxy, cyano, nitro, amino, C 1-6 1-6 alkyl and C 1-6 1-6 alkoxy; and 3-6 R 1-6 is selected from hydrogen, halogen, C 1- 1-6 alkyl and C 1-6 alkoxy. X 2 is selected from -S-, -SO-, -SO2-, and -S(O)(=NH)-; R 3 is hydrogen or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by one or more radicals selected from the group consisting of halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy; each R 4 and R 5 is each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy, said C 1-6 alkyl and C 1-6 alkoxy are each independently optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy, Or, R 4 R 5 Together with the attached carbon atom, they form C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 3-6 The cycloalkyl group and the 3- to 6-membered heterocycloalkyl group are each independently and optionally selected from one or more halogen, oxo, hydroxy, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 The alkoxy group is replaced; L 1 is 5-10 membered heterocycloalkyl or 5-10 membered heteroaryl, each independently optionally substituted with one or more radicals selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy, each independently optionally substituted with one or more radicals selected from the group consisting of halogen, hydroxy, cyano, nitro and amino; and 1-6 alkyl and C 1-6 alkoxy, each independently optionally substituted with one or more radicals selected from the group consisting of halogen, hydroxy, cyano, nitro and amino; and Ring A is a C6aromatic ring or a 5- to 6-membered heteroaromatic ring; R 6 selected from C 2-6 alkenyl, C 2-6 alkynyl and -O-C 2-6 alkenyl, said C 2-6 alkenyl, C 2-6 alkynyl and -O-C 2-6 alkenyl are each independently optionally substituted with one or more R 2a groups; R 2a Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl and 3 to 10-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 3- to 10-membered heterocyclic alkyl group are each independently and optionally selected from one or more groups selected from halogen, oxo, hydroxy, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 The group in the alkoxy group is replaced, or two R groups attached to the same carbon atom are replaced. 2a Formation C 3-8 Cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein C 3-8 The cycloalkyl group and the 3- to 8-membered heterocycloalkyl group are each independently and optionally selected from one or more halogen, oxo, hydroxy, cyano, nitro, amino, C 1-6 Alkyl and C 1-6 The alkoxy group is replaced; R 7 each independently is selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2- alkynyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 3-10 cycloalkoxy, 3- to 10-membered heterocycloalkoxy, and -O-C 2-6 alkenyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3- 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 3-10 cycloalkoxy, 3- to 10-membered heterocycloalkoxy, and -O-C 2-6 alkenyl, C 3a each independently is optionally substituted with one or more R R 3a each independently is selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl and 3- to 10-membered heterocycloalkyl, each independently optionally substituted with one or more radicals selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy; and 3-10 cycloalkyl and 3- to 10-membered heterocycloalkyl, each independently optionally substituted with one or more radicals selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy; and R 8 selected from hydrogen, halogen, hydroxyl, amino, C 1-6 alkyl and C 1-6 alkoxy, each independently optionally substituted with one or more moieties selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy, each independently optionally substituted with one or more moieties selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy, each independently optionally substituted with one or more moieties selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C R 9 each independently is selected from the group consisting of halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy, said C 1-6 alkyl and C 1-6 alkoxy are each independently optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy, or two R 9 form =0; X 3 is selected from O, NR 4a and C(R 4b )2, Z 1 and Z 2 are each independently selected from a bond, O and -C(R 5a )2-, and provided that when X 3 is O, then Z 1 and Z 2 are independently a bond or -C(R 5a )2-; R 4a is hydrogen or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by one or more radicals selected from the group consisting of halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy; R 4b each independently selected from hydrogen, halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3- 6cycloalkyl and 3- to 6-membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are each independently optionally substituted with one or more radicals selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1- 6alkyl and C 1-6 alkoxy; or, two R 4b together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl, said C 3-8 cycloalkyl and 3- to 8-membered heterocycloalkyl are each independently optionally substituted with one or more radicals selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy; R 5a are each independently selected from hydrogen, halogen, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3- 6cycloalkyl and 3- to 6-membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are each independently optionally substituted with one or more radicals selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy; or, two R 5a together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl, said C 3-8 cycloalkyl and 3- to 8-membered heterocycloalkyl are each independently optionally substituted with one or more radicals selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy; m is 0, 1, 2 or 3; n is 0, 1 or 2; o is 0, 1, 2, 3 or 4.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein X 1 is CR 1a , R 1a is as defined in claim 1.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein L 1 for Where X 4 X 5 X 6 X 7 X 8 and X 9 Each is independently N or CR 6a R 6a Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group and the 3- to 6-membered heterocycloalkyl group are each independently and optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 The alkoxy group is replaced; A 1 end-to-end Connected, A 2 End with bonded to each other.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein L 1 selected from preferably wherein A 1 and A 2 as defined in claim 3.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L 1 for Where X 4 X 5 X 6 and X 10 Each is independently N or CR 6a R 6a Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group and the 3- to 6-membered heterocycloalkyl group are each independently and optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 The alkoxy group is replaced; A 1 end-to-end Connected, A 2 End with bonded to each other. Further, L 1 Preferably R 6a each independently is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each independently optionally substituted with one or more radicals selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy; and wherein each R 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl is independently optionally substituted with one or more radicals selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy; and wherein each R A 1 end-to-end Connected, A 2 End with bonded to each other.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein X is O. 3 is O.

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Z is a bond or C(R 1 )2, R 5a )2, R 5a as defined in claim 1; further, Z 1 is preferably a bond.

8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen, methyl, ethyl and propyl, preferably hydrogen.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein X is -S- or -SO2-. 2 is -S- or -SO2-.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 and 3-9, wherein selected from the group consisting of 11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-10, wherein the compound of Formula I is a compound of Formula IIa or IIb, Where R 1 ~R 2 R 4 ~R 9 R 5a X 1 A, m, n, and o are defined as in claim 1; p is 0, 1, 2, 3, or 4; R 7a Each is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group and the 3- to 6-membered heterocycloalkyl group are each independently and optionally selected from one or more halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 The group in the alkoxy group is replaced.

12. The compound or pharmaceutically acceptable salt thereof according to claim 11, wherein, R 7a each independently selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 alkoxy, said C 1-6 alkyl and C 1-6 alkoxy are each independently optionally substituted with one or more radicals selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein the compound of Formula I is a compound of Formula IIa-1 or IIb-1, wherein R 1 ~R 2 , R 4 ~R 9 , R 5a , X 1 , ring A, m, n and o are as defined in claim 1.

14. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are each independently selected from hydrogen, halogen, and C 1-6 alkyl, preferably hydrogen.

15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-14, wherein ring A is a 5- to 6-membered heteroaromatic ring, preferably a pyridine ring, a pyrazine ring or a pyrimidine ring.

16. The compound according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein selected from: wherein R 6 , R 7 and o are as defined in claim 1.

17. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-16, wherein the compound of Formula I is selected from: wherein R 1 ~R 2 , R 4 ~R 9 , R 5a , X 1 , m, n and o are as defined in claim 1 ; R 6a as defined in claim 5.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-17, wherein R 6 C 2-6 alkenyl or C 2-6 alkynyl group, the C 2-6 alkenyl and C 2-6 Each alkynyl group is independently and optionally influenced by one or more R groups. 2a Replaced; further, R 6 Preferred selection is chosen from one or more Rs 2a The substituted vinyl, ethynyl, propynyl, and propynyl groups, R 2a As defined in claim 1.

19. The compound according to any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R 6 is -O-C 2-6 alkenyl, said -O-C 2-6 alkenyl is optionally substituted with one or more R 2a ; further, R 6 is preferably -O-vinyl or -O-propenyl optionally substituted with one or more R 2a ; and R 2a is as defined in claim 1.

20. The compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R 2a each is independently selected from the group consisting of halogen, amino, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, each of which is independently optionally substituted with one or more groups selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1- alkyl, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, each of which is independently optionally substituted with one or more groups selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, and C 1-6 alkoxy.

21. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-20, wherein R 2a each is independently selected from halogen, amino, hydroxyl, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, and cyclopentyl.

22. The compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R 7 each is independently selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl, each of which C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl is independently optionally substituted with one or more R 3a .

23. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-21, wherein R 7 each is independently selected from fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, cyclopropylmethyloxy, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.

24. The compound according to any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, halogen and C 1-6 alkyl, said alkyl being optionally substituted with one or more groups selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy; further, R 1 is preferably selected from hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl and propyl.

25. The compound according to any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, halogen and C 1-6 alkyl, said alkyl being optionally substituted with one or more groups selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy; further, R 2 is preferably selected from hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl and propyl.

26. The compound according to any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R 1a is selected from hydrogen, halogen and C 1-6 alkyl, said alkyl being optionally substituted with one or more groups selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy; further, R 1a is preferably selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, difluoromethyl, trifluoromethyl, ethyl and propyl.

27. The compound according to any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from hydrogen, halogen and C 1-6 alkyl, said alkyl being optionally substituted with one or more groups selected from halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy; further, R 8 is preferably selected from hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl and propyl.

28. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein X 3 is N.

29. The compound according to any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R 5a each is independently selected from the group consisting of hydrogen, halogen, and C 1-6 alkyl optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy; further, R 5a each is independently preferably hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl, and propyl.

30. The compound or pharmaceutically acceptable salt thereof for use according to any one of claims 1-29, wherein two R 2a forming C 3-8 cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

31. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-20, wherein R 2a is 3- to 6-membered heterocycloalkyl optionally substituted with one or more groups selected from halogen, oxo, hydroxy, cyano, nitro, amino, C 1-6 alkyl and C 1-6 alkoxy, for example tetrahydrofuranyl, tetrahydropyranyl, oxetanyl or morpholinyl.

32. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-20, wherein R 2a each is independently selected from halogen, -N(R a )2, hydroxyl, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, and morpholinyl, R a each is independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, or, two R 2a attached to the same carbon atom form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

33. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from:

34. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-33 and a pharmaceutically acceptable excipient.

35. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof comprising the step of reacting a compound of formula A with a compound of formula B to form a compound of formula I, wherein R 1 ~R 9 , X 1 , X 2 , X 3 , Z 1 , Z 2 , L 1 , ring A, m, n and o are as defined in claim 1, and PG1is a hydroxyl group or a leaving group (such as a halogen or an ester group).

36. A method for preventing and / or treating cancer, preferably lung cancer, intestinal cancer, breast cancer, melanoma, skin cancer, lymphoma or prostate cancer, by administering to a subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-33 or a pharmaceutical composition according to claim 34.

37. Use of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-33 or a pharmaceutical composition according to claim 34 for the manufacture of a medicament for preventing and / or treating cancer, preferably lung cancer, intestinal cancer, breast cancer, melanoma, skin cancer, lymphoma or prostate cancer.

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