Small molecule inhibitors of cathepsin C and their pharmaceutical uses

Abstract

This disclosure relates to small molecule inhibitors of cathepsin C and their pharmaceutical uses. Specifically, this disclosure provides an ammonium nitrile compound of formula VI, a pharmaceutical composition containing the compound, and its use in inhibiting cathepsin C.

Description

Technical Field

[0001] 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

[0002] 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.

[0003] 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. 2002 403:160-170. 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.

[0004] WO 2004 / 110988 relates to certain nitrile derivatives and their use as DPP1 inhibitors.

[0005] WO 2009 / 074829 relates to peptide nitriles and their use as DPP1 inhibitors.

[0006] WO 2010 / 128324 relates to α-aminoamidonitrile and its use as a DPP1 inhibitor.

[0007] WO 2012 / 119941 relates to peptide nitrile compounds and their use as DPP1 inhibitors.

[0008] 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.

[0009] WO 2001 / 096285 and WO 2003 / 048123 relate to β-aminoamide nitriles that have inhibitory activity against cysteine ​​proteases.

[0010] WO 2015 / 110826 relates to α-aminoamidonitrile and its use as a DPP1 inhibitor.

[0011] However, the amide nitrile compounds shown in this disclosure I have not been disclosed in any literature. Summary of the Invention

[0012] In the first aspect, this disclosure provides compounds of formula I or pharmaceutically acceptable salts thereof.

[0013]

[0014] in:

[0015] 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;

[0016] 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;

[0017] R1 is independently selected from halogen, hydroxyl, oxo, nitro, cyano, alkyl, cycloalkyl, amino, amide, acyl, alkoxy, alkenoxy, alkynoxy, and cycloalkoxy;

[0018] 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, C3-6 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;

[0019] 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 2-6 alkenyloxy group, C 2-6 Acryloxy group, C3-6 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;

[0020] n is an integer selected from 0 to 3; preferably, n is an integer selected from 1 to 3.

[0021] 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.

[0022] 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, C 6-8Aryl, 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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, C 1-6Alkoxy, 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.

[0028] 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.

[0029] 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 6-8 The aryl or fused ring may be selectively capped with 1-3 Rs.3b Replaced by, R 3b As defined in Equation I.

[0030] 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;

[0031] 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;

[0032] 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.

[0033] Secondly, this disclosure provides a compound as shown in Formula VII or a pharmaceutically acceptable salt thereof.

[0034]

[0035] in

[0036] Ring B is a 5-8 membered cycloalkyl group or a 5-8 membered heterocycloalkyl group containing 1-3 heteroatoms;

[0037] 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 3bReplaced;

[0038] 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;

[0039] R1, n, ring A and R 3b As defined in Equation I.

[0040] In some embodiments, in the compound of formula VII or its pharmaceutically acceptable salt, ring B is a 5-8 membered cycloalkyl group;

[0041] 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;

[0042] R1, n, ring A and R 3b As defined in Equation I.

[0043] 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;

[0044] 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;

[0045] R1, n, ring A and R 3b As defined in Equation I.

[0046] 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 1-6Alkyl, 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.

[0047] 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.

[0048] 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...

[0049]

[0050] R1, n, ring A, R4 and R 3b As defined in equation VII.

[0051] 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

[0052]

[0053] R1, n, ring A, R4 and R 3b As defined in equation VII.

[0054] Thirdly, this disclosure also provides compounds of formula VI or pharmaceutically acceptable salts thereof.

[0055]

[0056] 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-;

[0057] 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

[0058] R1, n, ring A and R 3b As defined in Equation I.

[0059] 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.

[0060]

[0061]

[0062] in

[0063] 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

[0064] R1, n, ring A and R 3b As defined in Equation I.

[0065] Fifthly, this disclosure also provides compounds of formula II or pharmaceutically acceptable salts thereof.

[0066]

[0067] in

[0068] 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-;

[0069] 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

[0070] 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 6-8 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 Equation I.

[0071] 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.

[0072] 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 1-6Alkyl 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.

[0073] 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.

[0074] 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.

[0075] 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 1-6Each alkoxy group is independently and optionally surrounded by 1-3 R groups. 3a Replaced by, R 3a As defined in Equation I.

[0076] In this disclosure, the aforementioned heteroatoms are selected from nitrogen atoms, oxygen atoms, and sulfur atoms; preferably nitrogen atoms or oxygen atoms.

[0077] 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

[0078]

[0079] 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.

[0080] 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

[0081]

[0082] 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.

[0083] 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

[0084] 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.

[0085] 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...

[0086] 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

[0087] 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;

[0088] 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...

[0089] 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.

[0090] 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.

[0091] 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'.

[0092]

[0093] in

[0094] Each R2 is independently selected from halogen, nitro, cyano, amino, oxo, and hydroxyl groups;

[0095] m is selected from integers between 0 and 3, preferably m is 0; and

[0096] R1, n, ring C and R 3b As defined in equation VI-a.

[0097] In a seventh 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".

[0098]

[0099] in

[0100] Each R2 is independently selected from halogen, nitro, cyano, amino, oxo, and hydroxyl groups; m is selected from integers from 0 to 3, preferably m is 0; and

[0101] R1, n, ring C and R 3b As defined in VI-a.

[0102] Eighthly, this disclosure also provides a compound of formula III or a pharmaceutically acceptable salt thereof.

[0103] R1, n, X1, X2 and ring C are defined as in Equation I or Equation II.

[0104] Ninthly, this disclosure also provides a compound of formula IV or a pharmaceutically acceptable salt thereof.

[0105] R1, n, X1, X2 and ring C are defined as in Equation I or Equation II.

[0106] In a tenth aspect, this disclosure also provides a compound of formula V or a pharmaceutically acceptable salt thereof.

[0107]

[0108] R1, n, X1, X2 and ring C are defined as in Equation I or Equation II.

[0109] In some embodiments, 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”, and 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.

[0110] 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 usable salts, R1 is selected from hydrogen, halogen, nitro, and cyano; preferably, R1 is a halogen; more preferably, R1 is fluorine.

[0111] 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.

[0112] 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”, and 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.

[0113] 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”, or a pharmaceutically acceptable salt thereof, wherein the ring C is selected from phenyl, The phenyl, Each can be independently selected by 1-3 Rs 3b What it replaced.

[0114] 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.

[0115] 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 their pharmaceutically acceptable salts, the ring C is The Choose 1-3 Rs 3b What it replaced.

[0116] 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 their pharmaceutically acceptable salts, the ring C is The Choose 1-3 Rs 3b What it replaced.

[0117] In some embodiments, each R 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, contains... 3a It is independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl and amide.

[0118] In some embodiments, each R 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, contains... 3a It is independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano and amino.

[0119] In some embodiments, each R 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, contains... 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 3-8 cycloalkenyloxy, 5- to 6-membered aryl and heteroaryl, the C 1-6 Alkyl, C 1-6Alkoxy, 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.

[0120] In some embodiments, each R 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, contains... 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.

[0121] In some embodiments, each R 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, contains... 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.

[0122] In some embodiments, each R 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, contains... 3b Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, and amino; preferably R 3b It is either halogen or cyano.

[0123] 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 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.

[0124] In some embodiments, each R 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, contains... 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

[0125] In some embodiments, each R 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, contains... 3b Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, amide, methanesulfonyl and

[0126] In some embodiments, each R 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, contains... 3b Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, amide, acetyl, methanesulfonyl,

[0127] In some embodiments, each R 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, contains... 3b Independently selected from cyano, methanesulfonyl and Preferred R 3b It is a cyano group.

[0128] 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.

[0129] In some embodiments, each R 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, contains... 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, 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.

[0130] In some embodiments, each R 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, contains... 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.

[0131] In some embodiments, each R 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, contains... 3b Independently selected from halogens, cyano groups, formamides, 3 to 6-membered heterocyclic alkyl groups and deuterium.

[0132] In some embodiments, each R 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, contains... 3bIndependently 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.

[0133] 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 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.

[0134] 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.

[0135] In an eleventh aspect, this disclosure also provides typical compounds of Formula I or pharmaceutically acceptable salts thereof, including but not limited to:

[0136]

[0137]

[0138]

[0139] In a twelfth aspect, this disclosure also provides typical compounds of Formula I or pharmaceutically acceptable salts thereof, including but not limited to:

[0140]

[0141]

[0142]

[0143] In a thirteenth aspect, this disclosure also provides typical compounds of Formula I or pharmaceutically acceptable salts thereof, including but not limited to:

[0144]

[0145]

[0146]

[0147]

[0148] 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.

[0149] 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.

[0150] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] This disclosure also provides a compound or intermediate of the following formula.

[0162]

[0163] Among them, R1, n, ring C and R 3b As defined in equation IV.

[0164] This disclosure also provides a compound or intermediate of the following formula.

[0165]

[0166] Among them, R1, n, ring C and R 3b As defined in equation IV.

[0167] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0168] 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.

[0169] 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).

[0170] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be or Or simultaneously include and Two configurations.

[0171] 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.

[0172]

[0173] 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.

[0174] 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 C13 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.

[0175] 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 incorporation). 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 even 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 the 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.

[0176] "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.

[0177] Terminology Explanation:

[0178] "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.

[0179] "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.

[0180] 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.

[0181] "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, 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.

[0182] "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, 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.

[0183] "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, 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.

[0184] 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, 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.

[0185] 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, 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.

[0186] 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, 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.

[0187] 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:

[0188]

[0189] etc.

[0190] 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:

[0191] wait.

[0192] 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, 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.

[0193] 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:

[0194]

[0195] 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, 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.

[0196] 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.

[0197] 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:

[0198]

[0199] 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, 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.

[0200] 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, wherein the C 1-6Alkyl, 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.

[0201] The term "hydroxyl group" refers to the -OH group.

[0202] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0203] The term "cyano" refers to -CN.

[0204] The term "nitro" refers to -NO2.

[0205] The term "oxo" refers to the =O substituent.

[0206] The term "amide" refers to R is selected from C 1-6 Alkyl groups, including but not limited to methyl, ethyl, propyl, etc.

[0207] 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 (e.g., -CH2CH2- or -CH(CH3)-), propylene (e.g., -CH2CH2CH2- or -CH(CH2CH3)-), and butylene (e.g., -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, wherein the C1-6 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.

[0208] Similarly, the definitions of "alkeneoxy", "alkenyl", "alkenyloxy", "cycloalkylene", and "heterocyclic alkylene" are the same as those for "alkylene". Attached Figure Description

[0209] Figure 1 Percentage inhibition rate 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).

[0210] Figure 2 Percentage 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

[0211] 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.

[0212] 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.

[0213] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (Methanol-d4). The internal standard was tetramethylsilane (TMS).

[0214] HPLC determination was performed using an Agilent 1100 high-performance liquid chromatograph, a GAS15B DAD UV detector, and a WaterVbridge C18 150*4.6mm 5um column.

[0215] 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.

[0216] The silica gel plates used for thin-layer chromatography are Yantai Huanghai HSGF254 silica gel plates. The silica gel plates used in 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.

[0217] Rapid column purification systems use either the Combiflash Rf150 (TELEDYNE ISCO) or Isolara One (Biotage).

[0218] 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).

[0219] 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.

[0220] Unless otherwise specified in the examples, all reactions can be carried out under a nitrogen atmosphere.

[0221] A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of approximately 1L.

[0222] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0223] Hydrogen was produced by the QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instruments Co., Ltd.

[0224] Nitrogen or hydrogen atmospheres are typically evacuated and then filled with nitrogen or hydrogen gas, and this process is repeated three times.

[0225] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0226] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0227] The reaction process in the examples was monitored using thin-layer chromatography (TLC).

[0228] Example 1

[0229] (S)-4-amino-N-(1-cyano-2-(1-oxy-2-phenylisoindol-5-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0230]

[0231]

[0232] Synthesis of Compounds 1-2

[0233] 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] + .

[0234] Synthesis of compounds 1-3

[0235] Under nitrogen protection at room temperature, activated zinc powder (900 mg, 137.76 mmol) was added to anhydrous N,N-dimethylformamide (5 mL), followed by iodine (350 mg, 1.38 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and then a solution of (R)-2-(((tert-butyloxycarbonyl)amino)methyl-3-iodopropionate methyl ester (1.50 g, 4.55 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added. The mixture was stirred at room temperature for another hour, and then compounds 1-2 (1.70 g, 5.92 mmol) and tris-(dibenzylacetone)di... Palladium (105 mg, 0.11 mmol) and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (94 mg, 0.23 mmol) were reacted and 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. After filtration, the organic phase was 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 = 1 / 1) to give compounds 1-3. MS-ESI: m / z 411.2 [M+1] + .

[0236] Synthesis of compounds 1-4

[0237] 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 / z 396.3 [M+1] + .

[0238] Synthesis of compounds 1-5

[0239] 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] + .

[0240] Synthesis of compounds 1-6

[0241] 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] + .

[0242] Synthesis of compounds 1-7

[0243] At room temperature, crude compounds 1-6 (180 mg, 0.65 mmol) and 4-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (175 mg, 0.71 mmol) were dissolved in N,N-dimethylformamide (5 mL), followed by the addition of 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] + .

[0244] Synthesis of Compound 1

[0245] Compounds 1-7 (150 mg, 0.30 mmol) were dissolved in acetonitrile (10 mL) at room temperature, followed by the sequential 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 residue 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 then separated by preparative high-performance liquid chromatography (HPLC) (column: Waters Xbridge C18, 250*19 mm, 10 μm; mobile phase: water (0.1% ammonium bicarbonate), acetonitrile; gradient ratio: acetonitrile phase 35-95%; flow rate: 20 mL / min; column temperature: room temperature) to obtain compound 1. MS-ESI: m / z 405.2 [M+1] + .1 H NMR(400MHz, CDCl3)δ8.30(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,1 H),2.24-2.16(m,1H),1.44(s,2H),1.30-1.26(m,1H),1.21-1.16(m,1H).

[0246] Intermediate 2-6

[0247]

[0248] Synthesis of compound 2-2

[0249] 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] + .

[0250] Synthesis of Compounds 2-3

[0251] Compound 2-2 (52 g, 157.96 mmol) and N,N-diisopropylethylamine (30.60 g, 236.77 mmol) were dissolved in dichloromethane (1000 mL) at 0 °C, 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) and extracted with dichloromethane (500 mL × 3). 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 2-3, which was directly used for the next reaction. MS-ESI: m / z 408.2 [M+1] + .

[0252] Synthesis of compounds 2-4

[0253] 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] + .

[0254] Synthesis of compounds 2-5

[0255] 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] + .

[0256] Synthesis of compounds 2-6

[0257] 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 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 / z190.1 [M-56+1] + . 1H NMR (400MHz, DMSO-d6): δ12.71(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).

[0258] Example 2

[0259] (S)-N-((S)-1-cyano-2-(1-oxo-2-phenylisoindol-5-yl)ethyl)-1,4-oxazetane-2-carboxamide

[0260]

[0261] Synthesis of compounds 2-7

[0262] 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 mixture was poured into a saturated aqueous sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (50 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 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] + .

[0263] Synthesis of Compound 2

[0264] Compounds 2-7 (200 mg, 0.39 mmol) were dissolved in acetonitrile (5 mL) at room temperature, followed by the sequential 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 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 then separated by preparative high-performance liquid chromatography (HPLC) (column: Waters Sunfire C18, 250*19 mm, 10 μm; mobile phase: water (0.1% formic acid), acetonitrile; gradient ratio: acetonitrile phase 25-95%; flow rate: 20 mL / min; column temperature: room temperature) to obtain compound 2. MS-ESI: m / z 405.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.87(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(d d,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).

[0265] Example 3

[0266] (2S)-N-(1-cyano-2-(5,6,7,8-tetrahydronaphthyl-2-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide trifluoroacetate

[0267]

[0268] Synthesis of compound 3-2

[0269] At room temperature, 10 g (67.53 mmol) of 5,6,7,8-tetrahydronaphthalene-2-ol (compound 3-1) was dissolved in 100 mL of dichloromethane. N,N-diisopropylethylamine (21.80 g, 168.68 mmol) and trifluoromethanesulfonic anhydride (22.85 g, 80.99 mmol) were added sequentially at 0 °C, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, 50 mL of water was added to the reaction mixture, and the mixture was extracted with 200 mL (2 x 2) of dichloromethane. The combined organic phases were washed with 100 mL of saturated brine 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 (400MHz, DMSO-d6) δ7.26-7.19(m,1H),7.16-7.14(m,2H),2.76-2.74(m,4H),1.74-1.71(m,4H).

[0270] Synthesis of compound 3-3

[0271] Compound 3-2 (10 g, 35.59 mmol) was dissolved in a mixed solvent of N,N-dimethylformamide (50 mL) and methanol (150 mL) at room temperature. Then, N,N-diisopropylethylamine (9.23 g, 71.42 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (3.00 g, 4.10 mmol) were added. The reaction mixture was refluxed and stirred for 12 hours under a carbon monoxide atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 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 (400MHz, DMSO-d6) δ7.69-7.60(m,2H),7.17(d,1H),3.83(s,3H),2.87-2.75(m,4H),1.75-1.72(m,4H).

[0272] Synthesis of compounds 3-4

[0273] 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 HNMR (400MHz, DMSO-d6) 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).

[0274] Synthesis of compounds 3-5

[0275] 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 (400MHz, DMSO-d6) δ7.15-7.10(m,2H),7.02(d,1H),4.63(s,2H),2.72-2.62(m,4H),1.77-1.66(m,4H).

[0276] Synthesis of compounds 3-6

[0277] Under nitrogen protection at 0°C, 1.40 g (6.26 mmol) of 2-((diphenylmethylene)amino)acetonitrile was dissolved in 20 mL of N,N-dimethylformamide. Sodium hydroxide (500 mg, 12.50 mmol, 60%) was added, and the reaction mixture was stirred at 0°C for 0.5 h. Then, a solution of 1.70 g (7.58 mmol) of compound 3-5 in 5 mL of N,N-dimethylformamide was added, and the reaction mixture was stirred at 0°C for another 2 h. 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, and the filtrate was concentrated under reduced pressure. 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] + .

[0278] Synthesis of compounds 3-7

[0279] Compound 3-6 (1.80 g, 4.94 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, 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] + .

[0280] Synthesis of compounds 3-8

[0281] 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-dimethylformamide (5 mL), followed by the addition of 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), and 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 to give crude compounds 3-8, which were used directly in the next reaction. MS-ESI: m / z 372.1 [M-56+1] + .

[0282] Synthesis of Compound 3

[0283] 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(400MHz,DMSO-d6)δ9.12-8.85(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).

[0284] Example 4

[0285] 4-Amino-N-(1-cyano-2-(5,6,7,8-tetrahydronaphth-2-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0286]

[0287] Synthesis of compound 4-1

[0288] 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-2H-pyran-4-carboxylic acid (164 mg, 0.67 mmol) were 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). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (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 and concentrated under reduced pressure. The residue was then separated by column chromatography (SiO2, dichloromethane / methanol = 10 / 1) to give compound 4-1. MS-ESI: m / z 328.2 [M-100+1] + .

[0289] Synthesis of Compound 4

[0290] 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 liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 4. MS-ESI: m / z 328.5 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ7.00-6.93(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).

[0291] Example 5

[0292] (2S)-N-(1-cyano-2-(2,3-dihydro-1H-inden-5-yl)ethyl)-1,4-oxazonylheptane-2-carboxamide trifluoroacetate

[0293]

[0294] Synthesis of Compound 5-2

[0295] At room temperature, 2,3-dihydro-1H-indene-5-carboxylic acid (compound 5-1) (2.00 g, 12.35 mmol) and iodomethane (1.2 mL, 19.27 mmol) were dissolved in N,N-dimethylformamide (10 mL), followed by the addition of potassium carbonate (3.41 g, 24.67 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was 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. 1H NMR (400MHz, DMSO-d6) δ7.80(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).

[0296] Synthesis of compound 5-3

[0297] 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 (400MHz, DMSO-d6) δ7.16-7.14(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).

[0298] Synthesis of Compound 5-4

[0299] 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 (400MHz, DMSO-d6) δ7.35-7.10(m,3H),4.67(s,2H),2.82(t,4H),2.08-1.96(m,2H).

[0300] Synthesis of compound 5-5

[0301] At 0 °C, 2-((diphenylmethylene)amino)acetonitrile (2.95 g, 13.40 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of sodium hydride (1.07 g, 26.75 mmol, 60%). The reaction mixture was stirred at 0 °C for 30 minutes, and then compound 5-4 (1.87 g, 8.90 mmol) was added. The reaction mixture was stirred at 0 °C for another 2 hours. 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, 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 5-5. MS-ESI: m / z 351.2 [M+1] + .

[0302] Synthesis of compounds 5-6

[0303] 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 organic phases were combined and 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] + .

[0304] Synthesis of compounds 5-7

[0305] Compounds 5-6 (100 mg, 0.54 mmol) and 2-6 (158 mg, 0.64 mmol) were dissolved in a mixed solvent of N,N-dimethylformamide (1 mL) and dichloromethane (5 mL) at room temperature. Then, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (306 mg, 0.81 mmol) and N,N-diisopropylethylamine (139 mg, 1.08 mmol) were 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 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] + .

[0306] Synthesis of Compound 5

[0307] Compounds 5-7 (100 mg, 0.24 mmol) were 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 dichloromethane (20 mL × 3) by adding saturated sodium bicarbonate aqueous solution. 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 then separated by preparative high-performance liquid chromatography (HPLC) (column: SunFire PrepC18, 250*19 mm, 10 μm; mobile phase: water (0.1% trifluoroacetic acid), acetonitrile; gradient ratio: acetonitrile phase 28-95%; flow rate: 20 mL / min; column temperature: room temperature) to obtain the trifluoroacetate of compound 5. MS-ESI: m / z 314.5 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ9.20-8.70(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).

[0308] Example 6

[0309] 4-Amino-N-(1-cyano-2-(2,3-dihydro-1H-inden-5-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0310]

[0311] Synthesis of Compound 6-1

[0312] At room temperature, 2-amino-3-(2,3-dihydro-1H-inden-5-yl)propionitrile (compounds 5-6) (150 mg, 0.81 mmol) and 4-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (237 mg, 0.97 mmol) were dissolved in a mixed solvent of N,N-dimethylformamide (1 mL) and dichloromethane (5 mL). Benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (458 mg, 1.21 mmol) and N,N-diisopropylethylamine (208 mg, 1.61 mmol) were 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] + .

[0313] Synthesis of Compound 6

[0314] 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 sodium bicarbonate aqueous solution (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 H NMR(400MHz,DMSO-d6)δ7.19-7.07(m,2H),7.05-6.99(m,1H),4.89(t,1H),3.70-3.54(m,3H),3.51-3.4 7(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).

[0315] Example 7

[0316] 4-Amino-N-(1-cyano-2-(9,10-dihydrophenanthrene-2-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0317]

[0318]

[0319] Synthesis of Compound 7-2

[0320] 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] + .

[0321] Synthesis of compound 7-3

[0322] At 0 °C, potassium hydroxide (3.30 g, 58.81 mmol) was dissolved in water (20 mL), 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 give compound 7-3. MS-ESI: m / z 225.2 [M+1] + .

[0323] Synthesis of compound 7-4

[0324] 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 then 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.

[0325] At 0°C, the intermediate obtained by the above method (600 mg, 2.86 mmol) was dissolved in dichloromethane (10 mL), followed by the sequential addition of N,N-diisopropylethylamine (738 mg, 5.72 mmol) and methanesulfonyl chloride (493 mg, 4.29 mmol). The reaction mixture was stirred at 0°C for 2 hours. After the reaction was complete, the reaction mixture was poured into ice water (50 mL) and extracted with dichloromethane (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 = 9 / 1) to obtain the intermediate for subsequent reactions.

[0326] At 0 °C, 2-((diphenylmethylene)amino)acetonitrile (462 mg, 2.10 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of sodium hydride (140 mg, 3.50 mmol, 60%). After stirring at room temperature for 0.5 hours, 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 crude compound 7-4, which was directly used for the next reaction. MS-ESI: m / z 413.1 [M+1] + .

[0327] Synthesis of Compound 7-5

[0328] 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] + .

[0329] Synthesis of Compounds 7-6

[0330] Compound 7-6 (150 mg, 0.60 mmol), 4-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (162 mg, 0.66 mmol), and N,N-dimethylformamide (5 mL) were dissolved at room temperature. Then, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (341 mg, 0.9 mmol) and N,N-diisopropylethylamine (155 mg, 1.20 mmol) were 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 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 compound 7-6. MS-ESI: m / z420.5 [M-56+1] + .

[0331] Synthesis of Compound 7

[0332] Compound 7-6 (75 mg, 0.16 mmol) was dissolved in acetonitrile (5 mL) at room temperature, followed by the sequential 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 organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Waters Xbridge C18, 250*19 mm, 10 μm; mobile phase: water (0.1% ammonium bicarbonate), acetonitrile; gradient ratio: acetonitrile phase 52-95%; flow rate: 20 mL / min; column temperature: room temperature) to obtain compound 7. MS-ESI: m / z 376.7 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ7.80-7.76(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).

[0333] Example 8

[0334] (S)-N-((S)-1-cyano-2-(9,10-dihydrophenanthrene-2-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide

[0335]

[0336] Synthesis of Compound 8-1

[0337] Compound 7-1 (2.50 g, 13.89 mol) was dissolved in acetonitrile (20 mL) at room temperature, followed by the addition of N-bromosuccinimide (2.70 g, 15.17 mmol) and p-toluenesulfonic acid (67 mg, 0.39 mmol). 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 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) to give compound 8-1.1 H NMR (400MHz, CDCl3) δ7.70(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).

[0338] Synthesis of compound 8-2

[0339] Synthesized according to compounds 1-3. MS-ESI: m / z 282.2 [M-100+1] + .

[0340] Synthesis of compound 8-3

[0341] Synthesized according to compounds 1-4. MS-ESI: m / z 267.2 [M-100+1] + .

[0342] Synthesis of compound 8-4

[0343] Synthesis of compounds 1-5 follows the same procedure. MS-ESI: m / z 349.2 [M+1] + .

[0344] Synthesis of Compound 8-5

[0345] Synthesized according to compounds 1-6. MS-ESI: m / z 232.2 [M-17+1] + .

[0346] Synthesis of Compound 8-6

[0347] The synthesis of compounds 1-7 was similar, except that N,N-dimethylformamide was replaced with dichloromethane. MS-ESI: m / z 420.1 [M-56+1] + .

[0348] Synthesis of Compound 8

[0349] Synthesis of compound 1 was performed as described above. MS-ESI: m / z 376.2 [M+1] + . 1H NMR (400MHz, 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).

[0350] Example 9

[0351] (S)-N-((S)-1-cyano-2-(2-methyl-1,2,3,4-tetrahydroisoquinoline-6-yl)ethyl)-1,4-oxazineheptane-2-carboxamide

[0352]

[0353] Synthesis of compound 9-2

[0354] Synthesized according to compounds 1-3. MS-ESI: m / z 331.2 [M+1] + .

[0355] Synthesis of compound 9-3

[0356] 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] + .

[0357] Synthesis of compound 9-4

[0358] At room temperature, crude compound 9-3 (1.70 g, 3.60 mmol) was dissolved in 30 mL of 7 M ammonia-methanol solution, 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] + .

[0359] Synthesis of Compound 9-5

[0360] 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 give compound 9-5. MS-ESI: m / z 334.2 [M+1] + .

[0361] Synthesis of Compounds 9-6

[0362] 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] + .

[0363] Synthesis of compounds 9-7

[0364] The synthesis of compounds 1-7 was similar, except that N,N-dimethylformamide was replaced with a mixed solvent (1 / 3) of N,N-dimethylformamide and dichloromethane. MS-ESI: m / z 461.3 [M+1] + .

[0365] Synthesis of compounds 9-8

[0366] Synthesized according to compounds 1-5. MS-ESI: m / z 443.6 [M+1] + .

[0367] Synthesis of Compound 9

[0368] Synthesis of compound 1 was performed as described above. MS-ESI: m / z 343.5 [M+1] + . 1 H NMR(400MHz,DMSO-d6)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).

[0369] Example 10

[0370] (S)-4-amino-N-(2-(chromen-7-yl)-1-cyanoethyl)tetrahydro-2H-pyran-4-carboxamide

[0371]

[0372]

[0373] Synthesis of compound 10-2

[0374] 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.

[0375] Synthesis of compound 10-3

[0376] Synthesized according to compounds 1-3. MS-ESI: m / z 236.1 [M-100+1] + .

[0377] Synthesis of compound 10-4

[0378] Synthesized according to compounds 1-4. MS-ESI: m / z 321.2 [M+1] + .

[0379] Synthesis of compound 10-5

[0380] Synthesized according to compounds 1-5. MS-ESI: m / z 247.4 [M-56+1] + .

[0381] Synthesis of compound 10-6

[0382] Compound 10⁻⁵ (200 mg, 0.66 mmol) was dissolved in 5 mL of dioxane hydrochloride solution 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] + .

[0383] Synthesis of compound 10-7

[0384] The synthesis of compounds 1-7 was similar, except that N,N-dimethylformamide was replaced with a mixed solvent (1 / 2) of N,N-dimethylformamide and dichloromethane. MS-ESI: m / z 448.3 [M+1] + .

[0385] Synthesis of Compound 10

[0386] Synthesis of compound 1 was performed as described above. MS-ESI: m / z 330.4 [M+1] + . 1 H NMR(400MHz,DMSO-d6)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),3.65-3.5 6(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).

[0387] Example 11

[0388] (2S)-N-(1-cyano-2-(8-fluoro-6H-benzo[c]chromo-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide carboxylate

[0389]

[0390] Synthesis of compound 11-2

[0391] Under nitrogen protection at room temperature, 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). 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] + .

[0392] Synthesis of compound 11-3

[0393] 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] + .

[0394] Synthesis of compound 11-4

[0395] 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 (400MHz, DMSO-d6) δ7.85(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).

[0396] Synthesis of Compound 11-5

[0397] Refer to the synthesis of compounds 3-5. 1 H NMR (400MHz, CDCl3) δ7.64–7.62(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).

[0398] Synthesis of Compound 11-6

[0399] Synthesized according to compounds 3-6. MS-ESI: m / z 433.1 [M+1] + .

[0400] Synthesis of Compound 11-7

[0401] Synthesized according to compounds 3-7. MS-ESI: m / z 252.1 [M-17+1] + .

[0402] Synthesis of Compound 11-8

[0403] The synthesis of compounds 3-8 was similar, except that N,N-dimethylformamide was replaced with a mixed solvent of N,N-dimethylformamide and dichloromethane (1 / 10). MS-ESI: m / z 396.3 [M-100+1] + .

[0404] Synthesis of Compound 11

[0405] Synthesis of compound 1 was performed as described above. MS-ESI: m / z 396.1 [M+1] + . 1 H NMR (400MHz, 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),3.7 6-3.67(m,1H),3.18-3.04(m,3H),2.92-2.57(m,3H),1.75-1.73(m,2H).

[0406] Example 12

[0407] (2S)-N-(1-cyano-2-(2,8-difluoro-6H-benzo[c]chroman-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide

[0408]

[0409] Synthesis of Compound 12-2

[0410] 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-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. 1H NMR (400MHz, CDCl3) δ7.57-7.50(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).

[0411] Synthesis of Compound 12-3

[0412] 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 N,N-dimethylformamide (100 mL) under nitrogen protection at room temperature. The reaction mixture was heated to 130 °C and stirred for 3 hours. After the reaction was complete, the 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 12-3. 1 HNMR (400MHz, CDCl3) δ7.66-7.61(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).

[0413] Synthesis of compound 12-4

[0414] 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 (400MHz, CDCl3) δ7.56(dd,1H),7.32(d,1H),7.11-7.03(m,2H),6.88(dd,1H),5.06(s,2H),4.73(d,2H).

[0415] Synthesis of Compound 12-5

[0416] 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 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 12-5. 1 H NMR (300MHz, CDCl3) δ7.65-7.57(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).

[0417] Synthesis of Compound 12-6

[0418] 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 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 = 7 / 3) to give compound 12-6. MS-ESI: m / z 451.1 [M+1] + .

[0419] Synthesis of Compound 12-7

[0420] Compound 12-6 (1.50 mg, 2.97 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 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 give compound 12-7. MS-ESI: m / z 287.1 [M+1] + .

[0421] Synthesis of Compound 12-8

[0422] Compound 12-7 (150 mg, 0.52 mmol), compound 2-6 (127 mg, 0.52 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (256 mg, 0.68 mmol), and N,N-diisopropylethylamine (200 mg, 1.56 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, compound 12-8 was obtained by preparative liquid chromatography (C18, acetonitrile / water system). MS-ESI: m / z 458.1 [M-56+1] + .

[0423] Synthesis of Compound 12

[0424] 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] + . 1 H NMR (400MHz, CDCl3) δ7.57(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).

[0425] Example 13

[0426] (2S)-N-(1-cyano-2-(8-cyano-6H-benzo[c]chromo-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide

[0427]

[0428]

[0429] Synthesis of Compound 13-2

[0430] At room temperature, 4-bromo-3-toluenenitrile (compound 13-1) (10 g, 51.29 mmol), N-bromosuccinimide (22.70 g, 127.54 mmol), and benzoyl peroxide (1.24 g, 5.12 mmol) were dissolved in 50 mL of 1,2-dichloroethane. The reaction mixture was heated to 100 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate solution (50 mL) was added. The mixture was extracted 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 HNMR (400MHz, CDCl3) δ7.77-7.69(m,2H),7.47-7.41(m,1H),4.57(s,2H).

[0431] Synthesis of compound 13-3

[0432] 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.

[0433] Synthesis of Compound 13-4

[0434] Refer to the synthesis of compound 12-3. 1 H NMR (400MHz, DMSO-d6) δ8.11(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).

[0435] Synthesis of Compound 13-5

[0436] Synthesis of compound 11-4 was performed according to the reference. MS-ESI: m / z 220.2 [M-18+1] + .

[0437] Synthesis of Compound 13-6

[0438] Refer to the synthesis of compounds 3-5.1 H NMR (400MHz, DMSO-d6) δ8.03(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).

[0439] Synthesis of Compounds 13-7

[0440] MS-ESI for the synthesis of compounds 3-6: m / z 440.3 [M+1] + .

[0441] Synthesis of Compounds 13-8

[0442] Synthesized according to compounds 3-7. MS-ESI: m / z 259.2 [M-17+1] + .

[0443] Synthesis of Compounds 13-9

[0444] The synthesis of compounds 1-7 was similar, except that N,N-dimethylformamide was replaced with a mixed solvent of N,N-dimethylformamide and dichloromethane (10 / 1). MS-ESI: m / z 447.3 [M-56+1] + .

[0445] Synthesis of Compound 13

[0446] Synthesis of compound 1 was performed as described above. MS-ESI: m / z 403.3 [M+1] + . 1 H NMR (400MHz, 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).

[0447] Example 14

[0448] (S)-N-((S)-1-cyano-2-(8-cyano-2-fluoro-6H-benzo[c]chroman-3-yl)ethyl)-1,4-oxazine-heptane-2-

[0449] formamide

[0450]

[0451] Synthetic Route A:

[0452]

[0453] Synthesis of compound 14-A1

[0454] 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-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 (400MHz, CDCl3) δ7.87(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).

[0455] Synthesis of compound 14-A2

[0456] 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 N,N-dimethylformamide (30 mL) under nitrogen protection at room temperature. The reaction mixture was heated to 120 °C and stirred for 1.5 hours. After the reaction was complete, the 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 = 4 / 1) to give compound 14-A2. 1 HNMR (400MHz, 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).

[0457] Synthesis of compound 14-A3

[0458] 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 HNMR (400MHz, CDCl3) δ7.67(s,2H),7.47(s,1H),7.38(d,1H),7.12(d,1H),5.11(s,2H),4.77(s,2H).

[0459] Synthesis of compound 14-A4

[0460] 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 HNMR (300MHz, CDCl3) δ7.73(s,2H),7.52(s,1H),7.45(d,1H),7.10(d,1H),5.17(s,2H),4.53(s,2H).

[0461] Synthesis of compound 14-A5

[0462] 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 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 / ethyl acetate = 4 / 1) to give compound 14-A5. MS-ESI: m / z 458.4 [M+1]+ .

[0463] Synthesis of compound 14-A6

[0464] 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 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 give compound 14-A6. MS-ESI: m / z 293.9 [M+1] + .

[0465] Synthesis of compound 14-A7

[0466] Compound 14-A6 (220 mg, 0.68 mmol), compound 2-6 (170 mg, 0.69 mmol), 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) were dissolved in N,N-dimethylformamide (5 mL) at room temperature. 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] + .

[0467] Synthesis of Compound 14-1

[0468] Compound 14-A7 (280 mg, 0.51 mmol) was chirally resolved (column: chiralpak IE, 250*25 mm, 5 μm; mobile phase: n-hexane, ethanol; gradient ratio: 30% n-hexane phase; flow rate: 15 mL / min; column temperature: 30 °C) to give compound 14-1 (two diastereomer peaks, compound 14-1 being the first eluted peak). 1H NMR(300MHz,DMSO-d6)δ8.89(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),5.09-5.0 7(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).

[0469] Synthesis of Compound 14

[0470] 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(400MHz,DMSO-d6)δ8.69(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),4.00-3.9 7(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).

[0471] Synthetic Route B:

[0472]

[0473] Synthesis of compound 14-B1

[0474] 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 N,N-dimethylformamide (100 mL) under nitrogen protection at room temperature. 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. The mixture was extracted with ethyl acetate (500 mL × 2). The organic phases were combined, 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 (300MHz, CDCl3): δ7.82(d,1H),7.46-7.39(m,2H),2.55(s,3H),1.35(s,12H).

[0475] Synthesis of compound 14-B2

[0476] 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. The mixture was extracted with ethyl acetate (500 mL × 2). The organic phases were combined, washed with saturated brine (500 × 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 = 9 / 1) to give compound 14-B2. 1 H NMR (300MHz, CDCl3) δ7.62-7.52(m,2H),7.45-7.36(m,1H),7.32-7.24(m,1H),7.06-6.97(m,1H),2.24(s,3H).

[0477] Synthesis of compound 14-B3

[0478] Compound 14-B2 (7.40 g, 24.02 mmol), N-bromosuccinimide (10.26 g, 57.64 mmol), and benzoyl peroxide (0.35 g, 1.44 mmol) were dissolved in carbon tetrachloride (80 mL) at room temperature and under nitrogen protection. 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 obtain compound 14-B3. 1 H NMR (300MHz, CDCl3): δ8.41(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).

[0479] Synthesis of compound 14-B4

[0480] At room temperature, compound 14-B3 (1.00 g, 2.15 mmol) was dissolved in acetonitrile (10 mL), 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 give crude compound 14-B4, which was used directly in the next reaction. 1 H NMR (300MHz, CDCl3): δ9.92(d,1H),8.32(s,1H),7.96(d,1H),7.57-7.43(m,2H),7.17-7.10(m,1H).

[0481] Synthesis of compound 14-B5

[0482] 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. Extraction was performed with ethyl acetate (50 mL × 3). The organic layers were combined, 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 (300MHz, 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).

[0483] Synthesis of compound 14-B6

[0484] Compound 14-B5 (6.50 g, 20.05 mmol) was dissolved in N,N-dimethylformamide (65 mL) at room temperature. Sodium hydride (0.48 g, 20.05 mmol, 60%) was added in portions 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 (300MHz, DMSO-d6): δ8.12-8.06(m,2H),7.94-7.86(m,1H),7.82(s,1H),7.46-7.40(m,1H),5.21(s,2H).

[0485] Synthesis of compound 14-B7

[0486] Under nitrogen protection at room temperature, zinc powder (40.00 g, 611.53 mmol) and iodine (0.5 g, 1.13 mmol) were added to N,N-dimethylformamide (50 mL), followed by a solution of (R)-2-(((tert-butoxycarbonyl)amino)methyl-3-iodopropionate (60.00 g, 182.30 mmol) in N,N-dimethylformamide (200 mL). The reaction mixture was heated to 50 °C and stirred for 1 hour. The supernatant was used as the zinc reagent.

[0487] In a separate reaction flask, under nitrogen protection at room temperature, crude reactant 14-B6 (20.00 g, 65.76 mmol) and palladium dichloride bis(triphenylphosphine) (4.00 g, 0.13 mmol) were dissolved in N,N-dimethylformamide (100 mL). The zinc reagent was then added to the reaction mixture, and 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 obtain compound 14-B7. 1 H NMR (400MHz, CDCl3) δ8.04-8.02(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).

[0488] Synthesis of compound 14-B8

[0489] 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] + .

[0490] Synthesis of compound 14-B9

[0491] 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] - .

[0492] Synthesis of compound 14-B10

[0493] 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 minutes. The mixture was then extracted with dichloromethane (100 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 to obtain crude compound 14-B10, which was used directly in the next reaction. MS-ESI: m / z 392.0 [M+1] + .

[0494] Synthesis of Compound 14-1

[0495] 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-dimethylformamide (100 mL). N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (10.89 g, 28.64 mmol) was added at 0 °C, and the mixture was stirred for 5 minutes. Then, N,N-diisopropylethylamine (4.63 g, 35.80 mmol) was added dropwise at 0 °C, 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 (300 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phases were 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] + .

[0496] Synthesis of Compound 14

[0497] 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 an aqueous solution of sodium carbonate (8.6 g, 4 eq) in 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] + .

[0498] 1 H NMR(400MHz, CDCl3)δ8.68(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).

[0499] 1H NMR(400MHz,DMSO-d6)δ8.68(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),4.00-3.9 7(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).

[0500] Example 15

[0501] (2S)-N-(1-cyano-2-(3-fluoro-6H-benzo[c]chroman-8-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide

[0502]

[0503]

[0504] Synthesis of Compound 15-2

[0505] 4-Bromo-3-methylbenzoate (compound 15-1) (11.30 g, 49.57 mmol) was dissolved in carbon tetrachloride (150 mL) at room temperature. N-bromosuccinimide (13.20 g, 74.17 mmol) and azobisisobutyronitrile (4.10 g, 24.97 mmol) were added, and the reaction mixture was heated to 80 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature, and saturated sodium bicarbonate aqueous solution (150 mL) was added. Extraction was performed with dichloromethane (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 15-2 (12 g). 1 H NMR (400MHz, DMSO-d6) δ8.21(d,1H),7.85-7.79(m,2H),4.83(s,2H),3.87(s,3H).

[0506] Synthesis of Compound 15-3

[0507] 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).

[0508] Synthesis of Compound 15-4

[0509] Synthesis of compound 11-2 was performed according to the reference. MS-ESI: m / z 275.1 [M-1] - .

[0510] Synthesis of Compound 15-5

[0511] Synthesis of compound 11-3 was performed according to the reference. MS-ESI: m / z 259.1 [M+1] + .

[0512] Synthesis of Compound 15-6

[0513] Synthesis of compound 11-4 was performed according to the reference. MS-ESI: m / z 213.4 [M-18+1] + .

[0514] Synthesis of Compound 15-7

[0515] Refer to the synthesis of compounds 3-5. 1 H NMR (400MHz, CDCl3) δ7.68-7.64(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).

[0516] Synthesis of Compound 15-8

[0517] Synthesized according to compounds 3-6. MS-ESI: m / z 433.1 [M+1] + .

[0518] Synthesis of Compounds 15-9

[0519] Synthesized according to compounds 3-7. MS-ESI: m / z 252.1 [M-17+1] + .

[0520] Synthesis of Compounds 15-10

[0521] The synthesis of compounds 3-8 was similar, except that N,N-dimethylformamide was replaced with a mixed solvent of N,N-dimethylformamide and dichloromethane (1 / 10). MS-ESI: m / z 440.1 [M-56+1] + .

[0522] Synthesis of Compound 15

[0523] Synthesis of compound 1 was performed as described above. MS-ESI: m / z 396.1 [M+1] + . 1 H NMR (400MHz, 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,3 H),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).

[0524] Example 16

[0525] (S)-N-((S)-1-cyano-2-(8,9-difluoro-6H-benzo[c]chroman-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide

[0526]

[0527]

[0528] Synthesis of Compound 16-2

[0529] At 0 °C, (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 obtain crude compound 16-2, which was used directly in the next reaction. MS-ESI: m / z 196.2 [M+1] + .

[0530] Synthesis of Compound 16-3

[0531] 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. Di-tert-butyl dicarbonate (7.38 g, 33.81 mmol) was then added, and 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] + .

[0532] Synthesis of compound 16-4

[0533] Compound 16-3 (3.38 g, 11.45 mmol) was dissolved in N,N-dimethylformamide (50 mL) at room temperature, followed by the sequential addition of 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). The reaction mixture was heated to 60 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate 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, 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] + .

[0534] Synthesis of Compound 16-5

[0535] Compound 16-4 (1.00 g, 2.00 mmol) was dissolved in N,N-dimethylacetamide (50 mL) at room temperature, followed by the addition of sodium acetate (0.33 g, 4.00 mmol) and palladium dichloride bis(triphenylphosphine) (0.78 g, 1.00 mmol). 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] + .

[0536] Synthesis of compound 16-6

[0537] Synthesized according to compounds 1-4. MS-ESI: m / z 305.3 [M-100+1] + .

[0538] Synthesis of Compound 16-7

[0539] Synthesized according to compounds 1-5, 1-6, and 3-8. MS-ESI: m / z 414.2 [M-100+1] + .

[0540] Synthesis of Compound 16

[0541] Synthesis of compound 1 was performed as described above. MS-ESI: m / z 414.2 [M+1] + . 1 H NMR (400MHz, 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).

[0542] Example 17

[0543] (S)-4-amino-N-(1-cyano-2-(8,9-difluoro-6H-benzo[c]chroman-3-yl)ethyl)tetrahydro-2H-pyran-4-carboxyl

[0544]

[0545] Synthesis of Compound 17-1

[0546] Synthesized according to compounds 1-7. MS-ESI: m / z 414.2 [M-100+1] + .

[0547] Synthesis of Compound 17

[0548] Synthesis of compound 1 was performed as described above. MS-ESI: m / z 414.2 [M+1] + . 1 H NMR (400MHz, 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).

[0549] Example 18

[0550] (2S)-N-(1-cyano-2-(3-cyano-9-fluoro-5H-chromeno[4,3-c]pyridin-8-yl)ethyl)-1,4-oxazetane-2-carboxamide

[0551]

[0552] Synthesis of compound 18-2

[0553] 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] + .

[0554] Synthesis of compound 18-3

[0555] 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] + .

[0556] Synthesis of compound 18-4

[0557] 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 N,N-dimethylacetamide (25 mL) under nitrogen protection at room temperature. 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] + .

[0558] Synthesis of compound 18-5

[0559] 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 N,N-dimethylformamide (15 mL) under nitrogen protection at room temperature. 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] + .

[0560] Synthesis of compound 18-6

[0561] Refer to the synthesis of compound 17-5.1 H NMR (400MHz, CDCl3) δ8.85(s,1H),7.43(s,1H),7.39(d,1H),7.09(d,1H),5.07(s,2H),4.72(s,2H).

[0562] Synthesis of compound 18-7

[0563] 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. 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 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 / ethyl acetate = 4 / 1) to give compound 18-7. 1 H NMR (400MHz, CDCl3) δ8.93(s,1H),7.52-7.47(m,2H),7.08(d,1H),5.15(s,2H),4.48(s,2H).

[0564] Synthesis of compound 18-8

[0565] Synthesis of compound 14-A5 was performed according to the reference. MS-ESI: m / z 459.2 [M+1] + .

[0566] Synthesis of Compound 18-9

[0567] Synthesis of compound 14-A6 was performed according to the reference method. MS-ESI: m / z 295.0 [M+1] + .

[0568] Synthesis of Compound 18-10

[0569] Synthesis of compound 14-A7 was performed according to the reference method. MS-ESI: m / z 422.1 [M-100+1] + .

[0570] Synthesis of Compound 18

[0571] Synthesis of compound 14 was referenced. MS-ESI: m / z 422.1 [M+1] + . 1H NMR(400MHz, 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).

[0572] Example 19

[0573] (S)-N-((S)-1-cyano-2-(3-cyano-9-fluoro-5H-chromo[4,3-c]pyridin-8-yl)ethyl)-1,4-oxazetane-2-carboxamide

[0574]

[0575] Synthesis of Compound 19

[0576] Compound 18 (50 mg, 0.312 mmol) was chirally resolved (column: Chiralpak IC, 250*30 mm, 5 μm; mobile phase: acetonitrile, isopropanol (0.2% diethylamine); gradient ratio: 60% acetonitrile phase; flow rate: 15 mL / min; column temperature: 30 °C) to give compound 19 (two diastereomer peaks, compound 19 being the second eluting peak). MS-ESI: m / z 422.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ9.24(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),4.01-3.9 5(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).

[0577] Example 20

[0578] (S)-N-((S)-1-cyano-2-(2,8-difluoro-6H-benzo[c]chroman-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide

[0579]

[0580] Synthesis of Compound 20-1

[0581] tert-butyl(2S)-2-((1-cyano-2-(2,8-difluoro-6H-benzo[c]chromatin-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 μm; mobile phase: n-hexane, ethanol; gradient ratio: n-hexane phase 50%; flow rate: 15 mL / min; column temperature: 30 °C) to give compound 20-1 (two diastereomer peaks, compound 20-1 being the first eluting peak).

[0582] Synthesis of Compound 20

[0583] Synthesis of compound 14 was referenced. MS-ESI: m / z 414.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ8.67(d,1H),7.93-7.88(m,1H),7.74(d,1H),7.2 8-7.17(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).

[0584] Example 21

[0585] (S)-N-((S)-2-(2-chloro-8-cyano-6H-benzo[c]chroman-3-yl)-1-cyanoethyl)-1,4-oxazine-heptane-2-

[0586] formamide

[0587]

[0588] Synthesis of compound 21-2

[0589] The synthesis of compound 14-A1 was similar, except that potassium carbonate was replaced with cesium carbonate. 1H NMR (400MHz, DMSO-d6) δ8.10(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).

[0590] Synthesis of compound 21-3

[0591] Compound 21-2 (13.30 g, 34.90 mmol) was dissolved in anhydrous N,N-dimethylacetamide (150 mL) under nitrogen protection at room temperature. Then, bis(triphenylphosphine)-palladium dichloride (2.45 g, 3.50 mmol) and anhydrous potassium acetate (10.30 g, 104.95 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 16 hours. The 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 (400MHz, DMSO-d6) δ8.22(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).

[0592] Synthesis of compound 21-4

[0593] Refer to the synthesis of compound 14-A3. 1 H NMR (400MHz, DMSO-d6) δ8.08(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).

[0594] Synthesis of compound 21-5

[0595] Refer to the synthesis of compound 14-A4. 1 H NMR (400MHz, DMSO-d6) δ8.16-8.11(m,2H),7.88(dd,1H),7.81(s,1H),7.32(s,1H),5.22(s,2H),4.71(s,2H).

[0596] Synthesis of compound 21-6

[0597] Under nitrogen protection at room temperature, sodium hydroxide (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 step. MS-ESI: m / z 474.1 [M+1] + .

[0598] Synthesis of Compound 21-7

[0599] 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] + .

[0600] Synthesis of Compound 21-8

[0601] At room temperature, crude compounds 21-7 (500 mg, 1.26 mmol) and compounds 2-6 (309 mg, 1.26 mmol) were dissolved in a mixed solvent of anhydrous N,N-dimethylformamide (3 mL) and anhydrous dichloromethane (6 mL). Then, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (955 mg, 2.52 mmol) and N,N-diisopropylethylamine (407 mg, 3.15 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium bicarbonate (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*40mm, 15μm; mobile phase: water (0.225% formic acid), acetonitrile; gradient ratio: acetonitrile phase 52-82%; flow rate: 60mL / min; column temperature: room temperature) to obtain compound 21-8. MS-ESI: m / z 481.1 [M-56+1] + .

[0602] Synthesis of Compounds 21-9

[0603] Compound 21-8 (390 mg, 0.73 mmol) was resolved by preparative SFC (column: DAICEL CHIRALCEL OJ, 250*30 mm, 10 μm; mobile phase: supercritical carbon dioxide, methanol (0.1% ammonia monohydrate); gradient ratio: 55% carbon dioxide phase; flow rate: 70 mL / min; column temperature: room temperature) to obtain compound 21-9 (two diastereomer peaks, compound 21-9 being the second eluted peak).

[0604] Synthesis of Compound 21

[0605] Synthesis of compound 14 was referenced. MS-ESI: m / z 437.2 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ8.70(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,1 H),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).

[0606] Example 22

[0607] 4-Amino-N-(1-cyano-2-(8-fluoro-6H-benzo[c]chroman-3-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide carboxylate

[0608]

[0609] Synthesis of compound 22-1

[0610] The synthesis of compounds 1-7 was similar, except that N,N-dimethylformamide was replaced with a mixed solvent of N,N-dimethylformamide and dichloromethane (10 / 1). MS-ESI: m / z 396.1 [M-100+1] + .

[0611] Synthesis of Compound 22

[0612] Synthesis of compound 1 was performed as described above. MS-ESI: m / z 396.1 [M+H] + . 1 H NMR(400MHz, 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).

[0613] Example 23

[0614] 4-Amino-N-(1-cyano-2-(3-fluoro-6H-benzo[c]chroman-8-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0615]

[0616]

[0617] Synthesis of Compound 23-1

[0618] The synthesis of compounds 1-7 was similar, except that N,N-dimethylformamide was replaced with a mixed solvent of N,N-dimethylformamide and dichloromethane (10 / 1). MS-ESI: m / z 396.1 [M-100+1] + .

[0619] Synthesis of Compound 23

[0620] Synthesis of compound 1 was performed as described above. MS-ESI: m / z 396.1 [M+H] + . 1 H NMR(400MHz,DMSO_d6)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).

[0621] Example 24

[0622] 4-Amino-N-(1-cyano-2-(2,8-difluoro-6H-benzo[c]chroman-3-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0623]

[0624] Synthesis of Compound 24-1

[0625] Synthesized according to compounds 1-7. MS-ESI: m / z 458.1 [M-56+1] + .

[0626] Synthesis of Compound 24

[0627] 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] + . 1H NMR(400MHz, CDCl3)δ8.29(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),2.3 2-2.22(m,1H),2.21-2.11(m,1H),1.32-1.26(m,1H),1.23-1.17(m,1H).

[0628] Example 25

[0629] 4-Amino-N-(1-cyano-2-(8-cyano-6H-benzo[c]chroman-3-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0630]

[0631] Synthesis of Compound 25-1

[0632] Synthesis of compound 21-8 was performed according to the reference. MS-ESI: m / z 403.3 [M-100+1] + .

[0633] Synthesis of Compound 25

[0634] Synthesis of compound 1 was performed as described above. MS-ESI: m / z 403.3 [M+1] + . 1 H NMR(400MHz, 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).

[0635] Example 26

[0636] (2S, 3aS, 6aS)-N-((S)-1-cyano-2-(8-cyano-2-fluoro-6H-benzo[c]chromo-3-yl)ethyl)octahydrocyclopentano[b]pyrrole-2-carboxamide

[0637]

[0638] Synthesis of compound 26-2

[0639] At room temperature, (2S,3aS,6aS)-1-(tert-butoxycarbonyl)octahydrocyclopentano[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 urea (259 mg, 0.68 mmol) were dissolved in N,N-dimethylformamide (5 mL). After stirring for ten minutes, 3-(2-amino-2-cyanoethyl)-2-fluoro-6H-benzo[c]chromium-8-carbamate (compound 14-A6) (200 mg, 0.68 mmol) and triethylamine (0.19 mL, 1.36 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, 10 mL of the solution 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] - .

[0640] Synthesis of compound 26-3

[0641] Compound 26-2 (300 mg, 0.57 mmol) was chirally resolved (column: chiralpak IE, 250*30 mm, 5 μm; mobile phase: n-hexane, ethanol; gradient ratio: 50% n-hexane phase; flow rate: 25 mL / min; column temperature: 30 °C) to give compound 26-3 (two diastereomer peaks, compound 26-3 being the second eluting peak).

[0642] Synthesis of Compound 26

[0643] The synthesis of compound 14 was similar, except the temperature was changed to 50℃. MS-ESI: m / z 431.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.53(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).

[0644] Example 27

[0645] (S)-N-((S)-1-cyano-2-(8-cyano-2-fluoro-6,6-dimethyl-6H-benzo[c]chroman-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide

[0646]

[0647]

[0648] Synthesis of Compound 27-2

[0649] Under nitrogen protection at room temperature, 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), and dichloromethyl methyl ether (13.9 mL, 153.68 mmol) was added at 0 °C. 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. 1 H NMR (300MHz, CDCl3) δ10.31(s,1H),7.45(d,1H),7.31(d,1H),3.93(s,3H).

[0650] Synthesis of compound 27-3

[0651] 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 (400MHz, CDCl3) δ7.25(d,1H),6.98(d,1H),4.71(s,2H),3.88(s,3H).

[0652] Synthesis of compound 27-4

[0653] 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 give compound 27-4. 1 H NMR (400MHz, CDCl3) δ7.70-7.64(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).

[0654] Synthesis of compound 27-5

[0655] Compound 27-4 (5.00 g, 10.88 mmol), pinacol diborate (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 HNMR (400MHz, 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).

[0656] Synthesis of compound 27-6

[0657] 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(400MHz, CDCl3)δ8.01(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).

[0658] Synthesis of compound 27-7

[0659] Compound 27-6 (4.20 g, 6.91 mmol) was dissolved in tetrahydrofuran (80 mL) under nitrogen protection at room temperature. 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(300MHz, CDCl3)δ7.79(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).

[0660] Synthesis of Compounds 27-8

[0661] 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 HNMR (400MHz, DMSO-d6) 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).

[0662] Synthesis of Compound 27-9

[0663] Compound 27-8 (100 mg, 0.29 mmol) and zinc cyanide (42 mg, 0.35 mmol) were dissolved in N,N-dimethylformamide (3 mL) under nitrogen protection at room temperature, followed by the addition of tetrakis(triphenylphosphine)palladium (34.3 mg, 0.031 mmol). 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 obtain compound 27-9. 1 H NMR (400MHz, DMSO-d6) δ8.05(d,1H),7.90-7.78(m,3H),7.02(d,1H),5.36(t,1H),4.53(d,2H),1.59(s,6H).

[0664] Synthesis of compound 27-10

[0665] Refer to the synthesis of compound 18-7. 1 H NMR (400MHz, DMSO-d6) δ8.08(d,1H),7.96-7.83(m,3H),7.15(d,1H),4.68(s,2H),1.60(s,6H).

[0666] Synthesis of compound 27-11

[0667] The synthesis of compound 14-A5 was similar, except that benzyltrimethylammonium chloride was replaced with benzyltriethylammonium chloride. 1 H NMR (300MHz, CDCl3) δ7.67-7.57(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).

[0668] Synthesis of compound 27-12

[0669] Refer to the synthesis of compound 14-A6. 1 H NMR (300MHz, CDCl3) δ7.71-7.60(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).

[0670] Synthesis of Compound 27-13

[0671] The synthesis of compound 14-A7 was similar, except that N,N-diisopropylethylamine was replaced with triethylamine. MS-ESI: m / z 547.2 [M-1] - .

[0672] Synthesis of Compound 27-14

[0673] Compound 27-13 (230 mg, 0.42 mmol) was first chirally resolved (column: chiralpak IC, 250*30 mm, 5 μm; mobile phase: n-hexane, ethanol; gradient ratio: 50% n-hexane phase; flow rate: 25 mL / min; column temperature: 30 °C) to obtain crude compound 27-14 (with three diastereomer peaks, the crude compound 27-14 being the first eluting peak). It was then chirally resolved again (column: chiralpak IG, 250*30 mm, 5 μm; mobile phase: n-hexane, ethanol; gradient ratio: 60% n-hexane phase; flow rate: 25 mL / min; column temperature: 30 °C) to obtain compound 27-14 (with two diastereomer peaks, compound 27-14 being the first eluting peak).

[0674] Synthesis of Compound 27

[0675] Synthesis of compound 14 was referenced. MS-ESI: m / z 449.2 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ8.67(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).

[0676] Example 28

[0677] (2S)-N-(1-cyano-2-(9-(oxetan-3-yl)-6H-benzo[c]chroman-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide

[0678]

[0679] Synthesis of Compound 28-2

[0680] At room temperature, 2-bromo-4-hydroxybenzaldehyde (compound 28-1) (4 g, 19.90 mmol) was dissolved in tetrahydrofuran (50 mL). 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 (400MHz, 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).

[0681] Synthesis of compound 28-3

[0682] 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 (300MHz, CDCl3) δ7.39-7.33(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).

[0683] Synthesis of compound 28-4

[0684] 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.

[0685] At room temperature, m-hydroxybenzoic acid (2.34 g, 15.38 mmol) was dissolved in N,N-dimethylformamide (50 mL), and sodium hydride (0.80 g, 19.99 mmol, 60%) was added at 0 °C. The mixture was stirred at 0 °C for 5 minutes, followed by the addition of a solution of the crude intermediate (5 g, 15.38 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed successively with water (25 mL) and 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 = 10 / 1) to give compound 28-4. 1 H NMR (300MHz, CDCl3) δ7.69-7.64(m,2H),7.47-7.30(m,3H),7.20-7.14(m,1 H),7.05-6.97(m,1H),5.30(s,2H),5.17(s,2H),3.92(s,3H),3.48(s,3H).

[0686] Synthesis of compound 28-5

[0687] 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 N,N-dimethylformamide (50 mL) under nitrogen protection at room temperature. 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 combined organic phases were 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 H NMR (300MHz, CDCl3) δ7.77-7.70(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).

[0688] Synthesis of compound 28-6

[0689] 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 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 = 4 / 1) to give compound 28-6. 1 H NMR(400MHz,DMSO-d6)δ9.67(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).

[0690] Synthesis of compound 28-7

[0691] Compound 28-6 (1.20 g, 4.68 mmol) and triethylamine (1.40 g, 13.84 mmol) were dissolved in dichloromethane (30 mL) at room temperature, followed by the addition of 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 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 28-7. 1 H NMR (400MHz, CDCl3) δ7.79-7.73(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).

[0692] Synthesis of Compound 28-8

[0693] 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) δ8.18(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).

[0694] Synthesis of Compounds 28-9

[0695] 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(400MHz,DMSO-d6)δ8.38(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).

[0696] Synthesis of Compound 28-10

[0697] Compound 28-9 (1.10 g, 3.87 mmol) and 3-iodooxetane (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) 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 give compound 28-10.

[0698] Synthesis of compound 28-11

[0699] Synthesis of compound 12-4 was performed according to the reference. MS-ESI: m / z 251.2 [M-18+1] + .

[0700] Synthesis of compound 28-12

[0701] The synthesis of compound 18-7 was similar, except that dichloromethane was replaced with tetrahydrofuran. 1 H NMR(400MHz, CDCl3)δ7.76-7.70(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).

[0702] Synthesis of Compound 28-13

[0703] At room temperature, diphenylmethyleneaminoacetonitrile (135 mg, 0.61 mmol) was dissolved in tetrahydrofuran (5 mL), 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 give compound 28-13. MS-ESI: m / z 471.5 [M+1] + .

[0704] Synthesis of Compound 28-14

[0705] Synthesis of compound 14-A6 was performed according to the reference method. MS-ESI: m / z 329.1 [M+1] + .

[0706] Synthesis of Compound 28-15

[0707] The synthesis of compound 14-A7 was similar, except that N,N-diisopropylethylamine was replaced with triethylamine. MS-ESI: m / z 434.5 [M-100+1] + .

[0708] Synthesis of Compound 28

[0709] Synthesis of compound 14 was referenced. MS-ESI: m / z 434.2 [M+1] + . 1 H NMR(400MHz,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).

[0710] Example 29

[0711] (2S)-N-(1-cyano-2-(2-fluoro-8-(methanesulfonyl)-6Hbenzo[c]chroman-3-yl)ethyl)-1,4-oxazine heptane

[0712] -2-Formamide

[0713]

[0714] Synthesis of Compound 29-2

[0715] Under nitrogen protection at room temperature, 13 g (64.67 mmol) of 2-bromo-5-hydroxybenzaldehyde (compound 29-1) was dissolved in 50 mL of N,N-dimethylformamide. Sodium hydride (1.63 g, 67.90 mmol, 60%) was added in portions at 0 °C, and the mixture was stirred for 10 minutes at 0 °C. Then, 8.49 g (67.90 mmol) of bromomethyl ether was added dropwise, and the reaction mixture was stirred for another 30 minutes at room temperature. After the reaction was complete, 100 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with 100 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 obtain compound 29-2. 1 H NMR (300MHz, CDCl3) δ10.31(s,1H),7.60-7.51(m,2H),7.15(dd,1H),5.20(s,2H),3.47(s,3H).

[0716] Synthesis of compound 29-3

[0717] Compound 29-2 (9.60 g, 39.17 mmol) was dissolved in a mixed solvent 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 (300MHz, CDCl3) δ7.43(d,1H),7.19(d,1H),6.86(dd,1H),5.17(s,2H),4.71(s,2H),3.47(s,3H).

[0718] Synthesis of Compound 29-4

[0719] Refer to the synthesis of compound 18-3. 1H NMR(300MHz, CDCl3)δ7.54-7.50(m,1H),7.47(d,1H),7.23(d,1H),7.18-7.0 1(m,2H),6.86(dd,1H),5.15(s,2H),5.07(s,2H),3.94(s,3H),3.46(s,3H).

[0720] Synthesis of Compound 29-5

[0721] Synthesis of compound 18-4 was performed according to the reference method. MS-ESI: m / z 319.2 [M+1] + .

[0722] Synthesis of Compound 29-6

[0723] 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 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 crude residue was slurried with ethyl acetate (30 mL) to give compound 29-6. MS-ESI: m / z 275.1 [M+1] + .

[0724] Synthesis of Compound 29-7

[0725] Compound 29-6 (2.40 g, 8.75 mmol) was dissolved in N,N-dimethylformamide (25 mL) at room temperature, followed by the addition of triethylamine (1.33 g, 13.13 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (3.75 g, 10.50 mmol). The reaction mixture was 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 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 = 4 / 1) to give compound 29-7. 1 H NMR (300MHz, CDCl3) δ7.73(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).

[0726] Synthesis of Compound 29-8

[0727] 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). 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 = 9 / 1) to give compound 29-8. MS-ESI: m / z 411.3 [M+1] + .

[0728] Synthesis of Compound 29-9

[0729] 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, and the residue was extracted with water (20 mL) and 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 dissolved in N,N-dimethylformamide (6 mL), and sodium hydride (32.23 mg, 1.34 mmol) was added in portions at 0 °C. After stirring at room temperature for 10 minutes, iodomethane (190 mg, 1.34 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, water (50 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, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 29-9. 1 H NMR (300MHz, CDCl3) δ7.98(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).

[0730] Synthesis of Compounds 29-10

[0731] 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 (300MHz, CDCl3) δ7.98(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).

[0732] Synthesis of Compound 29-11

[0733] Refer to the synthesis of compound 14-A3. 1 H NMR (400MHz, CDCl3) δ8.10(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).

[0734] Synthesis of Compounds 29-12

[0735] Refer to the synthesis of compound 14-A4. 1 H NMR (400MHz, CDCl3) δ7.96(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).

[0736] Synthesis of Compounds 29-13

[0737] Refer to the synthesis of compound 14-A5. 1 H NMR (300MHz, CDCl3) δ7.93(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).

[0738] Synthesis of compounds 29-14

[0739] Refer to the synthesis of compound 14-A6.

[0740] Synthesis of Compounds 29-15

[0741] Refer to the synthesis of compound 14-A7.

[0742] Synthesis of Compound 29

[0743] Synthesis of compound 14 was referenced. MS-ESI: m / z 474.2 [M+1] + . 1 H NMR(400MHz,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,3 H),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).

[0744] Example 30

[0745] (S)-N-((S)-1-cyano-2-(2-fluoro-8-(methanesulfonyl)-6Hbenzo[c]chroman-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide

[0746]

[0747] Synthesis of Compound 30-1

[0748] tert-butyl(2S)-2-((1-cyano-2-(2-fluoro-8-(methanesulfonyl)-6Hbenzo[c]chroman-3-yl)ethyl)carbamoyl)-1,4-oxazane-4-carboxylic acid ester (compound 29-15) (100 mg, 0.17 mmol) was chirally resolved (column: chiralpak IA, 250*25 mm, 5 μm; mobile phase: supercritical carbon dioxide, isopropanol; gradient ratio: 70% carbon dioxide phase; flow rate: 60 mL / min; column temperature: 30 °C) to give compound 30-1 (two diastereomer peaks, compound 30-1 being the first eluting peak).

[0749] Synthesis of Compound 30

[0750] Synthesis of compound 14 was referenced. MS-ESI: m / z 474.1 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ8.70(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).

[0751] Example 31

[0752]

[0753] (2S)-N-(1-cyano-2-(9-cyano-2-fluoro-6H-benzo[c]chromo-3-yl)ethyl)-1,4-oxazetane-2-carboxamide

[0754]

[0755] Synthesis of compound 31-1

[0756] 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.

[0757] At room temperature, methyl 1-fluoro-4-hydroxybenzoate (3 g, 17.63 mmol) was dissolved in dichloromethane (100 mL), 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 combined organic phases were 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 (400MHz, CDCl3) δ7.59(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).

[0758] Synthesis of compound 31-2

[0759] Compound 31-1 (1 g, 2.51 mmol) and palladium acetate (0.1 g, 0.445 mmol) were dissolved in N,N-dimethylformamide (30 mL) under nitrogen protection at room temperature. Potassium carbonate (0.50 g, 3.62 mmol) and tricyclohexyltetrafluoroborate (0.30 g, 0.63 mmol) were then added. 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 combined organic phases were washed with water (20 mL × 3) 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 (SiO2, petroleum ether / ethyl acetate = 5 / 1) to give compound 31-2. 1 H NMR (400MHz, CDCl3) δ7.56(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).

[0760] Synthesis of compound 31-3

[0761] 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-d6) δ7.74(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).

[0762] Synthesis of compound 31-4

[0763] Compound 31-3 (1.20 g, 3.94 mmol) and triethylamine (0.80 g, 7.88 mmol) were dissolved in N,N-dimethylformamide (10 mL), followed by the addition of N-phenylbis(trifluoromethanesulfonyl)imide (1.69 g, 4.73 mmol). The reaction mixture 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, 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 31-4. 1 H NMR (300MHz, DMSO-d6) δ8.26-8.21(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).

[0764] Synthesis of Compound 31-5

[0765] 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 N,N-dimethylformamide (20 mL) under nitrogen protection at room temperature. 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 (300MHz, DMSO-d6) 1 H NMR (300MHz, DMSO-d6) δ8.50(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).

[0766] Synthesis of Compound 31-6

[0767] 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 (300MHz, DMSO-d6) δ8.40(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).

[0768] Synthesis of Compounds 31-7

[0769] Refer to the synthesis of compound 18-7. 1 H NMR (300MHz, DMSO-d6) δ8.42(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).

[0770] Synthesis of Compounds 31-8

[0771] Synthesis of compound 14-A5 was performed according to the reference. MS-ESI: m / z 458.1 [M+1] + .

[0772] Synthesis of Compounds 31-9

[0773] Synthesis of compound 14-A6 was performed according to the reference method. MS-ESI: m / z 294.0 [M+1] + .

[0774] Synthesis of Compound 31-10

[0775] Synthesis of compound 14-A7 was performed according to the reference method. MS-ESI: m / z 538.2 [M+18] + .

[0776] Synthesis of Compound 31

[0777] Synthesis of compound 14 was referenced. MS-ESI: m / z 421.1 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ8.72-8.63(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).

[0778] Example 32

[0779] (S)-N-(S)-1-cyano-2-(9-cyano-2-fluoro-6H-benzo[c]chroman-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide

[0780]

[0781] Synthesis of Compound 32-1

[0782] tert-butyl(2S)-2-((1-cyano-2-(9-cyano-2-fluoro-6H-benzo[c]chroman-3-yl)ethyl)carbamoyl)-1,4-oxazine-4-carboxylic acid ester (compound 31-10) (350 mg, 0.67 mmol) was chirally resolved (column: chiralpak IC, 250*30 mm, 5 μm; mobile phase: n-hexane, ethanol; gradient ratio: n-hexane phase 30%; flow rate: 25 mL / min; column temperature: 30 °C) to give compound 32-1 (two diastereomer peaks, compound 32-1 being the second eluting peak).

[0783] Synthesis of Compound 32

[0784] Synthesis of compound 14 was referenced. MS-ESI: m / z 421.2 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ8.70(d,1H),8.39(s,1H),7.91(d,1H),7.82(d,1 H),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).

[0785] Example 33

[0786] (2S)-N-(1-cyano-2-(3-cyano-9-fluoro-5H-chromo[4,3-b]pyridin-8-yl)ethyl)-1,4-oxazine-heptane

[0787] -2-Formamide

[0788]

[0789] Synthesis of compound 33-2

[0790] 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 (400MHz, DMSO-d6) δ10.59(s,1H),7.56(d,1H),7.40(d,1H).

[0791] Synthesis of compound 33-3

[0792] 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 HNMR (400MHz, CDCl3) δ7.58(d,1H),7.32(d,1H),3.94(s,3H).

[0793] Synthesis of compound 33-4

[0794] 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 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 obtain compound 33-4. 1 H NMR (400MHz, CDCl3) δ7.50(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).

[0795] Synthesis of compound 33-5

[0796] 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 give compound 33-5. MS-ESI: m / z 439.2 [M+23] + . 1 H NMR (400MHz, CDCl3) δ7.53-7.40(m,4H),6.91(d,2H),5.06(s,2H),3.94(s,3H),3.83(s,3H),1.36(s,12H).

[0797] Synthesis of compound 33-6

[0798] Under nitrogen protection, 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). 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] + .

[0799] Synthesis of compound 33-7

[0800] 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 (400MHz, CDCl3) δ8.63(d,1H),8.31(d,1H),7.58(d,1H),7.33(d,1H),4.83(s,2H),3.96(s,3H).

[0801] Synthesis of compound 33-8

[0802] 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). The mixture was stirred at 0 °C for 30 minutes, and then 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 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 give compound 33-8. MS-ESI: m / z 338.0 [M+1] + . 1 H NMR (400MHz, CDCl3) δ8.66(s,1H),7.93(d,1H),7.63(s,1H),7.51(d,1H),5.22(s,2H),3.94(s,3H).

[0803] Synthesis of Compound 33-9

[0804] Compound 33-8 (2.60 g, 7.68 mmol) and cuprous cyanide (2.06 g, 23.00 mmol) were dissolved in N-methylpyrrolidone (20 mL) at room temperature. The reaction mixture was heated to 135 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed successively with water (30 mL) and saturated sodium chloride aqueous solution (30 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, dichloromethane) to obtain compound 33-9. MS-ESI: m / z 285.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.06(d,1H),8.31-8.27(m,1H),7.95(d,1H),7.45(d,1H),5.40(s,2H),3.87(s,3H).

[0805] Synthesis of compound 33-10

[0806] 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 (400MHz, DMSO-d6) δ8.99(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).

[0807] Synthesis of compound 33-11

[0808] The synthesis of compound 18-7 was similar, except the temperature was changed to 0℃. MS-ESI: m / z 319.0 [M+1] + .

[0809] Synthesis of compound 33-12

[0810] At room temperature, diphenylmethyleneaminoacetonitrile (221 mg, 1.00 mmol) was dissolved in tetrahydrofuran (3 mL). 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 1 M hydrochloric acid, and the reaction mixture was stirred at room temperature for another 15 hours. The reaction mixture was diluted with 1 M 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] + .

[0811] Synthesis of compound 33-13

[0812] The synthesis of compound 14-A7 was similar, except that N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate was replaced with benzotriazol-N,N,N',N'-tetramethylurea hexafluorophosphate. MS-ESI: m / z 422.1 [M-100+1] + .

[0813] Synthesis of Compound 33

[0814] Synthesis of compound 14 was referenced. MS-ESI: m / z 422.1 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ9.00(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).

[0815] Example 34

[0816] 4-Amino-N-(1-cyano-2-(9-(pyrrolidin-3-yl)-6Hbenzo[c]chroman-3-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0817]

[0818] Synthesis of compound 34-3

[0819] 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. The mixture was filtered, and 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 (300MHz, CDCl3) δ7.86-7.69(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).

[0820] Synthesis of compound 34-4

[0821] 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 completed, 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 directly used in the next reaction step. 1 H NMR (300MHz, CDCl3) δ7.85-7.74(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).

[0822] Synthesis of Compound 34-5

[0823] The synthesis of compound 14-A3 was similar, except that the temperature was changed from 55℃ to room temperature. 1 H NMR(300MHz, CDCl3)δ7.76-7.69(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).

[0824] Synthesis of Compound 34-6

[0825] Refer to the synthesis of compound 18-7. 1 H NMR (400MHz, CDCl3) δ7.91-7.83(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).

[0826] Synthesis of Compound 34-7

[0827] Synthesized with reference to compounds 14-A5, 14-A6, and 14-A7. MS-ESI: m / z 491.2 [M-100-56+1] + .

[0828] Synthesis of Compound 34

[0829] Synthesis of compound 14 was referenced. MS-ESI: m / z 447.3 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ7.85(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,3 H),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).

[0830] Example 35

[0831] (2S)-N-(2-(8-(azacyclobutane-1-ylsulfonyl)-2-fluoro-6H-benzo[c]chroman-3-yl)-1-cyanoethyl)-1,4-oxazetane-2-carboxamide

[0832]

[0833]

[0834] Synthesis of Compound 35-1

[0835] The synthesis of compound 29-8 was similar, except the reaction temperature was changed from 70℃ to 80℃. MS-ESI: m / z 437.1 [M+1] + .

[0836] Synthesis of Compound 35-2

[0837] 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). 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, dichloromethane / methanol = 24 / 1) to give compound 35-2. MS-ESI: m / z 378.2 [M+1] + .

[0838] Synthesis of compound 35-3

[0839] 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] + .

[0840] Synthesis of compound 35-4

[0841] Refer to the synthesis of compound 14-A4. 1 H NMR(400MHz, CDCl3)δ7.88(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).

[0842] Synthesis of compound 35-5

[0843] 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 solution. 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 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 = 3 / 1) to give compound 35-5. MS-ESI: m / z 552.4 [M+1] + .

[0844] Synthesis of Compound 35-6

[0845] Refer to the synthesis of compound 14-A6.

[0846] Synthesis of Compound 35-7

[0847] The synthesis of compound 14-A7 was similar, except that N,N-diisopropylethylamine was replaced with triethylamine. MS-ESI: m / z 515.4 [M-100+1] + .

[0848] Synthesis of Compound 35

[0849] Synthesis of compound 14 was performed according to the reference. MS-ESI: m / z 515.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ8.72-8.65(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).

[0850] Example 36

[0851] 4-Amino-N-(1-cyano-2-(9-fluoro-6,7-dihydrodibenzo[b,d]oxepin-3-yl)ethyl)tetrahydro

[0852] -2H-pyran-4-carboxamide

[0853]

[0854]

[0855] Synthesis of Compound 36-1

[0856] 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] + .

[0857] Synthesis of compound 36-2

[0858] 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 give compound 36-2. MS-ESI: m / z 323.1 [M+1] + .

[0859] Synthesis of compound 36-3

[0860] 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.

[0861] 1 H NMR (400MHz, CDCl3): δ7.59-7.55(m,1H),7.32-7.26(m,1H),7.00-6.95(m,1H),3.83(s,2H).

[0862] Synthesis of compound 36-4

[0863] 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.

[0864] 1 H NMR (400MHz, CDCl3): δ7.54-7.50(m,1H),7.06-7.03(m,1H),6.91-6.86(m,1H),3.77(s,2H),3.73(s,3H).

[0865] Synthesis of compound 36-5

[0866] 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 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 = 10 / 1) to obtain compound 36-5.1 H NMR (400MHz, CDCl3): δ7.57-7.52(m,1H),7.09-7.05(m,1H),6.91-6.85(m,1H),3.93(t,2H),3.04(t,2H).

[0867] Synthesis of compound 36-6

[0868] 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 (300MHz, CDCl3): δ7.88(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).

[0869] Synthesis of Compounds 36-7

[0870] 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 organic phases were combined, 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] - .

[0871] Synthesis of Compound 36-8

[0872] 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] + .

[0873] Synthesis of Compound 36-9

[0874] Refer to the synthesis of compound 12-4. 1 H NMR (300MHz, 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).

[0875] Synthesis of compound 36-10

[0876] Refer to the synthesis of compound 14-A4. 1 H NMR (300MHz, 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).

[0877] Synthesis of compound 36-11

[0878] Synthesis of compound 14-A5 was performed according to the reference. MS-ESI: m / z 447.1 [M+1] + .

[0879] Synthesis of compound 36-12

[0880] Synthesis of compound 14-A6 was performed according to the reference method. MS-ESI: m / z 283.1 [M+1] + .

[0881] Synthesis of compound 36-13

[0882] The synthesis of compound 14-A7 was similar, except that (S)-4-(tert-butoxycarbonyl)-1,4-oxazolidinyl-2-carboxylic acid was replaced with 4-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylic acid. MS-ESI: m / z 410.1 [M-100+1] + .

[0883] Synthesis of Compound 36

[0884] Synthesis of compound 14 was referenced. MS-ESI: m / z 410.3 [M+1] + . 1 H NMR(400MHz, 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).

[0885] Example 37

[0886] 4-Amino-N-(1-cyano-2-(9-fluoro-5,7-dihydrodibenzo[c,e]occipin-3-yl)ethyl)tetrahydro-2H-pyran-4-

[0887] formamide

[0888]

[0889] Synthesis of Compound 37-2

[0890] 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, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to give a white solid product 37-2. 1H NMR (300MHz, CDCl3) δ11.39(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).

[0891] Synthesis of compound 37-3

[0892] Compound 37-2 (2.00 g, 10.30 mmol) and triethylamine (4.3 mL, 30.9 mmol) were dissolved in dichloromethane (30 mL) at room temperature, followed by the addition of 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 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 = 5 / 1) to obtain compound 37-3. 1 H NMR (300MHz, CDCl3) δ10.29(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).

[0893] Synthesis of compound 37-4

[0894] Refer to the synthesis of compound 36-6. 1 H NMR(400MHz, CDCl3)δ9.88(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).

[0895] Synthesis of compound 37-5

[0896] 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 2N 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 give compound 37-5. 1 H NMR(400MHz, CDCl3)δ8.18(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).

[0897] Synthesis of compound 37-6

[0898] 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 (400MHz, DMSO-d6) δ13.08(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).

[0899] Synthesis of compound 37-7

[0900] 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 give compound 37-7. MS-ESI: m / z 226.9 [M-18+1] + .

[0901] Synthesis of Compound 37-8

[0902] 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. Extraction was performed 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 (300MHz, CDCl3) δ7.57-7.44(m,4H),7.25-7.12(m,2H),4.57(s,2H),4.35(s,2H),4.32(s,2H).

[0903] Synthesis of Compound 37-9

[0904] 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] + .

[0905] Synthesis of compound 37-10

[0906] Refer to the synthesis of compound 14-A6.

[0907] Synthesis of compound 37-11

[0908] The synthesis of compound 14-A7 was similar, except that (S)-4-(tert-butoxycarbonyl)-1,4-oxazolidinyl-2-carboxylic acid was replaced with 4-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylic acid. 1 H NMR (300MHz, CDCl3) δ7.54-7.46(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).

[0909] Synthesis of Compound 37

[0910] Synthesis of compound 14 was referenced. MS-ESI: m / z 410.1 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ7.65-7.60(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).

[0911] Examples 38A and 38B

[0912] 38A:

[0913] (S)-N-((S)-1-cyano-2-(2,8-difluoro-9-(occipitan-3-yl)-6Hbenzo[c]chroman-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide

[0914] 38B:

[0915] (S)-N-((R)-1-cyano-2-(2,8-difluoro-9-(occipitan-3-yl)-6Hbenzo[c]chroman-3-yl)ethyl)-1,4-oxazine-heptane-2-carboxamide

[0916]

[0917]

[0918] Synthesis of compound 38-2

[0919] 2-Bromo-4,5-difluorobenzoic acid (compound 38-1) (15 g, 63.29 mmol) was dissolved in methanol (150 mL) at room temperature, followed by the addition of concentrated sulfuric acid (1.24 g, 12.66 mmol). The reaction mixture was heated to 80 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 38-2. 1 H NMR (300MHz, CDCl3) δ7.81-7.74(m,1H),7.58-7.52(m,1H),3.97(s,3H).

[0920] Synthesis of compound 38-3

[0921] 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, then heated to 80 °C and stirred for 2 hours. Subsequently, a tetrahydrofuran solution of compound 38-2 (16 g, 57.36 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for another 3 hours. 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. 1 H NMR (300MHz, CDCl3) δ7.77-7.70(m,1H),7.49-7.38(m,5H),7.36-7.30(m,1H),5.22(s,2H),3.95(s,3H).

[0922] Synthesis of compound 38-4

[0923] Compound 38-3 (17 g, 45.11 mmol) was dissolved in dichloromethane (50 mL) at room temperature. A dichloromethane solution of boron tribromide (49.62 mL, 49.62 mmol, 1.0 M) was added dropwise at 0 °C. 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) and 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. 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] - .

[0924] Synthesis of compound 38-5

[0925] 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. Chloromethyl ether (11.16 g, 89.27 mmol) was added dropwise at 0 °C, and stirring was continued at room temperature for another 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). The mixture was 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 purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 10 / 1) to obtain compound 38-5. 1 H NMR (300MHz, CDCl3) δ7.72(d,1H),7.54(d,1H),5.31(s,2H),3.95(s,3H),3.57(s,3H).

[0926] Synthesis of compound 38-6

[0927] 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 and stirred 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. 1H NMR (300MHz, DMSO-d6) δ7.50(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).

[0928] Synthesis of compound 38-7

[0929] 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). Methylsulfonyl chloride (6.74 g, 58.85 mmol) was then 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 combined organic phases were 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 obtain the crude intermediate, which was used directly in the next reaction step.

[0930] At room temperature, methyl 2-fluoro-5-hydroxybenzoate (14.72 g, 86.55 mmol) was dissolved in N,N-dimethylformamide (165 mL). Sodium hydride (1.50 g, 62.51 mmol, 60%) was slowly added at 0 °C. The reaction mixture was stirred at room temperature for half an hour, followed by dropwise addition of a solution of the above-mentioned crude intermediate (16.5 g, 48.08 mmol) in N,N-dimethylformamide (30 mL). The reaction mixture was stirred at room temperature for another 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, and the filtrate was concentrated under reduced pressure. The residue was slurried in a mixture of petroleum ether and ethyl acetate (10 / 1) to give compound 38-7. 1 H NMR (400MHz, CDCl3): δ7.51-7.43(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).

[0931] Synthesis of compound 38-8

[0932] 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 N,N-dimethylformamide (160 mL) under nitrogen protection at room temperature. The 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 obtain compound 38-8. 1 HNMR (300MHz, 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).

[0933] Synthesis of Compounds 38-9

[0934] Compound 38-8 (7.50 g, 22.30 mmol) was dissolved in methanol (70 mL) with hydrochloric acid (20 mL) 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, and 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 (400MHz, DMSO-d6): δ10.13(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).

[0935]

[0936] Synthesis of compound 38-10

[0937] At room temperature, methyl 2,8-difluoro-9-hydroxy-6H-benzo[c]chromium-3-carboxylic acid (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 (400MHz, CDCl3) δ7.58(t,2H),7.37(d,1H),7.14(d,1H),5.12(s,2H),3.95(s,3H).

[0938] Synthesis of compound 38-11

[0939] Compound 38-10 (3.40 g, 8.01 mmol), bis-pinacol borate (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 organic phases were combined and washed successively with water (80 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 obtain the crude product, which was then slurried with methyl tert-butyl ether (10 mL) to obtain compound 38-11. MS-ESI: m / z 403.2 [M+1] + .

[0940] Synthesis of compound 38-12

[0941] 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) solutions. 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 (400MHz, DMSO-d6) δ8.35(d,1H),8.00(d,1H),7.39(m,2H),5.15(s,2H),3.85(s,3H).

[0942] Synthesis of compound 38-13

[0943] Compound 38-12 (2.00 g, 5.18 mmol), 3-iodooxetane (1.24 g, 6.73 mmol), [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine N1,N1]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) under nitrogen protection at room temperature. The reaction mixture was stirred at room temperature for 14 hours under 34 W blue LED light. 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 (400MHz, 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).

[0944] Synthesis of compound 38-14

[0945] 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 with saturated sodium potassium tartrate aqueous solution (10 mL) in an ice bath, extracted with ethyl acetate (100 mL × 3), and 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. 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 38-14. MS-ESI: m / z 287.1 [M-18+1] + . 1 H NMR (400MHz, CDCl3) δ7.69(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).

[0946] Synthesis of compound 38-15

[0947] 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.

[0948] 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 (400MHz, CDCl3) δ7.70(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).

[0949] Synthesis of compound 38-16

[0950] 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, 1 M hydrochloric acid (20 mL) was slowly added at 0 °C to adjust the pH to 2–3. The reaction mixture was diluted with 1 M 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 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, 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(400MHz,DMSO-d6)δ7.96(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).

[0951] Synthesis of Compound 38-17

[0952] At room temperature, crude compounds 38-16 (700 mg, 2.04 mmol), compounds 2-6 (551 mg, 2.24 mmol), and N,N-diisopropylethylamine (792 mg, 6.13 mmol) were dissolved in N,N-dimethylformamide (20 mL), followed by the addition of 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 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, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (SiO2, ethyl acetate / petroleum ether = 1 / 2) to obtain compound 38-17.

[0953] Synthesis of compounds 38-18A and 38-18B

[0954] Compound 38-17 (730 mg, 1.19 mmol) was prepared and resolved by SFC (column: DAICEL CHIRALCEL OJ, 250*30 mm, 10 μm; mobile phase: supercritical carbon dioxide, methanol (0.1% ammonia monohydrate); gradient ratio: 65% carbon dioxide phase; flow rate: 65 mL / min; column temperature: room temperature) to obtain 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).

[0955] Synthesis of Compound 38A

[0956] 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(400MHz,DMSO-d6)δ8.69(d,1H),7.98-7.87(m,2H),7.17(d,1H),6.97(d,1 H),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).

[0957] Synthesis of Compound 38B

[0958] 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(400MHz,DMSO-d6)δ8.65(d,1H),8.01-7.89(m,2H),7.17(d,1H),6.9 8(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).

[0959] Example 39

[0960] 4-Amino-N-(1-cyano-2-(3-fluoro-6,7-dihydrodibenzo[b,d]occipine-9-yl)ethyl)tetrahydro-2H-pyran-4-

[0961] formamide

[0962]

[0963] Synthesis of compound 39-2

[0964] Under nitrogen protection at room temperature, 10.00 g (52.65 mmol) of 2-bromo-5-fluorophenol (compound 39-1) was dissolved in tetrahydrofuran (50 mL). 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. Then, 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, 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 39-2. 1 H NMR (400MHz, 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).

[0965] Synthesis of compound 39-4

[0966] 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 N-succinimide bromide (11.70 g, 65.74 mmol) was added. The reaction mixture was 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, 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 39-4. 1 H NMR (400MHz, CDCl3) δ7.41(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).

[0967] Synthesis of compound 39-5

[0968] 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 give compound 39-5. 1 H NMR (400MHz, CDCl3) δ7.40(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).

[0969] Synthesis of compound 39-6

[0970] 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) under nitrogen protection at room temperature. 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 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 = 19 / 1) to give compound 39-6. 1 H NMR (400MHz, CDCl3) δ7.80-7.73(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).

[0971] Synthesis of Compound 39-7

[0972] The synthesis of compound 36-6 was similar, except that the temperature was changed from 80℃ to 95℃. 1 H NMR (300MHz, CDCl3) δ7.19-7.8(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).

[0973] Synthesis of Compound 39-8

[0974] 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 obtain compound 39-8. 1H NMR (400MHz, CDCl3) δ7.13-7.08(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).

[0975] Synthesis of compound 39-9

[0976] Refer to the synthesis of compounds 36-9. 1 H NMR (400MHz, CDCl3) δ7.35-7.28(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).

[0977] Synthesis of Compound 39-10

[0978] 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 HNMR(400MHz, 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).

[0979] Synthesis of compound 39-11

[0980] Compound 39-10 (500 mg, 2.17 mmol) and triethylamine (0.7 mL, 4.94 mmol) were dissolved in dichloromethane (10 mL) at room temperature, followed by the addition of N-phenylbis(trifluoromethanesulfonyl)imide (900 mg, 2.52 mmol). The reaction mixture was 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 (400MHz, CDCl3) δ7.47-7.41(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).

[0981] Synthesis of Compound 39-12

[0982] 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, followed by the addition of triethylamine (0.52 mL, 3.76 mmol). 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 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 = 9 / 1) to give compound 39-12 (220 mg). 1 H NMR (400MHz, 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).

[0983] Synthesis of Compounds 39-13

[0984] 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] + .

[0985] Synthesis of Compounds 39-14

[0986] Refer to the synthesis of compound 14-A4. 1 H NMR (400MHz, CDCl3) δ7.43-7.30(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).

[0987] Synthesis of Compound 39-15

[0988] The synthesis of compound 14-A5 was similar, except that benzyltrimethylammonium chloride was omitted. MS-ESI: m / z 447.3 [M+1] + .

[0989] Synthesis of Compounds 39-16

[0990] Synthesis of compound 14-A6 was performed according to the reference method. MS-ESI: m / z 266.1 [M-17+1] + .

[0991]

[0992] Synthesis of Compounds 39-17

[0993] At room temperature, 2-amino-3-(3-fluoro-6,7-dihydrodibenzo[b,d]oxicillin-9-yl)propionitrile (compound 39-16) (40 mg, 0.14 mmol), 4-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (40 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (2 mL), followed by the addition of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (55 mg, 0.15 mmol) and triethylamine (50 mg, 0.49 mmol). The reaction mixture was heated to 40 °C and stirred 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 combined organic phases were 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] + .

[0994] Synthesis of Compound 39

[0995] The synthesis of compound 14 was similar, except the temperature was changed from 40℃ to 50℃. MS-ESI: m / z 410.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ7.50-7.42(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).

[0996] Example 40

[0997] (S)-4-amino-N-(1-cyano-2-(9-fluoro-6-methyl-5-oxo-6,7-dihydro-5H-dibenzo[c,e]azepine)

[0998] (azepin)-3-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0999]

[1000] Synthesis of Compound 40-2

[1001] 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] + .

[1002] Synthesis of Compound 40-3

[1003] 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 extracted with dichloromethane (200 mL × 3) in a saturated sodium bicarbonate aqueous solution. 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 give compound 40-3. MS-ESI: m / z 252.3 [M-100+1] + . 1 HNMR (400MHz, CDCl3) δ7.85-7.78(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).

[1004] Synthesis of compound 40-4

[1005] 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). Extraction was performed 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, 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 40-4. MS-ESI: m / z 340.1 [M-100+1] + .

[1006] Synthesis of Compound 40-5

[1007] 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. The mixture was filtered and concentrated slightly under reduced pressure to obtain crude compound 40-5, which was used directly in the next reaction. MS-ESI: m / z 340.1 [M+1] + .

[1008] Synthesis of compound 40-6

[1009] 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] + .

[1010] Synthesis of compound 40-7

[1011] Compound 40-6 (800 mg, 2.60 mmol) was dissolved in N,N-dimethylformamide (200 mL) at room temperature. 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 methyl iodoforme (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] + .

[1012] Synthesis of compound 40-8

[1013] 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] + .

[1014] Synthesis of compound 40-9

[1015] Synthesized according to compounds 1-4. MS-ESI: m / z 428.6 [M+1] + .

[1016] Synthesis of compound 40-10

[1017] Synthesized according to compounds 1-5. MS-ESI: m / z 410.1 [M+1] + .

[1018] Synthesis of compound 40-11

[1019] Synthesized according to compounds 1-6. MS-ESI: m / z 310.1 [M+1] + .

[1020] Synthesis of compound 40-12

[1021] The synthesis of compounds 1-7 was similar, except that N,N-dimethylformamide was replaced with dichloromethane. MS-ESI: m / z 537.2 [M+1] + .

[1022] Synthesis of Compound 40

[1023] Synthesis of compound 1 was performed as described above. MS-ESI: m / z 437.3 [M+1] + . 1 H NMR (400MHz, 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).

[1024] Example 41

[1025] (S)-N-((S)-1-cyano-2-(9-cyano-2-fluoro-6-methyl-5-oxo-6,7-dihydro-5H-dibenzo[c,e]aza-3-yl)ethyl)-1,4-oxazacycloheptane-2-carboxamide

[1026]

[1027]

[1028] Synthesis of compound 41-2

[1029] 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 10 mL of water. At 0 °C, an aqueous solution of sodium nitrite (1.77 g, 25.65 mmol) (10 mL) was slowly added. After stirring the reaction mixture at 0 °C for 0.5 hours, a solution of potassium iodide (5.32 g, 32.00 mmol) in 10 mL of water 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 HNMR(400MHz,DMSO-d6)δ13.61(br s,1H),8.09-8.01(m,2H).

[1030] Synthesis of compound 41-3

[1031] 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 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 / 1) to obtain compound 41-3. 1 H NMR (400MHz, CDCl3) δ8.09(d,1H),7.76(d,1H),3.94(s,3H).

[1032] Synthesis of compound 41-4

[1033] At room temperature, methyl 4-bromo-3-(bromomethyl)benzoate (compound 15-2) (25.00 g, 69.00 mmol) was dissolved in dimethyl sulfoxide (150 mL), 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. 1H NMR (400MHz, CDCl3) δ8.00(d,1H),7.79(dd,1H),7.62(d,1H),4.47(s,2H),3.87(s,3H).

[1034] Synthesis of Compound 41-5

[1035] 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 combined organic phases were extracted with 1 M hydrochloric acid (100 mL × 2). The combined aqueous phases were then added sequentially with 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), and 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). The combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated 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 HNMR (400MHz, CDCl3) δ7.94(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).

[1036] Synthesis of Compound 41-6

[1037] 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] + . 1H NMR (400MHz, CDCl3) δ8.02(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).

[1038] Synthesis of Compound 41-7

[1039] The synthesis of compound 40-4 was similar, except the temperature was changed from 60℃ to 80℃. MS-ESI: m / z 398.0 [M-100+1] + . 1 H NMR(400MHz, CDCl3)δ8.28(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).

[1040] Synthesis of Compounds 41-8

[1041] 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 mixture was concentrated under reduced pressure, and toluene (30 mL) and N,N-diisopropylethylamine (5.00 mL, 30.20 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 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 (400MHz, DMSO-d6) δ8.76(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).

[1042] Synthesis of Compounds 41-9

[1043] At room temperature, compound 41-8 (900 mg, 2.47 mmol) was dissolved in N,N-dimethylformamide (20 mL). Sodium hydroxide (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 crude compound 41-9, which was directly used in the next reaction. MS-ESI: m / z 378.1 [M-100+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.18(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).

[1044] Synthesis of Compound 41-10

[1045] 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] + . 1 H NMR(400MHz, CDCl3)δ8.12(d,1H),8.01(s,1H),7.83(dd,1H),7.64(d,1H),7.24(dd,1H),5.17(t,1H),4.73-4.5 8(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).

[1046] Synthesis of Compound 41-11

[1047] 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] + .

[1048] Synthesis of Compounds 41-12

[1049] Synthesized according to compounds 1-5. MS-ESI: m / z 435.1 [M+1] + .

[1050] Synthesis of Compounds 41-13

[1051] Synthesis of compound 14 was referenced. MS-ESI: m / z 335.1 [M+1] + .

[1052] Synthesis of compounds 41-14

[1053] The synthesis of compounds 1-7 was similar, except that 4-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylic acid was replaced with (S)-4-(tert-butoxycarbonyl)-1,4-oxazolidinyl-2-carboxylic acid. MS-ESI: m / z 462.0 [M-100+1] + .

[1054] Synthesis of Compound 41

[1055] Synthesis of compound 14 was referenced. MS-ESI: m / z 462.3 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ8.59-8.45(m,1H),8.05(s,1H),7.96-7.86(m,3H),7.52(d,1H),5.18-5.04(m,1H),4.28(s,2H),3.99(dd,1H),3.94- 3.86(m,1H),3.77-3.70(m,1H),3.47-3.28(m,2H),3.09(s,3H),3.04- 2.97(m,1H),2.90-2.74(m,1H),2.70-2.57(m,2H),2.34-2.16(m,2H).

[1056] Example 42

[1057] (S)-4-amino-N-(1-cyano-2-(7-fluorodibenzo[b,d]furan-3-yl)ethyl)tetrahydrofuran-2H-pyran-4-carboxamide

[1058]

[1059] Synthesis of compound 42-2

[1060] Under nitrogen protection at room temperature, 4-bromo-2-fluoro-1-iodobenzene (compound 42-1) (6.00 g, 19.94 mmol) and compound 4-fluoro-2-methoxyphenylboronic acid (3.56 g, 20.94 mmol) were dissolved in toluene (60 mL), followed by the addition of a 30 mL solution of sodium carbonate (4.23 g, 39.88 mmol) in water and tetrakis(triphenylphosphine)palladium (0.69 g, 0.60 mmol). The reaction mixture was heated to 100 °C and stirred for 15 h. The reaction mixture was cooled to room temperature, poured into water (20 mL), 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, and the filtrate was subjected to reduced pressure. The residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1) to give compound 42-2. 1 H NMR (300MHz, CDCl3) δ7.35-7.24(m,2H),7.23-7.14(m,2H),6.77-6.67(m,2H),3.79(s,3H).

[1061] Synthesis of Compound 42-3

[1062] Compound 42-2 (3.80 g, 12.70 mmol) was dissolved in dichloromethane (50 mL) at room temperature. A boron tribromide dichloromethane solution (15.25 mL, 15.25 mmol, 1.0 mol / L) was added dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with water (30 mL) and 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 subjected to reduced pressure to give crude compound 42-3, which was used directly in the next reaction. 1 H NMR (300MHz, CDCl3) δ7.44-7.35(m,2H),7.26-7.22(m,1H),7.22-7.13(m,1H),6.78-6.68(m,2H),4.98(s,1H).

[1063] Synthesis of compound 42-4

[1064] At room temperature, crude compound 42-3 (3.50 g, 12.28 mmol) and potassium carbonate (3.39 g, 24.55 mmol) were dissolved in N-methylpyrrolidone (30 mL). The reaction mixture was heated to 170 °C and stirred for 2 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 (25 mL × 3). The organic phases were combined and washed successively with water (10 mL × 2) and saturated brine (10 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, petroleum ether / ethyl acetate = 10 / 1) to obtain compound 42-4. 1 H NMR (300MHz, CDCl3) δ7.89-7.81(m,1H),7.79-7.71(m,2H),7.51-7.44(m,1H),7.32-7.26(m,1H),7.16-7.05(m,1H).

[1065] Synthesis of Compound 42-5

[1066] The synthesis of compound 14-B7 was similar, except that the temperature was changed from 70°C to room temperature. 1 H NMR (300MHz, CDCl3) δ7.87-7.78(m,2H),7.35-7.27(m,1H),7.27-7.24(m,1H),7.15-7.03(m, 2H),5.05-5.00(m,1H),4.68-4.63(m,1H),3.74(s,3H),3.30-3.20(m,2H),1.47-1.40(m,9H).

[1067] Synthesis of Compound 42-6

[1068] Compound 42-5 was dissolved in 15 mL of a 5 M ammonia-methanol solution at room temperature. The reaction mixture was heated to 100 °C and stirred for 5 hours in a sealed container. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was slurried with a mixture of petroleum ether and ethyl acetate (3 / 1, 5 mL) to give compound 42-6. MS-ESI: m / z 272.9 [M-100+1] + .

[1069] Synthesis of Compound 42-7

[1070] Compound 42-6 (600 mg, 1.61 mmol) and N,N-diisopropylethylamine (416.46 mg, 3.22 mmol) were dissolved in dichloromethane (5 mL) at room temperature. Trifluoroacetic anhydride (508 mg, 2.42 mmol) was added dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 20 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was extracted with water (5 mL) and ethyl acetate (10 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 slurried under reduced pressure with a mixture of petroleum ether and ethyl acetate (3 / 1, 5 mL) to give compound 42-7. MS-ESI: m / z 355.2 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.93-7.83(m,2H),7.49(s,1H),7.32-7.25(m,2H),7.15-7.06(m,1H),4.91-4.80(m,2H),3.32-3.16(m,2H),1.44(s,9H).

[1071] Synthesis of Compound 42-8

[1072] The synthesis of compound 14 was similar, except the temperature was changed from 40℃ to 25℃. MS-ESI: m / z 238.0 [M-17+1] + .

[1073] Synthesis of Compounds 42-9

[1074] The synthesis of compound 14-A7 was similar, except that (S)-4-(tert-butoxycarbonyl)-1,4-oxazolidinyl-2-carboxylic acid was replaced with 4-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylic acid. MS-ESI: m / z 382.3 [M-100+1] + .

[1075] Synthesis of Compound 42

[1076] The synthesis of compound 14 was similar, except that the temperature was changed from 40°C to room temperature. MS-ESI: m / z 382.1 [M-100+1] + . 1H NMR(400MHz,DMSO-d6)δ8.17-8.12(m,1H),8.08-8.04(m,1H),7.68-7.63(m,2H),7.37-7.31(m,1H),7.31-7.23(m,1H),5.08(t,1H), 3.65-3.50(m,3H),3.45-3.36(m,1H),3.36-3.30(m,2H),1.92-1.82(m,1H),1.74-1.64(m,1H),1.21-1.15(m,1H),1.14-1.06(m,1H).

[1077] Example 43

[1078] (2S)-N-(1-cyano-2-(2-fluoro-9-(methanesulfonyl)-6Hbenzo[c]chro...

Claims

1. A compound of Formula VI-a or a pharmaceutically acceptable salt thereof, ###0001### VI-a wherein, n is an integer selected from 0-3.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0-2. Ring C is phenyl, which is optionally substituted with 1-3 R 3b substituted; Ring A is selected from the group consisting of optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 alkyl and C 1-6 substituted by one or more substituents selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C the C 1-6 alkyl and C 1-6 each R 3a substituted by one or more substituents selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C Each R 3a Independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Each of the cycloalkoxy groups and the 3- to 6-membered heterocycloalkoxy groups is 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, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocyclic alkoxy, methanesulfonyl and The C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Each of the cycloalkoxy groups and the 3- to 6-membered heterocycloalkoxy groups is independently and optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano groups; each R1is independently selected from halogen, hydroxyl, oxo, nitro, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, amino, C 1-6 alkoxy, and C 3-6 cycloalkoxy; and 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is ###0002### optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, cyano, amino, and nitro.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is ###0003### optionally substituted with one or more substituents selected from deuterium and halogen. Ring A is selected from the group consisting of optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 alkyl and C 1-6 substituted by one or more substituents selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C The C 1-6 alkyl and C 1-6 each independently optionally substituted by 1-3 R 3a substituted, R 3a as defined in claim 1.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 alkyl, and C 1-6 alkoxy.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 alkyl, and C 1-6 alkoxy. The C 1-6 alkyl and C 1-6 each independently optionally substituted by 1-3 R 3a substituted, R 3a as defined in claim 1.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is 7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is ###0004### optionally substituted with one or more halogens.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of Formula VI-a is selected from ###0005### 9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of Formula VI-a is selected from ###0006### 10. The compound of any one of claims 8-9 or a pharmaceutically acceptable salt thereof, wherein m is selected from 0.

13. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from halogen, nitro, and cyano.

14. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from halogen.

15. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from fluorine. R1, n, ring C, R 3b As defined in claim 1.

16. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 1-3.

17. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0-2.

18. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 1-2.

30. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from ###0007### R1, n, ring C and R 3b As defined in claim 1.

31. An isotopically-substituted compound of any one of claims 1-9, 29-30, wherein the isotopic substitution is deuterium.

11. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from halogen, hydroxy, cyano, amino, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 alkoxy.

12. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from halogen, hydroxy, C 1-6 alkyl and C 3-6 cycloalkyl.

32. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound of any one of claims 1-9, 29-30 or a pharmaceutically acceptable salt thereof or an isotopically-substituted compound of claim 31, and a pharmaceutically acceptable excipient.

33. Use of a compound of any one of claims 1-9, 29-30 or a pharmaceutically acceptable salt thereof or an isotopically-substituted compound of claim 31 or a pharmaceutical composition of claim 32 for the manufacture of a medicament for the prevention and / or treatment of a cathepsin C-associated disorder selected from asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, alpha 1 -antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, or rheumatoid arthritis. ​ ​ ​ ​ 19. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R 3a is independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, and amino.

20. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R 3a is independently selected from hydrogen, fluoro, chloro, deuterium, oxo (=0), hydroxyl, amino, methoxy, cyclopropoxy, cyclopropyl, cyclopentyl.

21. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R 3a is independently selected from hydrogen or amino.

22. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-9, wherein each R 3b is independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, and amino.

23. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each R 3b is independently selected from halogen or cyano.

24. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each R 3b is independently 3- to 6-membered heterocycloalkyl; said 3- to 6-membered heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, cyano, and hydroxy.

25. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein each R 3b is independently selected from the group consisting of hydrogen, halogen, deuterium, cyano, methylsulfonyl, and 26. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-9, wherein each R 3b is independently selected from hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, methylsulfonyl, 27. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each R 3b is independently selected from the group consisting of cyano, methylsulfonyl, and 28. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R 3b is cyano.

29. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula VI-a is selected from... ​ ​ ​ ​ 34. A compound of the formula ###0010### wherein R1, n, ring C and R 3b As defined in claim 1.

35. A compound of the formula ###0011### wherein R1, n, C and R 3b As defined in claim 1.

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