Cathepsin c small molecule inhibitors and medical uses thereof

Abstract

The present disclosure relates to cathepsin C small molecule inhibitors and their medical uses. In particular, the present disclosure provides an amide nitrile compound shown in formula VI, a pharmaceutical composition containing the compound and its use for inhibiting cathepsin C.

Description

[0001] This application is a divisional application of patent application No. 202180062277.5, filed on December 3, 2021, entitled "Cetase C Small Molecule Inhibitor and Its Pharmaceutical Use". Technical Field

[0002] This disclosure pertains to the pharmaceutical field and relates to the structure of a cathepsin C small molecule inhibitor and its preparation method. Background Technology

[0003] Cathepsins are a class of proteolytic enzymes widely found in lysosomes of various tissues and cells. Based on their structure and catalytic type, cathepsins are classified into three classes: serine proteases (cathepsins A and G), aspartic proteases (cathepsins D and E), and cysteine ​​proteases. Among them, cysteine ​​proteases constitute the largest family of cathepsins, including 11 proteases: cathepsins B, C, F, H, K, L, O, S, W, V, and Z.

[0004] Cathepsin C, also known as dipeptidyl peptidase I or “DPP1,” is constitutively expressed in many tissues, with the highest levels found in the lungs, kidneys, liver, and spleen. Recent studies have begun to describe the role of cathepsin C in certain inflammatory processes. For example, Adkison et al. published in J Clin Invest. 2002 Feb;109(3):363-71; and Tinh et al. published in Archives of Biochemistry and Biophysics. 2002403:160-170. These studies suggest that cathepsin C is co-expressed with certain serine proteases in granules and plays a role in processing the precursor forms of these proteases into their active forms, which are then released from inflammatory cell granules recruited to the site of inflammation. Once activated, these proteases have numerous functions, including the degradation of various extracellular matrix components, and together they can spread tissue damage and chronic inflammation.

[0005] WO 2004 / 110988 relates to certain nitrile derivatives and their use as DPP1 inhibitors.

[0006] WO 2009 / 074829 relates to peptide nitriles and their use as DPP1 inhibitors.

[0007] WO 2010 / 128324 relates to α-aminoamidonitrile and its use as a DPP1 inhibitor.

[0008] WO 2012 / 119941 relates to peptide nitrile compounds and their use as DPP1 inhibitors.

[0009] WO 2013 / 041497 relates to N-[1-cyano-2-(phenyl)ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide and its use as a DPP1 inhibitor.

[0010] WO 2001 / 096285 and WO 2003 / 048123 relate to β-aminoamide nitriles that have inhibitory activity against cysteine ​​proteases.

[0011] WO 2015 / 110826 relates to α-aminoamidonitrile and its use as a DPP1 inhibitor.

[0012] However, the amide nitrile compounds shown in this disclosure I have not been disclosed in any literature. Summary of the Invention

[0013] In the first aspect, this disclosure provides compounds of formula I or pharmaceutically acceptable salts thereof. I in: Ring A is selected from heterocyclic alkyl, heteroaryl, and aryl groups, each of which is independently and optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, acyl, amide, oxo, alkyl, and alkoxy groups; each of the alkyl and alkoxy groups is independently and optionally substituted by one or more R groups. 3a Replaced; Ring B is a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, alkoxy, alkyl, alkenoxy, alkynoxy, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, and cycloalkenoxy, and / or the cycloalkyl or heterocycloalkyl group is fused with an aryl or heteroaryl group, wherein the alkyl, alkoxy, alkenoxy, alkynoxy, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, cycloalkenoxy, or fused ring is optionally substituted by one or more R groups. 3b Replaced; R1 is independently selected from halogen, hydroxyl, oxo, nitro, cyano, alkyl, cycloalkyl, amino, amide, acyl, alkoxy, alkenoxy, alkynoxy, and cycloalkoxy; R 3a Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl, or 3- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, the 5- to 6-membered aryl group, and the 3- to 6-membered heteroaryl group are each independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups; R 3b Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5- to 6-membered aryl or 3- to 6-membered heteroaryl, methanesulfonyl and The C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, the 5- to 6-membered aryl group, and the 3- to 6-membered heteroaryl group are each independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups; preferably R 3b Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl and 3- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, the 5- to 6-membered aryl group, and the 3- to 6-membered heteroaryl group are each independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups; n is an integer selected from 0 to 3; preferably, n is an integer selected from 1 to 3.

[0014] In some embodiments, in the compound of Formula I or its pharmaceutically acceptable salt, ring B is a 3-15 membered cycloalkyl group or a 3-15 membered heterocycloalkyl group containing 1-3 heteroatoms, wherein the 3-15 membered cycloalkyl group or the 3-15 membered heterocycloalkyl group containing 1-3 heteroatoms is optionally composed of one or more elements selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 alkynyloxy, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, C 6-8 The alkyl group is substituted with aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, and cycloalkenoxy groups, and / or the 3-15 membered cycloalkyl group or a 3-15 membered heterocycloalkyl group containing 1-3 heteroatoms is fused with an aryl or heteroaryl group, wherein the alkyl, alkoxy, alkenoxy, alkynoxy, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, cycloalkenoxy, or fused ring is optionally substituted with one or more R groups. 3b Replaced by, R 3b As defined in Equation I.

[0015] In other embodiments, in the compound of Formula I or its pharmaceutically acceptable salt, ring B is a 3-10 membered cycloalkyl group or a 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms, wherein the 3-10 membered cycloalkyl group or the 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms is optionally composed of one or more elements selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 alkynyloxy, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, C 6-8 Substituents of aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, and cycloalkenoxy groups, and / or the 3-10 membered cycloalkyl group or a 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms and C 6-8 aryl or heteroaryl fusion, wherein the alkyl, alkoxy, alkenoxy, alkynoxy, 3-20 membered cycloalkyl, 3-20 membered heterocycloalkyl, C6-8 Aryl, heteroaryl, cycloalkoxy, cycloalkenoxy, or fused ring may optionally be surrounded by one or more R 3b Replaced by, R 3b As defined in Equation I.

[0016] In other embodiments, in the compound of Formula I or its pharmaceutically acceptable salt, ring B is a 3-10 membered cycloalkyl group or a 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms, wherein the 3-10 membered cycloalkyl group or the 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms is optionally composed of one or more elements selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-8 Substituents include aryl, 5-8 heteroaryl groups with 1-3 heteroatoms, and cycloalkoxy groups, and / or the 3-10 cycloalkyl group or a 3-10 heterocycloalkyl group containing 1-3 heteroatoms and C. 6-8 The aryl group or a 5-8 heteroaryl group with 1-3 heteroatoms is fused together, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 3-3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-8 Aryl, 5-8 membered heteroaryl with 1-3 heteroatoms, or fused ring optionally surrounded by one or more R 3b Replaced by, R 3b As defined in Equation I.

[0017] In other embodiments, in the compound of Formula I or its pharmaceutically acceptable salt, ring B is a 3-8 membered cycloalkyl group or a 3-8 membered heterocycloalkyl group containing 1-3 heteroatoms, wherein the 3-8 membered cycloalkyl group or the 3-8 membered heterocycloalkyl group containing 1-3 heteroatoms is optionally composed of one or more elements selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-8 Substituted with aryl, 5-8 heteroaryl groups with 1-3 heteroatoms, and cycloalkoxy groups, and / or the 3-8 cycloalkyl group or a 3-8 heterocycloalkyl group containing 1-3 heteroatoms and C 6-8 The aryl group or a 5-8 heteroaryl group with 1-3 heteroatoms is fused together, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-8 aryl, 5-8 membered heteroaryl with 1-3 heteroatoms, or fused ring optionally bounded by 1-3 R atoms 3b Replaced by, R 3b As defined in Equation I.

[0018] In other embodiments, in the compound of Formula I or its pharmaceutically acceptable salt, ring B is a 5-8 membered cycloalkyl group, or a 5-8 membered heterocycloalkyl group containing 1-3 heteroatoms, wherein the 5-8 membered cycloalkyl group or the 5-8 membered heterocycloalkyl group containing 1-3 heteroatoms is optionally selected from one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-8 Substituted with aryl, 5-8-membered heteroaryl with 1-3 heteroatoms, and cycloalkoxy, and / or the 5-8-membered cycloalkyl or 5-8-membered heterocycloalkyl containing 1-3 heteroatoms and C 6-8 The aryl group or a 5-8 heteroaryl group with 1-3 heteroatoms is fused together, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-8 aryl, 5-8 membered heteroaryl with 1-3 heteroatoms, or fused ring optionally bounded by 1-3 R atoms 3b Replaced by, R 3b As defined in Equation I.

[0019] In other embodiments, in the compound of Formula I or its pharmaceutically acceptable salt, ring B is a 5-8 membered cycloalkyl group or a 5-8 membered heterocycloalkyl group containing 1-3 heteroatoms, wherein the 5-8 membered cycloalkyl group or the 5-8 membered heterocycloalkyl group containing 1-3 heteroatoms is optionally selected from one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl and C 6-8 The aryl group is substituted by a substituent, and / or the 5-8 membered cycloalkyl group or a 5-8 membered heterocycloalkyl group containing 1-3 heteroatoms and C 6-8 Aryl fusion, the C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 6-8 The aryl or fused ring may be selectively capped with 1-3 Rs. 3b Replaced by, R 3b As defined in Equation I.

[0020] In other embodiments, in the compound of Formula I or its pharmaceutically acceptable salt, ring B is a 5-8 membered cycloalkyl or a 5-8 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the 5-8 membered cycloalkyl or the 5-8 membered heterocycloalkyl containing 1-3 heteroatoms is optionally composed of one or more elements selected from hydrogen, deuterium, halogen, oxo, C 1-6 Alkyl, C1-6 Alkoxy, 3-8 membered cycloalkyl, C 6-8 The aryl group is substituted by a substituent, and / or the 5-8 membered cycloalkyl group or a 5-8 membered heterocycloalkyl group containing 1-3 heteroatoms and C 6-8 Aryl fusion, the C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered cycloalkyl, C 6-8 The aryl or fused ring may be selectively capped with 1-3 Rs. 3b Replaced by, R 3b As defined in Equation I.

[0021] In other embodiments, in the compound of Formula I or its pharmaceutically acceptable salt, ring B is selected from 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocycloalkyl containing 1-3 heteroatoms, and 6-membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocycloalkyl containing 1-3 heteroatoms, and 6-membered heterocycloalkyl containing 1-3 heteroatoms is independently and optionally selected from one or more elements selected from hydrogen, deuterium, halogen, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered cycloalkyl and C 6-8 The aryl group is substituted, and / or the 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocycloalkyl containing 1-3 heteroatoms or 6-membered heterocycloalkyl containing 1-3 heteroatoms and C 6-8 Aryl fusion, the C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered cycloalkyl, C 6-8 The aryl or fused ring may be selectively capped with 1-3 Rs. 3b Replaced by, R 3b As defined in Equation I.

[0022] In other embodiments, in the compound of Formula I or a pharmaceutically acceptable salt thereof, ring B is selected from 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocycloalkyl containing one heteroatom, and 6-membered heterocycloalkyl containing one heteroatom, wherein each of the 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocycloalkyl containing one heteroatom, and 6-membered heterocycloalkyl containing one heteroatom is independently optionally selected from one or more elements selected from hydrogen, deuterium, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, C 6-8 The aryl group is substituted, and / or the 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocycloalkyl containing 1-3 heteroatoms or 6-membered heterocycloalkyl containing 1-3 heteroatoms and C 6-8 Aryl fusion, the C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered cycloalkyl, C 6-8The aryl or fused ring may be selectively capped with 1-3 Rs. 3b Replaced by, R 3b As defined in Equation I.

[0023] In other embodiments, in the compound of Formula I or a pharmaceutically acceptable salt thereof, ring B is selected from 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocycloalkyl containing one heteroatom, and 6-membered heterocycloalkyl containing one heteroatom, wherein each of the 5-membered cycloalkyl, 6-membered cycloalkyl, and 6-membered heterocycloalkyl containing one heteroatom is independently optionally selected from one or more elements selected from hydrogen, deuterium, halogen, oxo, C. 1-6 Alkyl, C 1-6 Substituents of alkoxy groups, and / or the 5-membered cycloalkyl, 6-membered cycloalkyl, or 6-membered heterocycloalkyl containing 1-3 heteroatoms and C 6-8 Aryl fusion; The five-membered heterocyclic alkyl group containing one heteroatom is optionally composed of one or more elements selected from hydrogen, deuterium, halogen, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, C 6-8 The aryl group is substituted by a substituent; The C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered cycloalkyl, C 6-8 The aryl or fused ring may be selectively capped with 1-3 Rs. 3b Replaced by, R 3b As defined in Equation I.

[0024] Secondly, this disclosure provides a compound as shown in Formula VII or a pharmaceutically acceptable salt thereof. VII in Ring B is a 5-8 membered cycloalkyl group or a 5-8 membered heterocycloalkyl group containing 1-3 heteroatoms; Each R4 group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-8 The C group is substituted with aryl, 5-8 heteroaryl groups with 1-3 heteroatoms, and cycloalkoxy groups. 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-8 aryl, 5-8 heteroaryl with 1-3 heteroatoms, optionally surrounded by 1-3 R 3b Replaced; r is selected from an integer between 0 and 3, preferably r is selected from an integer between 0 and 2, and more preferably r is an integer of 0 or 1; R1, n, ring A and R 3b As defined in Equation I.

[0025] In some embodiments, in the compound of formula VII or its pharmaceutically acceptable salt, ring B is a 5-8 membered cycloalkyl group; Each R4 group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-8 The C group is substituted with aryl, 5-8 heteroaryl groups with 1-3 heteroatoms, and cycloalkoxy groups. 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-8 aryl, 5-8 heteroaryl with 1-3 heteroatoms, optionally surrounded by 1-3 R 3b Replaced; R1, n, ring A and R 3b As defined in Equation I.

[0026] In some embodiments, in the compound of formula VII or its pharmaceutically acceptable salt, ring B is a 5-8 membered heterocyclic alkyl group containing 1-3 heteroatoms; Each R4 group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-8 The C group is substituted with aryl, 5-8 heteroaryl groups with 1-3 heteroatoms, and cycloalkoxy groups. 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-8 aryl, 5-8 heteroaryl with 1-3 heteroatoms, optionally surrounded by 1-3 R 3b Replaced; R1, n, ring A and R 3b As defined in Equation I.

[0027] In some embodiments, in the compound represented by Formula VII or a pharmaceutically acceptable salt thereof, each R4 is independently selected from hydrogen, deuterium, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-8 The C group is substituted with aryl, 5-8 heteroaryl groups with 1-3 heteroatoms, and 3-10 cycloalkoxy groups.1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C 6-8 aryl, 5-8 heteroaryl with 1-3 heteroatoms, optionally surrounded by 1-3 R 3b What it replaced.

[0028] In some embodiments, in the compound represented by Formula VII or a pharmaceutically acceptable salt thereof, each R4 is independently selected from hydrogen, deuterium, oxo, C 1-6 The C group is substituted by alkyl or phenyl substituents. 1-6 Alkyl or phenyl groups may be optionally surrounded by 1-3 R groups. 3b What it replaced.

[0029] In some embodiments, in the compound represented by Formula VII or its pharmaceutically acceptable salt, each R4 is independently selected from those substituted with hydrogen, deuterium, oxo, methyl, or phenyl substituents, wherein C 1-6 Alkyl or phenyl groups may be optionally surrounded by 1-3 R groups. 3b Replaced; preferably R4 is replaced by 1-3 R 3b The substituted phenyl group. In some embodiments, the compound represented by formula VII or a pharmaceutically acceptable salt thereof, wherein the compound represented by VII is selected from the following formula... ; R1, n, ring A, R4 and R 3b As defined in equation VII.

[0030] In other embodiments, the compound represented by formula VII or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula VII is selected from the following formula ; R1, n, ring A, R4 and R 3b As defined in equation VII.

[0031] Thirdly, this disclosure also provides compounds of formula VI or pharmaceutically acceptable salts thereof. VI X1 and X2 are each independently selected from single bonds, -C(R) 3b )2-O-、-C(R 3b )2- C(R 3b )2-、-OC(R 3b )2-、-C(R 3b )2-, oxygen atom and -NR 3b -, where at least one of X1 and X2 is -C(R) 3b )2-; The ring C is selected from phenyl, naphthyl, and 5-8-membered heteroaryl groups containing 1-3 heteroatoms, wherein the phenyl, naphthyl, and 5-8-membered heteroaryl groups containing 1-3 heteroatoms are each independently and optionally surrounded by 1-3 R atoms. 3b Replaced; and R1, n, ring A and R 3b As defined in Equation I.

[0032] Fourthly, this disclosure also provides compounds of formulas VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, and VI-i, or pharmaceutically acceptable salts thereof. and in The ring C is selected from phenyl, naphthyl, and 5-8-membered heteroaryl groups containing 1-3 heteroatoms, wherein the phenyl, naphthyl, and 5-8-membered heteroaryl groups containing 1-3 heteroatoms are each independently and optionally surrounded by 1-3 R atoms. 3b Replaced; and R1, n, ring A and R 3b As defined in Equation I.

[0033] Fifthly, this disclosure also provides compounds of formula II or pharmaceutically acceptable salts thereof. II in X1 and X2 are each independently selected from -C(R 3b )2-, oxygen atom and -NR 3b -, where at least one of X1 and X2 is -C(R) 3b )2-; The ring C is selected from phenyl, naphthyl, and 5-8-membered heteroaryl groups containing 1-3 heteroatoms, wherein the phenyl, naphthyl, and 5-8-membered heteroaryl groups containing 1-3 heteroatoms are optionally surrounded by 1-3 R atoms. 3b Replaced; and R1, n, ring A and R 3b As defined in Formula I. In some embodiments, in the compounds of Formula I, II, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, and VII, or pharmaceutically acceptable salts thereof, ring A is selected from 3-15-membered heterocyclic alkyl, 3-10-heteroaryl, and C. 6-8 Aryl, the 3-15 membered heterocyclic alkyl, 3-10 heteroaryl and C 6-8Each aryl group is independently and optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, acyl, amide, oxo, alkyl, and alkoxy; each of the alkyl and alkoxy groups is independently and optionally substituted by one or more R groups. 3a Replaced by, R 3a As defined in Equation I.

[0034] In other embodiments, in the compounds of formulas I, II, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, and VII, or pharmaceutically acceptable salts thereof, ring A is selected from 3-15-membered heterocyclic alkyl groups, 3-10-membered heteroaryl groups, and C... 6-8 Aryl, the 3-15 membered heterocyclic alkyl, 3-10 heteroaryl and C 6-8 Each aryl group is independently and optionally selected from one or more groups chosen from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted; the C 1-6 Alkyl and C 1-6 Alkoxy groups are optionally surrounded by one or more R groups. 3a Replaced by, R 3a As defined in Equation I.

[0035] In other embodiments, in compounds of formulas I, II, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, and VII, or pharmaceutically acceptable salts thereof, ring A is selected from 3-15 membered heterocyclic alkyl groups containing 1-3 heteroatoms, 3-10 heteroaryl groups containing 1-3 heteroatoms, and C 6-8 Aryl, the 1-3 heteroatom 3-15 membered heterocyclic alkyl, comprising 1-3 heteroatoms 3-10 heteroaryl and C 6-8 Each aryl group is independently and optionally selected from one or more groups chosen from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, C 1-6 Alkyl and C 1-6 The alkoxy group is substituted; the C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally influenced by one or more R groups. 3a Replaced by, R 3a As defined in Equation I.

[0036] In other embodiments, in the compounds of formulas I, II, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, and VII, or their pharmaceutically acceptable salts, ring A is a 3-15 membered heterocyclic alkyl group comprising 1-3 heteroatoms, wherein the 1-3 heteroatoms 3-15 membered heterocyclic alkyl group is optionally composed of one or more elements selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, C 1-6 Alkyl and C 1-6 The alkoxy group is substituted; the C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally surrounded by 1-3 R groups. 3a Replaced by, R 3a As defined in Equation I.

[0037] In other embodiments, in the compounds of formulas I, II, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, and VII, or their pharmaceutically acceptable salts, ring A is a 3-10 membered heterocyclic alkyl group comprising 1-3 heteroatoms, wherein the 1-3 heteroatoms 3-10 membered heterocyclic alkyl group is optionally composed of one or more elements selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, C 1-6 Alkyl and C 1-6 The alkoxy group is substituted; the C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally surrounded by 1-3 R groups. 3a Replaced by, R 3a As defined in Equation I.

[0038] In other embodiments, in the compounds of formulas I, II, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, and VII, or their pharmaceutically acceptable salts, ring A is a 3-10 membered heterocyclic alkyl group comprising 1-3 heteroatoms, wherein the 1-3 heteroatoms 3-10 membered heterocyclic alkyl group is optionally composed of one or more elements selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl and C 1-6 The alkoxy group is substituted; the C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally surrounded by 1-3 R groups. 3a Replaced by, R 3a As defined in Equation I.

[0039] In this disclosure, the aforementioned heteroatoms are selected from nitrogen atoms, oxygen atoms, and sulfur atoms; preferably nitrogen atoms or oxygen atoms.

[0040] In some embodiments, in the compounds of formula I, II, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, and VII, or their pharmaceutically acceptable salts, ring A is optionally composed of one or more elements selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl and C 1-6 Substituents of alkoxy groups or ; The C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally surrounded by 1-3 R groups. 3a Replaced by, R 3a As defined in Equation I.

[0041] In other embodiments, in the compounds of formulas I, II, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, and VII, or their pharmaceutically acceptable salts, ring A is optionally composed of one or more elements selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl and C 1-6 Substituents of alkoxy groups or ; The C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally surrounded by 1-3 R groups. 3a Replaced by, R 3a As defined in Equation I.

[0042] In other embodiments, in the compounds of formulas I, II, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, and VII, or their pharmaceutically acceptable salts, ring A is optionally composed of one or more elements selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl and C 1-6 Substituents of alkoxy groups ; The C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally surrounded by 1-3 R groups. 3a Replaced by, R 3a As defined in Equation I.

[0043] In other embodiments, in the compounds of formula I, II, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, and VII, or their pharmaceutically acceptable salts, A is... .

[0044] In other embodiments, in the compounds of formulas I, II, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, and VII, or their pharmaceutically acceptable salts, ring A is optionally composed of one or more elements selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl and C 1-6 Substituents of alkoxy groups ; The C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally surrounded by 1-3 R groups. 3a Replaced by, R 3a As defined in Equation I; In other embodiments, in the compounds of formulas I, II, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, and VII, or their pharmaceutically acceptable salts, ring A is... .

[0045] In some embodiments, in the compounds of formulas I, II, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, and VII, or their pharmaceutically acceptable salts, ring A is optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and nitro. Preferably, A is optionally substituted with one or more substituents selected from hydrogen, deuterium, and halogens. .

[0046] In some embodiments, in the compounds of formula I, II, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, and VII, or pharmaceutically acceptable salts thereof, ring A is selected from compounds optionally substituted with one or more halogens. .

[0047] In a sixth aspect, this disclosure also provides a compound or a pharmaceutically acceptable salt thereof represented by formula VI-a', VI-b', VI-c', VI-d', VI-e', VI-f', VI-g', VI-h', or VI-i'. and in Each R2 is independently selected from halogen, nitro, cyano, amino, oxo, and hydroxyl groups; m is selected from integers between 0 and 3, preferably m is 0; and R1, n, ring C and R 3b As defined in equation VI-a.

[0048] In a seventh aspect, this disclosure also provides a compound or a pharmaceutically acceptable salt thereof represented by formula VI-a'', formula VI-b'', formula VI-c'', formula VI-d'', formula VI-e'', formula VI-f'', formula VI-g'', formula VI-h'', or formula VI-i''. and in Each R2 is independently selected from halogen, nitro, cyano, amino, oxo, and hydroxyl groups; m is selected from integers between 0 and 3, preferably m is 0; and R1, n, ring C and R 3b As defined in VI-a.

[0049] Eighthly, this disclosure also provides a compound of formula III or a pharmaceutically acceptable salt thereof. III R1, n, X1, X2 and ring C are defined as in Equation I or Equation II.

[0050] Ninthly, this disclosure also provides a compound of formula IV or a pharmaceutically acceptable salt thereof. IV R1, n, X1, X2 and ring C are defined as in Equation I or Equation II.

[0051] In a tenth aspect, this disclosure also provides a compound of formula V or a pharmaceutically acceptable salt thereof. V R1, n, X1, X2 and ring C are defined as in Equation I or Equation II.

[0052] In some embodiments, the compounds shown in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c, Formula VI-d, Formula VI-e, Formula VI-f, Formula VI-g, Formula VI-h, Formula VI-i, Formula VI-a', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', Formula VI-a'', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', and Formula VII, or their pharmaceutically acceptable salts, wherein R1 is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 alkoxy group; R1 can also be selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 alkoxy group; R1 can also be selected from hydrogen, deuterium, halogen, hydroxyl group, C 1-6 Alkyl and C 3-6 cycloalkyl; R1 can also be selected from hydrogen, deuterium, halogen, hydroxyl and C. 1-6 Alkyl; R1 can also be selected from hydrogen, deuterium and halogen.

[0053] In some embodiments, in the compounds of formula I, II, III, IV, V, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-a', VI-b', VI-c', VI-d', VI-e', VI-f', VI-g', VI-h', VI-i', VI-a'', VI-b'', VI-c'', VI-d'', VI-e'', VI-f'', VI-g'', VI-h'', VI-i'', and VII, or their pharmaceutically acceptable salts, R1 is selected from hydrogen, halogen, nitro, and cyano; preferably, R1 is a halogen; more preferably, R1 is fluorine.

[0054] In some embodiments, in the compounds of formula I, II, III, IV, V, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-a', VI-b', VI-c', VI-d', VI-e', VI-f', VI-g', VI-h', VI-i', VI-a'', VI-b'', VI-c'', VI-d'', VI-e'', VI-f'', VI-g'', VI-h'', VI-i'', and VII, or their pharmaceutically acceptable salts, the n is selected from an integer from 0 to 2; preferably, n is selected from an integer from 1 to 2.

[0055] In some embodiments, in compounds of formulas I, II, III, IV, V, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-a', VI-b', VI-c', VI-d', VI-e', VI-f', VI-g', VI-h', VI-i', VI-a'', VI-b'', VI-c'', VI-d'', VI-e'', VI-f'', VI-g'', VI-h'', VI-i'', VII, or pharmaceutically acceptable salts thereof, the ring C is selected from phenyl, thiazolyl, and pyridinyl, each of which is independently optionally surrounded by 1-3 R... 3b What it replaced.

[0056] In some embodiments, the compound represented by formulas I, II, III, IV, V, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-a', VI-b', VI-c', VI-d', VI-e', VI-f', VI-g', VI-h', VI-i', VI-a'', VI-b'', VI-c'', VI-d'', VI-e'', VI-f'', VI-g'', VI-h'', VI-i'', VI-a'', VI-b'', VI-c'', VI-d'', VI-e'', VI-f'', VI-g'', VI-h'', VI-i'', or a pharmaceutically acceptable salt thereof, wherein the ring C is selected from phenyl, and The phenyl, and Each can be independently selected by 1-3 Rs. 3b What it replaced.

[0057] In some embodiments, in the compounds of formulas I, II, III, IV, V, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-a', VI-b', VI-c', VI-d', VI-e', VI-f', VI-g', VI-h', VI-i', VI-a'', VI-b'', VI-c'', VI-d'', VI-e'', VI-f'', VI-g'', VI-h'', VI-i'', or pharmaceutically acceptable salts thereof, the ring C is phenyl, and the phenyl group is optionally surrounded by 1-3 R... 3b What it replaced.

[0058] In some embodiments, in the compounds of formulas I, II, III, IV, V, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-a', VI-b', VI-c', VI-d', VI-e', VI-f', VI-g', VI-h', VI-i', VI-a'', VI-b'', VI-c'', VI-d'', VI-e'', VI-f'', VI-g'', VI-h'', VI-i'', or pharmaceutically acceptable salts thereof, the ring C is The Choose 1-3 Rs 3b What it replaced.

[0059] In some embodiments, in the compounds of formulas I, II, III, IV, V, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-a', VI-b', VI-c', VI-d', VI-e', VI-f', VI-g', VI-h', VI-i', VI-a'', VI-b'', VI-c'', VI-d'', VI-e'', VI-f'', VI-g'', VI-h'', VI-i'', or pharmaceutically acceptable salts thereof, the ring C is The Choose 1-3 Rs 3b What it replaced.

[0060] In some embodiments, each R in the compound shown in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c, Formula VI-d, Formula VI-e, Formula VI-f, Formula VI-g, Formula VI-h, Formula VI-i, Formula VI-a', Formula VI-b', Formula VI-c', Formula VI-d', Formula VI-e', Formula VI-f', Formula VI-g', Formula VI-h', Formula VI-i', Formula VI-a'', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', Formula VII, or a pharmaceutically acceptable salt thereof, 3a It is independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl and amide.

[0061] In some embodiments, each R in the compound shown in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c, Formula VI-d, Formula VI-e, Formula VI-f, Formula VI-g, Formula VI-h, Formula VI-i, Formula VI-a', Formula VI-b', Formula VI-c', Formula VI-d', Formula VI-e', Formula VI-f', Formula VI-g', Formula VI-h', Formula VI-i', Formula VI-a'', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', Formula VII, or a pharmaceutically acceptable salt thereof, 3a It is independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano and amino.

[0062] In some embodiments, each R in the compound shown in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c, Formula VI-d, Formula VI-e, Formula VI-f, Formula VI-g, Formula VI-h, Formula VI-i, Formula VI-a', Formula VI-b', Formula VI-c', Formula VI-d', Formula VI-e', Formula VI-f', Formula VI-g', Formula VI-h', Formula VI-i', Formula VI-a'', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', Formula VII, or a pharmaceutically acceptable salt thereof, 3a Selected independently from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8Cycloalkenyloxy, 5- to 6-membered aryl and heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy group and the 5- to 6-membered aryl heteroaryl group are each independently and optionally replaced by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro and cyano groups.

[0063] In some embodiments, each R in the compound shown in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c, Formula VI-d, Formula VI-e, Formula VI-f, Formula VI-g, Formula VI-h, Formula VI-i, Formula VI-a', Formula VI-b', Formula VI-c', Formula VI-d', Formula VI-e', Formula VI-f', Formula VI-g', Formula VI-h', Formula VI-i', Formula VI-a'', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', Formula VII, or a pharmaceutically acceptable salt thereof, 3a Selected independently from C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, 5- to 6-membered aryl and heteroaryl, wherein C 1-6 Alkoxy, C 3-6 The cycloalkoxy group, the 3- to 6-membered heterocycloalkoxy group, the 5- to 6-membered aryl group, and the heteroaryl group are each independently and optionally substituted by 1 to 3 substituents selected from fluorine, chlorine, deuterium, hydroxyl, oxo, nitro, and cyano.

[0064] In some embodiments, each R in the compound shown in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c, Formula VI-d, Formula VI-e, Formula VI-f, Formula VI-g, Formula VI-h, Formula VI-i, Formula VI-a', Formula VI-b', Formula VI-c', Formula VI-d', Formula VI-e', Formula VI-f', Formula VI-g', Formula VI-h', Formula VI-i', Formula VI-a'', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', Formula VII, or a pharmaceutically acceptable salt thereof, 3a Independently selected from hydrogen, fluorine, chlorine, deuterium, oxo (=O), hydroxyl, amino, methoxy, cyclopropoxy, cyclopropyl, cyclopentyl, pyridyl, piperidinyl, and phenyl, preferably R. 3a It is hydrogen or amino.

[0065] In some embodiments, each R in the compound shown in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c, Formula VI-d, Formula VI-e, Formula VI-f, Formula VI-g, Formula VI-h, Formula VI-i, Formula VI-a', Formula VI-b', Formula VI-c', Formula VI-d', Formula VI-e', Formula VI-f', Formula VI-g', Formula VI-h', Formula VI-i', Formula VI-a'', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', Formula VII, or a pharmaceutically acceptable salt thereof, 3b Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, and amino; preferably R 3b It is either halogen or cyano.

[0066] In some embodiments, in compounds of formulas I, II, III, IV, V, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-a', VI-b', VI-c', VI-d', VI-e', VI-f', VI-g', VI-h', VI-i', VI-a'', VI-b'', VI-c'', VI-d'', VI-e'', VI-f'', VI-g'', VI-h'', VI-i'', VII, or pharmaceutically acceptable salts thereof, R 3b It is a 3- to 6-membered heterocyclic alkyl group; the 3- to 6-membered heterocyclic alkyl group may be replaced by 1 to 3 substituents selected from halogen, cyano and hydroxyl groups.

[0067] In some embodiments, each R in the compound shown in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c, Formula VI-d, Formula VI-e, Formula VI-f, Formula VI-g, Formula VI-h, Formula VI-i, Formula VI-a', Formula VI-b', Formula VI-c', Formula VI-d', Formula VI-e', Formula VI-f', Formula VI-g', Formula VI-h', Formula VI-i', Formula VI-a'', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', Formula VII, or a pharmaceutically acceptable salt thereof, 3b Independently selected from hydrogen, halogen, deuterium, cyano, 3- to 6-membered heterocyclic alkyl, methanesulfonyl, and Preferably, 3 to 6-membered heterocyclic alkyl groups are selected from... , , and .

[0068] In some embodiments, each R in the compound shown in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c, Formula VI-d, Formula VI-e, Formula VI-f, Formula VI-g, Formula VI-h, Formula VI-i, Formula VI-a', Formula VI-b', Formula VI-c', Formula VI-d', Formula VI-e', Formula VI-f', Formula VI-g', Formula VI-h', Formula VI-i', Formula VI-a'', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', Formula VII, or a pharmaceutically acceptable salt thereof, 3b Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, amide, methanesulfonyl and .

[0069] In some embodiments, each R in the compound shown in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c, Formula VI-d, Formula VI-e, Formula VI-f, Formula VI-g, Formula VI-h, Formula VI-i, Formula VI-a', Formula VI-b', Formula VI-c', Formula VI-d', Formula VI-e', Formula VI-f', Formula VI-g', Formula VI-h', Formula VI-i', Formula VI-a'', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', Formula VII, or a pharmaceutically acceptable salt thereof, 3b Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, amide, acetyl, methanesulfonyl, and .

[0070] In some embodiments, each R in the compound shown in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c, Formula VI-d, Formula VI-e, Formula VI-f, Formula VI-g, Formula VI-h, Formula VI-i, Formula VI-a', Formula VI-b', Formula VI-c', Formula VI-d', Formula VI-e', Formula VI-f', Formula VI-g', Formula VI-h', Formula VI-i', Formula VI-a'', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', Formula VII, or a pharmaceutically acceptable salt thereof, 3b Independently selected from cyano, methanesulfonyl and Preferred R 3b It is a cyano group.

[0071] In some embodiments, each R of the compound shown in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c, Formula VI-d, Formula VI-e, Formula VI-f, Formula VI-g, Formula VI-h, Formula VI-i, Formula VI-a', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', Formula VI-a'', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', Formula VII, or a pharmaceutically acceptable salt thereof 3b It is independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, and amide.

[0072] In some embodiments, each R in the compound shown in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c, Formula VI-d, Formula VI-e, Formula VI-f, Formula VI-g, Formula VI-h, Formula VI-i, Formula VI-a', Formula VI-b', Formula VI-c', Formula VI-d', Formula VI-e', Formula VI-f', Formula VI-g', Formula VI-h', Formula VI-i', Formula VI-a'', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', Formula VII, or a pharmaceutically acceptable salt thereof, 3b Selected independently from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy group, phenyl group, and 5- to 6-membered heteroaryl group are each independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups.

[0073] In some embodiments, each R in the compound shown in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c, Formula VI-d, Formula VI-e, Formula VI-f, Formula VI-g, Formula VI-h, Formula VI-i, Formula VI-a', Formula VI-b', Formula VI-c', Formula VI-d', Formula VI-e', Formula VI-f', Formula VI-g', Formula VI-h', Formula VI-i', Formula VI-a'', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', Formula VII, or a pharmaceutically acceptable salt thereof, 3b Selected independently from C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, 5- to 6-membered aryl and heteroaryl, wherein C 1-6 Alkoxy, C 3-6 The cycloalkoxy group, the 3- to 6-membered heterocycloalkoxy group, the 5- to 6-membered aryl group, and the heteroaryl group are each independently and optionally substituted by 1 to 3 substituents selected from fluorine, chlorine, deuterium, hydroxyl, oxo, nitro, and cyano.

[0074] In some embodiments, each R in the compound shown in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c, Formula VI-d, Formula VI-e, Formula VI-f, Formula VI-g, Formula VI-h, Formula VI-i, Formula VI-a', Formula VI-b', Formula VI-c', Formula VI-d', Formula VI-e', Formula VI-f', Formula VI-g', Formula VI-h', Formula VI-i', Formula VI-a'', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', Formula VII, or a pharmaceutically acceptable salt thereof, 3b Independently selected from halogens, cyano groups, formamides, , 3 to 6-membered heterocyclic alkyl groups and deuterium.

[0075] In some embodiments, each R in the compound shown in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c, Formula VI-d, Formula VI-e, Formula VI-f, Formula VI-g, Formula VI-h, Formula VI-i, Formula VI-a', Formula VI-b', Formula VI-c', Formula VI-d', Formula VI-e', Formula VI-f', Formula VI-g', Formula VI-h', Formula VI-i', Formula VI-a'', Formula VI-b'', Formula VI-c'', Formula VI-d'', Formula VI-e'', Formula VI-f'', Formula VI-g'', Formula VI-h'', Formula VI-i'', Formula VII, or a pharmaceutically acceptable salt thereof, 3b Independently selected from hydrogen, fluorine, chlorine, deuterium, oxo (=O), hydroxyl, amino, methoxy, cyclopropoxy, cyclopropyl, cyclopentyl, pyridyl, piperidinyl, and phenyl, preferably R. 3b Selected from hydrogen, methyl, oxo, fluorine and chlorine.

[0076] In some embodiments, in compounds of formulas I, II, III, IV, V, VI, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-a', VI-b', VI-c', VI-d', VI-e', VI-f', VI-g', VI-h', VI-i', VI-a'', VI-b'', VI-c'', VI-d'', VI-e'', VI-f'', VI-g'', VI-h'', VI-i'', VII, or pharmaceutically acceptable salts thereof, R 3b C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 The alkoxy group may be optionally replaced by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro and cyano.

[0077] In some embodiments, in the compound of formula VII or its pharmaceutically acceptable salt, R 3b The phenyl group is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro and cyano groups.

[0078] In an eleventh aspect, this disclosure also provides typical compounds of Formula I or pharmaceutically acceptable salts thereof, including but not limited to: .

[0079] In a twelfth aspect, this disclosure also provides typical compounds of Formula I or pharmaceutically acceptable salts thereof, including but not limited to: .

[0080] In a thirteenth aspect, this disclosure also provides typical compounds of Formula I or pharmaceutically acceptable salts thereof, including but not limited to: .

[0081] In a fourteenth aspect, this disclosure also provides isotopic substitutes of the compounds shown in the first to twelfth aspects or pharmaceutically acceptable salts thereof, preferably, the isotopic substitutions being deuterium-substituted substitutes.

[0082] In a fifteenth aspect, this disclosure also provides a pharmaceutical composition comprising at least a therapeutically effective amount of a compound as shown in the first to thirteenth aspects or a pharmaceutically acceptable salt thereof, or an isotopic substitute as shown in the fourteenth aspect, and a pharmaceutically acceptable excipient.

[0083] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0084] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0086] This disclosure also provides a method for preventing and / or treating a patient with a cathepsin C-related condition, comprising administering to the patient a therapeutically effective amount of a compound as described in the first to thirteenth aspects or a pharmaceutically acceptable salt thereof, or an isotope substitute as described in the fourteenth aspect, or a pharmaceutical composition thereof.

[0087] In some implementations, the cathepsin C-related conditions include, but are not limited to, respiratory diseases such as asthma, obstructive pulmonary disease, bronchiectasis, and autoimmune diseases such as ANCA-associated vasculitis, psoriasis, α1-antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, or rheumatoid arthritis.

[0088] This disclosure also provides a method for preventing and / or treating a patient with asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, α1-antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, or rheumatoid arthritis, comprising administering to the patient a therapeutically effective amount of a compound as described in the first to thirteenth aspects or a pharmaceutically acceptable salt thereof, or an isotope substitute as described in the fourteenth aspect, or a pharmaceutical composition thereof.

[0089] This disclosure also provides the use of compounds as described in the first through thirteenth aspects or pharmaceutically acceptable salts thereof, or isotopic substitutes as described in the fourteenth aspect, or the aforementioned pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment of conditions related to cathepsin C.

[0090] This disclosure also provides the use of the compounds described in the first to thirteenth aspects or their pharmaceutically acceptable salts, or the isotopic substitutes described in the fourteenth aspect, or the aforementioned pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, α1-antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, or rheumatoid arthritis.

[0091] This disclosure also provides a compound as described in the first to thirteenth aspects, or a pharmaceutically acceptable salt thereof, or an isotope substitute as described in the fourteenth aspect, or a pharmaceutical composition thereof, for use as a medicine.

[0092] This disclosure also provides the use of the compound as described in the first to thirteenth aspects or a pharmaceutically acceptable salt thereof, or an isotope substitute as described in the fourteenth aspect, or the aforementioned pharmaceutical composition, for the prevention and / or treatment of patients with cathepsin C-related conditions.

[0093] This disclosure also provides the use of the compounds described in the first to thirteenth aspects or their pharmaceutically acceptable salts, or the isotope substitutes described in the fourteenth aspect, or the aforementioned pharmaceutical compositions, for the prevention and / or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, α1-antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, or rheumatoid arthritis.

[0094] This disclosure also provides a compound or intermediate of the following formula. Among them, R1, n, ring C and R 3b As defined in equation IV.

[0095] This disclosure also provides a compound or intermediate of the following formula. Among them, R1, n, ring C and R 3b As defined in equation IV.

[0096] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0097] The compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0098] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0099] In the chemical structure of the compounds described in this disclosure, the bond " "" indicates that the configuration is not specified, meaning that if a chiral isomer exists in the chemical structure, the bond " "can be " "or" , or both contain " "and" "Two configurations."

[0100] The compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine, lactam-lactamimide isomerization. Examples of lactam-lactamimide equilibria are between A and B as shown below. All compounds in this disclosure can be classified as type A or type B. All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0101] This disclosure also includes compounds identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, 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, etc.

[0102] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium doping). The natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or higher. This disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds of formula (I) with reference to relevant literature. Commercially available deuterated starting materials can be used to prepare the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0103] "Optional" or "optional" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0104] Terminology Explanation: "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0105] "Pharmaceutical excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0106] The term "effective amount" or "effective therapeutic amount" as used in this disclosure includes an amount sufficient to improve or prevent symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0107] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms are also included. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and their various branched isomers. Alkyl groups can be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point, preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy group, phenyl group, and 5- to 6-membered heteroaryl group are each independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups.

[0108] "Alkenyl" includes branched and straight-chain alkenes having 2 to 12 carbon atoms or alkenes containing aliphatic hydrocarbon groups. For example, "C 2-6"Alkenyl" refers to an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl, and 4-hexenyl. Alkenyl groups can be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy group, phenyl group, and 5- to 6-membered heteroaryl group are each independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups.

[0109] "Alynyl" includes branched and straight-chain alkynyl groups having 2 to 12 carbon atoms, or alkenes containing aliphatic hydrocarbon groups, or, if a specific number of carbon atoms is specified, that specific number. Examples include ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentyynyl, hexynyl, and 1-methylpentan-2-ynyl. The alkynyl group can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable linking point, preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy group, phenyl group, and 5- to 6-membered heteroaryl group are each independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups.

[0110] The term "cycloalkyl" or "carbocyclic" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. Cycloalkyl groups can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy group, phenyl group, and 5- to 6-membered heteroaryl group are each independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups.

[0111] The cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy group, phenyl group, and 5- to 6-membered heteroaryl group are each independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups.

[0112] The term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkenyl ring contains 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl, or cyclohexadienyl. The cycloalkenyl group can be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy group, phenyl group, and 5- to 6-membered heteroaryl group are each independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups.

[0113] The terms "heterocyclic alkyl" or "heterocyclic group" refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 15 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 10 ring atoms, and even more preferably, it contains 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclic alkyl groups include pyrrolidinyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic alkyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclic alkyl groups. Non-limiting examples of "heterocyclic alkyl" include: , , , ,etc.

[0114] The heterocyclic alkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocyclic alkyl ring, and non-limiting examples include: and wait.

[0115] Heterocyclic alkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl groups, oxo groups, nitro groups, cyano groups, and C4 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy group, phenyl group, and 5- to 6-membered heteroaryl group are each independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups.

[0116] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include: and ; The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy group, phenyl group, and 5- to 6-membered heteroaryl group are each independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups.

[0117] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 3 to 10-membered, more preferably 5 to 8-membered or 3 to 6-membered, and even more preferably 5-membered or 6-membered. For example, non-limiting examples include: imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, and pyrazine. , , ,etc.

[0118] The heteroaryl ring may be fused to an aryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include: and .

[0119] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy group, phenyl group, and 5- to 6-membered heteroaryl group are each independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups.

[0120] The term "alkoxy" refers to -O- (alkyl) and -O- (cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy. Alkoxy groups can be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryl groups are each independently and optionally substituted by one or more substituents selected from halogens, deuterium, hydroxyl, oxo, nitro, and cyano. Similarly, the definitions of "alkynyloxy", "alkenyloxy", "cycloalkoxy", "heterocycloalkoxy", and "cycloalkenyloxy" are the same as those for "alkoxy" above.

[0121] The term "hydroxyl group" refers to the -OH group.

[0122] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0123] The term "cyano" refers to -CN.

[0124] The term "nitro" refers to -NO2.

[0125] The term "oxo" refers to the =O substituent.

[0126] The term "amide" refers to R is selected from C 1-6 Alkyl groups, including but not limited to methyl, ethyl, propyl, etc.

[0127] A "monovalent group" refers to a compound in which one monovalent atom or group is "formally" eliminated. A "subgroup" refers to a compound in which two monovalent or one divalent atom or group is "formally" eliminated. For example, "alkyl" refers to the portion remaining after removing one hydrogen atom from an alkane molecule, including straight-chain and branched monovalent groups with 1 to 20 carbon atoms. "alkylene (-CH2-)" refers to the portion remaining after removing two hydrogen atoms from an alkane molecule, including straight-chain and branched subgroups with 1 to 20 carbon atoms. Alkylenes containing 1 to 6 carbon atoms, non-limiting examples include methylene (-CH2-), ethylene (such as -CH2CH2- or -CH(CH3)-), propylene (such as -CH2CH2CH2- or -CH(CH2CH3)-), and butylene (such as -CH2CH2CH2CH2-). The alkylene group can be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy group, phenyl group, and 5- to 6-membered heteroaryl group are each independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups.

[0128] Similarly, the definitions of "alkeneoxy", "alkenyl", "alkenyloxy", "cycloalkylene", and "heterocyclic alkylene" are the same as those for "alkylene". Attached Figure Description

[0129] Figure 1 Percentage inhibition rates of compound 32, AZD7986, and solvent control against CatC downstream neutrophil elastase in neutrophils (***P<0.0001; *P<0.05; t-test; vs. solvent control; N=3; repeated measurements of enzyme activity; percentage inhibition shown above each column).

[0130] Figure 2Percentage inhibition rate of compound 14, AZD7986, and solvent control against CatC downstream neutrophil elastase in neutrophils (***P<0.0001; *P<0.05; t-test; vs. solvent control; N=5 repeated measurements of enzyme activity; percentage inhibition shown above each column). Detailed Implementation

[0131] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0132] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0133] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shift ( ) with 10 -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO) as the solvent. d 6 ), deuterated chloroform (CDCl3), deuterated methanol (Methanol- d 4 The internal standard is tetramethylsilane (TMS).

[0134] HPLC determination was performed using an Agilent 1100 high-performance liquid chromatograph, a GAS15B DAD UV detector, and a WaterVbridge C18 150*4.6mm 5µm column.

[0135] MS measurements were performed using an Agilent 6120 triple quadrupole mass spectrometer with a G1315D DAD detector and a Waters Xbridge C18 4.6*50mm, 5µm column, in positive / negative ion mode, with a mass scan range of 80–1200.

[0136] The silica gel plates used for thin-layer chromatography are Yantai Huanghai HSGF254 silica gel plates. The silica gel plates used for thin-layer chromatography (TLC) have a size of 0.2mm ± 0.03mm, and the size used for thin-layer chromatography separation and purification of products is 0.4mm-0.5mm.

[0137] Rapid column purification systems use either the Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

[0138] Normal column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh or 300~400 mesh as the carrier, or Changzhou Santai pre-filled ultrapure normal phase silica gel column (40-63μm, 60g, 24g, 40g, 120g or other specifications).

[0139] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Bid Pharmaceuticals.

[0140] Unless otherwise specified in the examples, all reactions can be carried out under a nitrogen atmosphere.

[0141] A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of approximately 1L.

[0142] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0143] Hydrogen was produced by the QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instruments Co., Ltd.

[0144] Nitrogen or hydrogen atmospheres are typically evacuated and then filled with nitrogen or hydrogen gas, and this process is repeated three times.

[0145] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0146] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0147] The reaction process in the examples was monitored using thin-layer chromatography (TLC).

[0148] Example 1 ( S )-4-amino- N -(1-Cyano-2-(1-oxy-2-phenylisoindole-5-yl)ethyl)tetrahydro-2 H pyran-4-carboxamide Synthesis of Compounds 1-2 Compound 1-1 (5 g, 23.70 mmol) and phenylboronic acid (5.80 g, 47.52 mmol) were dissolved in dichloromethane (100 mL) at room temperature. Triethylamine (7.20 g, 71.15 mmol) and copper acetate (8.60 g, 47.35 mmol) were then added, and the reaction mixture was heated under reflux and stirred for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, dichloromethane / methanol = 9 / 1) to give compound 1-2. MS-ESI: m / z 290.1 ​​[M+1] + .

[0149] Synthesis of compounds 1-3 Under nitrogen protection at room temperature, activated zinc powder (900 mg, 137.76 mmol) was added to anhydrous... N , N In dimethylformamide (5 mL), iodine (350 mg, 1.38 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. Then (… R Anhydrous methyl 2-(((tert-Butoxycarbonyl)amino)methyl-3-iodopropionate (1.50 g, 4.55 mmol) N , N A solution of dimethylformamide (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. Compounds 1-2 (1.70 g, 5.92 mmol), tris-(dibenzylacetone)dipalladium (105 mg, 0.11 mmol), and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (94 mg, 0.23 mmol) were added. The reaction mixture was heated to 60 °C and stirred for 3 hours. After the reaction was complete, water (10 mL) and ethyl acetate (50 mL) were added to the reaction mixture. The mixture was filtered, and the organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered again, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compounds 1-3. MS-ESI: m / z 411.2 [M+1] + .

[0150] Synthesis of compounds 1-4 Compounds 1-3 (1.50 g, 3.66 mmol) were dissolved in 15 mL of 7 M ammonia-methanol solution at room temperature, and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was concentrated under reduced pressure to give crude compounds 1-4, which were used directly in the next reaction. MS-ESI: m / z396.3 [M+1] + .

[0151] Synthesis of compounds 1-5 At room temperature, crude compounds 1-4 (1.00 g, 2.53 mmol) were dissolved in dichloromethane (30 mL), followed by the addition of Burgess reagent (970 mg, 4.06 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (100 mL), extracted with dichloromethane (250 mL × 2), washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, dichloromethane / methanol = 9 / 1) to obtain crude compounds 1-5, which were directly used in the next reaction. MS-ESI: m / z 378.2 [M+1] + .

[0152] Synthesis of compounds 1-6 At room temperature, crude compounds 1-5 (300 mg, 0.80 mmol) were dissolved in acetonitrile (5 mL), followed by the sequential addition of trimethylchlorosilane (358 mg, 3.29 mmol) and sodium iodide (262 mg, 1.75 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, methanol (5 mL) was added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain crude compounds 1-6, which were used directly in the next reaction. MS-ESI: m / z 278.2 [M+1] + .

[0153] Synthesis of compounds 1-7 At room temperature, crude compounds 1-6 (180 mg, 0.65 mmol) and 4-((tert-butoxycarbonyl)amino)tetrahydro-2-dihydrogenase were reacted. H -pyran-4-carboxylic acid (175 mg, 0.71 mmol) soluble in N,N Add benzotriazole to dimethylformamide (5 mL) and then add benzotriazole. N,N,N',N' -Tetramethylurea hexafluorophosphate (370 mg, 0.98 mmol) and N,N-Diisopropylethylamine (168 mg, 1.35 mmol), the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (50 mL × 3), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, dichloromethane / methanol = 9 / 1) to give compounds 1-7. MS-ESI: m / z 449.2 [M-56+1] + .

[0154] Synthesis of Compound 1 Compounds 1-7 (150 mg, 0.30 mmol) were dissolved in acetonitrile (10 mL) at room temperature, followed by the addition of trimethylchlorosilane (447 mg, 4.11 mmol) and sodium iodide (324 mg, 2.16 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, methanol (5 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was then extracted with saturated sodium bicarbonate solution (20 mL) and precipitated with dichloromethane (50 mL × 2). The extract was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Waters Xbridge C18, 250*19 mm, 10...). m; Mobile phase: water (0.1% ammonium bicarbonate), acetonitrile; Gradient ratio: acetonitrile phase 35-95%; Flow rate: 20 mL / min; Column temperature: room temperature) Compound 1 was separated. MS-ESI: m / z 405.2 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 8.30 (d, 1H), 7.91 (d, 1H), 7.86 (d, 2H), 7.50(s, 1H), 7.47-7.43 (m, 2H), 7.37 (d, 1H), 7.20 (t, 1H), 5.18-5.13 (m, 1H),4.88 (s, 2H), 3.94-3.87 (m, 2H), 3.64-3.56 (m, 2H), 3.24 (d, 2H), 2.34-2.26(m, 1H), 2.24-2.16 (m, 1H), 1.44 (s, 2H), 1.30-1.26 (m, 1H), 1.21-1.16 (m, 1H).

[0155] Intermediate 2-6 Synthesis of compound 2-2 At room temperature, ( S 2-((benzyloxy)methyl)ethylene oxide (compound 2-1) (49.70 g, 302.90 mmol) and 3-(benzylamino)prop-1-ol (50 g, 302.81 mmol) were dissolved in ethanol (500 mL). The reaction mixture was heated to 40 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, dichloromethane / methanol = 19 / 1) to give compound 2-2. MS-ESI: m / z 330.2 [M+1] + .

[0156] Synthesis of Compounds 2-3 At 0 °C, compound 2-2 (52 g, 157.96 mmol) and N,N Diisopropylethylamine (30.60 g, 236.77 mmol) was dissolved in dichloromethane (1000 mL), followed by the dropwise addition of methanesulfonyl chloride (18.10 g, 158.01 mmol). The reaction mixture was stirred at 0 °C for 30 minutes. After the reaction was complete, the reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (1000 mL), extracted with dichloromethane (500 mL × 3), and the organic phases were combined, washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compounds 2-3, which were directly used for the next reaction. MS-ESI: m / z 408.2 [M+1] + .

[0157] Synthesis of compounds 2-4 At 0 °C, crude compounds 2-3 (32 g, 78.59 mmol) were dissolved in tetrahydrofuran (500 mL), and sodium hydride (9.40 g, 235.90 mmol, 60%) was added in portions. The reaction mixture was stirred at room temperature for 16 hours. Sodium sulfate decahydrate was added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give compounds 2-4. MS-ESI: m / z 312.1 [M+1] + .

[0158] Synthesis of compounds 2-5 Compounds 2-4 (28 g, 89.98 mmol) were dissolved in methanol (200 mL) at room temperature, followed by the addition of palladium hydroxide on carbon (2.80 g, 10%). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 48 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in methanol (200 mL), and di-tert-butyl dicarbonate (27.90 g, 127.84 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The residue was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give compounds 2-5. MS-ESI: m / z 176.1 [M-56+1] + .

[0159] Synthesis of compounds 2-6 Compound 2-5 (17 g, 73.6 mmol) was dissolved in acetone (1000 mL) at 0 °C, followed by the addition of sodium bromide (2.30 g, 22.35 mmol), 2,2,6,6-tetramethylpiperidine oxide (1.20 g, 7.68 mmol), and a saturated aqueous solution of sodium bicarbonate (280 mL). The mixture was stirred at room temperature for 30 minutes, and then urea trichloroisocyanurate (37.60 g, 161.78 mmol) was added. The mixture was stirred at room temperature for another 16 hours. Isopropanol (50 mL) was added to the mixture, and the mixture was stirred for 30 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was extracted with water (300 mL) and dichloromethane (500 mL × 2). The organic phases were combined, washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 2-6, which was used directly in the next reaction. MS-ESI: m / z 190.1 [M-56+1] + . 1 H NMR (400 MHz, DMSO-) d 6 ): δ 12.71 (s, 1H), 4.20-4.17 (m, 1H), 3.96-3.79 (m, 2H), 3.65-3.54 (m, 2H), 3.48-3.42 (m, 1H), 3.18-3.07 (m, 1H), 1.71 (s, 2H), 1.40 (s, 9H).

[0160] Example 2 ( S )- N -(( S)-1-cyano-2-(1-oxo-2-phenylisoindol-5-yl)ethyl)-1,4-oxazineheptane-2-carboxamide Synthesis of compounds 2-7 At room temperature, ( S 2-Amino-3-(1-oxo-2-phenylisoindol-5-yl)propionitrile (compounds 1-6) (320 mg, 1.16 mmol) and compounds 2-6 (311 mg, 1.27 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of benzotriazole. N,N,N',N' -Tetramethylurea hexafluorophosphate (659 mg, 1.74 mmol) and N,N -Diisopropylethylamine (299 mg, 2.32 mmol), the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (30 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give compounds 2-7. MS-ESI: m / z 449.2 [M-56+1] + .

[0161] Synthesis of Compound 2 Compound 2-7 (200 mg, 0.39 mmol) was dissolved in acetonitrile (5 mL) at room temperature, followed by the addition of trimethylchlorosilane (179 mg, 1.65 mmol) and sodium iodide (130 mg, 0.87 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, methanol (5 mL) was added to the reaction solution, and the mixture was concentrated under reduced pressure. The residue was then extracted with saturated sodium bicarbonate aqueous solution (20 mL) using dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Waters Sunfire C18, 250*19 mm, 10). m; Mobile phase: water (0.1% formic acid), acetonitrile; Gradient ratio: acetonitrile phase 25-95%; Flow rate: 20 mL / min; Column temperature: room temperature) Compound 2 was separated. MS-ESI: m / z 405.2 [M+H] + . 1H NMR (400 MHz, DMSO- d 6 ) δ 8.87 (d, 1H), 7.92 (d, 2H), 7.74 (d,1H), 7.58 (s, 1H), 7.47-7.43 (m, 3H), 7.18 (t, 1H), 5.13-5.05 (m, 1H), 5.05-4.96 (m, 2H), 4.20 (dd, 1H), 3.92-3.82 (m, 1H), 3.80-3.71 (m, 1H), 3.30-3.26(m, 2H), 3.21-3.17 (m, 1H), 3.04-2.98 (m, 1H), 2.87-2.80 (m, 1H), 2.66 (dd,1H), 1.86-1.85 (m, 2H).

[0162] Example 3 (2 S )- N -(1-cyano-2-(5,6,7,8-tetrahydronaphth-2-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide trifluoroacetate Synthesis of compound 3-2 At room temperature, 5,6,7,8-tetrahydronaphthalene-2-ol (compound 3-1) (10 g, 67.53 mmol) was dissolved in dichloromethane (100 mL), and then added sequentially at 0°C. N , N -Diisopropylethylamine (21.80 g, 168.68 mmol) and trifluoromethanesulfonic anhydride (22.85 g, 80.99 mmol) were reacted and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, water (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (200 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude compound 3-2. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.26-7.19 (m, 1H), 7.16-7.14 (m, 2H), 2.76-2.74 (m, 4H), 1.74-1.71(m, 4H).

[0163] Synthesis of compound 3-3 Compound 3-2 (10 g, 35.59 mmol) was dissolved at room temperature in... N,N In a mixed solvent of dimethylformamide (50 mL) and methanol (150 mL), then add N,N -Diisopropylethylamine (9.23 g, 71.42 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (3.00 g, 4.10 mmol) were mixed and refluxed under a carbon monoxide atmosphere with stirring for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was extracted with water (100 mL) and ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 8 / 1) to give compound 3-3. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.69 -7.60 (m, 2H), 7.17 (d, 1H), 3.83 (s,3H), 2.87-2.75 (m, 4H), 1.75-1.72 (m, 4H).

[0164] Synthesis of compounds 3-4 Compound 3-3 (3.10 g, 16.31 mmol) was dissolved in tetrahydrofuran (50 mL) at 0 °C under nitrogen protection. Lithium aluminum hydride (928 mg, 24.45 mmol) was added in portions, and the reaction mixture was stirred at 0 °C for 3 hours. After the reaction was complete, water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 3-4. 1 H NMR (400 MHz, DMSO- d 6 ) δ7.03-6.97 (m, 3H), 5.03 (s, 1H), 4.49 (s, 2H), 2.68-2.67 (m, 4H), 1.73-1.70 (m, 4H).

[0165] Synthesis of compounds 3-5 Compounds 3-4 (1.60 g, 9.87 mmol) were dissolved in toluene (20 mL) at 0 °C, followed by the dropwise addition of phosphorus tribromide (4 g, 14.78 mmol). The reaction mixture was stirred at room temperature for 12 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 2), washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 49 / 1) to give compounds 3-5. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.15-7.10 (m, 2H), 7.02 (d, 1H), 4.63 (s, 2H), 2.72-2.62 (m, 4H), 1.77-1.66 (m, 4H).

[0166] Synthesis of compounds 3-6 Under nitrogen protection at 0°C, 1.40 g (6.26 mmol) of 2-((diphenylmethylene)amino)acetonitrile was dissolved in... N,N In dimethylformamide (20 mL), sodium hydride (500 mg, 12.50 mmol, 60%) was added, and the reaction mixture was stirred at 0 °C for 0.5 hours. Then, compound 3-5 (1.70 g, 7.58 mmol) was added. N,N A 5 mL solution of dimethylformamide was added, and the reaction mixture was stirred at 0 °C for 2 hours. After the reaction was complete, 50 mL of saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 2), washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate) to give compounds 3-6. MS-ESI: m / z 365.2 [M+1] + .

[0167] Synthesis of compounds 3-7 Compounds 3-6 (1.80 g, 4.94 mmol) were dissolved in dioxane (10 mL) at 0 °C, followed by the addition of 1 M hydrochloric acid (10 mL). The reaction mixture was stirred at 0 °C for 4 hours. After the reaction was complete, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude compound 3-7, which was used directly in the next reaction. MS-ESI: m / z 184.1 [M-17+1] + .

[0168] Synthesis of compounds 3-8 At room temperature, crude compounds 3-7 (156 mg, 0.78 mmol) and compounds 2-6 (160 mg, 0.65 mmol) were dissolved in... N,N Add benzotriazole to dimethylformamide (5 mL) and then add benzotriazole. N,N,N',N' -Tetramethylurea hexafluorophosphate (370 mg, 0.98 mmol) and N,N -Diisopropylethylamine (170 mg, 1.32 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (10 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 3), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude compounds 3-8, which were used directly in the next reaction. MS-ESI: m / z 372.1 [M-56+1] + .

[0169] Synthesis of Compound 3 At room temperature, crude compounds 3-8 (230 mg, 0.54 mmol) were dissolved in formic acid (5 ml), and the reaction mixture was heated to 50°C and stirred for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated by preparative high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain trifluoroacetate of compound 3. MS-ESI: m / z 328.2 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.12-8.85 (m, 3H), 7.02-6.89(m, 3H), 4.94-4.85 (m, 1H), 4.47-4.33 (m, 1H), 3.99-3.87 (m, 1H), 3.83-3.68(m, 1H), 3.63-3.49 (m, 1H), 3.37-3.29 (m, 1H), 3.19-2.93 (m, 4H), 2.68 (s,4H), 2.06-1.93 (m, 2H), 1.74 (s, 4H).

[0170] Example 4 4-Amino- N -(1-cyano-2-(5,6,7,8-tetrahydronaphth-2-yl)ethyl)tetrahydro-2 H pyran-4-carboxamide Synthesis of compound 4-1 At room temperature, crude 2-amino-3-(5,6,7,8-tetrahydronaphthyl-2-yl)propionitrile (compounds 3-7) (150 mg, 0.75 mmol) and 4-((tert-butoxycarbonyl)amino)tetrahydro-2-yl)propionitrile were reacted. H 4-pyrano-carboxylic acid (164 mg, 0.67 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of benzotriazole. N,N,N',N' -Tetramethylurea hexafluorophosphate (345 mg, 0.91 mmol) and N,N -Diisopropylethylamine (155 mg, 1.20 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3) and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under slight reduced pressure, and the residue was separated by column chromatography (SiO2, dichloromethane / methanol = 10 / 1) to give compound 4-1. MS-ESI: m / z 328.2 [M-100+1] + .

[0171] Synthesis of Compound 4 Compound 4-1 (100 mg, 0.23 mmol) was dissolved in acetonitrile (5 mL) at room temperature. Trimethylchlorosilane (76 mg, 0.70 mmol) and sodium iodide (105 mg, 0.70 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, methanol was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was poured into a saturated sodium bicarbonate aqueous solution (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by preparative-grade liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 4. MS-ESI: m / z 328.5 [M+1] + . 1 H NMR (400MHz, DMSO- d 6 ) δ 7.00-6.93 (m, 3H), 4.88 (t, 1H), 3.67-3.55 (m, 3H), 3.52-3.48(m, 1H), 3.09-2.95 (m, 2H), 2.67 (brs, 4H), 1.95-1.84 (m, 1H), 1.82-1.74 (m,1H), 1.70 (brs, 4H), 1.27-1.10 (m, 2H).

[0172] Example 5 (2 S )- N -(1-Cyano-2-(2,3-dihydro-1) H -inden-5-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide trifluoroacetate Synthesis of compound 5-2 At room temperature, 2,3-dihydro-1 H Indene-5-carboxylic acid (compound 5-1) (2.00 g, 12.35 mmol) and iodomethane (1.2 mL, 19.27 mmol), soluble in... N,NIn a solution of 10 mL dimethylformamide, potassium carbonate (3.41 g, 24.67 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then poured into water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 2) to give compound 5-2. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.80 (s, 1H), 7.75 (d, 1H), 7.35 (d,1H), 3.83 (s, 3H), 2.92-2.88 (m, 4H), 2.12-1.98 (m, 2H).

[0173] Synthesis of compound 5-3 Compound 5-2 (2.13 g, 12.10 mmol) was dissolved in tetrahydrofuran (20 mL) at 0 °C under nitrogen protection, followed by the dropwise addition of lithium aluminum hydride tetrahydrofuran solution (11 mL, 33 mmol, 3.0 mol / L). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, sodium sulfate decahydrate was added to the reaction mixture, and the mixture was stirred for 0.5 hours. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain compound 5-3. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.16-7.14 (m, 2H), 7.05–7.03 (m,1H), 5.06 (t, 1H), 4.43 (d, 2H), 2.87–2.78 (m, 4H), 2.08-1.93 (m, 2H).

[0174] Synthesis of Compound 5-4 Compound 5-3 (1.60 g, 10.80 mmol) was dissolved in toluene (10 mL) at 0 °C, followed by the dropwise addition of phosphine tribromide (1.54 mL, 16.38 mmol). The reaction mixture was stirred at room temperature for 12 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed successively with water (20 mL) and saturated sodium chloride aqueous solution (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to give compound 5-4.1 H NMR (400 MHz, DMSO- d 6 ) δ 7.35-7.10(m, 3H), 4.67 (s, 2H), 2.82 (t, 4H), 2.08-1.96 (m, 2H).

[0175] Synthesis of compound 5-5 At 0°C, 2-((diphenylmethylene)amino)acetonitrile (2.95 g, 13.40 mmol) was dissolved in... N,N In dimethylformamide (10 mL), sodium hydride (1.07 g, 26.75 mmol, 60%) was added, and the reaction mixture was stirred at 0 °C for 30 min. Compound 5-4 (1.87 g, 8.90 mmol) was then added, and the reaction mixture was stirred at 0 °C for 2 h. After the reaction was complete, saturated sodium bicarbonate aqueous solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2), washed successively with water (20 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 5-5. MS-ESI: m / z 351.2 [M+1] + .

[0176] Synthesis of compounds 5-6 Compound 5-5 (1.05 g, 3.00 mmol) was dissolved in dioxane (10 mL) at 0 °C, followed by the addition of 1 M hydrochloric acid (10 mL). The reaction mixture was stirred at 0 °C for 4 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed successively with water (20 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 5-6. MS-ESI: m / z 187.2 [M+1] + .

[0177] Synthesis of compounds 5-7 Compounds 5-6 (100 mg, 0.54 mmol) and 2-6 (158 mg, 0.64 mmol) were dissolved at room temperature in... N,NIn a mixed solvent of dimethylformamide (1 mL) and dichloromethane (5 mL), benzotriazole was then added. N,N,N',N' -Tetramethylurea hexafluorophosphate (306 mg, 0.81 mmol) and N,N -Diisopropylethylamine (139 mg, 1.08 mmol), the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give compounds 5-7. MS-ESI: m / z 358.2 [M-56+1] + .

[0178] Synthesis of Compound 5 Compound 5-7 (100 mg, 0.24 mmol) was dissolved in acetonitrile (10 mL) at room temperature, followed by the sequential addition of trimethylchlorosilane (79 mg, 0.72 mmol) and sodium iodide (109 mg, 0.72 mmol). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, methanol (10 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was extracted with saturated sodium bicarbonate aqueous solution (20 mL) using dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: SunFire Prep C18, 250*19 mm, 10). m; Mobile phase: water (0.1% trifluoroacetic acid), acetonitrile; Gradient ratio: acetonitrile phase 28-95%; Flow rate: 20 mL / min; Column temperature: room temperature) The trifluoroacetate of compound 5 was separated. MS-ESI: m / z 314.5 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.20-8.70 (m, 3H),7.19-7.11 (m, 2H), 7.02 (d, 1H), 5.00-4.82 (m, 1H), 4.46-4.32 (m, 1H), 4.01-3.85 (m, 1H), 3.84-3.70 (m, 1H), 3.61-3.46 (m, 1H), 3.22-2.90 (m, 5H), 2.83-2.80 (m, 4H), 2.03-1.88 (m, 4H).

[0179] Example 6 4-Amino- N -(1-Cyano-2-(2,3-dihydro-1) H -indene-5-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide Synthesis of Compound 6-1 At room temperature, 2-amino-3-(2,3-dihydro-1-yl) H -inden-5-yl)propionitrile (compounds 5-6) (150 mg, 0.81 mmol) and 4-((tert-butoxycarbonyl)amino)tetrahydro-2 H -pyran-4-carboxylic acid (237 mg, 0.97 mmol) soluble in N,N Add benzotriazole to a mixed solvent of dimethylformamide (1 mL) and dichloromethane (5 mL). N,N, N',N' -Tetramethylurea hexafluorophosphate (458 mg, 1.21 mmol) and N,N -Diisopropylethylamine (208 mg, 1.61 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL × 3), washed with saturated brine (20 mL × 3), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give compound 6-1. MS-ESI: m / z 414.2 [M+1] + .

[0180] Synthesis of Compound 6 Compound 6-1 (180 mg, 0.44 mmol) was dissolved in acetonitrile (5 mL) at room temperature, followed by the sequential addition of trimethylchlorosilane (0.2 mL, 1.58 mmol) and sodium iodide (195 mg, 1.31 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, methanol (10 mL) was added dropwise to the reaction mixture, and the mixture was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate (20 mL) was added to the residue, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 6. MS-ESI: m / z 314.5 [M+1] + . 1 HNMR (400 MHz, DMSO- d 6 ) δ 7.19-7.07 (m, 2H), 7.05-6.99 (m, 1H), 4.89 (t, 1H), 3.70-3.54 (m, 3H), 3.51-3.47 (m, 1H), 3.16-2.98 (m, 2H), 2.84-2.76 (m, 4H), 2.06-1.84 (m, 3H), 1.85-1.68 (m, 1H), 1.23-1.15 (m, 2H).

[0181] Example 7 4-Amino- N -(1-Cyano-2-(9,10-dihydrophenanthrene-2-yl)ethyl)tetrahydro-2 H pyran-4-carboxamide Synthesis of Compound 7-2 At room temperature, 9,10-dihydrophenanthrene (compound 7-1) (2.00 g, 11.11 mmol) was dissolved in anhydrous dichloromethane (60 mL), followed by the addition of acetyl chloride (1.20 g, 15.28 mmol). Aluminum trichloride (2.00 g, 15.00 mmol) was added in portions at 0 °C, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (50 mL), extracted with dichloromethane (50 mL × 2), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude compound 7-2. MS-ESI:m / z 223.0 [M+1] + .

[0182] Synthesis of Compound 7-3 Potassium hydroxide (3.30 g, 58.81 mmol) was dissolved in water (20 mL) at 0 °C, followed by the addition of liquid bromine (0.9 mL, 17.56 mmol) and a 1,4-dioxane (10 mL) solution of compound 7-2 (1.00 g, 4.50 mmol). The reaction mixture was heated to 55 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, and saturated sodium bisulfite aqueous solution (20 mL) was added. The pH was adjusted to 1 with concentrated hydrochloric acid, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography to obtain compound 7-3. MS-ESI: m / z 225.2 [M+1] + .

[0183] Synthesis of compound 7-4 Compound 7-3 (930 mg, 4.15 mmol) was dissolved in tetrahydrofuran (10 mL) at 0 °C, followed by the addition of carbonyl diimidazole (874 mg, 5.39 mmol) in portions. The reaction mixture was stirred at room temperature for 1 hour, and sodium borohydride (470 mg, 12.42 mmol) was added. The reaction mixture was stirred at room temperature for another 16 hours. The reaction mixture was poured into ice water (50 mL) and extracted with dichloromethane (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to obtain an intermediate for subsequent reactions.

[0184] At 0°C, the intermediate obtained by the above method (600 mg, 2.86 mmol) was dissolved in dichloromethane (10 ml), and then added sequentially. N,N - Diisopropylethylamine (738 mg, 5.72 mmol) and methanesulfonyl chloride (493 mg, 4.29 mmol) were reacted and stirred at 0 °C for 2 hours. After the reaction was complete, the reaction mixture was poured into ice water (50 mL), extracted with dichloromethane (50 mL × 2), the organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain an intermediate for subsequent reactions.

[0185] At 0°C, 2-((diphenylmethylene)amino)acetonitrile (462 mg, 2.10 mmol) was dissolved in... N , N In dimethylformamide (3 mL), sodium hydride (140 mg, 3.50 mmol, 60%) was added, and the mixture was stirred at room temperature for 0.5 hours. Then, the intermediate prepared in the previous step (400 mg, 1.75 mmol) was added, and the reaction mixture was stirred at 0 °C for 2 hours. After the reaction was complete, saturated ammonium chloride aqueous solution (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of compound 7-4, which was directly used for the next reaction. MS-ESI: m / z 413.1 [M+1] + .

[0186] Synthesis of Compound 7-5 At 0 °C, crude compound 7-4 (720 mg, 1.75 mmol) was dissolved in dioxane (2 mL), followed by the addition of 4 M hydrochloric acid (1 mL). The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 2). The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, dichloromethane / methanol = 19 / 1) to obtain compound 7-5 (150 mg). MS-ESI: m / z 232.2 [M-17+1] + .

[0187] Synthesis of Compounds 7-6 At room temperature, compound 7-6 (150 mg, 0.60 mmol), 4-((tert-butoxycarbonyl)amino)tetrahydro-2- H -pyran-4-carboxylic acid (162 mg, 0.66 mmol) soluble in N,N Add benzotriazole to dimethylformamide (5 mL) and then add benzotriazole. N,N,N',N' -Tetramethylurea hexafluorophosphate (341 mg, 0.9 mmol) and N,N-Diisopropylethylamine (155 mg, 1.20 mmol) was used, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (20 mL) and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, dichloromethane / methanol = 19 / 1) to give compounds 7-6. MS-ESI: m / z 420.5 [M-56+1] + .

[0188] Synthesis of Compound 7 Compound 7-6 (75 mg, 0.16 mmol) was dissolved in acetonitrile (5 mL) at room temperature, followed by the addition of trimethylchlorosilane (72 mg, 0.66 mmol) and sodium iodide (52 mg, 0.35 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, methanol (5 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was poured into a saturated sodium bicarbonate aqueous solution (10 mL) and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Waters Xbridge C18, 250*19 mm, 10). m; Mobile phase: water (0.1% ammonium bicarbonate), acetonitrile; Gradient ratio: acetonitrile phase 52-95%; Flow rate: 20 mL / min; Column temperature: room temperature) Compound 7 was obtained after separation and purification. MS-ESI: m / z 376.7 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.80-7.76 (m, 2H), 7.32-7.22 (m, 4H), 7.18-7.17 (m, 1H), 4.99-4.96 (m, 1H), 3.64-3.53 (m, 3H), 3.48-3.45 (m, 1H), 3.19-3.04 (m, 2H), 2.80-2.76 (m, 4H), 1.93-1.86 (m, 1H), 1.80-1.71 (m, 1H), 1.22-1.13 (m, 2H).

[0189] Example 8 ( S)- N -(( S )-1-cyano-2-(9,10-dihydrophenanthrene-2-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide Synthesis of Compound 8-1 At room temperature, compound 7-1 (2.50 g, 13.89 mol) was dissolved in acetonitrile (20 mL), and then added... N 1,3-bromosuccinimide (2.70 g, 15.17 mmol) and p-toluenesulfonic acid (67 mg, 0.39 mmol) were added, and the reaction mixture was heated to 50 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, and saturated sodium bicarbonate aqueous solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether) to give compound 8-1. 1 H NMR(400 MHz, CDCl3) δ 7.70 (d, 1H), 7.60 (d, 1H), 7.43-7.40 (m, 1H), 7.38 (d,1H), 7.27-7.19 (m, 3H), 2.87-2.83 (m, 4H).

[0190] Synthesis of compound 8-2 Refer to the synthesis of compounds 1-3. MS-ESI: m / z 282.2 [M-100+1] + .

[0191] Synthesis of compound 8-3 Refer to the synthesis of compounds 1-4. MS-ESI: m / z 267.2 [M-100+1] + .

[0192] Synthesis of compound 8-4 Refer to the synthesis of compounds 1-5. MS-ESI: m / z 349.2 [M+1] + .

[0193] Synthesis of Compound 8-5 Refer to the synthesis of compounds 1-6. MS-ESI: m / z 232.2 [M-17+1] + .

[0194] Synthesis of Compound 8-6 Referring to the synthesis of compounds 1-7, except N , N -Other conditions are similar except that dimethylformamide is replaced with dichloromethane. MS-ESI: m / z 420.1 [M-56+1] + .

[0195] Synthesis of Compound 8 Refer to the synthesis of compound 1. MS-ESI: m / z 376.2 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ7.74-7.72 (m, 2H), 7.33-7.28 (m, 1H), 7.25-7.23 (m, 2H), 7.19-7.17 (m, 2H),5.21-5.15 (m, 1H), 4.10-4.07 (m, 1H), 3.99-3.94 (m, 1H), 3.77-3.69 (m, 1H), 3.33-3.28 (m, 1H), 3.10 (d, 1H), 3.04-.99 (m, 1H), 2.95-2.83 (m, 6H), 1.87-1.76 (m, 2H).

[0196] Example 9 ( S )- N -(( S )-1-cyano-2-(2-methyl-1,2,3,4-tetrahydroisoquinoline-6-yl)ethyl)-1,4-oxazineheptane-2-carboxamide Synthesis of compound 9-2 Refer to the synthesis of compounds 1-3. MS-ESI: m / z 331.2 [M+1] + .

[0197] Synthesis of compound 9-3 Compound 9-2 (1.50 g, 4.44 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, followed by the addition of iodomethane (2.97 g, 20.92 mmol). The reaction mixture was stirred at room temperature for 12 hours. The solution was concentrated under reduced pressure to obtain crude compound 9-3, which was used directly in the next reaction. MS-ESI:m / z 345.4 [M-127] + .

[0198] Synthesis of compound 9-4 At room temperature, crude compound 9-3 (1.70 g, 3.60 mmol) was dissolved in 7 M ammonia-methanol solution (30 mL), and the reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure to obtain crude compound 9-4, which was used directly in the next reaction. MS-ESI: m / z 330.1 [M-127] + .

[0199] Synthesis of Compound 9-5 At room temperature, crude compound 9-4 (1.20 g, 2.62 mmol) was dissolved in methanol (10 mL), followed by the addition of a small amount of platinum dioxide on carbon. The reaction mixture was stirred for 12 hours under a hydrogen atmosphere at room temperature. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, dichloromethane / methanol = 7 / 3) to obtain compound 9-5. MS-ESI: m / z 334.2 [M+1] + .

[0200] Synthesis of Compounds 9-6 Compound 9-5 (530 mg, 1.54 mmol) was dissolved in a 10 mL solution of dioxane in hydrogen chloride at room temperature, and the reaction mixture was stirred for 3 hours at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain crude compound 9-6, which was used directly in the next reaction. MS-ESI: m / z 234.2 [M+1] + .

[0201] Synthesis of compounds 9-7 Referring to the synthesis of compounds 1-7, except N,N -dimethylformamide was changed to N,N -A mixed solvent of dimethylformamide and dichloromethane (1 / 3), all other conditions are similar. MS-ESI: m / z 461.3 [M+1] + .

[0202] Synthesis of compounds 9-8 Refer to the synthesis of compounds 1-5. MS-ESI: m / z 443.6 [M+1] + .

[0203] Synthesis of Compound 9 Refer to the synthesis of compound 1. MS-ESI:m / z 343.5 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ8.55 (d, 1H), 7.08-6.92 (m, 3H), 4.93-4.88 (m,1H), 3.98 (dd, 1H), 3.85-3.80(m, 1H), 3.76-3.68 (m, 1H), 3.43 (s, 2H), 3.10-2.99 (m, 3H), 2.81-2.76 (m,3H), 2.59-2.50 (m, 4H), 2.30 (s, 3H), 1.81-1.67 (m, 2H).

[0204] Example 10 ( S )-4-amino- N -(2-(chromen-7-yl)-1-cyanoethyl)tetrahydro-2 H pyran-4-carboxamide Synthesis of compound 10-2 7-Bromochroman-4-one (compound 10-1) (3.00 g, 13.21 mmol) was dissolved in trifluoroacetic acid (50 mL) under nitrogen protection at room temperature, followed by the addition of triethylsilane (4.61 g, 39.64 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to give compound 10-2.

[0205] Synthesis of compound 10-3 Refer to the synthesis of compounds 1-3. MS-ESI: m / z 236.1 [M-100+1] + .

[0206] Synthesis of compound 10-4 Refer to the synthesis of compounds 1-4. MS-ESI: m / z 321.2 [M+1] + .

[0207] Synthesis of compound 10-5 Refer to the synthesis of compounds 1-5. MS-ESI: m / z247.4 [M-56+1] + .

[0208] Synthesis of compound 10-6 Compound 10⁻⁵ (200 mg, 0.66 mmol) was dissolved in a solution of dioxane (5 mL) of hydrogen chloride at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain crude compound 10⁻⁶, which was directly used for the next reaction. MS-ESI: m / z 203.5 [M+1] + .

[0209] Synthesis of compound 10-7 Referring to the synthesis of compounds 1-7, except N,N -dimethylformamide was changed to N,N -A mixed solvent of dimethylformamide and dichloromethane (1 / 2), except for other similar conditions. MS-ESI: m / z 448.3 [M+1] + .

[0210] Synthesis of Compound 10 Refer to the synthesis of compound 1. MS-ESI: m / z 330.4 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ8.18 (s, 1H), 6.97 (d, 1H), 6.71 (d, 1H), 6.66 (s, 1H), 4.88 (t, 1H), 4.16-4.06 (m, 2H), 3.65-3.56 (m, 3H), 3.52-3.44 (m, 1H), 3.07-2.94 (m, 2H), 2.69(t, 2H), 1.94-1.82 (m, 3H), 1.80-1.73 (m, 1H), 1.22-1.14 (m, 2H).

[0211] Example 11 (2 S )- N -(1-Cyano-2-(8-Fluoro-6) H -benzo[ c [Cr-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide carboxylate] Synthesis of compound 11-2 Methyl 4-bromo-3-hydroxybenzoate (compound 11-1) (3.00 g, 13.05 mmol), (4-fluoro-2-(hydroxymethyl)phenyl)boronic acid (2.64 g, 15.52 mmol), sodium bicarbonate (2.18 g, 25.95 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (537 mg, 0.73 mmol) were dissolved in a mixed solvent of dioxane (28 mL) and water (7 mL) under nitrogen protection at room temperature. The reaction mixture was heated to 100 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 2) to give compound 11-2. MS-ESI: m / z 259.1 [M-18+1] + .

[0212] Synthesis of compound 11-3 Compound 11-2 (800 mg, 2.90 mmol) and triphenylphosphine (0.900 g, 3.43 mmol) were dissolved in toluene (10 mL) at room temperature, followed by the dropwise addition of diethyl azodicarbonate (1.52 g, 8.73 mmol). The reaction mixture was heated to 100 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to give compound 11-3. MS-ESI: m / z 259.2 [M-18+1] + .

[0213] Synthesis of compound 11-4 Compound 11-3 (560 mg, 2.17 mmol) was dissolved in dichloromethane (10 mL) at 0 °C, followed by the addition of diisobutylaluminum hydride toluene solution (3.62 mL, 5.43 mmol, 1.5 mol / L). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, sodium sulfate decahydrate (10 g) was added to the reaction mixture, and stirring was continued for 30 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3) to obtain compound 11-4. 1 H NMR (400 MHz, DMSO- d6) δ 7.85 (dd, 1H), 7.80 (d, 1H), 7.27-7.13 (m, 2H), 7.02 (dd, 1H), 6.93 (s, 1H), 5.23 (t, 1H), 5.11 (s, 2H), 4.48 (d, 2H).

[0214] Synthesis of Compound 11-5 Refer to the synthesis of compounds 3-5. 1 H NMR (400 MHz, CDCl3) δ 7.64–7.62 (m, 2H), 7.10–7.05 (m, 2H), 7.05-7.02 (m, 1H), 6.87 (dd, 1H), 5.09 (s, 2H), 4.47 (s, 2H).

[0215] Synthesis of Compound 11-6 Refer to the synthesis of compounds 3-6. MS-ESI: m / z 433.1 [M+1] + .

[0216] Synthesis of Compound 11-7 Refer to the synthesis of compounds 3-7. MS-ESI: m / z 252.1 [M-17+1] + .

[0217] Synthesis of Compound 11-8 Referring to the synthesis of compounds 3-8, except N,N -dimethylformamide was changed to N,N -A mixed solvent of dimethylformamide and dichloromethane (1 / 10), all other conditions are similar. MS-ESI: m / z 396.3 [M-100+1] + .

[0218] Synthesis of Compound 11 Refer to the synthesis of compound 1. MS-ESI: m / z 396.1 [M+1] + . 1 H NMR (400 MHz, DMSO- d6) δ8.65-8.63 (m, 1H), 8.20 (s, 1H), 7.88-7.84 (m, 1H), 7.79 (dd, 1H), 7.25-7.17(m, 2H), 6.99 (d, 1H), 6.92 (s, 1H), 5.10-5.06 (m, 2H), 5.06-4.91 (m, 1H),4.04-3.95 (m, 1H), 3.92-3.82 (m, 1H), 3.76-3.67 (m, 1H), 3.18-3.04 (m, 3H),2.92-2.57 (m, 3H), 1.75-1.73 (m, 2H).

[0219] Example 12 (2 S )- N -(1-Cyano-2-(2,8-Difluoro-6) H -benzo[ c [Cr-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide] Synthesis of Compound 12-2 At room temperature, methyl 2-fluoro-5-hydroxybenzoate (4.80 g, 28.23 mmol), 1-bromo-2-(bromomethyl)-4-fluorobenzene (compound 12-1) (9.24 g, 34.75 mmol), and potassium carbonate (5.50 g, 39.79 mmol) were dissolved in... N , N In dimethylformamide (50 mL), the reaction mixture was heated to 40 °C and stirred for 12 hours. Water (300 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3) to give compound 12-2. 1 H NMR (400 MHz, CDCl3) δ 7.57-7.50 (m, 2H), 7.33-7.27 (m, 1H), 7.16-7.06 (m, 2H), 6.97-6.90 (m, 1H), 5.08 (s, 2H), 3.94 (s, 3H).

[0220] Synthesis of Compound 12-3 Compound 12-2 (5.00 g, 12.60 mmol), palladium acetate (0.28 g, 1.26 mmol), potassium carbonate (3.48 g, 25.18 mmol), and tricyclohexylphosphine tetrafluoroborate (0.46 g, 1.26 mmol) were dissolved in nitrogen at room temperature and under nitrogen protection. N , N In 100 mL of dimethylformamide, the reaction mixture was heated to 130 °C and stirred for 3 hours. After the reaction was complete, it was cooled to room temperature, and 200 mL of water was added. The mixture was extracted with 200 mL of ethyl acetate (200 mL × 2). The combined organic phases were washed with 200 mL of saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to give compound 12-3. 1 H NMR (400 MHz, CDCl3) δ 7.66-7.61 (m, 1H), 7.53 (d, 1H), 7.39 (d, 1H), 7.14-7.07 (m, 1H), 6.94-6.88 (m,1H), 5.10 (s, 2H), 3.93 (s, 3H).

[0221] Synthesis of compound 12-4 Compound 12-3 (2.40 g, 8.25 mmol) was dissolved in tetrahydrofuran (50 mL) at room temperature. Lithium aluminum hydride (0.31 g, 8.25 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 20 minutes. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 12-4. 1 H NMR (400 MHz, CDCl3) δ 7.56 (dd, 1H), 7.32 (d, 1H), 7.11-7.03 (m,2H), 6.88 (dd, 1H), 5.06 (s, 2H), 4.73 (d, 2H).

[0222] Synthesis of Compound 12-5 Compound 12-4 (1.60 g, 6.12 mmol) was dissolved in dichloromethane (20 mL) at room temperature, followed by the dropwise addition of phosphorus tribromide (1.66 g, 6.12 mmol). The reaction mixture was stirred at room temperature for 20 minutes. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 12-5. 1 H NMR (300 MHz, CDCl3) δ 7.65-7.57 (m, 1H), 7.38 (d, 1H), 7.17-7.07 (m, 1H), 7.04 (d, 1H), 6.93 (d, 1H), 5.11 (s, 2H), 4.52 (s, 2H).

[0223] Synthesis of Compound 12-6 At room temperature, diphenylmethyleneaminoacetonitrile (900 mg, 4.09 mmol), compound 12-5 (470 mg, 1.47 mmol), benzyltrimethylammonium chloride (80 mg, 0.41 mmol), and sodium hydroxide (210 mg, 5.31 mmol) were dissolved in a mixed solvent of dichloromethane (9 mL) and water (1 mL). The reaction mixture was heated to 35 °C and stirred for 24 hours. Water (30 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3) to obtain compound 12-6. MS-ESI: m / z 451.1 [M+1] + .

[0224] Synthesis of Compound 12-7 Compound 12-6 (1.50 mg, 2.97 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, followed by the dropwise addition of 1 M hydrochloric acid aqueous solution (4 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, saturated sodium bicarbonate aqueous solution (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 12-7. MS-ESI: m / z 287.1 [M+1] + .

[0225] Synthesis of Compound 12-8 At room temperature, compounds 12-7 (150 mg, 0.52 mmol) and 2-6 (127 mg, 0.52 mmol) were... N , N , N ', N '-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (256 mg, 0.68 mmol) and N , N -Diisopropylethylamine (200 mg, 1.56 mmol) soluble in N , N In dimethylformamide (5 mL), the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, compound 12-8 was isolated by preparative liquid chromatography (C18, acetonitrile / water system). MS-ESI: m / z 458.1 [M-56+1] + .

[0226] Synthesis of Compound 12 Compound 12-8 (70 mg, 0.16 mmol) was dissolved in formic acid (2 mL) at room temperature, and the reaction mixture was heated to 30 °C and stirred for 1 hour. After the reaction was complete, compound 12 was obtained by preparative liquid chromatography (C18, ammonium bicarbonate / acetonitrile / water system). MS-ESI: m / z 414.1 [M+1] + . 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, 1H),7.36 (d, 1H), 7.11-7.06 (m, 1H), 6.96-6.87 (m, 2H), 5.20-5.09 (m, 1H), 5.07(s, 2H), 4.09-4.00 (m, 2H), 3.81-3.73 (m, 1H), 3.40-3.26 (m, 1H), 3.20-3.11(m, 2H), 3.07-2.95 (m, 1H), 2.93-2.84 (m, 2H), 1.96-1.80 (m, 2H).

[0227] Example 13 (2 S )- N -(1-Cyano-2-(8-Cyano-6) H -benzo[ c [Cr-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide] Synthesis of Compound 13-2 At room temperature, 4-bromo-3-toluenenitrile (compound 13-1) (10 g, 51.29 mmol), N 1,2-Brominated succinimide (22.70 g, 127.54 mmol) and benzoyl peroxide (1.24 g, 5.12 mmol) were dissolved in 1,2-dichloroethane (50 mL). The reaction mixture was heated to 100 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature, and saturated sodium bicarbonate aqueous solution (50 mL) was added. Extraction was performed with ethyl acetate (50 mL × 2). The mixture was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3) to give compound 13-2. 1 H NMR (400 MHz, CDCl3) δ 7.77-7.69 (m, 2H), 7.47-7.41 (m, 1H), 4.57 (s, 2H).

[0228] Synthesis of compound 13-3 Compound 13-2 (140 mg, 0.44 mmol) and methyl 3-hydroxybenzoate (0.09 mL, 0.65 mmol) were dissolved in acetonitrile (10 mL) at room temperature, followed by the addition of potassium carbonate (120 mg, 0.87 mmol). The reaction mixture was heated to 100 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The extract was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 13-3.

[0229] Synthesis of Compound 13-4 Refer to the synthesis of compound 12-3. 1 H NMR (400 MHz, DMSO- d 6) δ 8.11 (d, 1H), 8.09(d, 1H), 7.90 (dd, 1H), 7.82 (d, 1H), 7.66 (dd, 1H), 7.49 (d, 1H), 5.24 (s,2H), 3.87 (s, 3H).

[0230] Synthesis of Compound 13-5 Refer to the synthesis of compound 11-4. MS-ESI: m / z 220.2 [M-18+1] + .

[0231] Synthesis of Compound 13-6 Refer to the synthesis of compounds 3-5. 1 H NMR (400 MHz, DMSO- d 6) δ 8.03 (d, 1H), 7.97 (d, 1H), 7.87 (d, 1H), 7.80 (s, 1H), 7.20 (d, 1H), 7.12 (s, 1H), 5.21 (d, 2H), 4.71 (s, 2H).

[0232] Synthesis of Compounds 13-7 MS-ESI of the synthesis of compounds 3-6: m / z 440.3 [M+1] + .

[0233] Synthesis of Compounds 13-8 Refer to the synthesis of compounds 3-7. MS-ESI: m / z259.2 [M-17+1] + .

[0234] Synthesis of Compounds 13-9 Referring to the synthesis of compounds 1-7, except N , N -dimethylformamide was changed to N , N -A mixed solvent of dimethylformamide and dichloromethane (10 / 1), all other conditions are similar. MS-ESI: m / z 447.3 [M-56+1] + .

[0235] Synthesis of Compound 13 Refer to the synthesis of compound 1. MS-ESI: m / z 403.3 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ7.77-7.71 (m, 2H), 7.66 (d, 1H), 7.45 (s, 1H), 7.39-7.29 (m, 1H), 7.05-7.01(m, 1H), 6.98-6.94 (m, 1H), 5.12-5.08 (m, 3H), 4.35-4.31 (m, 1H), 4.09-4.03(m, 1H), 3.85-3.78 (m, 2H), 3.65-3.54 (m, 1H), 3.16-3.07 (m, 5H), 2.09-2.05(m, 2H).

[0236] Example 14 ( S )- N -(( S )-1-cyano-2-(8-cyano-2-fluoro-6 H -benzo[ c [Cr-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide] Synthetic Route A: Synthesis of compound 14-A1 At room temperature, methyl 2-fluoro-5-hydroxybenzoate (4.30 g, 25.29 mmol), 4-bromo-3-(bromomethyl)benzonitrile (compound 13-2) (7.72 g, 25.30 mmol), and potassium carbonate (6.99 g, 50.58 mmol) were dissolved in...N , N In dimethylformamide (50 mL), the reaction mixture was heated to 40 °C and stirred for 12 hours. Water (300 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to give compound 14-A1. 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, 1H), 7.73 (d, 1H), 7.55-7.48 (m, 2H), 7.18-7.09 (m, 2H), 5.11 (s, 2H), 3.95 (s, 3H).

[0237] Synthesis of compound 14-A2 Compound 14-A1 (2.90 g, 6.37 mmol), palladium acetate (0.14 g, 0.64 mmol), potassium carbonate (1.76 g, 12.73 mmol), and tricyclohexylphosphine tetrafluoroborate (0.23 g, 0.64 mmol) were dissolved in nitrogen at room temperature and under nitrogen protection. N , N In dimethylformamide (30 mL), the reaction mixture was heated to 120 °C and stirred for 1.5 hours. After the reaction was complete, it was cooled to room temperature, and water (200 mL) was added. The mixture was extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to give compound 14-A2. 1 H NMR (400 MHz, CDCl3) δ7.80-7.72 (m, 2H), 7.60 (d, 1H), 7.52-7.49 (m, 2H), 5.18 (s, 2H), 3.98 (s,3H).

[0238] Synthesis of compound 14-A3 Compound 14-A2 (1.20 g, 3.81 mmol) and lithium borohydride (0.25 g, 11.47 mmol) were dissolved in tetrahydrofuran (25 mL) at room temperature. The reaction mixture was heated to 55 °C and stirred for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and water (200 mL) was added. The mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (200 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to give compound 14-A3. 1 H NMR (400 MHz, CDCl3) δ 7.67 (s,2H), 7.47 (s, 1H), 7.38 (d, 1H), 7.12 (d, 1H), 5.11 (s, 2H), 4.77 (s, 2H).

[0239] Synthesis of compound 14-A4 Compound 14-A3 (450 mg, 1.59 mmol) was dissolved in dichloromethane (15 mL) at room temperature, followed by the dropwise addition of phosphorus tribromide (520 mg, 1.92 mmol). The reaction mixture was stirred at room temperature for 20 minutes. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to give compound 14-A4. 1 H NMR (300 MHz, CDCl3) δ 7.73 (s, 2H), 7.52 (s, 1H), 7.45 (d, 1H), 7.10 (d, 1H), 5.17 (s, 2H), 4.53 (s, 2H).

[0240] Synthesis of compound 14-A5 At room temperature, diphenylmethyleneaminoacetonitrile (250 mg, 1.14 mmol), compound 14-A4 (470 mg, 1.26 mmol), benzyltrimethylammonium chloride (22 mg, 0.12 mmol), and sodium hydroxide (91 mg, 2.3 mmol) were dissolved in a mixed solvent of dichloromethane (6 mL) and water (6 mL). The reaction mixture was heated to 35 °C and stirred for 24 hours. Water (30 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to give compound 14-A5. MS-ESI: m / z 458.4 [M+1] + .

[0241] Synthesis of compound 14-A6 Compound 14-A5 (520 mg, 0.90 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, followed by the addition of 1 M hydrochloric acid aqueous solution (4 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, saturated sodium bicarbonate aqueous solution (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 14-A6. MS-ESI: m / z 293.9 [M+1] + .

[0242] Synthesis of compound 14-A7 At room temperature, compound 14-A6 (220 mg, 0.68 mmol) and compound 2-6 (170 mg, 0.69 mmol) were... N , N , N ', N '-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (360 mg, 0.95 mmol) and N , N -Diisopropylethylamine (250 mg, 1.93 mmol) soluble in N , NIn dimethylformamide (5 mL), the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, compound 14-A7 was obtained by preparative liquid chromatography (C18, acetonitrile / water system). MS-ESI: m / z 465.1 [M-56+1] + .

[0243] Synthesis of Compound 14-1 Compound 14-A7 (280 mg, 0.51 mmol) was resolved chirally (column: chiralpak IE, 250*25 mm, 5). m; mobile phase: n-hexane, ethanol; gradient ratio: n-hexane phase 30%; flow rate: 15 mL / min; column temperature: 30℃) yielded compound 14-1 (two diastereomer peaks, compound 14-1 being the first eluted peak). 1 HNMR (300 MHz, DMSO- d 6) δ 8.89 (d, 1H), 8.08 (d, 1H), 7.94-7.89 (m, 2H), 7.83(s, 1H), 7.07 (d, 1H), 5.24-5.14 (m, 2H), 5.09-5.07 (m, 1H), 4.15-4.12 (m,1H), 3.99-3.87 (m, 2H), 3.63-3.56 (m, 2H), 3.29-3.02 (m, 4H), 1.89-1.79 (m,2H), 1.41-1.36 (m, 9H).

[0244] Synthesis of Compound 14 Compound 14-1 (85 mg, 0.16 mmol) was dissolved in formic acid (1 mL) at room temperature, and the reaction mixture was heated to 40 °C and stirred for 1 hour. After the reaction was complete, compound 14 was obtained by preparative liquid chromatography (C18, ammonium bicarbonate / acetonitrile / water system). MS-ESI: m / z 421.2 [M+1] + . 1 H NMR (400 MHz, DMSO- d6) δ 8.69 (d, 1H), 8.05 (d, 1H), 7.89-7.86 (m, 2H), 7.80 (s, 1H), 7.03 (d, 1H), 5.20-5.12 (m, 2H), 5.09-5.02 (m, 1H), 4.00-3.97 (m, 1H), 3.88-3.83 (m, 1H), 3.77-3.68 (m,1H), 3.25-3.14 (m, 2H), 3.05-2.98 (m, 1H), 2.82-2.72 (m, 1H), 2.62-2.53 (m,2H) , 1.80-1.66 (m,2H).

[0245] Synthetic Route B: Synthesis of compound 14-B1 Compound 13-1 (10.00 g, 51.01 mmol), pinacol diborate (15.54 g, 61.21 mmol), potassium acetate (10.01 g, 102.02 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.75 g, 1.02 mmol) were dissolved in nitrogen at room temperature and under nitrogen protection. N , N In 100 mL of dimethylformamide, the reaction mixture was heated to 100 °C and stirred for 18 hours. The reaction mixture was cooled to room temperature, and water (1.0 L) was added. Extraction was performed with ethyl acetate (500 mL × 2). The combined organic phases were washed with saturated brine (500 mL × 2) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1) to give compound 14-B1. 1 H NMR (300 MHz, CDCl3): δ 7.82 (d, 1H), 7.46-7.39 (m, 2H), 2.55 (s, 3H), 1.35 (s,12H).

[0246] Synthesis of compound 14-B2 Compound 14-B1 (12.00 g, 43.19 mmol), 1,4-dibromo-2,5-difluorobenzene (23.49 g, 86.38 mmol), potassium carbonate (11.94 g, 86.38 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.26 g, 1.73 mmol) were dissolved in a mixed solvent of 1,4-dioxane (120 mL) and water (20 mL) under nitrogen protection at room temperature. The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, and water (1.0 L) was added. Extraction was performed with ethyl acetate (500 mL × 2). The combined organic phases were washed with saturated brine (500 × 2) and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 14-B2. 1 H NMR (300 MHz, CDCl3) δ 7.62-7.52 (m, 2H), 7.45-7.36 (m,1H), 7.32-7.24 (m, 1H), 7.06-6.97 (m, 1H), 2.24 (s, 3H).

[0247] Synthesis of compound 14-B3 Compound 14-B2 (7.40 g, 24.02 mmol) was subjected to nitrogen protection at room temperature. N 1,4-bromosuccinimide (10.26 g, 57.64 mmol) and benzoyl peroxide (0.35 g, 1.44 mmol) were dissolved in carbon tetrachloride (80 mL). The reaction mixture was heated to 90 °C and stirred for 18 hours. The reaction mixture was cooled to room temperature, and water (200 mL) was added. The mixture was extracted with dichloromethane (100 mL × 2). The combined organic phases were washed with saturated brine (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 6 / 1) to give compound 14-B3. 1 H NMR (300 MHz, CDCl3): δ 8.41 (s, 1H), 7.72-7.62 (m, 1H), 7.54-7.46 (m, 1H), 7.31-7.26 (m, 1H), 7.15-7.06 (m, 1H), 6.41 (s, 1H).

[0248] Synthesis of compound 14-B4 Compound 14-B3 (1.00 g, 2.15 mmol) was dissolved in acetonitrile (10 mL) at room temperature, and a solution of silver nitrate (0.80 g, 4.72 mmol) in water (2 mL) was added. The reaction mixture was heated to 90 °C and stirred for 18 hours. The reaction mixture was cooled to room temperature, filtered, and water (20 mL) was added to the filtrate. The filtrate was extracted with ethyl acetate (25 mL × 2 mL). The combined organic phases were washed with saturated brine (25 mL × 2) and dried over anhydrous sodium sulfate. The filtrate was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 14-B4, which was used directly in the next reaction. 1 H NMR (300 MHz, CDCl3): δ 9.92 (d, 1H), 8.32(s, 1H), 7.96 (d, 1H), 7.57-7.43 (m, 2H), 7.17-7.10 (m, 1H).

[0249] Synthesis of compound 14-B5 At room temperature, crude compound 14-B4 (7.20 g, 22.35 mmol) was dissolved in a mixed solvent of tetrahydrofuran (40 mL) and methanol (40 mL). Sodium borohydride (1.01 g, 26.82 mmol) was added in portions under ice-water bath, and the reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to one-third of its original volume, and slowly poured into 0.5 M hydrochloric acid (50 mL) while stirring. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine (100 mL × 2) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3) to obtain compound 14-B5. 1 H NMR (300 MHz, CDCl3): δ7.97 (s, 1H), 7.65 (d, 1H), 7.46-7.37 (m, 1H), 7.36-7.30 (m, 1H), 7.12-7.03(m, 1H), 4.58 (s, 2H).

[0250] Synthesis of compound 14-B6 Compound 14-B5 (6.50 g, 20.05 mmol) was dissolved at room temperature in... N , NSodium hydride (0.48 g, 20.05 mmol, 60%) was added in portions to dimethylformamide (65 mL) at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was poured into 0.25 M hydrochloric acid (500 mL) and stirred for 10 minutes. The mixture was filtered, and the filter cake was washed first with water (50 mL × 5), and then with a mixed solvent of petroleum ether and ethyl acetate (9 / 1, 50 mL × 3). The filter cake was dried under vacuum to constant weight to give crude compound 14-B6, which was used directly in the next reaction. 1 H NMR (300 MHz, DMSO- d 6 ): δ 8.12-8.06 (m, 2 H), 7.94-7.86 (m, 1H), 7.82 (s, 1H), 7.46-7.40 (m, 1H), 5.21 (s, 2H).

[0251] Synthesis of compound 14-B7 Zinc powder (40.00 g, 611.53 mmol) and iodine (0.5 g, 1.13 mmol) were added to the solution under nitrogen protection at room temperature. N , N Add (R)-2-(((tert-butoxycarbonyl)amino)methyl-3-iodopropionate (60.00 g, 182.30 mmol) to dimethylformamide (50 mL). N , N 200 mL of dimethylformamide solution was prepared, and the reaction mixture was heated to 50 °C and stirred for 1 hour. The supernatant was used as zinc reagent.

[0252] In a separate reaction flask, under nitrogen protection at room temperature, dissolve the crude product of reactant 14-B6 (20.00 g, 65.76 mmol) and palladium dichloride bis(triphenylphosphine) (4.00 g, 0.13 mmol) in... N , N The reaction mixture was prepared in dimethylformamide (100 mL), followed by the addition of the zinc reagent described above. The mixture was heated to 70 °C and stirred for 6 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and water (800 mL) was added. The mixture was extracted with ethyl acetate (250 mL × 3). The organic phases were combined, washed with water (100 mL × 3), and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was first separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1), and then slurried with ethanol (50 mL) to give compound 14-B7. 1H NMR (400 MHz, CDCl3) δ 8.04-8.02 (m, 1H), 7.88-7.85 (m, 2H), 7.82-7.79 (m, 1H), 7.37-7.35(m, 1H), 6.99-6.98 (m, 1H), 5.15 (s, 2H), 4.27-4.20 (m, 1H), 3.64 (s, 3H), 3.14-3.09 (m, 1H), 2.87-2.81 (m, 1H), 1.31 (s, 9H).

[0253] Synthesis of compound 14-B8 Compound 14-B7 (10.00 g, 23.45 mmol) was dissolved in tetrahydrofuran (100 mL) at room temperature, followed by the addition of a methanol solution containing 8 M ammonia (200 mL). The reaction mixture was heated to 40 °C and stirred for 60 hours in a sealed container. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain crude compound 14-B8, which was used directly in the next reaction. MS-ESI: m / z 356.0 [M-56+1] + .

[0254] Synthesis of compound 14-B9 At room temperature, crude compound 14-B8 (9.50 g, 23.09 mmol) and triethylamine (7.01 g, 69.27 mmol) were dissolved in tetrahydrofuran (100 mL). Trifluoroacetic anhydride (7.27 g, 34.64 mmol) was added dropwise at 0 °C, and the reaction mixture was naturally heated to room temperature and stirred for 2 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and water (100 mL) was added to the residue. The residue was extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated brine (25 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was first separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1), and then slurried with ethanol (20 mL) to give compound 14-B9. MS-ESI: m / z 392.0 [M-1] - .

[0255] Synthesis of compound 14-B10 Compound 14-B9 (7.80 g, 19.83 mmol) was dissolved in dichloromethane (20 mL) at room temperature, followed by the addition of formic acid (50 mL). The reaction mixture was heated to 35 °C and stirred for 1 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane (100 mL) and slowly poured into a 10% sodium carbonate aqueous solution (300 mL) while stirring for 5 min. The mixture was then extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated brine (25 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 14-B10, which was used directly in the next reaction. MS-ESI: m / z 392.0 [M+1] + .

[0256] Synthesis of Compound 14-1 At room temperature, crude compound 14-B10 (7.00 g, 23.87 mmol) and compound 2-6 (6.44 g, 26.25 mmol) were dissolved in... N , N Add to 100 mL of dimethylformamide at 0°C N , N , N ', N '-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (10.89 g, 28.64 mmol), stirred for 5 minutes, then added dropwise at 0°C. N , N -Diisopropylethylamine (4.63 g, 35.80 mmol), the reaction mixture was stirred at 0 °C for 30 min. After the reaction was complete, the reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (100 mL × 2). The organic phases were combined and washed successively with water (50 mL × 2) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give compound 14-1. MS-ESI: m / z 521.1 [M+1] + .

[0257] Synthesis of Compound 14 Compound 14-1 (10.50 g, 20.17 mmol) was dissolved in tetrahydrofuran (105 mL) at room temperature, followed by the addition of p-toluenesulfonic acid monohydrate (11.51 g, 60.51 mmol). The reaction mixture was heated to 35 °C and stirred for 18 hours, then heated to 45 °C and stirred for 5 hours. The reaction mixture was cooled to room temperature and poured into a solution of sodium carbonate (8.6 g, 4 eq) in water (200 mL). Extraction was performed with a mixed solvent of dichloromethane and methanol (10 / 1, 100 mL × 2). The organic phases were combined and washed with water (50 mL). The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with methanol (80 mL) and dried under reduced pressure to give compound 14. MS-ESI: m / z 421.2 [M+1] + .

[0258] 1 H NMR (400 MHz, CDCl3) δ 8.68 (d, 2H), 7.47-7.42 (m, 2H), 7.27-7.25(m, 1H), 7.00 (d, 1H), 5.22-5.16 (m, 1H), 5.11 (s, 2H), 4.10-4.07 (m, 1H),4.04-3.99 (m, 1H), 3.80-3.73 (m, 1H), 3.29-3.25 (m, 1H), 3.22-3.12 (m, 2H),3.01-2.93 (m, 2H), 2.89-2.83 (m, 1H), 1.93-1.77 (m, 2H).

[0259] 1 H NMR (400 MHz, DMSO- d6 ) δ 8.68 (d, 1H), 8.04 (d, 1H), 7.89-7.86 (m,2H), 7.80 (s, 1H), 7.03 (d, 1H), 5.20-5.12 (m, 2H), 5.09-5.03 (m, 1H), 4.00-3.97 (m, 1H), 3.88-3.82 (m, 1H), 3.75-3.69 (m, 1H), 3.28-3.15 (m, 2H), 3.04-3.00 (m, 1H), 2.79-2.73 (m, 1H), 2.63-2.54 (m, 2H) , 1.78-1.64 (m, 2H).

[0260] Example 15 (2 S )- N -(1-Cyano-2-(3-Fluoro-6) H -benzo[ c [Cr-8-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide] Synthesis of Compound 15-2 At room temperature, methyl 4-bromo-3-methylbenzoate (compound 15-1) (11.30 g, 49.57 mmol) was dissolved in carbon tetrachloride (150 mL), and then... N 1,5-bromosuccinimide (13.20 g, 74.17 mmol) and azobisisobutyronitrile (4.10 g, 24.97 mmol) were mixed, and the reaction mixture was heated to 80 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature, and 150 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with dichloromethane (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3) to give compound 15-2 (12 g). 1 H NMR (400 MHz, DMSO- d 6) δ 8.21 (d, 1H), 7.85-7.79 (m, 2H), 4.83 (s, 2H), 3.87 (s, 3H).

[0261] Synthesis of Compound 15-3 Compound 15-2 (24.0 g, 79.70 mmol) and potassium acetate (15.60 g, 158.96 mmol) were dissolved in acetic acid (200 mL) at room temperature. The reaction mixture was heated to 100 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 2) to give compound 15-3. ¹H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H), 7.85 (dd, 1H), 7.66 (d, 1H), 5.22(s, 2H), 3.93 (s, 3H), 2.17 (s, 3H).

[0262] Synthesis of Compound 15-4 Refer to the synthesis of compound 11-2. MS-ESI: m / z 275.1 [M-1] - .

[0263] Synthesis of Compound 15-5 Refer to the synthesis of compound 11-3. MS-ESI: m / z 259.1 [M+1] + .

[0264] Synthesis of Compound 15-6 Refer to the synthesis of compound 11-4. MS-ESI: m / z 213.4 [M-18+1] + .

[0265] Synthesis of Compound 15-7 Refer to the synthesis of compounds 3-5. 1 H NMR (400 MHz, CDCl3) δ 7.68-7.64 (m, 1H), 7.60 (d, 1H), 7.39 (dd, 1H), 7.19 (s, 1H), 6.80-6.75 (m, 1H), 6.73-6.70 (m, 1H), 5.11 (s, 2H), 4.51 (s, 2H).

[0266] Synthesis of Compound 15-8 Refer to the synthesis of compounds 3-6. MS-ESI: m / z 433.1 [M+1] + .

[0267] Synthesis of Compounds 15-9 Refer to the synthesis of compounds 3-7. MS-ESI: m / z 252.1 [M-17+1] + .

[0268] Synthesis of Compounds 15-10 Referring to the synthesis of compounds 3-8, except N,N -dimethylformamide was changed to N,N -A mixed solvent of dimethylformamide and dichloromethane (1 / 10), all other conditions are similar. MS-ESI: m / z 440.1 [M-56+1] + .

[0269] Synthesis of Compound 15 Refer to the synthesis of compound 1. MS-ESI: m / z 396.1 [M+1] +. 1 H NMR (400 MHz, CDCl3) δ7.69-7.61 (m, 2H), 7.33-7.26 (m, 1H), 7.19-7.16 (m, 1H), 7.09 (d, 1H), 6.78(td, 1H), 6.72 (dd, 1H), 5.19-5.09 (m, 3H), 4.10-4.07 (m, 1H), 4.03-3.96 (m,1H), 3.80-3.72 (m, 1H), 3.38-3.28 (m, 1H), 3.17-3.01 (m, 3H), 2.96-2.87 (m,2H), 1.88-1.78 (m,2H).

[0270] Example 16 ( S )- N -(( S )-1-cyano-2-(8,9-difluoro-6 H -benzo[ c [Cr-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide] Synthesis of Compound 16-2 At 0℃, ( S 2-Amino-3-(3-hydroxyphenyl)propionic acid (compound 16-1) (4.50 g, 24.84 mmol) was dissolved in methanol (50 mL), followed by the slow dropwise addition of thionyl chloride (3.84 g, 32.29 mmol). The reaction mixture was heated to 75 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give crude compound 16-2, which was used directly in the next reaction. MS-ESI: m / z 196.2 [M+1] + .

[0271] Synthesis of Compound 16-3 Compound 16-2 (6.00 g, 30.74 mmol) and sodium bicarbonate (7.75 g, 92.20 mmol) were dissolved in a mixed solvent of tetrahydrofuran (40 mL) and water (10 mL) at 0 °C, followed by the addition of di-tert-butyl dicarbonate (7.38 g, 33.81 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 1) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to give compound 16-3. MS-ESI: m / z 196.2 [M-100+1] + .

[0272] Synthesis of compound 16-4 Compound 16-3 (3.38 g, 11.45 mmol) was dissolved at room temperature in... N,N In dimethylformamide (50 mL), potassium carbonate (2.37 g, 17.17 mmol), potassium iodide (1.90 g, 11.45 mmol), and 1-bromo-2-(bromomethyl)-4,5-difluorobenzene (2.40 g, 1.73 mmol) were added sequentially. The reaction mixture was heated to 60 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature, and saturated sodium bicarbonate aqueous solution (50 mL) was added. Extraction was performed with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3) to give compound 16-4. MS-ESI: m / z 402.2[M-100+1] + .

[0273] Synthesis of compound 16-5 Compound 16-4 (1.00 g, 2.00 mmol) was dissolved at room temperature in... N,NIn dimethylacetamide (50 mL), sodium acetate (0.33 g, 4.00 mmol) and palladium dichloride bis(triphenylphosphine) (0.78 g, 1.00 mmol) were added. The reaction mixture was microwaved to 130 °C and stirred for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and saturated sodium bicarbonate aqueous solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3) to give compound 16-5. MS-ESI: m / z 320.3 [M-100+1] + .

[0274] Synthesis of compound 16-6 Refer to the synthesis of compounds 1-4. MS-ESI: m / z 305.3 [M-100+1] + .

[0275] Synthesis of Compound 16-7 Refer to the synthesis of compounds 1-5, 1-6, and 3-8. MS-ESI: m / z 414.2 [M-100+1] + .

[0276] Synthesis of Compound 16 Refer to the synthesis of compound 1. MS-ESI: m / z 414.2 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ7.72-7.64 (m, 2H), 7.18 (dd, 1H), 7.01 (d, 1H), 6.92 (s, 1H), 5.12-4.99 (m,3H), 4.49-4.34 (m, 1H), 4.15-4.02 (m, 1H), 3.86-3.81 (m, 1H), 3.73-3.57 (m,1H), 3.44-3.35 (m, 2H), 3.26-3.02 (m, 3H), 2.21-2.01 (m, 2H).

[0277] Example 17 ( S )-4-amino- N -(1-Cyano-2-(8,9-Difluoro-6) H -benzo[ c[Cr-3-yl)ethyl)tetrahydro-2 H pyran-4-carboxamide Synthesis of Compound 17-1 Refer to the synthesis of compounds 1-7. MS-ESI: m / z 414.2 [M-100+1] + .

[0278] Synthesis of Compound 17 Refer to the synthesis of compound 1. MS-ESI: m / z 414.2 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ7.73-7.64 (m, 2H), 7.21-7.15 (m, 1H), 7.02 (dd, 1H), 6.92 (d, 1H), 5.22-5.16(m, 1H), 5.04 (s, 2H), 3.86-3.80 (m, 1H), 3.74-3.57 (m, 3H), 3.30-3.25 (m,1H), 3.19-3.12 (m, 1H), 2.32-2.23 (m, 1H), 2.18–2.09 (m, 1H), 1.80-1.75 (m,1H), 1.62-1.56 (m,1H).

[0279] Example 18 (2 S )- N -(1-Cyano-2-(3-Cyano-9-Fluoro-5-) H -color full union (chromeno[4,3-) c ]pyridin-8-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide Synthesis of compound 18-2 Compound 18-1 (4.50 g, 17.97 mmol) was dissolved in a mixed solvent of tetrahydrofuran (40 mL) and methanol (5 mL) at room temperature. Lithium borohydride (0.78 g, 35.93 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 18-2. MS-ESI: m / z 221.9 [M+1] + .

[0280] Synthesis of compound 18-3 Compound 18-2 (4.20 g, 17.56 mmol), methyl 2-fluoro-5-hydroxybenzoate (4.18 g, 24.58 mmol), and triphenylphosphine (6.91 g, 26.34 mmol) were dissolved in tetrahydrofuran (50 mL) at room temperature. Diisopropyl azodicarbonate (5.33 g, 26.34 mmol) was added dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to give compound 18-3. MS-ESI: m / z 373.9 [M+1] + .

[0281] Synthesis of compound 18-4 Compound 18-3 (2.30 g, 5.96 mmol), palladium acetate (0.13 g, 0.60 mmol), potassium carbonate (1.65 g, 11.91 mmol), and tricyclohexylphosphine tetrafluoroborate (0.22 g, 0.60 mmol) were dissolved in nitrogen at room temperature and under nitrogen protection. N , N In dimethylacetamide (25 mL), the reaction mixture was heated to 110 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to give compound 18-4. MS-ESI: m / z 293.9 [M+1] + .

[0282] Synthesis of compound 18-5 Compound 18-4 (1.10 g, 3.63 mmol), zinc cyanide (0.64 g, 5.45 mmol), and tetraphenylphosphine palladium (0.63 g, 0.55 mmol) were dissolved in nitrogen at room temperature and under nitrogen protection. N , N In dimethylformamide (15 mL), the reaction mixture was heated to 90 °C and stirred for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to give compound 18-5. MS-ESI: m / z 284.9 [M+1] + .

[0283] Synthesis of compound 18-6 Refer to the synthesis of compound 17-5. 1 H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 7.43 (s,1H), 7.39 (d, 1H), 7.09 (d, 1H), 5.07 (s, 2H), 4.72 (s, 2H).

[0284] Synthesis of compound 18-7 Compound 18-6 (120 mg, 0.40 mmol), carbon tetrabromide (145 mg, 0.44 mmol), and triphenylphosphine (115 mg, 0.44 mmol) were dissolved in dichloromethane (1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to obtain compound 18-7. 1 H NMR (400 MHz, CDCl3) δ 8.93 (s,1H), 7.52-7.47 (m, 2H), 7.08 (d, 1H), 5.15 (s, 2H), 4.48 (s, 2H).

[0285] Synthesis of compound 18-8 Refer to the synthesis of compound 14-A5. MS-ESI: m / z 459.2 [M+1] + .

[0286] Synthesis of Compound 18-9 Refer to the synthesis of compound 14-A6. MS-ESI: m / z 295.0 [M+1] + .

[0287] Synthesis of Compound 18-10 Refer to the synthesis of compound 14-A7. MS-ESI: m / z 422.1 [M-100+1] + .

[0288] Synthesis of Compound 18 Refer to the synthesis of compound 14. MS-ESI: m / z 422.1 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ9.24 (s, 1H), 8.71-8.65 (m, 1H), 8.05-8.00 (m, 1H), 7.98 (s, 1H), 7.08-7.05(m, 1H), 5.28-5.22 (m, 2H), 5.10-4.95 (m, 1H), 4.01-3.82 (m, 2H), 3.76-3.66(m, 1H), 3.25-3.00 (m, 3H), 2.84-2.51 (m, 3H), 1.80-1.69 (m, 2H).

[0289] Example 19 ( S )- N -(( S )-1-cyano-2-(3-cyano-9-fluoro-5 H - Chromium[4,3-c]pyridin-8-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide Synthesis of Compound 19 Compound 18 (50 mg, 0.312 mmol) was resolved chirally (column: chiralpak IC, 250*30 mm, 5). m; Mobile phase: acetonitrile, isopropanol (diethylamine 0.2%); Gradient ratio: acetonitrile phase 60%; Flow rate: 15 mL / min; Column temperature: 30℃) yielded compound 19 (two diastereomer peaks, compound 19 being the second eluting peak). MS-ESI: m / z 422.2 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (s, 1H), 8.69 (d, 1H), 8.02 (d, 1H), 7.98 (s, 1H), 7.06 (d, 1H), 5.29-5.21 (m, 2H), 5.11-5.01 (m,1H), 4.01-3.95 (m, 1H), 3.89-3.81 (m, 1H), 3.77-3.68 (m, 1H), 3.30-3.20 (m,2H), 3.02 (dd, 1H), 2.80-2.72 (m, 1H), 2.62-2.50 (m, 2H), 1.81-1.62 (m, 2H).

[0290] Example 20 ( S )- N -(( S )-1-cyano-2-(2,8-difluoro-6 H -benzo[ c [Cr-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide] Synthesis of Compound 20-1 tert-butyl (2 S )-2-((1-cyano-2-(2,8-difluoro-6) H -benzo[ c Chromium-3-yl)ethyl)carbamoyl)-1,4-oxazine-4-carboxylic acid ester (compound 12-8) (160 mg, 0.31 mmol) was chirally resolved (column: chiralpak IC, 250*30 mm, 5). m; mobile phase: n-hexane, ethanol; gradient ratio: n-hexane phase 50%; flow rate: 15 mL / min; column temperature: 30℃) yielded compound 20-1 (two diastereomer peaks, compound 20-1 being the first eluted peak).

[0291] Synthesis of Compound 20 Refer to the synthesis of compound 14. MS-ESI: m / z 414.2 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6)δ 8.67 (d, 1H), 7.93-7.88 (m, 1H), 7.74 (d, 1H), 7.28-7.17 (m, 2H), 6.98 (d,1H), 5.15-5.08 (m, 2H), 5.07-4.99 (m, 1H), 4.02-3.96 (m, 1H), 3.89-3.82 (m,1H), 3.77-3.69 (m, 1H), 3.26-3.11 (m, 2H), 3.07-2.99 (m, 1H), 2.81-2.73 (m,1H), 2.64-2.52 (m, 2H), 1.80-1.65 (m, 2H).

[0292] Example 21 ( S )- N -(( S )-2-(2-chloro-8-cyano-6 H -benzo[ c Chromium-3-yl)-1-cyanoethyl)-1,4-oxazine-heptane-2-carboxamide Synthesis of compound 21-2 The synthesis of compound 14-A1 was similar, except that potassium carbonate was replaced with cesium carbonate. 1 H NMR (400MHz, DMSO- d 6) δ 8.10 (d, 1H), 7.93 (d, 1H), 7.80 (dd, 1H), 7.52 (d, 1H), 7.49(d, 1H), 7.30 (dd, 1H), 5.19 (s, 2H), 3.87 (s, 3H).

[0293] Synthesis of compound 21-3 Compound 21-2 (13.30 g, 34.90 mmol) was dissolved in anhydrous water under nitrogen protection at room temperature. N , NIn dimethylacetamide (150 mL), palladium dichloride bis(triphenylphosphine) chloride (2.45 g, 3.50 mmol) and anhydrous potassium acetate (10.30 g, 104.95 mmol) were added, and the reaction mixture was heated to 100°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with saturated brine (100 mL × 3), and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with ethyl acetate (50 mL) to give compound 21-3. 1 H NMR (400 MHz, DMSO- d 6) δ 8.22 (s, 1H), 8.19 (d,1H), 7.91 (dd, 1H), 7.84 (s, 1H), 7.42 (s, 1H), 5.26 (s, 2H), 3.86 (s, 3H).

[0294] Synthesis of compound 21-4 Refer to the synthesis of compound 14-A3. 1 H NMR (400 MHz, DMSO- d 6) δ 8.08 (d, 1H), 8.02(s, 1H), 7.85 (dd, 1H), 7.79 (s, 1H), 7.16 (s, 1H), 5.50 (t, 1H), 5.20 (s,2H), 4.54 (d, 2H).

[0295] Synthesis of compound 21-5 Refer to the synthesis of compound 14-A4. 1 H NMR (400 MHz, DMSO- d 6) δ 8.16-8.11 (m, 2H), 7.88 (dd, 1H), 7.81 (s, 1H), 7.32 (s, 1H), 5.22 (s, 2H), 4.71 (s, 2H).

[0296] Synthesis of compound 21-6 Under nitrogen protection at room temperature, sodium hydrogen (167 mg, 4.18 mmol, 60%) was added to anhydrous tetrahydrofuran (10 mL). Then, a tetrahydrofuran solution (10 mL) of diphenylmethyleneaminoacetonitrile (1.84 g, 8.37 mmol) was added at -10 °C. After stirring for 10 minutes at -10 °C, a tetrahydrofuran solution (8 mL) of compound 21-5 (700 mg, 2.09 mmol) was added. The reaction mixture was stirred at -10 °C for 20 minutes. A tetrahydrofuran solution of crude compound 21-6 was obtained and used directly in the next reaction. MS-ESI: m / z 474.1 [M+1] + .

[0297] Synthesis of Compound 21-7 At room temperature, a tetrahydrofuran solution (1.27 g, 2.69 mmol) of the crude compound 21-6 was added to anhydrous tetrahydrofuran (10 mL), and the pH was adjusted to 5-6 with 1M hydrochloric acid (10 mL). The reaction mixture was stirred at room temperature for 16 hours. Water (30 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (50 mL × 2). The aqueous phase was adjusted to pH 7-8 with saturated sodium bicarbonate solution, and extracted with ethyl acetate (30 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound 21-7, which was used directly in the next reaction. MS-ESI: m / z 310.1 [M+1] + .

[0298] Synthesis of Compound 21-8 At room temperature, crude compound 21-7 (500 mg, 1.26 mmol) and compound 2-6 (309 mg, 1.26 mmol) were dissolved in anhydrous water. N , N In a mixed solvent of dimethylformamide (3 mL) and anhydrous dichloromethane (6 mL), benzotriazole was then added. N , N , N ', N '-Tetramethylurea hexafluorophosphate (955 mg, 2.52 mmol) and N , N- Diisopropylethylamine (407 mg, 3.15 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. Saturated sodium bicarbonate aqueous solution (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was first separated by column chromatography (SiO2, ethyl acetate), and then by preparative liquid chromatography (column: Phenomenex luna C18, 150*40 mm, 15...). m; Mobile phase: water (0.225% formic acid), acetonitrile; Gradient ratio: acetonitrile phase 52-82%; Flow rate: 60 mL / min; Column temperature: room temperature) Separation yielded compounds 21-8. MS-ESI: m / z 481.1 [M-56+1] + .

[0299] Synthesis of Compounds 21-9 Compound 21-8 (390 mg, 0.73 mmol) was obtained via preparative-grade SFC (column: DAICEL CHIRALCELOJ, 250*30 mm, 10). m; mobile phase: supercritical carbon dioxide, methanol (0.1% ammonia monohydrate); gradient ratio: carbon dioxide phase 55%; flow rate: 70 mL / min; column temperature: room temperature) resolution yielded compound 21-9 (two diastereomer peaks, compound 21-9 being the second eluted peak).

[0300] Synthesis of Compound 21 Refer to the synthesis of compound 14. MS-ESI: m / z 437.2 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6)δ 8.70 (d, 1H), 8.14-8.09 (m, 2H), 7.87 (dd, 1H), 7.80 (d, 1H), 7.07 (s, 1H), 5.25-5.15 (m, 2H), 5.07-4.99 (m, 1H), 3.94-3.85 (m, 2H), 3.74-3.66 (m, 1H), 3.32-3.20 (m, 2H), 3.12 (dd, 1H), 2.84-2.76 (m, 1H), 2.74-2.62 (m, 2H), 1.84-1.64 (m, 2H).

[0301] Example 22 4-Amino- N -(1-Cyano-2-(8-Fluoro-6) H -Benzo[c]chromo-3-yl)ethyl)tetrahydro-2 H pyran-4-carboxamide carboxylate Synthesis of compound 22-1 Referring to the synthesis of compounds 1-7, except N,N -dimethylformamide was changed to N,N -A mixed solvent of dimethylformamide and dichloromethane (10 / 1), all other conditions are similar. MS-ESI: m / z 396.1 [M-100+1] + .

[0302] Synthesis of Compound 22 Refer to the synthesis of compound 1. MS-ESI: m / z 396.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ:8.25 (d, 1H), 8.00, (s, 1H), 7.66-7.63 (m, 2H), 7.07 (td, 1H), 6.99-6.96 (m,1H), 6.89-6.87 (m, 2H), 5.13–5.08 (m, 3H), 3.93–3.83 (m, 2H), 3.65–3.56 (m,2H), 3.08 (d, 2H), 2.33–2.16 (m, 2H), 1.32–1.22 (m, 2H).

[0303] Example 23 4-Amino- N -(1-Cyano-2-(3-Fluoro-6) H -benzo[ c [Cr-8-yl)ethyl)tetrahydro-2 H pyran-4-carboxamide Synthesis of Compound 23-1 Referring to the synthesis of compounds 1-7, except N,N -dimethylformamide was changed to N,N -A mixed solvent of dimethylformamide and dichloromethane (10 / 1), all other conditions are similar. MS-ESI:m / z 396.1 [M-100+1] + .

[0304] Synthesis of Compound 23 Refer to the synthesis of compound 1. MS-ESI: m / z 396.1 [M+H] + . 1 H NMR (400 MHz, DMSO) d 6 )δ: 7.93-7.88 (m, 1H), 7.76 (d, 1H), 7.33 (d, 1H), 7.18 (s, 1H), 6.95-6.84 (m,2H), 6.06 (br s, 2H), 5.13 (s, 2H), 5.00-4.96 (m, 1H), 3.63–3.50 (m, 3H), 3.49-3.38 (m, 1H), 3.18-3.14 (m, 2H), 1.93-1.85 (m, 1H), 1.78-1.71 (m, 1H), 1.23-1.11 (m, 2H).

[0305] Example 24 4-Amino- N -(1-Cyano-2-(2,8-Difluoro-6) H -Benzo[c]chromo-3-yl)ethyl)tetrahydro-2 H pyran-4-carboxamide Synthesis of Compound 24-1 Refer to the synthesis of compounds 1-7. MS-ESI: m / z 458.1 [M-56+1] + .

[0306] Synthesis of Compound 24 The synthesis of compound 14 was similar, except the reaction temperature was changed from 40℃ to 30℃. MS-ESI: m / z 414.2 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 8.29 (d, 1H), 7.59-7.54 (m, 1H), 7.35(d, 1H), 7.12-7.05 (m, 1H), 6.91-6.86 (m, 1H), 5.16-5.08 (m, 1H), 5.06 (s,2H), 3.94-3.81 (m, 2H), 3.65-3.55 (m, 2H), 3.24-3.17 (m, 1H), 3.13-3.06 (m,1H), 2.32-2.22 (m, 1H), 2.21-2.11 (m, 1H), 1.32-1.26 (m, 1H), 1.23-1.17 (m,1H).

[0307] Example 25 4-Amino- N -(1-Cyano-2-(8-Cyano-6) H -benzo[ c [Cr-3-yl)ethyl)tetrahydro-2 H pyran-4-carboxamide Synthesis of Compound 25-1 Refer to the synthesis of compound 21-8. MS-ESI: m / z 403.3 [M-100+1] + .

[0308] Synthesis of Compound 25 Refer to the synthesis of compound 1. MS-ESI: m / z 403.3 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ8.28 (d, 1H), 7.77-7.71 (m, 2H), 7.67 (d, 1H), 7.46 (s, 1H), 7.02 (d, 1H), 6.91 (d, 1H), 5.15–5.07 (m, 3H), 3.94–3.84 (m, 2H), 3.65–3.56 (m, 2H), 3.10 (d, 2H), 2.34–2.16 (m, 2H), 1.31–1.21 (m, 2H).

[0309] Example 26 (2 S ,3a S ,6a S )- N -(( S )-1-cyano-2-(8-cyano-2-fluoro-6 H -benzo[c [Cr-3-yl)ethyl)octahydrocyclopentane[ b ]Pyrrole-2-carboxamide Synthesis of compound 26-2 At room temperature, (2) S ,3a S ,6a S )-1-(tert-Butoxycarbonyl)octahydrocyclopentane[ b Pyrrole-2-carboxylic acid (compound 26-1) (174 mg, 0.68 mmol) and N , N , N ', N '-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (259 mg, 0.68 mmol) soluble in N , N Add 3-(2-amino-2-cyanoethyl)-2-fluoro-6-dimethylformamide (5 mL) to the mixture after stirring for ten minutes. H -benzo[ c Chromium-8-carbamate (compound 14-A6) (200 mg, 0.68 mmol) and triethylamine (0.19 mL, 1.36 mmol) were reacted and stirred at room temperature for 2 hours. After the reaction was complete, 10 mL of ethyl acetate was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative thin-layer chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 26-2. MS-ESI: m / z 529.1 [M-1] - .

[0310] Synthesis of compound 26-3 Compound 26-2 (300 mg, 0.57 mmol) was resolved chirally (column: chiralpak IE, 250*30 mm, 5). m; mobile phase: n-hexane, ethanol; gradient ratio: n-hexane phase 50%; flow rate: 25 mL / min; column temperature: 30℃) yielded compound 26-3 (two diastereomer peaks, compound 26-3 being the second eluted peak).

[0311] Synthesis of Compound 26 The synthesis of compound 14 was similar, except the temperature was changed to 50℃. MS-ESI: m / z 431.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 8.53 (d, 1H), 8.04 (d, 1H), 7.91-7.83 (m,2H), 7.79 (s, 1H), 7.03 (d, 2H), 5.20-5.11 (m, 2H), 5.10-5.04 (m, 1H), 3.57(t, 1H), 3.42-3.36 (m, 1H), 3.26-3.21 (m, 2H), 2.43-2.37 (m, 1H), 2.09-2.00(m, 1H), 1.62-1.49 (m, 2H), 1.45-1.35 (m, 3H), 1.24-1.14 (m, 1H), 1.02-0.93(m, 1H).

[0312] Example 27 ( S )- N -(( S )-1-cyano-2-(8-cyano-2-fluoro-6,6-dimethyl-6 H -benzo[ c [Cr-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide] Synthesis of Compound 27-2 2-Bromo-4-fluoro-1-methoxybenzene (compound 27-1) (9.24 g, 45.29 mmol) was dissolved in titanium tetrachloride (16.8 mL, 153.23 mmol) at room temperature and under nitrogen protection. Dichloromethyl methyl ether (13.9 mL, 153.68 mmol) was added at 0 °C, and the reaction mixture was heated to 30 °C and stirred for 1.5 hours. After the reaction was complete, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (25 mL × 3), the organic phases were combined, washed with saturated brine (25 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1) to obtain compound 27-2. 1H NMR (300 MHz, CDCl3) δ 10.31 (s, 1H), 7.45 (d, 1H), 7.31 (d,1H), 3.93 (s, 3H).

[0313] Synthesis of compound 27-3 Compound 27-2 (7.00 g, 30.18 mmol) was dissolved in methanol (60 mL) at room temperature. Sodium borohydride (1.14 g, 30.14 mmol) was added at 0 °C, and the reaction mixture was slowly heated to room temperature and stirred for 1 hour. After the reaction was complete, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (25 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 27-3. 1 H NMR (400 MHz, CDCl3) δ 7.25 (d, 1H), 6.98 (d, 1H), 4.71 (s, 2H), 3.88 (s, 3H).

[0314] Synthesis of compound 27-4 Compound 27-3 (4.20 g, 17.86 mmol) was dissolved in dichloromethane (60 mL) at room temperature, followed by the addition of imidazole (1.46 g, 21.44 mmol) and tert-butyldiphenylchlorosilane (5.57 mL, 21.44 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (25 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 70 / 1) to obtain compound 27-4. 1 H NMR (400 MHz, CDCl3) δ 7.70-7.64 (m, 4H), 7.46-7.34 (m, 6H), 7.25-7.15 (m, 2H), 4.79 (s, 2H), 3.86 (s, 3H), 1.12 (s, 9H).

[0315] Synthesis of compound 27-5 Compound 27-4 (5.00 g, 10.88 mmol), pinacol diboronate (3.59 g, 14.14 mmol), 1,1'-bis(diphenylphosphine)ferrocene and palladium chloride (0.80 g, 1.08 mmol), and potassium acetate (3.20 g, 32.64 mmol) were dissolved in 1,4-dioxane (80 mL) at room temperature and under nitrogen protection. The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (25 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 70 / 1) to give compound 27-5. 1 H NMR (400 MHz, CDCl3) δ7.71-7.64 (m, 4H), 7.44-7.33 (m, 6H), 7.26 (d, 1H), 7.16 (d, 1H), 4.84 (s, 2H), 3.81 (s, 3H), 1.35 (s, 12H), 1.10 (s, 9H).

[0316] Synthesis of compound 27-6 Compound 27-5 (6.00 g, 11.53 mmol), methyl 5-bromo-2-iodobenzoate (4.72 g, 13.83 mmol), 1,1'-bis(diphenylphosphine)ferrocene and palladium chloride (0.85 g, 1.15 mmol), and potassium carbonate (4.78 g, 34.58 mmol) were dissolved in a mixed solvent of 1,4-dioxane (80 mL) and water (16 mL) under nitrogen protection at room temperature. The reaction mixture was heated to 50 °C and stirred for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (25 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1) to obtain compound 27-6. 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, 1H), 7.74-7.67 (m, 4H),7.66 (dd, 1H), 7.46-7.35 (m, 6H), 7.16 (d, 2H), 6.87 (d, 1H), 4.88 (s, 2H), 3.69 (s, 3H), 3.67 (s, 3H), 1.12 (s, 9H).

[0317] Synthesis of compound 27-7 Compound 27-6 (4.20 g, 6.91 mmol) was dissolved in tetrahydrofuran (80 mL) at room temperature and under nitrogen protection. Methyllithium (9.9 mL, 19.80 mmol, 2.0 mol / L) was added dropwise at 0 °C, and the reaction mixture was slowly heated to room temperature and stirred for 2 hours. After the reaction was complete, water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (25 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain compound 27-7. 1 H NMR (300 MHz, CDCl3) δ 7.79 (s, 1H), 7.71 (d, 4H), 7.43-7.34 (m, 7H), 7.25-7.16 (m, 1H), 6.87 (d, 1H), 6.76 (d, 1H), 4.89 (s, 2H), 3.71 (s, 3H), 1.49 (s, 3H), 1.35 (s, 3H), 1.13 (s, 9H).

[0318] Synthesis of Compounds 27-8 Compound 27-7 (2.00 g, 3.29 mmol) was dissolved in acetonitrile (30 mL) at room temperature, followed by the dropwise addition of hydroiodic acid (7.5 mL, 55% aqueous solution). The reaction mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, saturated sodium thiosulfate aqueous solution (250 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to give compound 27-8. 1 H NMR (400 MHz, DMSO- d 6) δ7.82 (d, 1H), 7.71 (d, 1H), 7.59-7.53 (m, 2H), 6.98 (d, 1H), 5.30 (t, 1H), 4.52 (d, 2H), 1.56 (s, 6H).

[0319] Synthesis of Compound 27-9 Compound 27-8 (100 mg, 0.29 mmol) and zinc cyanide (42 mg, 0.35 mmol) were dissolved in nitrogen at room temperature and under nitrogen protection. N , N In dimethylformamide (3 mL), tetrakis(triphenylphosphine)palladium (34.3 mg, 0.031 mmol) was added, and the reaction mixture was heated to 140 °C and stirred in a sealed container for 16 hours. The reaction mixture was cooled to room temperature, and saturated sodium bicarbonate aqueous solution (20 mL) was added. Extraction was performed with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (25 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compounds 27-9. 1 H NMR (400 MHz, DMSO- d 6) δ 8.05 (d, 1H), 7.90-7.78 (m, 3H), 7.02 (d, 1H), 5.36 (t, 1H), 4.53 (d, 2H), 1.59 (s, 6H).

[0320] Synthesis of compound 27-10 Refer to the synthesis of compound 18-7. 1 H NMR (400 MHz, DMSO- d 6) δ 8.08 (d, 1H), 7.96-7.83 (m, 3H), 7.15 (d, 1H), 4.68 (s, 2H), 1.60 (s, 6H).

[0321] Synthesis of compound 27-11 The synthesis of compound 14-A5 was similar, except that benzyltrimethylammonium chloride was replaced with benzyltriethylammonium chloride. 1H NMR (300 MHz, CDCl3) δ 7.67-7.57 (m, 4H), 7.53-7.40 (m, 5H), 7.40-7.30 (m, 3H), 7.05-6.94 (m, 2H), 6.90 (d, 1H), 4.51 (t, 1H), 3.38-3.22 (m,2H), 1.66 (s, 3H), 1.56 (s, 3H).

[0322] Synthesis of compound 27-12 Refer to the synthesis of compound 14-A6. 1 H NMR (300 MHz, CDCl3) δ 7.71-7.60 (m, 2H),7.52 (s, 1H), 7.42 (d, 1H), 6.91 (d, 1H), 4.01 (s, 1H), 3.10-3.05 (m, 2H),1.71 (s, 3H), 1.64 (s, 3H).

[0323] Synthesis of Compound 27-13 Referring to the synthesis of compound 14-A7, except N , N -Other conditions are similar except that diisopropylethylamine is replaced with triethylamine. MS-ESI: m / z 547.2 [M-1] - .

[0324] Synthesis of Compound 27-14 Compound 27-13 (230 mg, 0.42 mmol) was first separated by chirality (column: chiralpak IC, 250*30 mm, 5). m; Mobile phase: n-hexane, ethanol; Gradient ratio: 50% n-hexane phase; Flow rate: 25 mL / min; Column temperature: 30℃) The crude compound 27-14 was obtained (three diastereomer peaks, with the crude compound 27-14 being the first eluted peak). Further chiral resolution was performed (column: chiralpak IG, 250*30 mm, 5...). m; mobile phase: n-hexane, ethanol; gradient ratio: n-hexane phase 60%; flow rate: 25 mL / min; column temperature: 30℃) yielded compound 27-14 (two diastereomer peaks, compound 27-14 being the first eluted peak).

[0325] Synthesis of Compound 27 Refer to the synthesis of compound 14. MS-ESI: m / z 449.2 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6)δ 8.67 (d, 1H), 8.06 (d, 1H), 7.90-81 (m, 3H), 6.95 (d, 1H), 5.11-5.02 (m,1H), 4.01-3.94 (m, 1H), 3.88-3.80 (m, 1H), 3.76-3.67 (m, 1H), 3.24-3.16 (m,2H), 3.00 (dd, 1H), 2.80-2.71 (m, 1H), 2.62-2.52 (m, 2H), 1.77-1.67 (m, 2H), 1.58 (s, 6H).

[0326] Example 28 (2 S )- N -(1-Cyano-2-(9-(oxetan)-3-yl)-6 H -benzo[ c [Cr-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide] Synthesis of Compound 28-2 2-Bromo-4-hydroxybenzaldehyde (compound 28-1) (4 g, 19.90 mmol) was dissolved in tetrahydrofuran (50 mL) at room temperature. Sodium hydride (1.19 g, 29.85 mmol, 60%) was added in portions at 0 °C, and the mixture was stirred at 0 °C for 5 minutes. Then, bromomethyl methyl ether (2.98 g, 23.88 mmol) was added dropwise, and the reaction mixture was stirred at 0 °C for another 30 minutes. After the reaction was complete, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (25 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain product compound 28-2. 1 H NMR (400 MHz, CDCl3) δ10.24 (d, 1H), 7.88 (d, 1H), 7.30 (d, 1H), 7.10-7.03 (m., 1H), 5.23 (s, 2H), 3.49 (s, 3H).

[0327] Synthesis of Compound 28-3 Compound 28-2 (4.40 g, 17.95 mmol) was dissolved in methanol (50 mL) at room temperature. Sodium borohydride (1.36 g, 35.91 mmol) was added in portions at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. After the reaction was complete, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phases were washed with saturated brine (25 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude compound 28-3. 1 H NMR (300 MHz, CDCl3) δ 7.39-7.33 (m, 1H), 7.30-7.24 (m, 1H), 7.03-6.96 (m, 1H), 5.15 (s, 2H), 4.69 (s, 2H), 3.47 (s, 3H).

[0328] Synthesis of compound 28-4 At room temperature, crude compound 28-3 (5.00 g, 20.24 mmol) and triethylamine (6.14 g, 60.71 mmol) were dissolved in dichloromethane (50 mL), and methanesulfonyl chloride (3.48 g, 30.35 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 20 minutes. After the reaction was complete, the reaction mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL × 2). The combined organic phases were washed with saturated brine (25 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude intermediate.

[0329] At room temperature, m-hydroxybenzoic acid (2.34 g, 15.38 mmol) was dissolved in... N , N In 50 mL of dimethylformamide, sodium hydride (0.80 g, 19.99 mmol, 60%) was added at 0 °C and stirred for 5 minutes at 0 °C. Then, the crude intermediate (5 g, 15.38 mmol) was added. N , N A 10 mL solution of dimethylformamide was added, and the reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was poured into 150 mL of water and extracted with ethyl acetate (50 mL × 2). The organic phases were combined and washed successively with 25 mL of water and 10 mL of saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to give compound 28-4. 1 H NMR (300 MHz, CDCl3) δ 7.69-7.64 (m, 2H), 7.47-7.30 (m, 3H), 7.20-7.14(m, 1H), 7.05-6.97 (m, 1H), 5.30 (s, 2H), 5.17 (s, 2H), 3.92 (s, 3H), 3.48 (s, 3H).

[0330] Synthesis of compound 28-5 Compound 28-4 (4.90 g, 12.85 mmol), potassium carbonate (3.55 g, 25.71 mmol), tricyclohexylphosphide tetrafluoroborate (0.47 g, 1.28 mmol), and palladium acetate (0.29 g, 1.28 mmol) were dissolved in nitrogen at room temperature and under nitrogen protection. N , NIn dimethylformamide (50 mL), the reaction mixture was heated to 120 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, poured into water (200 mL), and extracted with ethyl acetate (50 mL × 2). The organic phases were combined and washed successively with water (25 mL × 2) and saturated brine (25 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to give compound 28-5. 1 HNMR (300 MHz, CDCl3) δ 7.77-7.70 (m, 2H), 7.69-7.62 (m, 1H), 7.43-7.38 (m,1H), 7.13-7.07 (m, 1H), 7.06-6.98 (m, 1H), 5.23 (s, 2H), 5.10 (s, 2H), 3.92 (s, 3H), 3.51 (s, 3H).

[0331] Synthesis of compound 28-6 Compound 28-5 (4.00 g, 13.33 mmol) was dissolved in tetrahydrofuran (40 mL) at room temperature. Concentrated hydrochloric acid (4 mL) was then added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to obtain compound 28-6. 1 H NMR (400 MHz, DMSO- d 6) δ 9.67 (s, 1H), 7.87 (d,1H), 7.67-7.61 (m, 1H), 7.45 (s, 1H), 7.23 (d, 1H), 7.13 (d, 1H), 6.85-6.78(m, 1H), 5.09 (s, 2H), 3.86 (s, 3H).

[0332] Synthesis of compound 28-7 At room temperature, compound 28-6 (1.20 g, 4.68 mmol) and triethylamine (1.40 g, 13.84 mmol) were dissolved in dichloromethane (30 mL), and then added... N-Phenylbis(trifluoromethanesulfonyl)imide (2.00 g, 5.60 mmol), the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was poured into water (30 mL) and extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to give compound 28-7. 1 H NMR (400 MHz, CDCl3) δ 7.79-7.73 (m, 1H), 7.73-7.69 (m, 1H), 7.67 (d,1H), 7.60 (d, 1H), 7.29-7.22 (m, 2H), 5.16 (s, 2H), 3.93 (s, 3H).

[0333] Synthesis of Compound 28-8 Compound 28-7 (1.60 g, 4.12 mmol) and pinacol diborate (1.20 g, 4.73 mmol) were dissolved in 1,4-dioxane (40 mL) at room temperature and under nitrogen protection. Potassium acetate (1.20 g, 12.23 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (300 mg, 0.410 mmol) were then added. The reaction mixture was heated to 85 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, poured into water (100 mL), extracted with ethyl acetate (80 mL × 3), washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to obtain compound 28-8. 1 H NMR (400MHz, CDCl3) δ 8.18 (s, 1H), 7.90 (d, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.63(s, 1H), 7.18 (d, 1H), 5.16 (s, 2H), 3.92 (s, 3H),1.37 (s, 12H).

[0334] Synthesis of Compounds 28-9 Compound 28-8 (1.50 g, 4.10 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, followed by the addition of sodium periodate (2.65 g, 12.27 mmol), ammonium acetate (0.95 g, 12.32 mmol), and water (10 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with a mixture of ethyl acetate and petroleum ether (50 mL) to give compound 28-9. 1 H NMR (400 MHz, DMSO- d 6) δ 8.38 (s, 1H), 8.23 ​​(s, 2H), 8.03 (d, 1H), 7.81(d, 1H), 7.72-7.65 (m, 1H), 7.47 (d, 1H), 7.28 (d, 1H), 5.21 (s, 2H), 3.86(s, 3H).

[0335] Synthesis of Compound 28-10 Compound 28-9 (1.10 g, 3.87 mmol) and 3-iodoxetane (800 mg, 4.35 mmol) were dissolved in isopropanol (30 mL) under nitrogen protection at room temperature. Then, nickel iodide (300 mg, 0.96 mmol), 2-aminocyclohexanol hydrochloride (100 mg, 0.87 mmol), and potassium bis(trimethylsilyl)amino (8.0 mL, 8.00 mmol, 1.0 mol / L tetrahydrofuran solution) solution were added. The reaction mixture was heated to 100 °C and stirred for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to obtain compound 28-10.

[0336] Synthesis of compound 28-11 Refer to the synthesis of compound 12-4. MS-ESI: m / z 251.2 [M-18+1] + .

[0337] Synthesis of compound 28-12 The synthesis of compound 18-7 was similar, except that dichloromethane was replaced with tetrahydrofuran. 1 H NMR (400MHz, CDCl3) δ 7.76-7.70 (m, 2H), 7.34 (d, 1H), 7.16 (d, 1H), 7.13-7.07 (m,1H), 7.03 (s, 1H), 5.16-5.08 (m, 4H), 4.80 (t, 2H), 4.47 (s, 2H), 4.32-4.21(m, 1H).

[0338] Synthesis of Compound 28-13 Diphenylmethyleneaminoacetonitrile (135 mg, 0.61 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature, followed by the addition of sodium hydroxide (75 mg, 1.88 mmol) and water (3 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then compound 28-12 (200 mg, 0.604 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to obtain compound 28-13. MS-ESI: m / z 471.5 [M+1] + .

[0339] Synthesis of Compound 28-14 Refer to the synthesis of compound 14-A6. MS-ESI: m / z 329.1 [M+1] + .

[0340] Synthesis of Compound 28-15 Referring to the synthesis of compound 14-A7, except N , N -Other conditions are similar except that diisopropylethylamine is replaced with triethylamine. MS-ESI: m / z 434.5 [M-100+1] + .

[0341] Synthesis of Compound 28 Refer to the synthesis of compound 14. MS-ESI: m / z 434.2 [M+1] + . 1H NMR (400 MHz, CD3OD) δ7.83 (d, 1H), 7.79 (s, 1H), 7.41-7.38 (m, 1H), 7.24 (d, 1H), 7.04-7.01 (m,1H), 6.93 (d, 1H), 5.18-5.01 (m, 5H), 4.85-4.78 (m, 2H), 4.41-4.31 (m, 1H), 4.15-3.94 (m, 2H), 3.83-3.75 (m, 1H), 3.31-3.10 (m, 3H), 2.99-2.63 (m, 3H), 1.97-1.79 (m, 2H).

[0342] Example 29 (2 S )- N -(1-Cyano-2-(2-Fluoro-8-(Methanesulfonyl)-6 H Benzo[ c [Cr-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide] Synthesis of Compound 29-2 2-Bromo-5-hydroxybenzaldehyde (compound 29-1) (13 g, 64.67 mmol) was dissolved in nitrogen at room temperature and under nitrogen protection. N , N In dimethylformamide (50 mL), sodium hydride (1.63 g, 67.90 mmol, 60%) was added in portions at 0 °C, and the mixture was stirred at 0 °C for 10 minutes. Then, bromomethyl ether (8.49 g, 67.90 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for another 30 minutes. After the reaction was complete, water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to give compound 29-2. 1 H NMR(300 MHz, CDCl3) δ 10.31 (s, 1H), 7.60-7.51 (m, 2H), 7.15 (dd, 1H), 5.20 (s,2H), 3.47 (s, 3H).

[0343] Synthesis of Compound 29-3 Compound 29-2 (9.60 g, 39.17 mmol) was dissolved in a mixture of water (10 mL) and methanol (100 mL) at room temperature. Sodium borohydride (2.22 g, 58.76 mmol) was slowly added at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, ethyl acetate (20 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was then extracted with water (30 mL) and ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 29-3. 1 H NMR (300 MHz, CDCl3) δ 7.43 (d, 1H), 7.19 (d, 1H), 6.86 (dd, 1H), 5.17 (s, 2H), 4.71 (s, 2H), 3.47 (s, 3H).

[0344] Synthesis of Compound 29-4 Refer to the synthesis of compound 18-3. 1 H NMR (300 MHz, CDCl3) δ 7.54-7.50 (m, 1H), 7.47(d, 1H), 7.23 (d, 1H), 7.18-7.01 (m, 2H), 6.86 (dd, 1H), 5.15 (s, 2H), 5.07(s, 2H), 3.94 (s, 3H), 3.46 (s, 3H).

[0345] Synthesis of Compound 29-5 Refer to the synthesis of compound 18-4. MS-ESI: m / z 319.2 [M+1] + .

[0346] Synthesis of Compound 29-6 Compound 29-5 (3.50 g, 11.00 mmol) was dissolved in methanol (20 mL) at room temperature, and 6 M hydrochloric acid (20 mL) was added. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was slurried with ethyl acetate (30 mL) to give compound 29-6. MS-ESI:m / z 275.1 [M+1] + .

[0347] Synthesis of Compound 29-7 Compound 29-6 (2.40 g, 8.75 mmol) was dissolved at room temperature in... N , N In dimethylformamide (25 mL), triethylamine (1.33 g, 13.13 mmol) was subsequently added and N -Phenylbis(trifluoromethanesulfonyl)imide (3.75 g, 10.50 mmol) was reacted with the reaction mixture stirred at room temperature for 1.5 hours. After the reaction was complete, water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to give compound 29-7. 1 H NMR (300 MHz, CDCl3) δ 7.73 (d, 1H), 7.57 (d, 1H), 7.44 (d, 1H), 7.35-7.26 (m, 1H), 7.14 (d, 1H), 5.14 (s, 2H), 3.94 (s, 3H).

[0348] Synthesis of Compound 29-8 Compound 29-7 (1.00 g, 2.46 mmol), tris(dibenzylacetone)dipalladium (0.20 g, 0.25 mmol), potassium carbonate (0.68 g, 4.92 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (0.28 g, 0.49 mmol) were dissolved in 1,4-dioxane (10 mL) at room temperature and under nitrogen protection. Then, 4-methoxybenzylthiol (0.42 g, 2.72 mmol) was added, and the reaction mixture was heated to 70 °C and stirred for 1.5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to give compound 29-8. MS-ESI: m / z 411.3 [M+1] + .

[0349] Synthesis of Compound 29-9 Compound 29-8 (860 mg, 1.86 mmol) was dissolved in trifluoroacetic acid (9 mL) at room temperature. The reaction mixture was heated to 70 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (25 mL × 3). The combined organic phases were washed with saturated brine (25 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude intermediate. This crude intermediate was then used... N , N Dissolve dimethylformamide (6 mL), add sodium hydride (32.23 mg, 1.34 mmol) in portions at 0 °C, stir at room temperature for 10 min, then add iodomethane (190 mg, 1.34 mmol) dropwise, and stir the reaction mixture at room temperature for 30 min. After the reaction is complete, add water (50 mL) and extract with ethyl acetate (50 mL × 3). Combine the organic phases, wash with saturated brine (50 mL), and dry to anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, and separate the residue by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 29-9. 1 H NMR (300 MHz, CDCl3) δ 7.98 (d, 1H), 7.83 (d, 1H), 7.79 (s, 1H), 7.58 (d, 1H), 7.52 (d, 1H), 5.20 (s, 2H), 3.95 (s, 3H), 3.10 (s, 3H).

[0350] Synthesis of Compound 29-10 Compound 29-9 (400 mg, 1.32 mmol) and m-chloroperoxybenzoic acid (22 mg, 0.13 mmol, 85%) were dissolved in dichloromethane (5 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (25 mL × 3). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 29-10. 1 H NMR (300 MHz, CDCl3) δ 7.98 (d, 1H),7.83 (d, 1H), 7.79 (s, 1H), 7.58 (d, 1H), 7.52 (d, 1H), 5.20 (s, 2H), 3.95 (s, 3H), 3.10 (s, 3H).

[0351] Synthesis of Compound 29-11 Refer to the synthesis of compound 14-A3. 1 H NMR (400 MHz, CDCl3) δ 8.10 (d, 1H), 7.91(dd, 1H), 7.89 (s, 1H), 7.83 (d, 1H), 7.09 (d, 1H), 5.37 (t, 1H), 5.24 (s, 2H), 4.55 (d, 2H), 3.24 (s, 3H).

[0352] Synthesis of Compounds 29-12 Refer to the synthesis of compound 14-A4. 1 H NMR (400 MHz, CDCl3) δ 7.96 (dd, 1H), 7.82-7.62 (d, 2H), 7.45 (d, 1H), 7.06 (d, 1H), 5.17 (s, 2H), 4.49 (s, 2H), 3.09 (s, 3H).

[0353] Synthesis of Compounds 29-13 Refer to the synthesis of compound 14-A5. 1 H NMR (300 MHz, CDCl3) δ 7.93 (dd, 1H), 7.76-7.71 (m, 2H), 7.65-7.59 (m, 2H), 7.50-7.42 (m, 4H), 7.38-7.32 (m, 3H), 7.09-6.99 (m, 2H), 6.91 (d, 1H), 5.12 (s, 2H), 4.54 (t, 1H), 3.36-3.15 (m, 2H), 3.08 (s, 3H).

[0354] Synthesis of compounds 29-14 Refer to the synthesis of compound 14-A6.

[0355] Synthesis of Compounds 29-15 Refer to the synthesis of compound 14-A7.

[0356] Synthesis of Compound 29 Refer to the synthesis of compound 14. MS-ESI: m / z 474.2 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ8.50 (s, 1H), 7.99-7.89 (m, 2H), 7.82 (s, 1H), 7.66 (d, 1H), 6.97 (d, 1H),5.17 (s, 2H), 5.16-5.03 (m, 1H), 4.23-4.10 (m, 1H), 4.07-3.94 (m, 1H), 3.81-3.71 (m, 1H), 3.45-3.38 (m, 0.5H), 3.32-3.28 (m, 0.5H), 3.27-3.14 (m, 2H),3.13 (s, 3H), 3.09-2.95 (m, 2H), 2.95-2.87 (m, 0.5H), 2.80-2.73 (m, 0.5H), 2.03-1.83 (m, 2H).

[0357] Example 30 ( S )- N -(( S )-1-cyano-2-(2-fluoro-8-(methanesulfonyl)-6 H Benzo[ c [Cr-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide] Synthesis of Compound 30-1 tert-butyl (2 S )-2-((1-cyano-2-(2-fluoro-8-(methanesulfonyl)-6 H Benzo[ c Chromium-3-yl)ethyl)carbamoyl)-1,4-oxazine-4-carboxylic acid ester (compounds 29-15) (100 mg, 0.17 mmol) was chirally resolved (column: chiralpak IA, 250*25 mm, 5). m; mobile phase: supercritical carbon dioxide, isopropanol; gradient ratio: carbon dioxide phase 70%; flow rate: 60 mL / min; column temperature: 30℃) yielded compound 30-1 (two diastereomer peaks, compound 30-1 being the first eluted peak).

[0358] Synthesis of Compound 30 Refer to the synthesis of compound 14. MS-ESI: m / z 474.1 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6)δ 8.70 (d, 1H), 8.15-8.09 (m, 1H), 7.96-7.85 (m, 3H), 7.04 (d, 1H), 5.29-5.17(m, 2H), 5.12-5.02 (m, 1H), 4.03-3.96 (m, 1H), 3.90-3.81 (m, 1H), 3.78-3.68(m, 1H), 3.25 (s, 3H), 3.23-3.13 (m, 2H), 3.07-2.98 (m, 1H), 2.82-2.72 (m,1H), 2.65-2.53 (m, 2H), 1.82-1.64 (m, 2H).

[0359] Example 31 (2 S )- N -(1-Cyano-2-(9-Cyano-2-Fluoro-6) H -benzo[ c [Cr-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide] Synthesis of compound 31-1 At room temperature, crude (2-bromo-4-(methoxymethoxy)phenyl)methanol (compound 28-3) (3.00 g, 12.14 mmol) and triethylamine (3.00 g, 29.65 mmol) were dissolved in dichloromethane (60 mL), followed by dropwise addition of methanesulfonyl chloride (2.00 g, 1.35 mL, 17.46 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was washed with water (10 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude intermediate.

[0360] Methyl 1-fluoro-4-hydroxybenzoate (3 g, 17.63 mmol) was dissolved in dichloromethane (100 mL) at room temperature, followed by the addition of triethylamine (3 g, 29.65 mmol). After stirring at room temperature for 10 minutes, the crude intermediate prepared by the above method (5 g, 15.38 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with water (100 mL × 3), and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was subjected to reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 8 / 1) to give compound 31-1. 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, 1H),7.49 (d, 1H), 7.38 (s, 1H), 7.22-7.07 (m, 3H), 5.29 (s, 2H), 5.14 (s, 2H),4.00 (s, 3H), 3.57 (s, 3H).

[0361] Synthesis of compound 31-2 Compound 31-1 (1 g, 2.51 mmol) and palladium acetate (0.1 g, 0.445 mmol) were dissolved in nitrogen at room temperature and under nitrogen protection. N , N In dimethylformamide (30 mL), potassium carbonate (0.50 g, 3.62 mmol) and tricyclohexyltetrafluoroborate (0.30 g, 0.63 mmol) were added, and the reaction mixture was heated to 100 °C and stirred for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with saturated ammonium chloride aqueous solution (60 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (20 mL × 3), and dried over anhydrous magnesium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to give compound 31-2. 1 H NMR (400MHz, CDCl3) δ 7.56 (d, 1H), 7.46 (d, 1H), 7.36 (s, 1H), 7.18-7.08 (m, 2H), 5.27 (s, 2H), 5.12 (s, 2H), 3.97 (s, 3H), 3.55(s, 3H).

[0362] Synthesis of compound 31-3 Compound 31-2 (5 g, 15.71 mmol) was dissolved in tetrahydrofuran (30 mL) at room temperature, followed by the addition of 2 M hydrochloric acid (5 mL). The reaction mixture was stirred at room temperature for 20 minutes. After the reaction was complete, dichloromethane (50 mL) was added to the reaction mixture, and the mixture was separated. The organic phase was washed with saturated sodium bicarbonate aqueous solution (30 mL × 3) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with ethyl acetate (20 mL) to give compound 31-3. 1 H NMR (400MHz, DMSO- d 6 ) δ 7.74 (d, 1H), 7.36 (d, 1H), 7.25 (s, 1H), 7.14 (d, 1H), 6.85 (dd, 1H), 5.07 (s, 2H), 3.85 (s, 3H).

[0363] Synthesis of compound 31-4 Compound 31-3 (1.20 g, 3.94 mmol) and triethylamine (0.80 g, 7.88 mmol) were dissolved in... N , N Add to dimethylformamide (10 mL), then add N The reaction mixture of 1.69 g (4.73 mmol) phenylbis(trifluoromethanesulfonyl)imide was stirred at room temperature for 1 hour. After the reaction was complete, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to give compound 31-4. 1 H NMR (300 MHz, DMSO- d 6) δ 8.26-8.21 (m, 1H), 8.12 (d, 1H), 7.64-7.52(m, 2H), 7.48-7.42 (m, 1H), 5.28 (s, 2H), 3.90 (s, 3H).

[0364] Synthesis of Compound 31-5 Compound 31-4 (1.80 g, 3.54 mmol), zinc cyanide (0.62 g, 5.32 mmol), and tetraphenylphosphine palladium (0.61 g, 0.53 mmol) were dissolved in nitrogen at room temperature and under nitrogen protection. N ,N In dimethylformamide (20 mL), the reaction mixture was heated to 90 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 1), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 31-5. 1 H NMR (300 MHz, DMSO- d 6) 1 H NMR (300 MHz, DMSO- d 6) δ 8.50(s, 1H), 8.09-8.05 (m, 1H), 7.91-7.89 (m, 1H), 7.56-7.53 (m, 1H), 7.42-7.40(m, 1H), 5.28 (s, 2H), 3.86 (s, 3H).

[0365] Synthesis of Compound 31-6 The synthesis of compound 14-A3 was similar, except that tetrahydrofuran was replaced with a mixed solvent of tetrahydrofuran and methanol (volume ratio 10 / 1). 1 H NMR (300 MHz, DMSO- d 6) δ 8.40 (s, 1H), 7.92-7.82 (m, 2H), 7.55-7.50 (m, 1H), 7.12-7.07 (m, 1H), 5.39 (s, 2H), 4.59-4.54 (m, 2H).

[0366] Synthesis of Compounds 31-7 Refer to the synthesis of compound 18-7. 1 H NMR (300 MHz, DMSO- d 6) δ 8.42 (s, 1H), 8.01-7.96 (m, 1H), 7.90-7.85 (m, 1H), 7.57-7.52 (m, 1H), 7.27-7.21 (m, 1H), 5.26 (s, 2H), 4.71 (s, 2H).

[0367] Synthesis of Compounds 31-8 Refer to the synthesis of compound 14-A5. MS-ESI: m / z 458.1 [M+1] + .

[0368] Synthesis of Compounds 31-9 Refer to the synthesis of compound 14-A6. MS-ESI: m / z 294.0 [M+1] + .

[0369] Synthesis of Compound 31-10 Refer to the synthesis of compound 14-A7. MS-ESI: m / z 538.2 [M+18] + .

[0370] Synthesis of Compound 31 Refer to the synthesis of compound 14. MS-ESI: m / z 421.1 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6 )δ 8.72-8.63 (m, 1H), 8.39 (s, 1H), 7.94-7.87 (m, 1H), 7.85-7.79 (m, 1H), 7.53-7.47 (m, 1H), 7.05-7.00 (m, 1H), 5.26-5.15 (m, 2H), 5.10-4.93 (m, 1H), 4.02-3.81 (m, 2H), 3.77-3.65 (m, 1H), 3.27-2.98 (m, 3H), 2.84-2.52 (m, 3H), 1.82-1.64 (m, 2H).

[0371] Example 32 ( S )- N -( S )-1-cyano-2-(9-cyano-2-fluoro-6 H -benzo[ c [Cr-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide] Synthesis of Compound 32-1 tert-butyl (2 S )-2-((1-Cyano-2-(9-Cyano-2-Fluoro-6) H -benzo[ cChromium-3-yl)ethyl)carbamoyl)-1,4-oxazine-4-carboxylic acid ester (compounds 31-10) (350 mg, 0.67 mmol) was chirally resolved (column: chiralpak IC, 250*30 mm, 5). m; mobile phase: n-hexane, ethanol; gradient ratio: n-hexane phase 30%; flow rate: 25 mL / min; column temperature: 30 °C) yielded compound 32-1 (two diastereomer peaks, compound 32-1 being the second eluted peak).

[0372] Synthesis of Compound 32 Refer to the synthesis of compound 14. MS-ESI: m / z 421.2 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6)δ 8.70 (d, 1H), 8.39 (s, 1H), 7.91 (d, 1H), 7.82 (d, 1H), 7.50 (d, 1H), 7.02(d, 1H), 5.26-5.14 (m, 2H), 5.10-5.00 (m, 1H), 4.02-3.95 (m, 1H), 3.89-3.82(m, 1H), 3.77-3.69 (m, 1H), 3.28-3.12 (m, 2H), 3.05-2.98 (m, 1H), 2.81-2.72(m, 1H), 2.63-2.51 (m, 2H), 1.81-1.64 (m, 2H).

[0373] Example 33 (2 S )- N -(1-Cyano-2-(3-Cyano-9-Fluoro-5-) H -color full and [4,3- b ]pyridin-8-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide Synthesis of compound 33-2 At room temperature, 2-fluoro-5-hydroxybenzoic acid (compound 33-1) (25.00 g, 146.93 mmol) was dissolved in chloroform (300 mL). A solution of liquid bromine (76.70 g, 480.00 mmol) in acetic acid (300 mL) was slowly added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. At 0°C, a saturated aqueous solution of sodium thiosulfate (300 mL) was slowly added and stirred for 15 minutes. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (300 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with dichloromethane (50 mL) to give compound 33-2. 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.59 (s, 1H), 7.56 (d, 1H), 7.40 (d, 1H).

[0374] Synthesis of compound 33-3 Compound 33-2 (22.60 g, 84.60 mmol) was dissolved in methanol (100 mL) at room temperature, followed by the slow addition of thionyl chloride (20.10 g, 177.36 mmol). The reaction mixture was heated to 70°C and stirred for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate (150 mL), washed successively with water (50 mL) and saturated sodium chloride aqueous solution (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude compound 33-3. 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, 1H), 7.32 (d, 1H), 3.94 (s, 3H).

[0375] Synthesis of compound 33-4 Compound 33-3 (20.70 g, 69.80 mmol), potassium carbonate (19.30 g, 139.64 mmol), and p-methoxybenzyl chloride (12.00 g, 76.62 mmol) were dissolved in acetonitrile (100 mL) at room temperature. The reaction mixture was heated to 80°C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (300 mL), and extracted with ethyl acetate (150 mL × 4). The organic phases were combined and washed successively with water (200 mL) and saturated sodium chloride aqueous solution (200 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 33-4. 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, 1H), 7.42-7.37(m, 3H), 6.96-6.92 (m, 2H), 5.09 (s, 2H), 3.94 (s, 3H), 3.83 (s, 3H).

[0376] Synthesis of compound 33-5 Compound 33-4 (24.30 g, 45.40 mmol), bis(diphenylphosphine)boronic acid ester (13.80 g, 54.34 mmol), potassium acetate (8.91 g, 90.78 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium chloride (3.32 g, 4.54 mmol) were dissolved in dioxane (100 mL) at room temperature and under nitrogen protection. The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed successively with water (100 mL) and saturated sodium chloride aqueous solution (80 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 33-5. MS-ESI: m / z 439.2 [M+23] + . 1 H NMR (400 MHz, CDCl3) δ 7.53-7.40 (m, 4H), 6.91(d, 2H), 5.06 (s, 2H), 3.94 (s, 3H), 3.83 (s, 3H), 1.36 (s, 12H).

[0377] Synthesis of compound 33-6 Compound 33-5 (16.50 g, 31.70 mmol), 2,5-dibromopyridin-3-ylmethanol (10.80 g, 38.00 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium chloride (2.32 g, 3.17 mmol), and sodium carbonate (6.72 g, 63.4 mmol) were dissolved in a mixed solvent of dioxane (150 mL) and water (5 mL) at room temperature and under nitrogen protection. The reaction mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (300 mL), and extracted with ethyl acetate (150 mL × 3). The combined organic phases were washed successively with water (200 mL) and saturated sodium chloride aqueous solution (200 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give compound 33-6. MS-ESI: m / z 476.1 [M+1] + .

[0378] Synthesis of compound 33-7 Compound 33-6 (6.80 g, 9.56 mmol) was dissolved in dichloromethane (10 mL) at room temperature, followed by the addition of trifluoroacetic acid (30 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give compound 33-7. MS-ESI: m / z 355.9 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 8.63 (d, 1H), 8.31 (d, 1H), 7.58 (d, 1H), 7.33 (d, 1H), 4.83 (s, 2H), 3.96 (s, 3H).

[0379] Synthesis of compound 33-8 Compound 33-7 (3.70 g, 10.10 mmol) was dissolved in tetrahydrofuran (100 mL) under nitrogen protection at room temperature, followed by the addition of triphenylphosphine (3.45 g, 13.15 mmol). After stirring at 0°C for 30 minutes, diisopropyl azodicarbonate (2.66 g, 13.15 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (80 mL) and saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 33-8. MS-ESI: m / z 338.0 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.93 (d, 1H), 7.63 (s, 1H), 7.51 (d, 1H), 5.22 (s, 2H), 3.94 (s, 3H).

[0380] Synthesis of Compound 33-9 At room temperature, compound 33-8 (2.60 g, 7.68 mmol) and cuprous cyanide (2.06 g, 23.00 mmol) were dissolved in... N In 20 mL of methylpyrrolidone, the reaction mixture was heated to 135 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with 50 mL of water, and extracted with 40 mL × 3 ethyl acetate solutions. The combined organic phases were washed successively with 30 mL of water and 30 mL of saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, dichloromethane) to give compound 33-9. MS-ESI: m / z 285.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (d, 1H), 8.31-8.27 (m, 1H), 7.95 (d, 1H), 7.45 (d, 1H), 5.40 (s, 2H), 3.87 (s, 3H).

[0381] Synthesis of compound 33-10 The synthesis of compound 14-A3 was similar, except that the temperature was changed to room temperature. MS-ESI: m / z 257.1[M+1] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.99 (d, 1H), 8.22 (d, 1H), 7.77 (d, 1H), 7.11 (d, 1H), 5.45 (t, 1H), 5.33 (s, 2H), 4.57 (d, 2H).

[0382] Synthesis of compound 33-11 The synthesis of compound 18-7 was similar, except the temperature was changed to 0℃. MS-ESI: m / z 319.0 [M+1] + .

[0383] Synthesis of compound 33-12 Diphenylmethyleneaminoacetonitrile (221 mg, 1.00 mmol) was dissolved in tetrahydrofuran (3 mL) at room temperature. Sodium hydroxide (20 mg, 0.50 mmol, 60%) was slowly added at 0°C, and the mixture was stirred at 0°C for 30 minutes. Then, compound 33-11 (90 mg, 0.25 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The pH was then adjusted to 2 with 1M hydrochloric acid, and the reaction mixture was stirred for another 15 hours at room temperature. The reaction mixture was diluted with 1M hydrochloric acid (10 mL) and washed with ethyl acetate (20 mL × 3). The aqueous phase was adjusted to pH 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed successively with water (20 mL) and saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude compound 33-12. MS-ESI: m / z 295.0 [M+1] + .

[0384] Synthesis of compound 33-13 Referring to the synthesis of compound 14-A7, except N , N , N ', N Replace '-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea with benzotriazine- N,N,N',N '-Tetramethylurea hexafluorophosphate' is used under similar conditions. MS-ESI: m / z 422.1 [M-100+1]+ .

[0385] Synthesis of Compound 33 Refer to the synthesis of compound 14. MS-ESI: m / z 422.1 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6 )δ 9.00 (d, 1H), 8.67 (dd, 1H), 8.22 (s, 1H), 7.80 (dd, 1H), 7.07 (d, 1H),5.39-5.27 (m, 2H), 5.12-4.96 (m, 1H), 4.00-3.90 (m, 1H), 3.89-3.81 (m, 1H), 3.77-3.66 (m, 1H), 3.27-3.17 (m, 2H), 3.14-2.98 (m, 1H), 2.84-2.66 (m, 2H), 2.64-2.54 (m, 1H), 1.82-1.63 (m, 2H).

[0386] Example 34 4-Amino- N -(1-Cyano-2-(9-(pyrrolid-3-yl)-6 H Benzo[ c [Cr-3-yl)ethyl)tetrahydro-2 H pyran-4-carboxamide Synthesis of compound 34-3 Compounds 34-1 (900 mg, 3.05 mmol) and 34-2 (957 mg, 3.24 mmol) were dissolved in a mixed solvent of toluene (50 mL) and water (5 mL) under nitrogen protection at room temperature. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (100 mg, 0.12 mmol) and potassium acetate (1.00 g, 10.19 mmol) were added. The mixture was heated to 100 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature, diluted with saturated ammonium chloride solution (40 mL), and extracted with ethyl acetate (25 mL × 3). The combined organic phases were washed with water (10 mL × 3) and dried over anhydrous magnesium sulfate. After filtration, the residue was concentrated under reduced pressure and separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain compound 34-3.1 H NMR (300 MHz, CDCl3) δ 7.86-7.69 (m, 4H),7.43-7.37 (m,1H), 7.21 (d, 1H), 6.27 (d, 1H), 5.20 (s, 2H), 4.66-4.52 (m, 2H), 4.50–4.32 (m, 4H), 1.59–1.50 (m, 9H), 1.45 (t, 3H).

[0387] Synthesis of compound 34-4 Compound 34-3 (350 mg, 0.830 mmol) and palladium on carbon (100 mg, 10%) were dissolved in methanol (20 mL) at room temperature. The reaction mixture was heated to 50 °C and stirred for 4 hours under a hydrogen balloon atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 34-4, which was used directly in the next reaction step. 1 H NMR(300 MHz, CDCl3) δ 7.85-7.74 (m, 2H), 7.66 (d, 2H), 7.27-7.16 (m, 2H), 5.16(s, 2H), 4.41 (q, 2H), 3.97–3.80 (m, 1H), 3.76-3.58 (m,1H), 3.57-3.25 (m,3H), 2.41-2.25 (m, 1H), 2.14-1.98 (m, 1H), 1.52 (s, 9H), 1.44(t, 3H).

[0388] Synthesis of Compound 34-5 The synthesis of compound 14-A3 was similar, except that the temperature was changed from 55℃ to room temperature. 1 H NMR (300MHz, CDCl3) δ 7.76-7.69 (m, 1H),7.58 (s, 1H), 7.24-7.01 (m, 4H), 5.18 (s,2H), 4.52 (s, 2H), 4.00-3.78 (m, 1H), 3.75-3.55 (m,1H), 3.53-3.28 (m, 3H), 2.41-2.25 (m, 1H), 2.17-2.00 (m, 1H), 1.45 (s, 9H).

[0389] Synthesis of Compound 34-6 Refer to the synthesis of compound 18-7. 1H NMR (400 MHz, CDCl3) δ 7.91-7.83 (m, 1H),7.82-7.74 (m, 1H), 7.67-7.51 (m, 2H), 7.23-7.10 (m, 1H), 7.08-6.96 (m, 1H),5.15 (s, 2H), 3.97-3.81 (m, 1H), 3.79-3.59 (m, 1H), 3.56-3.31 (m, 3H), 3.07(d, 2H), 2.42-2.26 (m, 1H), 2.14-2.01 (m, 1H), 1.54 (s, 9H).

[0390] Synthesis of Compound 34-7 Refer to the synthesis of compounds 14-A5, 14-A6, and 14-A7. MS-ESI: m / z 491.2 [M-100-56+1] + .

[0391] Synthesis of Compound 34 Refer to the synthesis of compound 14. MS-ESI: m / z 447.3 [M+1] + . 1 H NMR (400 MHz, DMSO- d6 )δ 7.85 (d, 1H),7.73 (s, 1H), 7.25-7.18 (m, 2H), 6.99 (d, 1H), 6.91 (s, 1H),5.07 (s, 2H), 4.98 (t, 1H), 3.78-3.69 (m, 1H), 3.64-3.55 (m, 3H), 3.54-3.40(m, 3H), 3.30-3.20 (m, 2H), 3.15-3.10 (m, 2H), 2.27-2.17 (m, 1H), 2.08-1.97(m, 1H), 1.94-1.83 (m, 1H), 1.78-1.68 (m, 1H), 1.25–1.08 (m, 2H).

[0392] Example 35 (2 S )- N -(2-(8-(azacyclobutane-1-ylsulfonyl)-2-fluoro-6 H -benzo[ c [Cr-3-yl)-1-cyanoethyl)-1,4-oxazine-heptane-2-carboxamide] Synthesis of Compound 35-1 The synthesis of compound 29-8 was similar, except that the reaction temperature was changed from 70℃ to 80℃. MS-ESI: m / z 437.1 [M+1] + .

[0393] Synthesis of Compound 35-2 Compound 35-1 (300 mg, 0.69 mmol) and acetic acid (0.5 mL) were dissolved in tetrahydrofuran (5 mL) at room temperature. Water (0.5 mL) and dichlorohydantoin (300 mg, 1.52 mmol) were added at 0 °C, and the reaction mixture was stirred at room temperature for 5 minutes. After the reaction was complete, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude intermediate. The crude intermediate was dissolved in dichloromethane (5 mL), and aziridine (50 mg, 0.88 mmol) and triethylamine (170 mg, 1.68 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was poured into water (10 mL) and extracted with dichloromethane (10 mL × 3). Combine the organic phases, wash with saturated brine (30 mL), and dry to anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, and separate the residue by column chromatography (SiO2, dichloromethane / methanol = 24 / 1) to obtain compound 35-2. MS-ESI: m / z 378.2 [M+1] + .

[0394] Synthesis of compound 35-3 The synthesis of compound 12-4 was similar, except that the temperature was changed from 0°C to room temperature. MS-ESI: m / z 350.2 [M+1] + .

[0395] Synthesis of compound 35-4 Refer to the synthesis of compound 14-A4. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, 1H), 7.76-7.67 (m, 2H), 7.43 (d, 1H), 7.06 (d, 1H), 5.15 (s, 2H), 4.49 (s, 2H), 3.48-3.41 (m, 2H), 3.23-3.14 (m, 2H), 2.12-2.05 (m, 2H).

[0396] Synthesis of compound 35-5 Diphenylmethyleneaminoacetonitrile (90 mg, 0.49 mmol) was dissolved in tetrahydrofuran (5 mL). Sodium hydroxide (45 mg, 1.13 mmol) and water (2 mL) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 10 minutes, followed by the addition of compound 35-4 (150 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to obtain compound 35-5. MS-ESI: m / z 552.4 [M+1] + .

[0397] Synthesis of Compound 35-6 Refer to the synthesis of compound 14-A6.

[0398] Synthesis of Compound 35-7 Referring to the synthesis of compound 14-A7, except N , N -Other conditions are similar except that diisopropylethylamine is replaced with triethylamine. MS-ESI: m / z 515.4 [M-100+1] + .

[0399] Synthesis of Compound 35 Refer to the synthesis of compound 14. MS-ESI: m / z 515.2 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6)δ 8.72-8.65 (m, 1H), 8.17-8.11 (m, 1H), 7.93-7.86 (m, 1H), 7.81-7.76 (m, 2H),7.05 (d, 1H), 5.33-5.20 (m, 2H), 5.12-4.94 (m, 1H), 4.03-3.81 (m, 2H), 3.78-3.67 (m, 5H), 3.30-3.00 (m, 3H), 2.86-2.51 (m, 3H), 2.06-1.96 (m, 2H), 1.83-1.65 (m, 2H).

[0400] Example 36 4-Amino- N -(1-cyano-2-(9-fluoro-6,7-dihydrodibenzo[] b , d Oxepin-3-yl)ethyl)tetrahydro-2 H pyran-4-carboxamide Synthesis of Compound 36-1 Compound 11-1 (3.00 g, 12.99 mmol) was dissolved in tetrahydrofuran (25 mL) at room temperature. Sodium hydride (1.04 g, 25.97 mmol, 60%) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. Then, bromomethyl methyl ether (3.25 g, 25.97 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 12 h. After the reaction was complete, the reaction was quenched with water (100 mL), and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1) to give compound 36-1. MS-ESI: m / z 274.9 [M+1] + .

[0401] Synthesis of compound 36-2 Compound 36-1 (5.40 g, 19.63 mmol), pinacol diborate (6.98 g, 27.48 mmol), potassium acetate (3.85 g, 39.26 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.44 g, 1.96 mmol) were dissolved in dioxane (50 mL) at room temperature and under nitrogen protection. The reaction mixture was heated to 90 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain compound 36-2. MS-ESI: m / z 323.1 [M+1] + .

[0402] Synthesis of compound 36-3 Compound 12-1 (5.00 g, 18.66 mmol) and sodium cyanide (1.30 g, 27.99 mmol) were dissolved in dimethyl sulfoxide (50 mL) at room temperature. The reaction mixture was heated to 35 °C and stirred for 3 hours. After the reaction was complete, water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1) to give compound 36-3. 1 H NMR (400 MHz, CDCl3): δ 7.59-7.55 (m, 1H), 7.32-7.26 (m, 1H), 7.00-6.95 (m, 1H), 3.83 (s, 2H).

[0403] Synthesis of compound 36-4 Compound 36-3 (3.60 g, 15.98 mmol) was dissolved in 20 mL of 8 M hydrogen chloride in methanol at room temperature. The reaction mixture was heated to 80 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the residue was adjusted to pH 7 with 50 mL of saturated sodium bicarbonate solution. Extraction was performed with ethyl acetate (50 mL × 2), the organic phases were combined, washed with 30 mL of saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, yielding the crude product of compound 36-4. 1 H NMR (400 MHz, CDCl3): δ 7.54-7.50 (m, 1H), 7.06-7.03 (m, 1H), 6.91-6.86 (m, 1H), 3.77 (s, 2H), 3.73 (s, 3H).

[0404] Synthesis of compound 36-5 Compound 36-4 (3 g, 10.93 mmol) was dissolved in tetrahydrofuran (30 mL) at room temperature. Lithium aluminum hydride (0.41 g, 10.93 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 20 min. After the reaction was complete, water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain compound 36-5. 1 H NMR (400 MHz, CDCl3): δ 7.57-7.52 (m, 1H), 7.09-7.05 (m, 1H), 6.91-6.85 (m, 1H), 3.93 (t, 2H), 3.04 (t, 2H).

[0405] Synthesis of compound 36-6 Compound 36-5 (2.40 g, 10.41 mmol), compound 36-2 (4.01 g, 11.45 mmol), 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (0.76 g, 1.04 mmol), and potassium carbonate (2.88 g, 20.82 mmol) were dissolved in a mixed solvent of dioxane (40 mL) and water (7 mL) under nitrogen protection at room temperature. The reaction mixture was heated to 80 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain 36-6. 1 H NMR (300 MHz, CDCl3): δ 7.88 (s, 1H), 7.82-7.78 (m, 1H), 7.25(d, 1H), 7.20-7.10 (m, 2H), 7.08-6.97 (m, 1H), 5.21-5.13 (m, 2H), 3.99 (s,3H), 3.75-3.67 (m, 2H), 3.38 (s, 3H), 2.79-2.74 (m, 2H).

[0406] Synthesis of Compounds 36-7 Compound 36-6 (3.20 g, 8.61 mmol) was dissolved in 30 mL of 8 M hydrogen chloride methanol solution at room temperature, and the reaction mixture was stirred for 1.5 hours at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was adjusted to pH 7 with 50 mL of saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 36-7, which was used directly in the next reaction. MS-ESI: m / z 289.0 [M-1] - .

[0407] Synthesis of Compound 36-8 Compound 36-7 (2.60 mg, 8.15 mmol) and triphenylphosphine (2.99 g, 11.41 mmol) were dissolved in tetrahydrofuran (150 mL) at room temperature, followed by the dropwise addition of diisopropyl azodicarbonate (2.05 g, 9.781 mmol). The reaction mixture was stirred at room temperature for 12 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL × 2), washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1) to give compound 36-8. MS-ESI: m / z 273.1 [M+1] + .

[0408] Synthesis of Compounds 36-9 Refer to the synthesis of compound 12-4. 1 H NMR (300 MHz, CDCl3) δ7.44-7.32 (m, 2H), 7.25-7.16 (m, 2H), 7.12-6.98 (m, 2H), 4.73 (s,2H), 4.57 (t, 2H), 2.79 (t, 2H).

[0409] Synthesis of compound 36-10 Refer to the synthesis of compound 14-A4. 1 H NMR (300 MHz, CDCl3) δ7.47-7.36 (m, 2H),7.35-7.28 (m, 1H), 7.25-7.20 (m, 1H), 7.17-7.03 (m, 2H), 4.62 (t, 2H), 4.56(s, 2H), 2.85 (t, 2H).

[0410] Synthesis of compound 36-11 Refer to the synthesis of compound 14-A5. MS-ESI: m / z 447.1 [M+1] + .

[0411] Synthesis of compound 36-12 Refer to the synthesis of compound 14-A6. MS-ESI: m / z 283.1 [M+1] + .

[0412] Synthesis of compound 36-13 Referring to the synthesis of compound 14-A7, except ( S )-4-(tert-butoxycarbonyl)-1,4-oxazine-2-carboxylic acid is replaced with 4-((tert-butoxycarbonyl)amino)tetrahydro-2 H Other conditions are similar except for pyran-4-carboxylic acid. MS-ESI: m / z 410.1 [M-100+1] + .

[0413] Synthesis of Compound 36 Refer to the synthesis of compound 14. MS-ESI: m / z 410.3 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ8.23 (d, 1H), 7.42-7.33 (m, 2H), 7.20-7.12 (m, 1H), 7.11-6.98 (m, 3H), 5.17-5.08 (m, 1H), 4.55 (t, 2H), 3.95-3.82 (m, 2H), 3.65-3.52 (m, 2H), 3.12 (d,2H), 2.78 (t, 2H), 2.36-2.12 (m, 2H), 1.32-1.15 (m, 2H).

[0414] Example 37 4-Amino- N -(1-cyano-2-(9-fluoro-5,7-dihydrodibenzo[] c , e Oxypiken-3-yl)ethyl)tetrahydro-2 H pyran-4-carboxamide Synthesis of Compound 37-2 At room temperature, ethyl 4-hydroxybenzoate (compound 37-1) (3.00 g, 18.05 mmol) and triethylamine (15.1 mL, 108.32 mmol) were dissolved in 1,2-dichloroethane (100 mL), and anhydrous magnesium chloride (8.59 g, 90.27 mmol) was added. The reaction mixture was heated to 40 °C and stirred for 1 h, followed by the addition of paraformaldehyde (6.2 mL, 180.53 mmol), and the mixture was heated to 80 °C and stirred for another 15 h. The reaction mixture was cooled to room temperature, and water (100 mL) and concentrated hydrochloric acid (5 mL) were added. The mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain a white solid product 37-2. 1 H NMR (300 MHz, CDCl3) δ 11.39 (s, 1H), 9.96 (s, 1H), 8.35-8.30 (m, 1H), 8.24-8.17 (m, 1H), 7.04 (q, 1H), 4.39 (q, 2H), 1.41 (t, 3H).

[0415] Synthesis of compound 37-3 At room temperature, compound 37-2 (2.00 g, 10.30 mmol) and triethylamine (4.3 mL, 30.9 mmol) were dissolved in dichloromethane (30 mL), and then added... N -Phenylbis(trifluoromethanesulfonyl)imide (4.42 g, 12.36 mmol), the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, water (30 mL) was added and the mixture was extracted with dichloromethane (25 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to give compound 37-3. 1 H NMR (300 MHz, CDCl3) δ 10.29 (s, 1H), 8.68-8.63 (d, 1H), 8.43-8.35 (m, 1H), 7.54-7.47 (m, 1H), 4.44 (q, 2H), 1.43 (t, 3H).

[0416] Synthesis of compound 37-4 Refer to the synthesis of compound 36-6.1 H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 9.75 (d,1H), 8.68 (d, 1H), 8.36-8.30 (m, 1H), 7.78-7.71 (m, 1H), 7.45-7.37 (m, 2H),7.35-7.30 (m, 1H), 4.46 (q, 2H), 1.45 (t, 3H).

[0417] Synthesis of compound 37-5 Compound 37-4 (2.20 g, 7.33 mmol) was dissolved in a mixed solvent of tetrahydrofuran (20 mL) and ethanol (10 mL) at room temperature. Sodium borohydride (0.28 g, 7.33 mmol) was added in portions at 0 °C, and the reaction mixture was stirred at 0 °C for 20 min. After the reaction was complete, the reaction mixture was poured into water (20 mL), adjusted to pH 6 with 2 N hydrochloric acid, and extracted with ethyl acetate (25 mL × 3). The combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 8 / 1) to obtain compound 37-5. 1 H NMR (400 MHz, CDCl3) δ 8.18 (d, 1H), 8.05-7.98 (m, 1H), 7.30-7.26 (m, 1H), 7.25-7.20 (m, 1H), 7.10-7.01 (m, 2H), 4.46-4.37 (m, 4H), 4.33-4.28 (m, 2H), 1.42 (t, 3H).

[0418] Synthesis of compound 37-6 Compound 37-5 (2.15 g, 7.07 mmol) was dissolved in phosphoric acid (30 mL) at room temperature, and the reaction mixture was heated to 150 °C and stirred for 1 h. After the reaction was complete, the reaction mixture was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl acetate (25 mL × 3). The organic phases were combined, washed with water (10 mL × 2) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude compound 37-6. 1 H NMR (400 MHz, DMSO- d6) δ 13.08(s, 1H), 8.12-8.06 (m, 2H), 7.76-7.68 (m, 2H), 7.51-7.40 (m, 1H), 4.33 (s,2H), 4.26 (s, 2H).

[0419] Synthesis of compound 37-7 Compound 37-6 (1.60 g, 6.20 mmol) was dissolved in tetrahydrofuran (40 mL) at 0 °C, and a borane tetrahydrofuran solution (9.29 mL, 9.29 mmol, 1.0 mol / L) was added dropwise. The reaction mixture was heated to 50 °C and stirred for 3 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and water (30 mL) was added to the residue. The residue was extracted with ethyl acetate (25 mL × 3). The combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to obtain compound 37-7. MS-ESI: m / z 226.9 [M-18+1] + .

[0420] Synthesis of Compound 37-8 Compound 37-7 (1.50 g, 6.14 mmol) was dissolved in chloroform (10 mL) at room temperature, followed by the dropwise addition of phosphorus tribromide (0.7 mL, 7.37 mmol). The reaction mixture was heated to 50 °C and stirred for 30 minutes. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (20 mL) and ethyl acetate (20 mL) were added to the residue, and the pH was adjusted to 7 with a saturated sodium carbonate aqueous solution. The mixture was extracted with a mixture of petroleum ether and ethyl acetate (5 / 1, 25 mL × 3). The combined organic phases were washed with saturated brine (5 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude compound 37-8, which was used directly in the next reaction. 1 H NMR (300 MHz, CDCl3) δ 7.57-7.44 (m, 4H), 7.25-7.12 (m, 2H), 4.57 (s, 2H), 4.35 (s, 2H), 4.32 (s, 2H).

[0421] Synthesis of Compound 37-9 The synthesis of compound 14-A5 was similar, except that the temperature was changed from 35℃ to room temperature. MS-ESI: m / z 447.3 [M+1] +.

[0422] Synthesis of compound 37-10 Refer to the synthesis of compound 14-A6.

[0423] Synthesis of Compound 37-11 Referring to the synthesis of compound 14-A7, except ( S )-4-(tert-butoxycarbonyl)-1,4-oxazine-2-carboxylic acid is replaced with 4-((tert-butoxycarbonyl)amino)tetrahydro-2 H Other conditions are similar except for pyran-4-carboxylic acid. 1 H NMR (300 MHz, CDCl3)δ 7.54-7.46 (m, 2H), 7.46-7.41 (m, 1H), 7.35-7.27 (m, 1H), 7.24-7.13 (m, 2H), 5.20-5.09 (m, 1H), 4.37-4.29 (m, 4H), 3.84-3.61 (m, 4H), 3.17-3.15 (m, 2H), 2.28-2.17 (m, 2H), 2.05-1.80 (m, 2H), 1.44 (s, 9H).

[0424] Synthesis of Compound 37 Refer to the synthesis of compound 14. MS-ESI: m / z 410.1 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6)δ 7.65-7.60 (m, 1H), 7.56-7.52 (m, 1H), 7.49-7.44 (m, 1H), 7.44-7.34 (m, 3H), 5.08-5.01 (m, 1H), 4.27-4.16 (m, 4H), 3.66-3.52 (m, 3H), 3.49-3.40 (m, 1H), 3.26-3.20 (m, 2H), 1.93-1.83 (m, 1H), 1.76-1.66 (m, 1H), 1.22-1.08 (m, 2H).

[0425] Examples 38A and 38B 38A: ( S )- N -(( S )-1-cyano-2-(2,8-difluoro-9-(occitan-3-yl)-6 H Benzo[c [Cr-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide] 38B: ( S )- N -(( R )-1-cyano-2-(2,8-difluoro-9-(occitan-3-yl)-6 H Benzo[ c [Cr-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide] Synthesis of compound 38-2 At room temperature, 2-bromo-4,5-difluorobenzoic acid (compound 38-1) (15 g, 63.29 mmol) was dissolved in methanol (150 mL), followed by the addition of concentrated sulfuric acid (1.24 g, 12.66 mmol). The reaction mixture was heated to 80°C. o Stirring at C for 12 hours. Cool the reaction mixture to room temperature, concentrate under reduced pressure, add water (100 mL) to the residue, and extract with ethyl acetate (100 mL × 2). Combine the organic phases, wash with saturated brine (100 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give compound 38-2. 1 H NMR (300 MHz, CDCl3) δ 7.81-7.74 (m, 1H), 7.58-7.52 (m, 1H), 3.97 (s, 3H).

[0426] Synthesis of compound 38-3 At room temperature, benzyl alcohol (6.82 mL, 63.10 mmol) was dissolved in tetrahydrofuran (100 mL), and sodium hydride (2.52 g, 63.10 mmol, 60%) was added in portions. The reaction mixture was stirred at room temperature for 10 minutes and then heated to 80°C. o The mixture was stirred at C for 2 hours, followed by the addition of a tetrahydrofuran (100 mL) solution of compound 38-2 (16 g, 57.36 mmol) at 0 °C. The reaction mixture was stirred for another 3 hours at room temperature. After the reaction was complete, the reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, ethyl acetate / petroleum ether = 9 / 1) to obtain compound 38-3. 1H NMR (300 MHz, CDCl3) δ 7.77-7.70 (m, 1H), 7.49-7.38 (m, 5H), 7.36-7.30 (m, 1H), 5.22 (s, 2H), 3.95 (s, 3H).

[0427] Synthesis of compound 38-4 At room temperature, compound 38-3 (17 g, 45.11 mmol) was dissolved in dichloromethane (50 mL). o A solution of boron tribromide in dichloromethane (49.62 mL, 49.62 mmol, 1.0 M) was added dropwise at C, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was poured into water (200 mL), extracted with dichloromethane (200 mL × 2), the organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, ethyl acetate / petroleum ether = 5 / 1) to give compound 38-4. MS-ESI: m / z 246.9 [M-1] - .

[0428] Synthesis of compound 38-5 Compound 38-4 (19 g, 68.67 mmol) was dissolved in tetrahydrofuran (200 mL) at room temperature. Sodium hydride (3.57 g, 89.27 mmol, 60%) was added in portions. The reaction mixture was stirred at room temperature for 1 hour. o Chloromethyl ether (11.16 g, 89.27 mmol) was added dropwise at C, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 2), washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 10 / 1) to obtain compound 38-5. 1 H NMR (300 MHz, CDCl3) δ 7.72 (d, 1H), 7.54 (d, 1H), 5.31 (s, 2H), 3.95 (s, 3H), 3.57 (s, 3H).

[0429] Synthesis of compound 38-6 Compound 38-5 (17 g, 52.20 mmol) was dissolved in a mixed solvent of tetrahydrofuran (180 mL) and methanol (45 mL) at room temperature, followed by the addition of lithium borohydride (4.55 g, 208.81 mmol) in portions. The reaction mixture was heated to 55°C. o Stirring at C for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and water (400 mL) was added. Extraction was performed with ethyl acetate (200 mL × 2). The organic phases were combined, washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, ethyl acetate / petroleum ether = 3 / 1) to give compound 38-6. 1 H NMR (300 MHz, DMSO- d 6) δ 7.50 (d, 1H), 7.36 (d, 1H), 5.55-5.51 (m, 1H), 5.29 (s, 2H), 4.48-4.43 (m, 2H), 3.44 (s, 3H).

[0430] Synthesis of compound 38-7 Compound 6 (13 g, 49.04 mmol) was dissolved in dichloromethane (130 mL) at room temperature, followed by the addition of triethylamine (10.2 mL, 73.56 mmol), and then methanesulfonyl chloride (6.74 g, 58.85 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (100 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined and washed with saturated brine (250 mL × 2). The mixture was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude intermediate, which was used directly in the next reaction step.

[0431] At room temperature, methyl 2-fluoro-5-hydroxybenzoate (14.72 g, 86.55 mmol) was dissolved in... N , N Sodium hydride (1.50 g, 62.51 mmol, 60%) was slowly added to dimethylformamide (165 mL) at 0 °C. The reaction mixture was stirred at room temperature for half an hour, followed by dropwise addition of the crude intermediate (16.5 g, 48.08 mmol). N , NA solution of 30 mL dimethylformamide was added, and the reaction mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, water (500 mL) was added, and the mixture was extracted with ethyl acetate (250 mL × 3). The organic phases were combined, washed with saturated brine (250 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was slurried in a mixture of petroleum ether and ethyl acetate (10 / 1) to give compound 38-7. 1 H NMR (400 MHz, CDCl3): δ 7.51-7.43 (m, 2H), 7.29 (d, 1H), 7.15-7.07(m, 2H), 5.21 (s, 2H), 5.03 (s, 2H), 3.94 (s, 3H), 3.53 (s, 3H).

[0432] Synthesis of compound 38-8 Compound 38-7 (15.50 g, 37.15 mmol), potassium carbonate (10.27 g, 74.31 mmol), palladium acetate (0.83 g, 3.70 mmol), and tricyclohexylphosphine tetrafluoroborate (1.25 g, 3.72 mmol) were dissolved in nitrogen at room temperature and under nitrogen protection. N , N In dimethylformamide (160 mL), the reaction mixture was heated to 115 °C and stirred for 2 hours. After the reaction was complete, water (600 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (500 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, ethyl acetate / petroleum ether = 5 / 1) to give compound 38-8. 1 H NMR (300 MHz, CDCl3): δ7.56-7.44 (m, 2H), 7.37 (d, 1H), 6.94 (d, 1H), 5.28 (s, 2H), 5.04 (s, 2H), 3.93 (s, 3H), 3.58 (s, 3H).

[0433] Synthesis of Compounds 38-9 Compound 38-8 (7.50 g, 22.30 mmol) was dissolved in methanol (70 mL) with hydrochloric acid (20 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was slurried with a mixture of petroleum ether and ethyl acetate (2 / 1) to give compound 38-9. MS-ESI: m / z 293.2 [M+1] + . 1 H NMR (400 MHz, DMSO- d6 ): δ 10.13 (s, 1H), 7.70 (dd, 1H), 7.44 (d, 1H), 7.36 (dd, 1H), 7.18 (d, 1H), 5.06 (s, 2H), 3.85 (s, 3H). Synthesis of compound 38-10 At room temperature, 2,8-difluoro-9-hydroxy-6 H -benzo[ c Methyl thiocarboxylate (compound 38-9) (5.30 g, 18.10 mmol) and pyridine (5.73 g, 72.50 mmol) were dissolved in dichloromethane (30 mL), and trifluoromethanesulfonic anhydride (7.67 g, 27.18 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (80 mL), extracted with ethyl acetate (80 mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, ethyl acetate / petroleum ether = 1 / 1) to give compound 38-10. MS-ESI: m / z 425.0 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 7.58 (t, 2H), 7.37 (d, 1H), 7.14 (d, 1H), 5.12 (s, 2H), 3.95 (s, 3H).

[0434] Synthesis of compound 38-11 Compound 38-10 (3.40 g, 8.01 mmol), bis-pinacolborate (4.07 g, 16.03 mmol), potassium acetate (2.36 g, 24.04 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (586 mg, 0.80 mmol) were dissolved in dioxane (20 mL) at room temperature and under nitrogen protection. The reaction mixture was heated to 110°C and stirred for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed successively with water (80 mL) and saturated sodium chloride aqueous solution (50 mL), and dried over anhydrous sodium sulfate. Filtration was performed, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, ethyl acetate / petroleum ether = 1 / 1) to obtain the crude product, which was then slurried with methyl tert-butyl ether (10 mL) to give compound 38-11. MS-ESI: m / z 403.2 [M+1] + .

[0435] Synthesis of compound 38-12 Compound 38-11 (5.70 g, 14.10 mmol) was dissolved in methanol (170 mL) at room temperature, followed by the addition of copper bromide aqueous solution (170 mL, 42.50 mmol, 0.25 M). The reaction mixture was heated to 80°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was extracted with (80 mL × 3) water. The combined organic phases were washed successively with water (50 mL) and saturated sodium chloride aqueous solution (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, ethyl acetate / petroleum ether = 2 / 1) to give compound 38-12. MS-ESI: m / z 355.0 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.35 (d, 1H), 8.00 (d, 1H), 7.39 (m,2H), 5.15 (s, 2H), 3.85 (s, 3H).

[0436] Synthesis of compound 38-13 Compound 38-12 (2.00 g, 5.18 mmol), 3-iodoxetane (1.24 g, 6.73 mmol), and [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine] were subjected to nitrogen protection at room temperature. N 1, N 1]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl] N ]Phenyl- C Iridium(III) hexafluorophosphate (58.3 mg, 0.05 mmol), sodium carbonate (1.09 g, 10.28 mmol), nickel dichloro(4,4′-di-tert-butyl-2,2′-bipyridine) (10.2 mg, 0.03 mmol), and tris(trimethylsilyl)silane (1.29 g, 5.18 mmol) were dissolved in ethylene glycol dimethyl ether (80 mL). The reaction mixture was stirred at room temperature for 14 hours under a 34 W blue LED lamp. The reaction mixture was diluted with water (50 mL × 3) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed successively with water (50 mL) and saturated sodium chloride aqueous solution (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, ethyl acetate / petroleum ether = 1 / 1) to give compound 38-13. MS-ESI: m / z 333.1 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ7.75 (d, 1H), 7.55 (d, 1H), 7.48 (d, 1H), 6.90 (d, 1H), 5.12 (dd, 2H), 5.09(s, 2H), 4.87 (t, 2H), 4.61-4.51 (m, 1H), 3.95 (s, 3H).

[0437] Synthesis of compound 38-14 Compound 38-13 (1.80 g, 4.71 mmol) was dissolved in tetrahydrofuran (15 mL) at room temperature and under nitrogen protection. A tetrahydrofuran solution of lithium aluminum hydride (5.2 mL, 5.20 mmol, 1 mol / L) was slowly added dropwise at 0°C. The reaction mixture was stirred at room temperature for 20 minutes. After the reaction was complete, the reaction mixture was quenched in an ice bath with a saturated sodium potassium tartrate aqueous solution (10 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed successively with water (80 mL) and a saturated sodium chloride aqueous solution (50 mL). The mixture was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, ethyl acetate / petroleum ether = 1 / 1) to obtain compound 38-14. MS-ESI: m / z 287.1 [M-18+1] + . 1 HNMR (400 MHz, CDCl3) δ 7.69 (d, 1H), 7.41 (d, 1H), 7.08 (d, 1H), 6.88 (d,1H), 5.12 (dd, 2H), 5.06 (s, 2H), 4.88 (t, 2H), 4.76 (s, 2H), 4.61-4.52 (m,1H).

[0438] Synthesis of compound 38-15 Compound 38-14 (1.10 g, 3.61 mmol) and diisopropylethylamine (1.87 g, 14.47 mmol) were dissolved in dichloromethane (20 mL) at room temperature. Methanesulfonic anhydride (1.26 g, 7.23 mmol) was slowly added at 0 °C, and the reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude intermediate, which was used directly in the next reaction step.

[0439] At room temperature, the crude intermediate (1.30 g, 3.40 mmol) and sodium bromide (3.50 g, 34.02 mmol) were dissolved in acetone (10 mL), and the reaction mixture was heated to 60°C and stirred for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, ethyl acetate / petroleum ether = 5 / 1) to give compound 38-15. 1H NMR (400 MHz, CDCl3) δ 7.70 (d, 1H), 7.42 (d, 1H), 7.02(d, 1H), 6.88 (d, 1H), 5.12 (dd, 2H), 5.07 (s, 2H), 4.88 (t, 2H), 4.62-4.51(m, 1H), 4.50(s, 2H).

[0440] Synthesis of compound 38-16 At room temperature, diphenylmethyleneaminoacetonitrile (2.64 g, 12.56 mmol) was dissolved in tetrahydrofuran (50 mL). Sodium hydroxide (263 mg, 6.59 mmol, 60%) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 30 minutes. Compound 38-15 (1.10 g, 2.99 mmol) was then added, and stirring continued at room temperature for 2 hours. After the reaction was complete, 1M hydrochloric acid (20 mL) was slowly added at 0 °C to adjust the pH to 2-3. The reaction mixture was diluted with 1M hydrochloric acid aqueous solution (30 mL), washed with ethyl acetate (50 mL × 3), and the aqueous phase was adjusted to pH 8 with sodium bicarbonate solid and extracted with ethyl acetate (80 mL × 3). The organic phases were combined and washed successively with water (50 mL) and saturated sodium chloride aqueous solution (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 38-16, which was used directly in the next reaction. MS-ESI: m / z 343.2 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.96 (d, 1H), 7.91 (d, 1H), 7.17 (d, 1H), 7.01(d, 1H), 5.09 (s, 2H), 4.96-4.89 (m, 2H), 4.88-4.82 (m, 2H), 4.59-4.47 (m,1H), 4.02-3.94 (m,1H), 2.94 (dd, 2H).

[0441] Synthesis of Compound 38-17 At room temperature, the crude product of compound 38-16 (700 mg, 2.04 mmol) and compound 2-6 (551 mg, 2.24 mmol) were... N , N -Diisopropylethylamine (792 mg, 6.13 mmol) soluble in N ,N Add benzotriazole to dimethylformamide (20 mL) and then add benzotriazole. N , N , N , N -Tetramethylurea hexafluorophosphate (930 mg, 2.45 mmol), the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed successively with water (20 mL) and saturated sodium chloride aqueous solution (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, ethyl acetate / petroleum ether = 1 / 2) to give compound 38-17.

[0442] Synthesis of compounds 38-18A and 38-18B Compound 38-17 (730 mg, 1.19 mmol) was prepared and resolved by SFC (column: DAICELCHIRALCEL OJ, 250*30 mm, 10). m; mobile phase: supercritical carbon dioxide, methanol (0.1% ammonia monohydrate); gradient ratio: carbon dioxide phase 65%; flow rate: 65 mL / min; column temperature: room temperature) yielded compounds 38-18A and 38-18B (two diastereomer peaks, compound 38-18A being the second eluted peak and compound 38-18B being the first eluted peak).

[0443] Synthesis of Compound 38A The synthesis of compound 14 was similar, except the temperature was changed to 50°C. MS-ESI: m / z 468.2 [M-1] - . 1 H NMR (400 MHz, DMSO- d 6) δ 8.69 (d, 1H), 7.98-7.87 (m, 2H), 7.17 (d, 1H), 6.97 (d, 1H), 5.13-4.98 (m, 3H), 4.94-4.88 (m, 2H), 4.84 (t, 2H), 4.57-4.48(m, 1H), 3.99 (dd, 1H), 3.90-3.81 (m, 1H), 3.77-3.67 (m, 1H), 3.26-3.20 (m,1H), 3.18-3.12 (m, 1H), 3.02 (dd, 1H), 2.82-2.73 (m, 1H), 2.63-2.53 (m, 2H), 1.81-1.62 (m, 2H).

[0444] Synthesis of Compound 38B The synthesis of compound 14 was similar, except the temperature was changed to 50°C. MS-ESI: m / z 470.1 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.65 (d, 1H), 8.01-7.89 (m, 2H), 7.17 (d, 1H), 6.98 (d, 1H), 5.09 (s, 2H), 4.99-4.94 (m, 1H), 4.92 (dd, 2H), 4.84 (t, 2H),4.57-4.47 (m, 1H), 3.94-3.86 (m, 2H), 3.72-3.68 (m, 1H), 3.26-3.18 (m, 2H),3.16-3.08 (m, 1H), 2.83-2.77 (m, 1H), 2.73-2.66 (m, 2H), 1.81-1.66 (m, 2H).

[0445] Example 39 4-Amino- N- (1-Cyano-2-(3-Fluoro-6,7-dihydrodibenzo[ b,d Oxypiken-9-yl)ethyl)tetrahydro-2 H pyran-4-carboxamide Synthesis of compound 39-2 2-Bromo-5-fluorophenol (compound 39-1) (10.00 g, 52.65 mmol) was dissolved in tetrahydrofuran (50 mL) under nitrogen protection at room temperature. Sodium hydride (3.10 g, 77.50 mmol, 60%) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 1 hour. Subsequently, bromomethyl methyl ether (9.50 g, 76.02 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was poured into ice water (50 mL), extracted with ethyl acetate (50 mL × 3), washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 39-2. 1 H NMR (400 MHz, CDCl3) δ7.50-7.44 (m, 1H), 6.93 (dd, 1H), 6.68-6.60 (m, 1H), 5.23 (s, 2H), 3.51 (s,3H).

[0446] Synthesis of compound 39-4 At room temperature, 2-(3-methoxyphenyl)ethane-1-ol (compound 39-3) (10.00 g, 65.75 mmol) was dissolved in acetonitrile (80 mL), and then... N - Succinimide bromide (11.70 g, 65.74 mmol) was reacted with the reaction mixture stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to give compound 39-4. 1 H NMR (400MHz, CDCl3) δ 7.41 (d, 1H), 6.82 (d, 1H), 6.68-6.61 (m, 1H), 3.88-3.78 (m,2H), 3.76 (s, 3H), 3.00-2.92 (m, 2H), 2.05-1.96 (m, 1H).

[0447] Synthesis of compound 39-5 Compound 39-4 (12.50 g, 54.10 mmol) was dissolved in dichloromethane (150 mL) at room temperature. Tert-butyldimethylchlorosilane (10.00 g, 66.40 mmol) and imidazole (6.00 g, 88.10 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was poured into water (100 mL) and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 19 / 1) to obtain compound 39-5. 1 H NMR (400MHz, CDCl3) δ 7.40 (d, 1H), 6.83 (d, 1H), 6.68-6.62 (m, 1H), 3.87-3.80 (m,2H), 3.78 (s, 3H), 2.98-2.90 (m, 2H), 0.88 (s, 9H), 0.01 (s, 6H).

[0448] Synthesis of compound 39-6 Compound 39-5 (15.00 g, 43.40 mmol) and pinacol diborate (15.00 g, 59.07 mmol) were dissolved in 1,4-dioxane (200 mL) at room temperature and under nitrogen protection. Potassium acetate (13.00 g, 132.46 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (2.00 g, 2.73 mmol) were then added. The reaction mixture was heated to 95 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 19 / 1) to give compound 39-6. 1 H NMR (400 MHz, CDCl3) δ 7.80-7.73 (m, 1H), 6.84-6.72 (m, 2H), 3.86-3.76 (m, 5H), 3.14 (t, 2H), 1.34 (s, 12H), 0.89 (s, 9H), 0.01 (s, 6H).

[0449] Synthesis of Compound 39-7 The synthesis of compound 36-6 was similar, except that the temperature was changed from 80℃ to 95℃. 1 H NMR (300MHz, CDCl3) δ 7.19-7.8 (m, 2H), 7.06-6.99 (m, 1H), 6.97-6.92 (m, 1H), 6.90-6.77 (m, 2H), 5.16-5.08 (m, 2H), 3.90 (s, 3H), 3.70-3.61 (m, 2H), 3.42 (s, 3H), 2.80-2.70 (m, 2H), 0.88 (s, 9H), 0.00 (s, 6H).

[0450] Synthesis of Compound 39-8 Compound 39-7 (5.80 g, 13.80 mmol) was dissolved in tetrahydrofuran (30 mL) at room temperature, followed by the addition of concentrated hydrochloric acid (5 mL). The reaction mixture was stirred at 40 °C for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (80 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to give compound 39-8. 1 H NMR (400 MHz, CDCl3) δ 7.13-7.08 (m, 1H),7.03-6.97 (m, 1H), 6.93-6.88 (m, 1H), 6.87-6.83 (m, 1H), 6.70-6.61 (m, 2H),3.83 (s, 3H), 3.76-3.71 (m, 2H), 2.76-2.60 (m, 2H).

[0451] Synthesis of compound 39-9 Refer to the synthesis of compounds 36-9. 1 H NMR (400 MHz, CDCl3) δ 7.35-7.28 (m, 2H), 6.97-6.89 (m, 2H), 6.88-6.83 (m, 2H), 4.56 (t, 2H), 3.85 (s, 3H), 2.78 (t, 2H).

[0452] Synthesis of Compound 39-10 Compound 39-9 (2.00 g, 8.19 mmol) was dissolved in dichloromethane (20 mL) under nitrogen protection at room temperature, followed by the dropwise addition of boron tribromide (12.0 mL, 12.00 mmol, 1.0 mol / L dichloromethane solution). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was poured into water (30 mL), extracted with dichloromethane (30 mL × 3), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 39-10. 1 H NMR (400 MHz, CDCl3) δ7.34-7.27 (m, 1H), 7.27-7.24 (m, 1H), 6.96-6.89 (m, 1H), 6.88-6.81 (m, 2H), 6.79-6.75 (m, 1H), 4.97 (s, 1H), 4.56 (t, 2H), 2.76 (t, 2H).

[0453] Synthesis of compound 39-11 At room temperature, compound 39-10 (500 mg, 2.17 mmol) and triethylamine (0.7 mL, 4.94 mmol) were dissolved in dichloromethane (10 mL), and then added... N 3-Phenylbis(trifluoromethanesulfonyl)imide (900 mg, 2.52 mmol) was reacted with the reaction mixture stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was poured into water (30 mL) and extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under slight reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to give compound 39-11. 1 H NMR (400 MHz, CDCl3) δ 7.47-7.41 (m, 1H), 7.39-7.27 (m, 2H), 7.24-7.18 (m, 1H), 7.02-6.95 (m, 1H), 6.93-6.87 (m, 1H), 4.58 (t, 2H), 2.84 (t,2H).

[0454] Synthesis of Compound 39-12 Compound 39-11 (450 mg, 1.24 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (200 mg, 0.27 mmol) were dissolved in methanol (10 mL) at room temperature. Triethylamine (0.52 mL, 3.76 mmol) was then added, and the reaction mixture was heated to 100 °C and stirred for 18 hours under a carbon monoxide (5 MPa) atmosphere. The reaction mixture was cooled to room temperature, poured into water (30 mL), and extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to give compound 39-12 (220 mg). 1 H NMR (400 MHz, CDCl3) δ8.07-8.02 (m, 1H), 7.98-7.94 (m, 1H), 7.49-7.43 (m, 1H), 7.42-7.36 (m, 1H),7.01-6.94 (m, 1H), 6.92-6.85 (m, 1H), 4.59 (t, 2H), 3.95 (s, 3H), 2.87 (t, 2H).

[0455] Synthesis of Compounds 39-13 The synthesis of compound 12-4 was similar, except that the temperature was changed from 0°C to room temperature. MS-ESI: m / z 227.1 [M-18+1] + .

[0456] Synthesis of Compounds 39-14 Refer to the synthesis of compound 14-A4. 1 H NMR (400 MHz, CDCl3) δ 7.43-7.30 (m, 4H), 6.99-6.92 (m, 1H), 6.90-6.84 (m, 1H), 4.57 (t, 2H), 4.54 (s, 2H), 2.81 (t, 2H).

[0457] Synthesis of Compound 39-15 The synthesis of compound 14-A5 was similar, except that benzyltrimethylammonium chloride was omitted. MS-ESI: m / z 447.3 [M+1] + .

[0458] Synthesis of Compounds 39-16 Refer to the synthesis of compound 14-A6. MS-ESI: m / z 266.1 [M-17+1] + . Synthesis of Compounds 39-17 At room temperature, 2-amino-3-(3-fluoro-6,7-dihydrodibenzo[] b , d Oxypifenyl-9-yl)propionitrile (compound 39-16) (40 mg, 0.14 mmol), 4-((tert-butoxycarbonyl)amino)tetrahydro-2 H -pyran-4-carboxylic acid (40 mg, 0.16 mmol) dissolved in N , N Add to dimethylformamide (2 mL), then add N , N , N ', N '-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (55 mg, 0.15 mmol) and triethylamine (50 mg, 0.49 mmol) were reacted and heated to 40 °C with stirring for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give compound 39-17. MS-ESI: m / z 410.3 [M-100+1] + .

[0459] Synthesis of Compound 39 The synthesis of compound 14 was similar, except that the temperature was changed from 40℃ to 50℃. MS-ESI: m / z 410.2 [M+1] + . 1 H NMR (400 MHz, DMSO- d6) δ 7.50-7.42 (m, 1H), 7.39-7.35 (m, 1H), 7.33-7.29 (m, 1H), 7.26 (s, 1H), 7.15-7.08 (m, 1H), 7.03-6.97 (m, 1H), 5.03-4.97 (m, 1H), 4.52-4.45 (m, 2H), 3.68-3.54 (m, 3H), 3.52-3.44 (m, 1H), 3.23-3.12 (m, 2H), 2.78-2.70 (m, 2H), 1.93-1.85 (m, 1H), 1.80-1.70 (m, 1H), 1.24–1.10 (m, 2H).

[0460] Example 40 ( S )-4-amino- N -(1-Cyano-2-(9-Fluoro-6-methyl-5-oxo-6,7-dihydro-5- H -Dibenzo[c,e]azepin-3-yl)ethyl)tetrahydro-2 H pyran-4-carboxamide Synthesis of Compound 40-2 At room temperature, (2-bromo-5-fluorophenyl)methylamine (compound 40-1) (10.00 g, 49.01 mmol) and triethylamine (6.8 mL, 49.01 mmol) were dissolved in dichloromethane (100 mL), followed by the addition of di-tert-butyl dicarbonate (16.04 g, 73.52 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give compound 40-2. MS-ESI: m / z 248.1 [M-56+1] + .

[0461] Synthesis of Compound 40-3 Compound 40-2 (11.00 g, 36.17 mmol), pinacol diborate (18.37 g, 72.33 mmol), and potassium acetate (7.10 g, 72.33 mmol) were dissolved in dioxane (50 mL) at room temperature and under nitrogen protection. Then, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (2.95 g, 3.62 mmol) was added, and the reaction mixture was heated to 80 °C and stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and poured into a saturated sodium bicarbonate aqueous solution (200 mL). Extraction was performed using dichloromethane (200 mL × 3). The combined organic phases were washed with saturated brine (200 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 40-3. MS-ESI: m / z 252.3 [M-100+1] + . 1 H NMR (400 MHz, CDCl3) δ 7.85-7.78 (m, 1H), 7.12-7.07 (m, 1H), 6.98-6.90 (m, 1H), 5.39 (s, 1H), 4.44 (s,2H), 1.43 (s, 9H), 1.53 (s, 12H).

[0462] Synthesis of compound 40-4 Compound 40-3 (8.00 g, 22.78 mmol), methyl 5-bromo-2-iodobenzoate (8.54 g, 25.06 mmol), and sodium carbonate (2.41 g, 22.78 mmol) were dissolved in a mixed solvent of dioxane (80 mL) and water (20 mL) under nitrogen protection at room temperature. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.93 g, 1.14 mmol) was added, and the reaction mixture was heated to 60 °C and stirred for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of sodium bicarbonate (200 mL), and extracted with dichloromethane (200 mL × 3). The combined organic phases were washed with saturated brine (200 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to give compound 40-4. MS-ESI: m / z 340.1 [M-100+1] + .

[0463] Synthesis of Compound 40-5 Compound 40-4 (1.32 g, 3.01 mmol) was dissolved in dichloromethane (20 mL) at 0 °C, and trifluoroacetic acid (4 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was extracted with dichloromethane (100 mL × 3) by adding saturated sodium bicarbonate aqueous solution. The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under slight reduced pressure to obtain crude compound 40-5, which was used directly in the next reaction. MS-ESI: m / z 340.1 [M+1] + .

[0464] Synthesis of compound 40-6 At room temperature, crude compound 40-5 (1.00 g, 2.96 mmol) was dissolved in toluene (20 mL), and the reaction mixture was heated to 120 °C and stirred for 18 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to give compound 40-6. MS-ESI: m / z 306.1 [M+1] + .

[0465] Synthesis of compound 40-7 Compound 40-6 (800 mg, 2.60 mmol) was dissolved at room temperature in... N,N In dimethylformamide (200 mL), sodium hydride (156 mg, 3.89 mmol, 60%) was added in portions at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour, followed by the addition of iodomethane (1.11 g, 7.79 mmol). The reaction mixture was stirred at 0 °C for another 2 hours. After the reaction was complete, water (150 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to give compound 40-7. MS-ESI: m / z 320.1 [M+1] + .

[0466] Synthesis of compound 40-8 The synthesis of compounds 1-3 was similar, except that the temperature was changed from 60℃ to 70℃. MS-ESI: m / z 443.4 [M+1] + .

[0467] Synthesis of compound 40-9 Refer to the synthesis of compounds 1-4. MS-ESI: m / z 428.6 [M+1] + .

[0468] Synthesis of compound 40-10 Refer to the synthesis of compounds 1-5. MS-ESI: m / z 410.1 [M+1] + .

[0469] Synthesis of Compound 40-11 Refer to the synthesis of compounds 1-6. MS-ESI: m / z 310.1 [M+1] + .

[0470] Synthesis of compound 40-12 Referring to the synthesis of compounds 1-7, except N,N -Other conditions are similar except that dimethylformamide is replaced with dichloromethane. MS-ESI: m / z 537.2 [M+1] + .

[0471] Synthesis of Compound 40 Refer to the synthesis of compound 1. MS-ESI: m / z 437.3 [M+1] + . 1 H NMR (400 MHz, DMSO- d6 ) δ7.73–7.66 (m, 2H), 7.57-7.52 (m, 2H), 7.50–7.43 (m, 1H), 7.38-7.328 (m, 1H), 5.09-4.99 (m, 1H), 4.24–4.07 (m, 2H), 3.67-3.46 (m, 3H), 3.42-3.31 (m, 1H), 3.30-3.24 (m, 2H), 3.06 (s, 3H), 1.92-1.82 (m, 1H), 1.72–1.67 (m, 1H), 1.24–0.98 (m, 2H).

[0472] Example 41 ( S )-N-(( S )-1-cyano-2-(9-cyano-2-fluoro-6-methyl-5-oxo-6,7-dihydro-5- H -dibenzo[ c, e (Zaza-3-yl)ethyl)-1,4-oxazacycloheptane-2-carboxamide Synthesis of compound 41-2 At room temperature, 2-amino-5-bromo-4-fluorobenzoic acid (compound 41-1) (5.00 g, 21.40 mmol) was added to a solution of concentrated hydrochloric acid (17.8 mL, 214.00 mmol) in water (10 mL). A solution of sodium nitrite (1.77 g, 25.65 mmol) in water (10 mL) was slowly added at 0 °C. After stirring the reaction mixture at 0 °C for 0.5 hours, a solution of potassium iodide (5.32 g, 32.00 mmol) in water (10 mL) was slowly added. The reaction mixture was then stirred at 0 °C for another two hours. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted with methyl tert-butyl ether (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 41-2, which was used directly in the next reaction. 1 H NMR (400 MHz, DMSO- d 6 ) δ 13.61 (br s, 1H), 8.09-8.01 (m, 2H).

[0473] Synthesis of compound 41-3 Compound 41-2 (6.50 g, 18.80 mmol) was dissolved in methanol (100 mL) at room temperature, and concentrated sulfuric acid (3.77 g, 37.70 mmol) was slowly added. The mixture was heated to 65 °C and stirred for 15 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and slowly poured into a saturated aqueous solution of sodium bicarbonate (300 mL). The system pH was 9. Extraction was performed with methyl tert-butyl ether (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to obtain compound 41-3. 1 H NMR (400 MHz, CDCl3) δ 8.09 (d, 1H), 7.76 (d, 1H), 3.94 (s, 3H).

[0474] Synthesis of compound 41-4 Methyl 4-bromo-3-(bromomethyl)benzoate (compound 15-2) (25.00 g, 69.00 mmol) was dissolved in dimethyl sulfoxide (150 mL) at room temperature, followed by the addition of sodium azide (5.39 g, 82.91 mmol) in portions. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was diluted with ice water (300 mL), filtered, and the filter cake was washed with ice water (100 mL) to obtain crude compound 41-4, which was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ8.00 (d, 1H), 7.79 (dd, 1H), 7.62 (d, 1H), 4.47 (s, 2H), 3.87 (s, 3H).

[0475] Synthesis of Compound 41-5 At room temperature, crude compound 41-4 (18.60 g, 68.90 mmol) was dissolved in a mixed solvent of water (15 mL) and tetrahydrofuran (200 mL), followed by the addition of triphenylphosphine (21.70 g, 82.73 mmol) in portions. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (200 mL), washed with saturated brine (100 mL), and the organic phases were combined and extracted with 1 M hydrochloric acid (100 mL × 2). The aqueous phases were combined, and di-tert-butyl dicarbonate (22.1 mL, 96.20 mmol), water (15 mL), tetrahydrofuran (200 mL), and sodium bicarbonate (28.90 g, 344.01 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated sodium chloride aqueous solution (150 mL) and extracted with ethyl acetate (300 mL × 2). Combine the organic phases and dry them over anhydrous sodium sulfate. Filter and concentrate the filtrate under reduced pressure. Separate the residue by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to give compound 41-5. MS-ESI: m / z 288.0 [M-56+1] + . 1 H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.72 (dd, 1H), 7.55 (d, 1H), 5.09-4.92 (m, 1H), 4.35 (d, 2H), 3.84 (s, 3H), 1.40 (s, 9H).

[0476] Synthesis of Compound 41-6 Compound 41-5 (5.50 g, 14.70 mmol), bis-pinacolborate (5.71 mL, 22.10 mmol), and potassium acetate (2.89 g, 29.40 mmol) were dissolved in dioxane (150 mL) at room temperature and under nitrogen protection. Then, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (538 mg, 0.74 mmol) was added. The reaction mixture was heated to 100 °C and stirred for 12 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 6 / 1) to give compound 41-6. MS-ESI: m / z 292.0 [M-100+1] + . 1 HNMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.97-7.87 (m, 2H), 5.44-5.32 (m, 1H), 4.50 (d, 2H), 3.92 (s, 3H), 1.44 (s, 9H), 1.38 (s, 12H).

[0477] Synthesis of Compound 41-7 The synthesis of compound 40-4 was similar, except that the temperature was changed from 60℃ to 80℃. MS-ESI: m / z 398.0 [M-100+1] + . 1 H NMR (400 MHz, CDCl3) δ 8.28 (d, 1H), 8.08 (s, 1H), 7.97(dd, 1H), 7.12 (d, 1H), 7.01 (d, 1H), 4.85-4.76 (m, 1H), 4.23-4.02 (m, 2H), 3.94 (s, 3H), 3.68 (s, 3H), 1.40 (s, 9H).

[0478] Synthesis of Compounds 41-8 Compound 41-7 (3.00 g, 6.04 mmol) was dissolved in dichloromethane (20 mL) at room temperature, followed by the dropwise addition of trifluoroacetic acid (4 mL). The reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the solution was concentrated under reduced pressure, and toluene (30 mL) and... N , N-Diisopropylethylamine (5.00 mL, 30.20 mmol), the reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was slurried with a mixture of petroleum ether and ethyl acetate (5 / 1, 100 mL) to give compound 41-8. MS-ESI: m / z 363.7 [M-100+1] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.76 (t, 1H), 8.09 (d, 1H), 8.06-7.97 (m, 2H), 7.85 (d, 1H), 7.74(d, 1H), 4.19-4.00 (m, 2H), 3.90 (s, 3H).

[0479] Synthesis of Compounds 41-9 At room temperature, compound 41-8 (900 mg, 2.47 mmol) soluble in N , N In dimethylformamide (20 mL), sodium hydride (148 mg, 3.71 mmol, 60%) was slowly added at 0 °C, and the mixture was stirred at 0 °C for 20 minutes. Then, iodomethane (0.3 mL, 4.94 mmol) was added, and the mixture was stirred at 0 °C for another 30 minutes. After the reaction was complete, the reaction mixture was quenched with water (30 mL), filtered, and the filter cake was collected and concentrated under reduced pressure to obtain the crude product of compound 41-9, which was used directly in the next reaction. MS-ESI: m / z 378.1 [M-100+1] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.18 (d, 1H), 8.08 (d, 1H), 8.05(dd, 1H), 7.88 (d, 1H), 7.74 (d, 1H), 4.47-4.30 (m, 2H), 3.90 (s, 3H), 3.06(s, 3H).

[0480] Synthesis of Compound 41-10 The synthesis of compounds 1-3 was similar, except that the temperature was changed from 60℃ to 80℃. MS-ESI: m / z 501.1 [M+1] + . 1H NMR (400 MHz, CDCl3) δ 8.12 (d, 1H), 8.01 (s, 1H), 7.83 (dd,1H), 7.64 (d, 1H), 7.24 (dd, 1H), 5.17 (t, 1H), 4.73-4.58 (m, 1H), 4.52-4.43(m, 1H), 4.02-3.93 (m, 4H), 3.78 (d, 3H), 3.42-3.27 (m, 1H), 3.18 (s, 3H), 3.16-2.99 (m, 1H).

[0481] Synthesis of Compound 41-11 Compound 41-10 (1.00 g, 2.00 mmol) was dissolved in methanol (10 mL) at room temperature, followed by the addition of 7 M ammonia-methanol solution (30 mL). The reaction mixture was heated to 70 °C and stirred for 16 hours in a sealed container. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, ethyl acetate) to give compound 41-11. MS-ESI: m / z 471.1 [M+1] + .

[0482] Synthesis of Compounds 41-12 Refer to the synthesis of compounds 1-5. MS-ESI: m / z 435.1 [M+1] + . [...

Claims

1. A pharmaceutical composition comprising 0.01-99.99% of a compound of formula VI or a pharmaceutically acceptable salt thereof. VI in, X1 and X2 are each independently selected from single bonds, -C(R) 3b )2-O-、-C(R 3b )2-C(R 3b )2-、-OC(R 3b )2-、-C(R 3b )2-, oxygen atom and -NR 3b -, where at least one of X1 and X2 is -C(R) 3b )2-; The ring C is selected from phenyl, naphthyl, and 5-8-membered heteroaryl groups containing 1-3 heteroatoms, wherein the phenyl, naphthyl, and 5-8-membered heteroaryl groups containing 1-3 heteroatoms are each independently and optionally surrounded by 1-3 R atoms. 3b Replaced; Ring A is selected from heterocyclic alkyl, heteroaryl, and aryl groups, each of which is independently and optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, acyl, amide, oxo, alkyl, and alkoxy groups; each of the alkyl and alkoxy groups is independently and optionally substituted by one or more R groups. 3a Replaced; Each R 3a Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl and 3- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, the 5- to 6-membered aryl group, or the 3- to 6-membered heteroaryl group are each independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups; Each R 3b Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5- to 6-membered aryl, 3- to 6-membered heteroaryl, methanesulfonyl and The C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, the 5- to 6-membered aryl group, and the 3- to 6-membered heteroaryl group are each independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups; Each R1 is independently selected from halogen, hydroxyl, oxo, nitro, cyano, alkyl, cycloalkyl, amino, amide, acyl, alkoxy, alkenoxy, alkynoxy, and cycloalkoxy; and n is an integer selected from 0 to 3; preferably, n is an integer selected from 1 to 3.

2. The pharmaceutical composition according to claim 1, wherein the compound represented by formula VI is selected from... and in, The ring C is selected from phenyl, naphthyl, and 5-8-membered heteroaryl groups containing 1-3 heteroatoms, wherein the phenyl, naphthyl, and 5-8-membered heteroaryl groups containing 1-3 heteroatoms are each independently and optionally surrounded by 1-3 R atoms. 3b Replaced; and R1, n, ring A and R 3b As defined in claim 1.

3. The pharmaceutical composition according to claim 1, wherein the compound of formula VI or a pharmaceutically acceptable salt thereof is the compound of formula II or a pharmaceutically acceptable salt thereof. II in, X1 and X2 are each independently selected from -C(R 3b )2-, oxygen atom and -NR 3b -, where at least one of X1 and X2 is -C(R) 3b )2-; preferably X1 is an oxygen atom or -NR 3b -, X2 is -C(R) 3b )2-; more preferably, X1 is an oxygen atom, and X2 is -C(R) 3b )2-; The ring C is selected from phenyl, naphthyl, and 5-8-membered heteroaryl groups containing 1-3 heteroatoms, wherein the phenyl, naphthyl, and 5-8-membered heteroaryl groups containing 1-3 heteroatoms are each independently and optionally surrounded by 1-3 R atoms. 3b Replaced; and R1, n, ring A and R 3b As defined in claim 1.

4. The pharmaceutical composition according to any one of claims 1-3, wherein Ring A is selected from 3-15 membered heterocyclic alkyl groups, 3-10 heteroaryl groups, and C. 6-8 Aryl, the 3-15 membered heterocyclic alkyl, 3-10 heteroaryl and C 6-8 Each aryl group is independently and optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, acyl, amide, oxo, alkyl, and alkoxy; each of the alkyl and alkoxy groups is independently and optionally substituted by one or more R groups. 3a Replaced by, R 3a As defined in claim 1; Preferably, ring A is a 3-10 membered heterocyclic alkyl group containing 1-3 heteroatoms, wherein the 3-10 membered heterocyclic alkyl group containing 1-3 heteroatoms is optionally surrounded by one or more elements selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl and C 1-6 The alkoxy group is substituted; the C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally surrounded by 1-3 R groups. 3a Replaced by, R 3a As defined in claim 1.

5. The pharmaceutical composition according to any one of claims 1-4, wherein the heteroatom is selected from nitrogen, oxygen and sulfur atoms; preferably nitrogen or oxygen atoms.

6. The pharmaceutical composition according to any one of claims 1-5, wherein Ring A is selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C. 1-6 Alkyl and C 1-6 Substituents of alkoxy groups , and ; The C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally surrounded by 1-3 R groups. 3a Replaced by, R 3a As defined in claim 1; Preferably, ring A is selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl and C 1-6 Substituents of alkoxy groups , and ; The C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally surrounded by 1-3 R groups. 3a Replaced by, R 3a As defined in claim 1; More preferably, ring A is optionally composed of one or more elements selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl and C 1-6 Substituents of alkoxy groups ； The C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally surrounded by 1-3 R groups. 3a Replaced by, R 3a As defined in claim 1; The optimal choice A is .

7. The pharmaceutical composition according to claim 6, wherein ring A is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, cyano, amino, and nitro. ； Preferably, ring A is optionally substituted with one or more substituents selected from deuterium and halogens. ； More preferably, ring A is optionally replaced by one or more halogens. 。 8. The pharmaceutical composition according to claim 1, wherein the compound represented by formula VI is selected from... and , in Each R2 is independently selected from halogen, nitro, cyano, amino, oxo, and hydroxyl groups; m is selected from integers between 0 and 3, preferably m is 0; and R1, n, ring C, R 3b As defined in claim 1.

9. The pharmaceutical composition according to claim 2, wherein the compound represented by formula VI is selected from... and , in Each R2 is independently selected from halogen, nitro, cyano, amino, oxo, and hydroxyl groups; m is selected from integers between 0 and 3, preferably m is 0; and R1, n, ring C and R 3b As defined in claim 2.

10. The pharmaceutical composition according to claim 1, wherein the compound of formula VI or a pharmaceutically acceptable salt thereof is the compound of formula III or a pharmaceutically acceptable salt thereof. III Wherein R1, n, X1, X2 and ring C are defined as in claim 3; Preferably, it is a compound of formula IV or a pharmaceutically acceptable salt thereof. IV Wherein R1, n, X1, X2 and ring C are defined as in claim 3; More preferably, it is a compound of formula V or a pharmaceutically acceptable salt thereof. V R1, n, X1, X2 and ring C are defined as in claim 3.

11. The pharmaceutical composition according to any one of claims 1-10, wherein R1 is selected from halogen, hydroxyl, cyano, amino, nitro, acyl, amide, C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Alkyl group; preferably R1 is selected from halogen, hydroxyl, cyano, amino, nitro, C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Alkyl group; more preferably, R1 is selected from halogen, hydroxyl group, C 1-6 Alkyl and C 3-6 Cycloalkyl.

12. The pharmaceutical composition according to any one of claims 1-10, wherein R1 is selected from halogen, nitro and cyano; preferably R1 is halogen; more preferably R1 is fluorine.

13. The pharmaceutical composition according to any one of claims 1-10, wherein n is selected from an integer from 0 to 2; preferably n is selected from an integer from 1 to 2.

14. The pharmaceutical composition according to any one of claims 1-13, wherein the cyclic C is selected from phenyl, and The phenyl, and Each can be independently selected by 1-3 Rs. 3b Replaced by, R 3b As defined in claim 1.

15. The pharmaceutical composition according to any one of claims 1-13, wherein the ring C is phenyl, and the phenyl group is optionally surrounded by 1-3 R groups. 3b Replaced by, R 3b As defined in claim 1.

16. The pharmaceutical composition according to any one of claims 1-16, wherein each R 3a It is independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano and amino.

17. The pharmaceutical composition according to any one of claims 1-16, wherein each R 3a Independently selected from hydrogen, fluorine, chlorine, deuterium, oxo (=O), hydroxyl, amino, methoxy, cyclopropoxy, cyclopropyl, cyclopentyl, pyridyl, piperidinyl, and phenyl, preferably R. 3a It is hydrogen or amino.

18. The pharmaceutical composition according to any one of claims 1-17, wherein Each R 3b Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl and 3- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyl group, the 5- to 6-membered aryl group, and the 3- to 6-membered heteroaryl group are each independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups; preferably each R 3b It is independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano and amino.

19. The pharmaceutical composition according to any one of claims 1-17, wherein each R 3b Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, and amide; preferably each R 3b It can be halogen or cyano group independently.

20. The pharmaceutical composition according to any one of claims 1-17, wherein each R 3b Independently selected from hydrogen, halogen, deuterium, cyano, 3 to 6-membered heterocyclic alkyl, methanesulfonyl and Preferably, 3 to 6-membered heterocyclic alkyl groups are selected from... , , and .

21. The pharmaceutical composition according to any one of claims 1-17, wherein each R 3b Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, amide, acetyl, methanesulfonyl, and .

22. The pharmaceutical composition according to any one of claims 1-17, wherein each R 3b Independently selected from hydrogen, cyano, methanesulfonyl and Preferred R 3b It is a cyano group.

23. The pharmaceutical composition according to any one of claims 1-17, wherein Each R 3b Independently hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 The alkoxy group may be optionally replaced by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro and cyano.

24. The pharmaceutical composition according to any one of claims 1-17, wherein Each R 3b Independently selected from hydrogen, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, phenyl, and 5- to 6-membered heteroaryl, wherein C 1-6 Alkoxy, C 3-6 The cycloalkoxy, 3- to 6-membered heterocycloalkoxy, phenyl, and 5- to 6-membered heteroaryl groups are each independently and optionally substituted by 1 to 3 substituents selected from fluorine, chlorine, deuterium, hydroxyl, oxo, nitro, and cyano.

25. The pharmaceutical composition according to any one of claims 1-17, wherein Each R 3b Independently selected from hydrogen, fluorine, chlorine, deuterium, oxo (=O), hydroxyl, amino, methoxy, cyclopropoxy, cyclopropyl, cyclopentyl, pyridyl, piperidinyl, and phenyl, preferably R. 3b Selected from hydrogen, methyl, oxo, fluorine and chlorine.

26. The pharmaceutical composition according to claim 1, wherein the compound represented by formula VI is selected from... 。 27. Use of the pharmaceutical composition according to any one of claims 1-26 in the preparation of a medicament for the prevention and / or treatment of conditions related to cathepsin C.

28. Use of the pharmaceutical composition according to any one of claims 1-26 in the preparation of a medicament for the prevention and / or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, α1-antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, or rheumatoid arthritis.

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