Small molecule inhibitors of cathepsin C and their pharmaceutical use

Abstract

The present disclosure relates to small molecule inhibitors of cathepsin C and their pharmaceutical uses. Specifically, provided in the present disclosure are amidonitrile compounds represented by Formula VI, pharmaceutical compositions containing the compounds, and their use in inhibiting cathepsin C. JPEG2023551488000167.jpg34170

Description

[Technical Field]

[0001] This disclosure relates to the medical field and concerns small molecule inhibitors of cathepsin C and methods for preparing them. [Background technology]

[0002] Cathepsins are a class of proteolytic enzymes widely present in the lysosomes of various tissue cells. Based on their structure and catalytic type, cathepsins are divided into three classes: serine proteases (cathepsins A and G), aspartate proteases (cathepsins D and E), and cysteine ​​proteases. Cysteine ​​proteases constitute the largest family of cathepsins and include 11 proteases: cathepsins B, C, F, H, K, L, O, S, W, V, and Z.

[0003] Cathepsin C is also known as dipeptidyl peptidase I or "DPP1". DPP1 is constitutively expressed in many tissues, with the highest levels in the lungs, kidneys, liver, and spleen. Several recently published studies have described the role played by cathepsin C in certain inflammatory processes. For example, Adkison et al., J Clin Invest, 2002 Feb; 109(3):363~71; Tinh et al., Archives of Biochemistry and Biophysics, 2002 403:160~170. These studies suggest that cathepsin C is co-expressed in granules with certain serine proteases and functions to process the precursor form of these proteases into the active form, which is 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 that can together 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 peptidylnitrile and its use as a DPP1 inhibitor.

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

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

[0008] WO 2013 / 041497 relates to N-[1-cyano-2-(phenyl)ethyl]-2-azabicyclo[2.2.1]heptan-3-carboxamide and its use as a DPP1 inhibitor.

[0009] WO 2001 / 096285 and WO 2003 / 048123 relate to β-aminoamidonitriles having inhibitory activity against cysteine ​​proteases.

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

[0011] However, the amidonitrile compound of formula I described herein is not disclosed in any other literature. [Prior art documents] [Patent Documents]

[0012] [Patent Document 1] WO 2004 / 110988 [Patent Document 2] WO 2009 / 074829 [Patent Document 3] WO 2010 / 128324 [Patent Document 4] WO 2012 / 119941 [Patent Document 5] WO 2013 / 041497 [Patent Document 6] WO 2001 / 096285 [Patent Document 7] WO 2003 / 048123 [Patent Document 8] WO 2015 / 110826 [Patent Document 9] CN105980367 [Non-patent literature]

[0013] [Non-Patent Document 1] Adkison et al., J Clin Invest, 2002 Feb; 109(3):363~71; Tinh et al., Archives of Biochemistry and Biophysics, 2002 403:160~170 [Overview of the Initiative] [Means for solving the problem]

[0014] In a first embodiment, the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof.

[0015] [ka]

[0016] During the ceremony: Ring A is selected from the group consisting of heterocycloalkyl, heteroaryl, and aryl, and each heterocycloalkyl, heteroaryl, and aryl is independently optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, cyano, nitro, amino, acyl, amide, oxo, alkyl, and alkoxy, and each alkyl and alkoxy is independently substituted with one or more R 3a It is replaced by choice; Ring B is cycloalkyl or heterocycloalkyl, and cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, acyl, amide, oxo, alkoxy, alkyl, alkenyloxy, alkynyloxy, 3- to 20-membered cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy and cycloalkenyloxy, and / or cycloalkyl or heterocycloalkyl is fused to aryl or heteroaryl, and alkyl, alkoxy, alkenyloxy, alkynyloxy, 3- to 20-membered cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, cycloalkenyloxy or fused ring is optionally substituted by one or more R 3b ; and is optionally substituted by; R1 is independently selected from the group consisting of halogen, hydroxy, oxo, nitro, cyano, alkyl, cycloalkyl, amino, amide, acyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkoxy; R 3a is hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C<o000004>alkyl, C 1~6 alkoxy, C 2~6 alkenyloxy, C 2~6 alkynyloxy, C 3~6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3~6 cycloalkoxy, 3- to / -membered heterocycloalkoxy, C 3~8 cycloalkenyloxy, 5- to 6-membered aryl and 3- to 6-membered heteroaryl, and C 1~6 alkyl, C 1~6 alkoxy, C 2~6 alkenyloxy, C 2~6 alkynyloxy, C 3~6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C It should be noted that there seems to be a small error in the original text where "C " appears multiple times in a row. This might be a formatting issue in the original input. The translation has been done as accurately as possible based on the provided text.3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 Cycloalkenyloxys, 5- to 6-membered aryls, and 3- to 6-membered heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano; R 3b These are hydrogen, halogens, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, and C. 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 Cycloalkenyloxy, 5- to 6-membered aryls, 3- to 6-membered heteroaryls, methanesulfonyls and

[0017] [ka]

[0018] Independently selected from the group consisting of C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 Cycloalkenyloxy, 5- to 6-membered aryls, and 3- to 6-membered heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano; preferably, R 3b These are hydrogen, halogens, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, and C. 1~6 Alkyl, C1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 A cycloalkenyloxy is independently selected from the group consisting of 5- to 6-membered aryls and 3- to 6-membered heteroaryls, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 Cycloalkenyloxys, 5- to 6-membered aryls, and 3- to 6-membered heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano; n is an integer selected from the group consisting of 0 to 3; preferably, n is an integer selected from the group consisting of 1 to 3.

[0019] In some embodiments, in a compound of formula I or a pharmaceutically acceptable salt thereof, ring B is a 3- to 15-membered cycloalkyl or a 3- to 15-membered heterocycloalkyl containing one to three heteroatoms, wherein the 3- to 15-membered cycloalkyl or the 3- to 15-membered heterocycloalkyl containing one to three heteroatoms may be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, or C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, 3- to 20-membered cycloalkyl, 3- to 20-membered heterocycloalkyl, C 6~8Optionally substituted with one or more substituents selected from the group consisting of aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy and cycloalkenyloxy, and / or 3- to 15-membered cycloalkyl or 3- to 15-membered heterocycloalkyl containing one to three heteroatoms, condensed with an aryl or heteroaryl, and alkyl, alkoxy, alkenyloxy, alkynyloxy, 3- to 20-membered cycloalkyl, 3- to 20-membered heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, cycloalkenyloxy or condensed ring, one or more R 3b It is replaced by choice, R 3b This is as defined in Equation I.

[0020] In other embodiments, in a compound of formula I or a pharmaceutically acceptable salt thereof, ring B is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocycloalkyl containing one to three heteroatoms, wherein the 3- to 10-membered cycloalkyl or the 3- to 10-membered heterocycloalkyl containing one to three heteroatoms may be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, or C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, 3- to 20-membered cycloalkyl, 3- to 20-membered heterocycloalkyl, C 6~8 Optionally substituted with one or more substituents selected from the group consisting of aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy and cycloalkenyloxy, and / or 3-membered to 10-membered cycloalkyl or 3-membered to 10-membered heterocycloalkyl containing one to three heteroatoms, C 6~8 Condensed with aryl or heteroaryl, alkyl, alkoxy, alkenyloxy, alkynyloxy, 3- to 20-membered cycloalkyl, 3- to 20-membered heterocycloalkyl, C 6~8Aryl, heteroaryl, cycloalkoxy, cycloalkenyloxy, or condensed rings are one or more R 3b It is replaced by choice, R 3b This is as defined in Equation I.

[0021] In other embodiments, in a compound of formula I or a pharmaceutically acceptable salt thereof, ring B is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocycloalkyl containing one to three heteroatoms, wherein the 3- to 10-membered cycloalkyl or the 3- to 10-membered heterocycloalkyl containing one to three heteroatoms may be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, or C 1~6 Alkyl, C 1~6 Alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6~8 aryls, 5- to 8-membered heteroaryls containing 1 to 3 heteroatoms, and cycloalkoxys are optionally substituted with one or more substituents selected from this group, and / or 3- to 10-membered cycloalkyls or 3- to 10-membered heterocycloalkyls containing 1 to 3 heteroatoms, C 6~8 It is condensed with an aryl or a 5- to 8-membered heteroaryl containing 1 to 3 heteroatoms, C 1~6 Alkyl, C 1~6 Alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6~8 An aryl, a 5- to 8-membered heteroaryl or fused ring containing 1 to 3 heteroatoms, has one or more R 3b It is replaced by choice, R 3b This is as defined in Equation I.

[0022] In other embodiments, in a compound of formula I or a pharmaceutically acceptable salt thereof, ring B is a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocycloalkyl containing one to three heteroatoms, wherein the 3- to 8-membered cycloalkyl or the 3- to 8-membered heterocycloalkyl containing one to three heteroatoms may be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, or C 1~6 Alkyl, C 1~6 Alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6~8 Optionally substituted with one or more substituents selected from the group consisting of aryls, 5- to 8-membered heteroaryls containing 1 to 3 heteroatoms, and cycloalkoxys, and / or 3- to 8-membered cycloalkyls or 3- to 8-membered heterocycloalkyls containing 1 to 3 heteroatoms, C 6~8 It is condensed with an aryl or a 5- to 8-membered heteroaryl containing 1 to 3 heteroatoms, C 1~6 Alkyl, C 1~6 Alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6~8 Aryls, 5- to 8-membered heteroaryls or fused rings containing 1 to 3 heteroatoms, have 1 to 3 R 3b It is replaced by choice, R 3b This is as defined in Equation I.

[0023] In other embodiments, in a compound of formula I or a pharmaceutically acceptable salt thereof, ring B is a 5- to 8-membered cycloalkyl or a 5- to 8-membered heterocycloalkyl containing one to three heteroatoms, wherein the 5- to 8-membered cycloalkyl or the 5- to 8-membered heterocycloalkyl containing one to three heteroatoms may be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, or C 1~6 Alkyl, C 1~6 Alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6~8Aryl, a 5- to 8-membered heteroaryl containing 1 to 3 heteroatoms, and cycloalkoxy, optionally substituted by one or more substituents selected from the group consisting of, and / or a 5- to 8-membered cycloalkyl or a 5- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms, is C 6~8 Fused to an aryl or a 5- to 8-membered heteroaryl containing 1 to 3 heteroatoms, C 1~6 Alkyl, C 1~6 Alkoxy, a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, C 6~8 Aryl, a 5- to 8-membered heteroaryl containing 1 to 3 heteroatoms, or a fused ring is optionally substituted by one to three R 3b , wherein R 3b is as defined in formula I.

[0024] In other embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, ring B is a 5- to 8-membered cycloalkyl or a 5- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms, and the 5- to 8-membered cycloalkyl or the 5- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms is hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, acyl, amide, oxo, C 1~6 Alkyl, C 1~6 Alkoxy, a 3- to 8-membered cycloalkyl, a 3- to 8-membered heterocycloalkyl, and C 6~8 Aryl, optionally substituted by one or more substituents selected from the group consisting of, and / or the 5- to 8-membered cycloalkyl or the 5- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms is fused to C 6~8 Aryl, C 1~6 Alkyl, C 1~6 Alkoxy, a 3- to 8-membered cycloalkyl, a 3- to 8-membered heterocycloalkyl, C 6~8 Aryl or a fused ring is optionally substituted by one to three R 3b , wherein R3b This is as defined in Equation I.

[0025] In other embodiments, in a compound of formula I or a pharmaceutically acceptable salt thereof, ring B is a 5- to 8-membered cycloalkyl group or a 5- to 8-membered heterocycloalkyl group containing one to three heteroatoms, wherein the 5- to 8-membered cycloalkyl group or the 5- to 8-membered heterocycloalkyl group containing one to three heteroatoms may contain hydrogen, deuterium, halogen, oxo, or C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 8-membered cycloalkyl and C 6~8 Optionally substituted with one or more substituents selected from the group consisting of aryls, and / or 5- to 8-membered cycloalkyls or 5- to 8-membered heterocycloalkyls containing one to three heteroatoms, C 6~8 It is condensed with aryl, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 8-membered cycloalkyl, C 6~8 The aryl or fused ring has one to three R 3b It is replaced by choice, R 3b This is as defined in Equation I.

[0026] In other embodiments, in a compound of formula I or a pharmaceutically acceptable salt thereof, ring B is selected from the group consisting of a 5-membered cycloalkyl, a 6-membered cycloalkyl, a 5-membered heterocycloalkyl containing one to three heteroatoms, and a 6-membered heterocycloalkyl containing one to three heteroatoms, where each of the 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocycloalkyl containing one to three heteroatoms, and 6-membered heterocycloalkyl containing one to three heteroatoms is independently hydrogen, deuterium, halogen, oxo, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 8-membered cycloalkyl and C 6~8Optionally substituted with one or more substituents selected from the group consisting of aryls, and / or 5-membered cycloalkyls, 6-membered cycloalkyls, 5-membered heterocycloalkyls containing one to three heteroatoms, or 6-membered heterocycloalkyls containing one to three heteroatoms, C 6~8 It is condensed with aryl, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 8-membered cycloalkyl, C 6~8 The aryl or fused ring has one to three R 3b It is replaced by choice, R 3b This is as defined in Equation I.

[0027] In other embodiments, in a compound of formula I or a pharmaceutically acceptable salt thereof, ring B is selected from the group consisting of a 5-membered cycloalkyl, a 6-membered cycloalkyl, a 5-membered heterocycloalkyl containing one heteroatom, and a 6-membered heterocycloalkyl containing one heteroatom, where each of the 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocycloalkyl containing one heteroatom, and 6-membered heterocycloalkyl containing one heteroatom is independently hydrogen, deuterium, halogen, oxo, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 6-membered cycloalkyl and C 6~8 Optionally substituted with one or more substituents selected from the group consisting of aryls, and / or 5-membered cycloalkyls, 6-membered cycloalkyls, 5-membered heterocycloalkyls containing one to three heteroatoms, or 6-membered heterocycloalkyls containing one to three heteroatoms, C 6~8 It is condensed with aryl, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 8-membered cycloalkyl, C 6~8 The aryl or fused ring has one to three R 3b It is replaced by choice, R 3b This is as defined in Equation I.

[0028] In other embodiments, in a compound of formula I or a pharmaceutically acceptable salt thereof, ring B is selected from the group consisting of a 5-membered cycloalkyl group, a 6-membered cycloalkyl group, a 5-membered heterocycloalkyl group containing one heteroatom, and a 6-membered heterocycloalkyl group containing one heteroatom, where each of the 5-membered cycloalkyl group, the 6-membered cycloalkyl group, and the 6-membered heterocycloalkyl group containing one heteroatom is independently hydrogen, deuterium, halogen, oxo, C 1~6 Alkyl and C 1~6 Optionally substituted with one or more substituents selected from the group consisting of alkoxys, and / or 5-membered cycloalkyls, 6-membered cycloalkyls, or 6-membered heterocycloalkyls containing one to three heteroatoms, C 6~8 It is condensed with aryl; A five-membered heterocycloalkyl group containing one heteroatom is a group of hydrogen, deuterium, halogen, oxo, or C. 1~6 Alkyl, C 1~6 Alkoxy, 3- to 6-membered cycloalkyl and C 6~8 It is optionally substituted with one or more substituents selected from the group consisting of aryl compounds; C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 8-membered cycloalkyl, C 6~8 The aryl or fused ring has one to three R 3b It is replaced by choice, R 3b This is as defined in Equation I.

[0029] In a second embodiment, the Disclosure provides a compound of formula VII or a pharmaceutically acceptable salt thereof.

[0030] [ka]

[0031] During the ceremony, Ring B is a 5- to 8-membered cycloalkyl group or a 5- to 8-membered heterocycloalkyl group containing one to three heteroatoms; Each R4 is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, C 1~6 Alkyl, C 1~6 Alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6~8 Independently selected from the group consisting of aryls, 5- to 8-membered heteroaryls containing 1 to 3 heteroatoms, and cycloalkoxys, C 1~6 Alkyl, C 1~6 Alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6~8 5- to 8-membered heteroaryls, each containing an aryl and one to three heteroatoms, each have one to three R 3b It is replaced by choice; r is an integer selected from the group consisting of 0 to 3, preferably an integer selected from the group consisting of 0 to 2, and more preferably an integer of 0 or 1; R1, n, ring A and R 3b This is as defined in Equation I.

[0032] In some embodiments, in a compound of formula VII or a pharmaceutically acceptable salt thereof, ring B is a 5- to 8-membered cycloalkyl group; Each R4 is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, C 1~6 Alkyl, C 1~6 Alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6~8 Independently selected from the group consisting of aryls, 5- to 8-membered heteroaryls containing 1 to 3 heteroatoms, and cycloalkoxys, C 1~6 Alkyl, C 1~6 Alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6~8 5- to 8-membered heteroaryls, each containing an aryl and one to three heteroatoms, each have one to three R 3b It is replaced by choice; R1, n, ring A and R 3b This is as defined in Equation I.

[0033] In some embodiments, in a compound of formula VII or a pharmaceutically acceptable salt thereof, ring B is a 5- to 8-membered heterocycloalkyl group containing one to three heteroatoms; Each R4 is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, C 1~6 Alkyl, C 1~6 Alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6~8 Independently selected from the group consisting of aryls, 5- to 8-membered heteroaryls containing 1 to 3 heteroatoms, and cycloalkoxys, C 1~6 Alkyl, C 1~6 Alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6~8 5- to 8-membered heteroaryls, each containing an aryl and one to three heteroatoms, each have one to three R 3b It is replaced by choice; R1, n, ring A and R 3b This is as defined in Equation I.

[0034] In some embodiments, in a compound of formula VII or a pharmaceutically acceptable salt thereof, each R4 is hydrogen, deuterium, oxo, or C 1~6 Alkyl, C 1~6 Alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6~8 A molecule independently selected from the group consisting of aryls, 5- to 8-membered heteroaryls containing 1 to 3 heteroatoms, and 3- to 10-membered cycloalkoxys, C 1~6 Alkyl, C 1~6 Alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6~8 5- to 8-membered heteroaryls, each containing an aryl and one to three heteroatoms, each have one to three R 3bIt is replaced by choice.

[0035] In some embodiments, in a compound of formula VII or a pharmaceutically acceptable salt thereof, each R4 is hydrogen, deuterium, oxo, or C 1~6 Independently selected from the group consisting of alkyl and phenyl, C 1~6 Alkyl and phenyl each have one to three R 3b It is replaced by choice.

[0036] In some embodiments, in a compound of formula VII or a pharmaceutically acceptable salt thereof, each R4 is independently selected from the group consisting of hydrogen, deuterium, oxo, methyl, and phenyl, C 1~6 Alkyl and phenyl each have one to three R 3b It is optionally replaced by; preferably R4 is one to three R 3b It is a phenyl substituted by. In some embodiments, in a compound of formula VII or a pharmaceutically acceptable salt thereof, the compound of formula VII is

[0037] [ka]

[0038] Selected from the group consisting of; R1, n, ring A, R4 and R 3b This is as defined in equation VII.

[0039] In other embodiments, in a compound of formula VII or a pharmaceutically acceptable salt thereof, the compound of formula VII is

[0040] [ka]

[0041] Selected from the group consisting of; R1, n, ring A, R4 and R 3bThis is as defined in equation VII.

[0042] In a third aspect, the Disclosure also provides compounds of formula VI or pharmaceutically acceptable salts thereof.

[0043] [ka]

[0044] In the formula, X1 and X2 are each independently 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 -Selected from the group consisting of, where at least one of X1 and X2 is -C(R 3b )2-; Ring C is selected from the group consisting of phenyl, naphthyl, and 5- to 8-membered heteroaryls containing 1 to 3 heteroatoms, where each of the phenyl, naphthyl, and 5- to 8-membered heteroaryls containing 1 to 3 heteroatoms independently comprises 1 to 3 R 3b It is replaced by choice; R1, n, ring A and R 3b This is as defined in Equation I.

[0045] In a fourth aspect, the Disclosure also provides compounds of formulas VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i or pharmaceutically acceptable salts thereof.

[0046] [ka]

[0047] During the ceremony, Ring C is selected from the group consisting of phenyl, naphthyl, and 5- to 8-membered heteroaryls containing 1 to 3 heteroatoms, where each of the phenyl, naphthyl, and 5- to 8-membered heteroaryls containing 1 to 3 heteroatoms independently comprises 1 to 3 R 3b It is replaced by choice; R1, n, ring A and R 3b This is as defined in Equation I.

[0048] In a fifth aspect, the disclosure also provides compounds of formula II or pharmaceutically acceptable salts thereof.

[0049] [ka]

[0050] During the ceremony, X1 and X2 are each independently -C(R 3b )2-, oxygen atom and -NR 3b -Selected from the group consisting of, where at least one of X1 and X2 is -C(R 3b )2-; Ring C is selected from the group consisting of phenyl, naphthyl, and 5- to 8-membered heteroaryls containing 1 to 3 heteroatoms, where each of the phenyl, naphthyl, and 5- to 8-membered heteroaryls containing 1 to 3 heteroatoms contains 1 to 3 R 3b It is replaced by choice; R1, n, ring A and R 3b This is as defined in Formula I. In some embodiments, in compounds of Formula I, Formula II, 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 VII or pharmaceutically acceptable salts thereof, ring A is a 3- to 15-membered heterocycloalkyl, a 3- to 10-membered heteroaryl, and C 6~8 Selected from the group consisting of aryls, including 3- to 15-membered heterocycloalkyls, 3- to 10-membered heteroaryls, and C 6~8Each aryl is independently optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, cyano, nitro, amino, acyl, amide, oxo, alkyl, and alkoxy, and each alkyl and alkoxy is independently substituted with one or more R 3a It is replaced by choice, R 3a This is as defined in Equation I.

[0051] 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 comprises a 3- to 15-membered heterocycloalkyl group, a 3- to 10-membered heteroaryl group, and C 6~8 Selected from the group consisting of aryls, including 3- to 15-membered heterocycloalkyls, 3- to 10-membered heteroaryls, and C 6~8 Aryls are, independently of each other, hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, and C. 1~6 Alkyl and C 1~6 It is optionally substituted with one or more substituents selected from the group consisting of alkoxys, C 1~6 Alkyl and C 1~6 Each alkoxy has one or more R 3a It is replaced by choice, R 3a This is as defined in Equation I.

[0052] 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 comprises a 3- to 15-membered heterocycloalkyl group containing one to three heteroatoms, a 3- to 10-membered heteroaryl group containing one to three heteroatoms, and C 6~8Selected from the group consisting of aryls, 3- to 15-membered heterocycloalkyls containing 1 to 3 heteroatoms, 3- to 10-membered heteroaryls containing 1 to 3 heteroatoms, and C 6~8 Aryls are, independently of each other, hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, and C. 1~6 Alkyl and C 1~6 It is optionally substituted with one or more substituents selected from the group consisting of alkoxys, C 1~6 Alkyl and C 1~6 Each alkoxy independently contains one or more R 3a It is replaced by choice, R 3a This is as defined in Equation I.

[0053] 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 a 3- to 15-membered heterocycloalkyl group containing one to three heteroatoms, and the 3- to 15-membered heterocycloalkyl group containing one to three heteroatoms may be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, or C. 1~6 Alkyl and C 1~6 It is optionally substituted with one or more substituents selected from the group consisting of alkoxys, C 1~6 Alkyl and C 1~6 Each alkoxy independently contains one to three R 3a It is replaced by choice, R 3a This is as defined in Equation I.

[0054] 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 a 3- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms, and the 3- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms may be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, oxo, or C. 1~6 Alkyl and C 1~6 It is optionally substituted with one or more substituents selected from the group consisting of alkoxys, C 1~6 Alkyl and C 1~6 Each alkoxy independently contains one to three R 3a It is replaced by choice, R 3a This is as defined in Equation I.

[0055] 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 a 3- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms, and the 3- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms may be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, or C. 1~6 Alkyl and C 1~6 It is optionally substituted with one or more substituents selected from the group consisting of alkoxys, C 1~6 Alkyl and C 1~6 Each alkoxy independently contains one to three R 3a It is replaced by choice, R 3a This is as defined in Equation I.

[0056] The aforementioned heteroatoms in this disclosure are selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, and are preferably nitrogen atoms or oxygen atoms.

[0057] In some 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 hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1~6 Alkyl and C 1~6 It is optionally substituted with one or more substituents selected from the group consisting of alkoxys.

[0058] [ka]

[0059] and; C 1~6 Alkyl and C 1~6 Each alkoxy independently contains one to three R 3a It is replaced by choice, R 3a This is as defined in Equation I.

[0060] 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 hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1~6 Alkyl and C 1~6 It is optionally substituted with one or more substituents selected from the group consisting of alkoxys.

[0061] [ka]

[0062] and; C 1~6 Alkyl and C 1~6 Each alkoxy independently contains one to three R 3a It is replaced by choice, R3a This is as defined in Equation I.

[0063] 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 hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1~6 Alkyl and C 1~6 It is optionally substituted with one or more substituents selected from the group consisting of alkoxys.

[0064] [ka]

[0065] and; C 1~6 Alkyl and C 1~6 Each alkoxy independently contains one to three R 3a It is replaced by choice, R 3a This is as defined in Equation I.

[0066] In other embodiments, in compounds of formula I, formula II, formula VI, formula VI-a, formula VI-b, formula VI-c, formula VI-d, formula VI-e, formula VI-f, formula VI-g, VI-h, VI-i, formula VII or pharmaceutically acceptable salts thereof, ring A is

[0067] [ka]

[0068] That is the case.

[0069] 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 hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1~6 Alkyl and C 1~6 It is optionally substituted with one or more substituents selected from the group consisting of alkoxys.

[0070] [ka]

[0071] and; C 1~6 Alkyl and C 1~6 Each alkoxy independently contains one to three R 3a It is replaced by choice, R 3a This is as defined in Equation I.

[0072] In other embodiments, in compounds of formula I, formula II, formula VI, formula VI-a, formula VI-b, formula VI-c, formula VI-d, formula VI-e, formula VI-f, formula VI-g, VI-h, VI-i, formula VII or pharmaceutically acceptable salts thereof, ring A is

[0073] [ka]

[0074] That is the case.

[0075] In some 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 optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and nitro.

[0076] [ka]

[0077] Preferably, A is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, and halogens.

[0078] [ka]

[0079] That is the case.

[0080] In some 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 optionally substituted with one or more halogens.

[0081] [ka]

[0082] That is the case.

[0083] In a sixth aspect, the Disclosure also provides compounds of formula VI-a', formula VI-b', formula VI-c', formula VI-d', formula VI-e', formula VI-f', formula VI-g', formula VI-h', and formula VI-i' or pharmaceutically acceptable salts thereof.

[0084] [ka]

[0085] During the ceremony, Each R2 is independently selected from the group consisting of halogen, nitro, cyano, amino, oxo, and hydroxy; m is an integer selected from the group consisting of 0 to 3, preferably m is 0; R1, n, ring C and R 3b This is as defined in equation VI-a.

[0086] In a seventh aspect, the Disclosure also provides compounds of formula VI-a", formula VI-b", formula VI-c", formula VI-d", formula VI-e", formula VI-f", formula VI-g", formula VI-h", and formula VI-i" or pharmaceutically acceptable salts thereof.

[0087] [ka]

[0088] During the ceremony, Each R2 is independently selected from the group consisting of halogen, nitro, cyano, amino, oxo, and hydroxy; m is an integer selected from the group consisting of 0 to 3, preferably m is 0; R1, n, ring C and R 3b This is as defined in equation VI-a.

[0089] In the eighth aspect, the disclosure also provides compounds of formula III or pharmaceutically acceptable salts thereof.

[0090] [ka]

[0091] In the formula, R1, n, X1, X2 and ring C are as defined in formula I or formula II.

[0092] In a ninth aspect, the disclosure also provides compounds of formula IV or pharmaceutically acceptable salts thereof.

[0093] [ka]

[0094] In the formula, R1, n, X1, X2 and ring C are as defined in formula I or formula II.

[0095] In a tenth aspect, the Disclosure also provides compounds of formula V or pharmaceutically acceptable salts thereof.

[0096] [ka]

[0097] In the formula, R1, n, X1, X2 and ring C are as defined in formula I or formula II.

[0098] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, R1 is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, acyl, amide, C 1~6 Alkyl, C 3~6 Cycloalkyl and C 1~6 Selected from the group consisting of alkoxys; R1 is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1~6 Alkyl, C 3~6 Cycloalkyl and C 1~6 You can also choose from the group consisting of alkoxys; R1 is hydrogen, deuterium, halogen, hydroxyl, C 1~6 Alkyl and C 3~6 It may also be selected from the group consisting of cycloalkyls; R1 is hydrogen, deuterium, halogen, hydroxyl, and C 1~6 The group consisting of alkyls may also be selected; R1 may also be selected from the group consisting of hydrogen, deuterium, and halogens.

[0099] 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, R1 is selected from the group consisting of hydrogen, halogens, nitro, and cyano; preferably, R1 is a halogen; more preferably, R1 is fluorine.

[0100] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, n is an integer selected from the group consisting of 0 to 2; preferably, n is an integer selected from the group consisting of 1 to 2.

[0101] 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, ring C is selected from the group consisting of phenyl, thiazolyl, and pyridinyl, and each of phenyl, thiazolyl, and pyridinyl independently comprises one to three R3b It is replaced by choice.

[0102] 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" or pharmaceutically acceptable salts thereof, ring C is phenyl,

[0103] [ka]

[0104] Selected from the group consisting of phenyl,

[0105] [ka]

[0106] Each of these independently generates one to three R's. 3b It is replaced by choice.

[0107] 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" or pharmaceutically acceptable salts thereof, the ring C is phenyl, and the phenyl has one to three R 3b It is replaced by choice.

[0108] 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", or pharmaceutically acceptable salts thereof, ring C is

[0109] [ka]

[0110] And,

[0111] [ka]

[0112] is one to three R 3b It is replaced by choice.

[0113] 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", or pharmaceutically acceptable salts thereof, ring C is

[0114] [ka]

[0115] And,

[0116] [ka]

[0117] is one to three R 3b It is replaced by choice.

[0118] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, each R 3a The element is independently selected from the group consisting of hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, and amide.

[0119] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, each R 3a This is independently selected from the group consisting of hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, and amino.

[0120] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, each R 3a C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 A cycloalkenyloxy is independently selected from the group consisting of 5- to 6-membered aryls and heteroaryls, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 Cycloalkenyloxys, 5- to 6-membered aryls, and heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano.

[0121] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, each R 3a C 1~6Alkoxy, C 3~6 Independently selected from the group consisting of cycloalkoxys, 3- to 6-membered heterocycloalkoxys, 5- to 6-membered aryls, and heteroaryls, C 1~6 Alkoxy, C 3~6 Cycloalkoxys, 3- to 6-membered heterocycloalkoxys, 5- to 6-membered aryls, and heteroaryls are each independently optionally substituted with one to three substituents selected from the group consisting of fluorine, chlorine, deuterium, hydroxyl, oxo, nitro, and cyano.

[0122] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, each R 3a is independently selected from the group consisting of hydrogen, fluorine, chlorine, deuterium, oxo(=O), hydroxy, amino, methoxy, cyclopropoxy, cyclopropyl, cyclopentyl, pyridinyl, piperidinyl, and phenyl, preferably R 3a It is either hydrogen or amino acid.

[0123] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, each R 3bis independently selected from the group consisting of hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, and amino; preferably, R 3b These are halogens or cyanoacrylates.

[0124] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, R 3b is a 3- to 6-membered heterocycloalkyl group; the 3- to 6-membered heterocycloalkyl group may be substituted with one to three substituents selected from the group consisting of halogens, cyanos, and hydroxyls.

[0125] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, each R 3b These include hydrogen, halogens, deuterium, cyano, 3- to 6-membered heterocycloalkyls, methanesulfonyl and

[0126] [ka]

[0127] Independently selected from the group consisting of; preferably, a 3-membered to 6-membered heterocycloalkyl,

[0128] [ka]

[0129] It is selected from the group consisting of the following.

[0130] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, each R 3b This includes hydrogen, halogens, deuterium, hydroxy, oxo, nitro, cyano, amino, amide, methanesulfonyl and

[0131] [ka]

[0132] It is independently selected from the group consisting of [the specified elements].

[0133] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, each R 3b These include hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, amide, acetyl, methanesulfonyl,

[0134] [ka]

[0135] It is independently selected from the group consisting of [the specified elements].

[0136] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, each R 3b cyano, methanesulfonyl and

[0137] [ka]

[0138] Independently selected from the group consisting of; preferably, R 3b It is cyano.

[0139] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, each R 3b The element is independently selected from the group consisting of hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, and amide.

[0140] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, each R 3b C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 A cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryl are independently selected from the group consisting of C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano.

[0141] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, each R 3b C 1~6Alkoxy, C 3~6 Independently selected from the group consisting of cycloalkoxys, 3- to 6-membered heterocycloalkoxys, 5- to 6-membered aryls, and heteroaryls, C 1~6 Alkoxy, C 3~6 Cycloalkoxys, 3- to 6-membered heterocycloalkoxys, 5- to 6-membered aryls, and heteroaryls are each independently optionally substituted with one to three substituents selected from the group consisting of fluorine, chlorine, deuterium, hydroxyl, oxo, nitro, and cyano.

[0142] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, each R 3b These include halogens, cyanos, methanesulfonyls,

[0143] [ka]

[0144] It is independently selected from the group consisting of 3- to 6-membered heterocycloalkyls and deuterium.

[0145] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, each R 3b is independently selected from the group consisting of hydrogen, fluorine, chlorine, deuterium, oxo(=O), hydroxy, amino, methoxy, cyclopropoxy, cyclopropyl, cyclopentyl, pyridinyl, piperidinyl, and phenyl, preferably R 3b This is selected from the group consisting of hydrogen, methyl, oxo, fluorine, and chlorine.

[0146] In some embodiments, in 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 formula VII, or pharmaceutically acceptable salts thereof, R 3b C 1~6 Alkyl or C 1~6 It is an alkoxy, C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxyl, oxo, nitro, and cyano.

[0147] In some embodiments, in a compound of formula VII or a pharmaceutically acceptable salt thereof, R 3bis phenyl, which is optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano.

[0148] In an eleventh aspect, the disclosure also provides typical compounds of formula I or pharmaceutically acceptable salts thereof, including, but not limited to, compounds of formula I:

[0149] [ka]

[0150] [ka]

[0151] [ka]

[0152] These are some examples.

[0153] In a twelfth aspect, the disclosure also provides typical compounds of formula I or pharmaceutically acceptable salts thereof, including, but not limited to, compounds of formula I:

[0154] [ka]

[0155] [ka]

[0156] [ka]

[0157] These are some examples.

[0158] In a thirteenth aspect, the disclosure also provides typical compounds of formula I or pharmaceutically acceptable salts thereof, including, but not limited to, compounds of formula I:

[0159] [ka]

[0160] [ka]

[0161] [ka]

[0162] [ka]

[0163] These are some examples.

[0164] In a fourteenth aspect, the disclosure also provides isotopic substitutions of the compounds according to the first to twelfth aspects or pharmaceutically acceptable salts thereof, preferably the isotopic substitutions being deuterium atom substitutions.

[0165] In a 15th aspect, the Disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt thereof according to the first to 13th aspects, or an isotope substitution thereof according to the 14th aspect, and a pharmaceutically acceptable excipient.

[0166] In some embodiments, the unit dose of the pharmaceutical composition is between 0.001 mg and 1000 mg.

[0167] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total mass of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% of pharmaceutically acceptable excipients based on the total mass of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% of pharmaceutically acceptable excipients.

[0169] The Disclosure also provides a method for preventing and / or treating cathepsin C-related disorders in a patient, comprising the step of administering to a patient a therapeutically effective amount of a compound according to the first to thirteenth aspects or a pharmaceutically acceptable salt thereof, or an isotope-substituted compound according to the fourteenth aspect, or the aforementioned pharmaceutical composition.

[0170] In some embodiments, cathepsin C-related disorders include, but are not limited to, respiratory diseases such as asthma, obstructive pulmonary disease, and bronchiectasis, as well as autoimmune diseases such as ANCA-associated vasculitis, psoriasis, alpha-1 antitrypsin deficiency, lupus nephritis, diabetes mellitus, inflammatory bowel disease, or rheumatoid arthritis.

[0171] The Disclosure also provides a method for preventing and / or treating asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, alpha-1 antitrypsin deficiency, lupus nephritis, diabetes mellitus, inflammatory bowel disease, or rheumatoid arthritis in a patient, comprising the step of administering to the patient a therapeutically effective amount of a compound according to the first to thirteenth aspects or a pharmaceutically acceptable salt thereof, or an isotope-substituted compound according to the fourteenth aspect, or the aforementioned pharmaceutical composition.

[0172] This disclosure also provides the use of compounds according to the first to thirteenth embodiments or pharmaceutically acceptable salts thereof, or isotopic substitutions according to the fourteenth embodiment, or the aforementioned pharmaceutical compositions, in the preparation of pharmaceuticals for preventing and / or treating cathepsin C-related disorders.

[0173] This disclosure also provides the use of compounds according to the first to thirteenth embodiments or pharmaceutically acceptable salts thereof, or isotopic substitutions according to the fourteenth embodiment, or the aforementioned pharmaceutical compositions, in the preparation of pharmaceuticals for the prevention and / or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, alpha-1 antitrypsin deficiency, lupus nephritis, diabetes mellitus, inflammatory bowel disease, or rheumatoid arthritis.

[0174] This disclosure also provides compounds according to the first to thirteenth embodiments or pharmaceutically acceptable salts thereof, or isotopic substitutions according to the fourteenth embodiment, or the aforementioned pharmaceutical compositions, for use as pharmaceuticals.

[0175] The Disclosure also provides compounds according to the first to thirteenth embodiments or pharmaceutically acceptable salts thereof, or isotopic substitutions according to the fourteenth embodiment, or the aforementioned pharmaceutical compositions, for use in preventing and / or treating cathepsin C-related disorders in patients.

[0176] The disclosure also provides compounds according to the first to thirteenth embodiments or pharmaceutically acceptable salts thereof, or isotopic substitutions according to the fourteenth embodiment, or the aforementioned pharmaceutical compositions, for use in preventing and / or treating asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, alpha-1 antitrypsin deficiency, lupus nephritis, diabetes mellitus, inflammatory bowel disease, or rheumatoid arthritis.

[0177] This disclosure is based on the following formula

[0178] [ka]

[0179] We also provide compounds or intermediates of the same, In the formula, R1, n, ring C and R 3b This is as defined in Equation IV.

[0180] This disclosure is based on the following formula

[0181] [ka]

[0182] We also provide compounds or intermediates of the same, In the formula, R1, n, ring C and R 3b This is as defined in Equation IV.

[0183] The pharmaceutically acceptable salts of the compounds of this disclosure can be selected from the group consisting of inorganic salts and organic salts.

[0184] The compounds of this disclosure may exist in specific stereoisomer 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 and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of which are within the scope of this disclosure. Additional chiral carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are within the scope of this disclosure. Compounds of this disclosure containing one or more chiral carbon atoms may be isolated in optically pure or racemic forms. Optically pure forms can be isolated from racemic mixtures or synthesized using chiral starting materials or reagents.

[0185] Optically active (R)- and (S)-enantiomers, as well as D- and L-isomers, can be prepared by chiral synthesis, chiral reagents, or other prior art. If one enantiomer of a particular compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization using chiral auxiliaries, where the resulting mixture of diastereomers is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a salt of the diastereomer is formed with a suitable optically active acid or base, the diastereomer is then divided by conventional methods known in the art, and the pure enantiomer is then obtained by recovery. Furthermore, the separation of enantiomers and diastereomers is typically achieved by chromatography using a chiral stationary phase in combination with chemical derivatization (e.g., carbamates formed from amines) by optional means.

[0186] In the chemical structure of the compound disclosed herein, the bond "

[0187] [ka]

[0188] " represents an unspecified stereoconfiguration, that is, if chiral isomers exist in the chemical structure, then the bond "

[0189] [ka]

[0190] "teeth,"

[0191] [ka]

[0192] " or "

[0193] [ka]

[0194] It is acceptable for it to be " or "

[0195] [ka]

[0196] " and "

[0197] [ka]

[0198] It includes both three-dimensional configurations.

[0199] The compounds and intermediates of this disclosure may also exist in different tautomerized forms, and all such forms are included within the scope of this disclosure. The terms “tautomer” or “tautomerized form” refer to structural isomers of different energies that can be interconverted across a low-energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol, imine-enamine, and lactam-lactim isomerization. An example of lactam-lactim equilibrium exists between A and B, as shown below.

[0200] [ka]

[0201] All compounds in this disclosure may be described as Form A or Form B. All tautomer forms are within the scope of this disclosure. The nomenclature of the compounds does not exclude any tautomers.

[0202] This disclosure also includes isotope-labeled compounds having one or more atoms that are identical to those enumerated herein but have atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this disclosure include: 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as Cl.

[0203] Unless otherwise specified, when a position is specifically designated as deuterium (D), it is understood that the position has a deuterium abundance at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The compounds of the examples contain deuterium having an abundance 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 a higher multiple than the natural abundance. This disclosure also includes various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. Those skilled in the art can synthesize the compounds of formula (I) in deuterated forms by referring to relevant literature. Commercially available deuterated starting materials can be used to prepare compounds of formula (I) in their deuterated form, or they can be synthesized using conventional techniques with deuterating reagents, including, but not limited to, deuterated borane, trihydrogenated borane in tetrahydrofuran, lithium aluminum hydride deuterated, deuterated iodoethane, deuterated iodomethane, etc.

[0204] "Optionally" or "optionally" means that the event or situation described thereafter may or may not occur, and such description includes the circumstances under which the event or situation may or may not occur. For example, "C optionally substituted with halogen or cyano 1~6 The term "alkyl" means that a halogen or cyano compound may or may not be present, and such descriptions include situations of alkyl compounds substituted with a halogen or cyano compound and alkyl compounds that are not substituted with a halogen or cyano compound.

[0205] Definitions of terms: "Pharmaceutical composition" means one or more of the compounds or physiologically / pharmaceutically acceptable salts or other chemical components thereof of the prodrugs described herein, as well as a mixture of other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to a living organism in a manner that contributes to the absorption of the active ingredient in order to exhibit biological activity.

[0206] "Pharmacologically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, humectants, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers approved by the U.S. Food and Drug Administration for use in humans or livestock animals.

[0207] As used in this disclosure, “effective dose” or “therapeutic effective dose” includes an amount sufficient to alleviate or prevent the symptoms or condition of a medical disorder. An effective dose also means an amount sufficient to enable or facilitate a diagnosis. Effective doses for specific patients or veterinary subjects may vary depending on factors such as the disorder being treated, the patient’s overall health, the method of administration, the route and amount of administration, and the severity of adverse reactions. An effective dose may be the maximum dose or dosing regimen that avoids serious adverse reactions or toxic effects.

[0208] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including linear and branched groups with 1 to 20 carbon atoms. Alkyls containing 1 to 6 carbon atoms are preferred. 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. Alkyls may be substituted or unsubstituted. If substituted, substituents may be substituted at any available connection point. Substituents are preferably halogens, deuterium, hydroxyl, oxo, nitro, cyano, and C. 1~6 Alkyl, C 1~6 Alkoxy, C 2~6Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 One or more groups independently selected from the group consisting of cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano.

[0209] Examples of "alkenyls" include branched and straight alkenes, or alkenes containing an aliphatic hydrocarbon group having 2 to 12 carbon atoms. For example, "C 2~6 An "alkenyl" refers to an alkenyl having two, three, four, five, or six carbon atoms. Examples of alkenyls include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbuta-2-enyl, 3-methylbuta-1-enyl, 1-pentenyl, 3-pentenyl, and 4-hexenyl. Alkenyls may be substituted or unsubstituted. If substituted, the substituent may be substituted at any available connection point. Substituents are preferably halogens, deuterium, hydroxyl, oxo, nitro, cyano, and C. 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 One or more groups independently selected from the group consisting of cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls, C 1~6 Alkyl, C1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano.

[0210] "Alkynnyl" refers to branched and linear alkynyls, or alkynes containing an aliphatic hydrocarbon group having 2 to 12 carbon atoms, or, if the number of carbon atoms is specified, alkynyl refers to that specific number. Examples include ethynyl, propynyl (1-propynyl, 2-propynyl, etc.), 3-butynyl, pentynyl, hexynyl, and 1-methylpenta-2-inyl. Alkynnyl may be substituted or unsubstituted. If substituted, the substituent may be substituted at any available connection point. Substituents are preferably halogens, deuterium, hydroxyl, oxo, nitro, cyano, and C. 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 One or more groups independently selected from the group consisting of cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano.

[0211] The terms "cycloalkyl" or "carbocyclic" refer to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents, where a cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cyclohexadienyl. Polycyclic cycloalkyls include cycloalkyls having a spirocycle, fused ring, or crosslinked ring. Cycloalkyls may be substituted or unsubstituted. If substituted, the substituent may be substituted at any available connection point. Substituents are preferably halogens, deuterium, hydroxyl, oxo, nitro, cyano, and C. 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 One or more groups independently selected from the group consisting of cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano.

[0212] The cycloalkyl ring may be fused to an aryl or heteroaryl ring, where the ring bonded to the parent structure is a cycloalkyl ring. Non-limiting examples include indanyl, tetrahydronaphthyl, and benzocycloheptyl. The cycloalkyl ring may be optionally substituted or unsubstituted. If substituted, the substituents are preferably halogen, deuterium, hydroxyl, oxo, nitro, cyano, or C. 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 One or more groups independently selected from the group consisting of cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano.

[0213] The term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic hydrocarbon substituent, where 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. Cycloalkenyls may be optionally substituted or unsubstituted. If substituted, the substituents are preferably halogens, deuterium, hydroxyl, oxo, nitro, cyano, or C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 One or more groups independently selected from the group consisting of cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano.

[0214] The terms "heterocycloalkyl" or "heterocyclyl" refer to three- to twenty-membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents, where one or more ring atoms are N, O, and S(O). m A heteroatom selected from the group consisting of (where m is an integer from 0 to 2), excluding -OO-, -OS-, or -SS- in the ring, and the remaining ring atoms are carbon atoms. Preferably, the heterocycloalkyl has 3 to 15 ring atoms, where 1 to 4 atoms are heteroatoms; more preferably, it has 3 to 10 ring atoms; even more preferably, it has 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocycloalkyls include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocycloalkyls include heterocycloalkyls having a spiro ring, a fused ring, or a bridging ring. Non-limiting examples of "heterocycloalkyl" include:

[0215] [ka]

[0216] These are some examples.

[0217] A heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, where the ring bonded to the parent structure is a heterocycloalkyl ring. Non-limiting examples include:

[0218] [ka]

[0219] These are some examples.

[0220] The heterocycloalkyl group may be optionally substituted or unsubstituted. If substituted, the substituents are preferably halogen, deuterium, hydroxyl, oxo, nitro, cyano, or C. 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 One or more groups independently selected from the group consisting of cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano.

[0221] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or polycyclic fused ring having a conjugated π-electron system (i.e., each ring in the system shares an adjacent pair of carbon atoms with another ring in the system), with 6- to 12-membered aryls being preferred, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring. Non-limiting examples include:

[0222] [ka]

[0223] These are some examples.

[0224] The aryl group may be substituted or unsubstituted. If substituted, the substituent is preferably a halogen, deuterium, hydroxyl, oxo, nitro, cyano, or C. 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 One or more groups independently selected from the group consisting of cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano.

[0225] The term "heteroaryl" refers to a 5- to 14-membered heteroaromatic system having one to four heteroatoms selected from the group consisting of O, S, and N. Heteroaryls are preferably 3- to 10-membered heteroaryls, more preferably 5- to 8-membered heteroaryls or 3- to 6-membered heteroaryls, and even more preferably 5- or 6-membered heteroaryls. For example, non-limiting examples include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazolyl, pyrazinyl,

[0226] [ka]

[0227] These are some examples.

[0228] A heteroaryl ring may be fused to an aryl, heterocycloalkyl, or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring. Non-restrictive examples include:

[0229] [ka]

[0230] These are some examples.

[0231] The heteroaryl group may be optionally substituted or unsubstituted. If substituted, the substituents are preferably halogen, deuterium, hydroxyl, oxo, nitro, cyano, or C. 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 One or more groups independently selected from the group consisting of cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls, C 1~6Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano.

[0232] The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted. If substituted, the substituents are preferably halogens, deuterium, hydroxy, oxo, nitro, cyano, and C. 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 One or more groups independently selected from the group consisting of cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano. Similarly, "alkynyloxy," "alkenyloxy," "cycloalkoxy," "heterocycloalkoxy," and "cycloalkenyloxy" are defined as "alkoxy" above.

[0233] The term "hydroxy" refers to the -OH group.

[0234] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0235] The term "cyano" refers to the -CN group.

[0236] The term "nitro" refers to the -NO2 group.

[0237] The term "oxo" refers to the =O group.

[0238] The term "amide" is

[0239] [ka]

[0240] This refers to C, where R is not limited to the following, but includes methyl, ethyl, propyl, etc. 1~6 It is alkyl.

[0241] A "monovalent group" refers to a group formed by "formally" removing a monovalent atom or group from a compound. A "-ylene group" refers to a group formed by "formally" removing two monovalent or one divalent atom or group from a compound. For example, "alkyl" refers to the residue after removing one hydrogen atom from an alkane molecule, including a linear or branched monovalent group containing one to twenty carbon atoms. "Alkylene (-CH2-)" refers to the residue after removing two hydrogen atoms from an alkane molecule, including a linear or branched -ylene group containing one to twenty carbon atoms. Alkylenes containing one to six carbon atoms are preferred, and non-limiting examples include methylene (-CH2-), ethylene (-CH2CH2- or -CH(CH3)-, etc.), propylene (-CH2CH2CH2- or -CH(CH2CH3)-, etc.), and butylene (-CH2CH2CH2CH2-, etc.). The alkylene may be substituted or unsubstituted. If substituted, the substituent may be substituted at any available connection point. The substituent is preferably a halogen, deuterium, hydroxyl, oxo, nitro, cyano, or C. 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 One or more groups independently selected from the group consisting of cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, C 2~6 Alkynyloxy, C 3~6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3~8 Cycloalkenyloxy, phenyl, and 5- to 6-membered heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano.

[0242] Similarly, "alkylene oxy," "alkenylene," "alkylene oxy," "cycloalkylene," and "heterocycloalkylene" are defined as described above for "alkylene." [Brief explanation of the drawing]

[0243] [Figure 1] This figure shows the inhibition percentages of compound 32, AZD7986, and vehicle control against CatC downstream neutrophil elastase in neutrophils (***P<0.0001; *P<0.05; t-test; vs vehicle control; N=3 repeated measures of enzyme activity; inhibition percentages are shown above each column). [Figure 2] This figure shows the inhibition percentages of compound 14, AZD7986, and vehicle control against CatC downstream neutrophil elastase in neutrophils (***P<0.0001; *P<0.05; t-test; vs vehicle control; N=5 repeated measures of enzyme activity; inhibition percentages are shown above each column). [Modes for carrying out the invention]

[0244] This disclosure is further described with reference to the following embodiments, which should not be considered to limit the scope of this disclosure.

[0245] The experimental methods in the examples of this disclosure, unless otherwise specified, are typically carried out under conventional conditions or conditions suggested by the raw material or product manufacturer. Reagents whose specific source is not specified are conventional reagents purchased from the market.

[0246] The structure of the compound was identified by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) was 10–6. 6The values ​​are expressed in ppm. NMR was determined by a Bruker AVANCE-400 machine. The solvents used for determination were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and methanol-d4, with tetramethylsilane (TMS) as the internal standard.

[0247] High-performance liquid chromatography (HPLC) was performed on an Agilent 1100 high-pressure liquid chromatograph equipped with a GAS15B DAD UV detector and a Water Vbridge C18 150*4.6mm 5μm column.

[0248] MS was determined using an Agilent 6120 triple quadrupole mass spectrometer equipped with a G1315D DAD detector and a Waters Xbridge C18 4.6*50 mm, 5 μm column, scanning in positive / negative ion mode. The mass scanning range was 80 to 1200.

[0249] Yantai Huanghai HSGF254 was used as a thin-layer silica gel chromatography (TLC) plate. The dimensions of the silica gel plates used in TLC were 0.2 mm ± 0.03 mm, and the dimensions of the silica gel plates used in product purification by thin-layer chromatography were 0.4 mm to 0.5 mm.

[0250] The flash column purification systems used were either Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

[0251] Yantai Huanghai 200-300 mesh or 300-400 mesh silica gel was commonly used as a support for normal-phase column chromatography, or pre-packed ultrapure normal-phase silica gel columns (40-63 μm, 60 g, 24 g, 40 g, 120 g, or other specifications) from Santai Technologies (Changzhou), Inc. were used.

[0252] The known starting materials of this disclosure can be prepared by methods known in the art, or can be purchased from Shanghai Titan Scientific Co., Ltd., ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc., Bide Pharmatech Co., etc.

[0253] Unless otherwise specified, reactions were carried out in a nitrogen atmosphere.

[0254] "Nitrogen atmosphere" means that the reaction flask is equipped with a nitrogen balloon (approximately 1L).

[0255] "Hydrogen atmosphere" means that the reaction flask is equipped with a hydrogen balloon (approximately 1L).

[0256] Hydrogen was produced using a QPH-1L hydrogen generator from Shanghai Quan Pu Scientific Instruments Co., Ltd.

[0257] In a nitrogen or hydrogen atmosphere, the reaction system was generally evacuated, filled with nitrogen or hydrogen, and the above procedure was repeated three times.

[0258] Unless otherwise specified, "solution" refers to an aqueous solution.

[0259] Unless otherwise specified, the reaction temperature is room temperature between 20°C and 30°C.

[0260] The reaction process in the examples was monitored by thin-layer chromatography (TLC). [Examples]

[0261] (Example 1) (S)-4-amino-N-(1-cyano-2-(1-oxo-2-phenylisoindoline-5-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0262] [ka]

[0263] Synthesis of Compounds 1-2 At room temperature, compound 1-1 (5 g, 23.70 mmol) and phenylboronic acid (5.80 g, 47.52 mmol) were dissolved in dichloromethane (100 mL), followed by the addition of triethylamine (7.20 g, 71.15 mmol) and copper acetate (8.60 g, 47.35 mmol). 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 resulting residue was purified by column chromatography (SiO2, dichloromethane / methanol = 9 / 1) to obtain compound 1-2. MS-ESI: m / z 290.1 ​​[M+1] + .

[0264] Synthesis of Compounds 1-3 At room temperature, under a nitrogen atmosphere, activated zinc powder (900 mg, 137.76 mmol) was added to anhydrous N,N-dimethylformamide (5 mL), followed by the addition of iodine (350 mg, 1.38 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. A solution of methyl(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (1.50 g, 4.55 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. Compound 1-2 (1.70 g, 5.92 mmol), tris-(dibenzylideneacetone)dipalladium (105 mg, 0.11 mmol), and 2-bicyclohexylphosphino-2',6'-dimethoxybiphenyl (94 mg, 0.23 mmol) were added, 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. The reaction mixture was filtered and separated into two phases. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compounds 1-3. MS-ESI: m / z 411.2 [M+1] + .

[0265] Synthesis of Compounds 1-4 At room temperature, compounds 1-3 (1.50 g, 3.66 mmol) were dissolved in a 7 M solution of ammonia in methanol (15 mL), and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain crude compounds 1-4, which were used directly in the next step. MS-ESI: m / z 396.3 [M+1] + .

[0266] Synthesis of Compounds 1-5 At room temperature, crude compounds 1-4 (1.00 g, 2.53 mmol) were dissolved in dichloromethane (30 ml), followed by the addition of Burgess reagent (970 mg, 4.06 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (100 mL), extracted with dichloromethane (250 mL x 2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, dichloromethane / methanol = 9 / 1) to obtain crude compounds 1-5, which were used directly in the next step. MS-ESI: m / z 378.2 [M+1] + .

[0267] Synthesis of compounds 1-6 At room temperature, crude compounds 1-5 (300 mg, 0.80 mmol) were dissolved in acetonitrile (5 mL), followed by the successive 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, and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain crude compounds 1-6, which were used directly in the next step. MS-ESI: m / z 278.2 [M+1] + .

[0268] Synthesis of Compounds 1-7 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 O-benzotriazole-N,N,N',N'-tetramethyluronium 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 saturated sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, dichloromethane / methanol = 9 / 1) to obtain compound 1-7. MS-ESI: m / z 449.2 [M-56+1] + .

[0269] Synthesis of Compound 1 At room temperature, compounds 1-7 (150 mg, 0.30 mmol) were dissolved in acetonitrile (10 mL), followed by the successive 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, and the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate solution (20 mL) was added to the resulting residue, the mixture was extracted with dichloromethane (50 mL x 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge C18, 250 × 19 mm, 10 μm; mobile phase: water (0.1% ammonium bicarbonate), acetonitrile; gradient: 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] + . 1H NMR (400 MHz, CDCl3) δ 8.30 (d, 1H), 7.91 (d, 1H), 7.86 (d, 2H), 7.50 (s, 1H), 7.47-7.43 (m, 2H), 7.37 (d, 1H), 7.20 (t, 1H), 5.18-5.13 (m, 1H), 4.88 (s, 2H), 3.94-3.87 (m, 2H), 3.64-3.56 (m, 2H), 3.24 (d, 2H), 2.34-2.26 (m, 1H), 2.24-2.16 (m, 1H), 1.44 (s, 2H), 1.30-1.26 (m, 1H), 1.21-1.16 (m, 1H).

[0270] Intermediate 2-6

[0271] [ka]

[0272] Synthesis of compound 2-2 At room temperature, (S)-2-((benzyloxy)methyl)oxirane (compound 2-1) (49.70 g, 302.90 mmol) and 3-(benzylamino)propan-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 resulting residue was purified by column chromatography (SiO2, dichloromethane / methanol = 19 / 1) to obtain compound 2-2. MS-ESI: m / z 330.2 [M+1] + .

[0273] Synthesis of Compounds 2-3 At 0°C, compound 2-2 (52 g, 157.96 mmol) and N,N-diisopropylethylamine (30.60 g, 236.77 mmol) were dissolved in dichloromethane (1000 mL), and then methanesulfonyl chloride (18.10 g, 158.01 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 30 minutes. After the reaction was complete, the reaction mixture was poured into saturated sodium bicarbonate aqueous solution (1000 mL) and extracted with dichloromethane (500 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 2-3, which was used directly in the next step. MS-ESI: m / z 408.2 [M+1] + .

[0274] Synthesis of Compounds 2-4 At 0°C, crude compound 2-3 (32 g, 78.59 mmol) was dissolved in tetrahydrofuran (500 mL), followed by batch addition of sodium hydride (9.40 g, 235.90 mmol, 60%). The reaction mixture was stirred at room temperature for 16 hours. Sodium sulfate decahydrate was added, and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 2-4. MS-ESI: m / z 312.1 [M+1] + .

[0275] Synthesis of Compounds 2-5 At room temperature, compound 2-4 (28 g, 89.98 mmol) was dissolved in methanol (200 mL), followed by the addition of palladium-carbon hydroxide (2.80 g, 10%). The reaction mixture was stirred in a hydrogen atmosphere at room temperature for 48 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in methanol (200 mL), followed by the addition of di-tert-butyl dicarbonate (27.90 g, 127.84 mmol). The reaction mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 2-5. MS-ESI: m / z 176.1 [M-56+1]+ .

[0276] Synthesis of Compounds 2-6 At 0°C, compound 2-5 (17 g, 73.6 mmol) was dissolved in acetone (1000 mL), followed by the addition of sodium bromide (2.30 g, 22.35 mmol), 2,2,6,6-tetramethylpiperidinooxy (1.20 g, 7.68 mmol), and saturated sodium bicarbonate aqueous solution (280 mL). The reaction mixture was stirred at room temperature for 30 minutes. Trichloroisocyanuric acid (37.60 g, 161.78 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. Isopropanol (50 mL) was added, and the reaction mixture was stirred for 30 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Water (300 mL) was added to the resulting residue, and the mixture was extracted with dichloromethane (500 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 2-6, which was used directly in the next step. MS-ESI: m / z 190.1 [M-56+1] + . 1 H NMR(400 MHz, DMSO-d6): δ 12.71 (s, 1H), 4.20-4.17 (m, 1H), 3.96-3.79 (m, 2H), 3.65-3.54 (m, 2H), 3.48-3.42 (m, 1H), 3.18-3.07 (m, 1H), 1.71 (s, 2H), 1.40 (s, 9H).

[0277] (Example 2) (S)-N-((S)-1-cyano-2-(1-oxo-2-phenylisoindoline-5-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0278] [ka]

[0279] Synthesis of Compounds 2-7 At room temperature, (S)-2-amino-3-(1-oxo-2-phenylisoindolin-5-yl)propanenitrile (compound 1-6) (320 mg, 1.16 mmol) and compound 2-6 (311 mg, 1.27 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (659 mg, 1.74 mmol) and N,N-diisopropylethylamine (299 mg, 2.32 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was poured into saturated sodium bicarbonate aqueous solution (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 2-7. MS-ESI: m / z 449.2 [M-56+1] + .

[0280] Synthesis of Compound 2 At room temperature, compound 2-7 (200 mg, 0.39 mmol) was dissolved in acetonitrile (5 mL), followed by the successive 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, and the reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution (20 mL) was added to the resulting residue, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative high-performance liquid chromatography (column: Waters Sunfire C18, 250 × 19 mm, 10 μm; mobile phase: water (0.1% formic acid), acetonitrile; gradient: 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] + . 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, 1H), 7.92 (d, 2H), 7.74 (d, 1H), 7.58 (s, 1H), 7.47-7.43 (m, 3H), 7.18 (t, 1H), 5.13-5.05 (m, 1H), 5.05-4.96 (m, 2H), 4.20 (dd, 1H), 3.92-3.82 (m, 1H), 3.80-3.71 (m, 1H), 3.30-3.26 (m, 2H), 3.21-3.17 (m, 1H), 3.04-2.98 (m, 1H), 2.87-2.80 (m, 1H), 2.66 (dd, 1H), 1.86-1.85 (m, 2H).

[0281] (Example 3) (2S)-N-(1-cyano-2-(5,6,7,8-tetrahydronaphthalene-2-yl)ethyl)-1,4-oxazepan-2-carboxamide trifluoroacetate

[0282] [ka]

[0283] Synthesis of compound 3-2 At room temperature, 5,6,7,8-tetrahydronaphthalen-2-ol (compound 3-1) (10 g, 67.53 mmol) was dissolved in dichloromethane (100 mL), and then N,N-diisopropylethylamine (21.80 g, 168.68 mmol) and trifluoromethanesulfonic anhydride (22.85 g, 80.99 mmol) were added successively at 0°C. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, water (50 mL) was added, and the reaction mixture was extracted with dichloromethane (200 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 3-2. 1H NMR (400 MHz, DMSO-d6) δ 7.26-7.19 (m, 1H), 7.16-7.14 (m, 2H), 2.76-2.74 (m, 4H), 1.74-1.71 (m, 4H).

[0284] Synthesis of compound 3-3 At room temperature, compound 3-2 (10 g, 35.59 mmol) was dissolved in a mixed solvent of N,N-dimethylformamide (50 mL) and methanol (150 mL), followed by the addition of N,N-diisopropylethylamine (9.23 g, 71.42 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (3.00 g, 4.10 mmol). The reaction mixture was stirred under reflux in a carbon monoxide atmosphere for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (100 mL) was added to the resulting residue, and the mixture was extracted with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 8 / 1) to obtain compound 3-3. 1 H NMR (400 MHz, DMSO-d6) δ 7.69 -7.60 (m, 2H), 7.17 (d, 1H), 3.83 (s, 3H), 2.87-2.75 (m, 4H), 1.75-1.72 (m, 4H).

[0285] Synthesis of Compounds 3-4 At 0°C under a nitrogen atmosphere, compound 3-3 (3.10 g, 16.31 mmol) was dissolved in tetrahydrofuran (50 mL), followed by batch addition of lithium aluminum hydride (928 mg, 24.45 mmol). The reaction mixture was stirred at 0°C for 3 hours. After the reaction was complete, water (100 mL) was added, and the reaction mixture was extracted with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 3-4. 1 H NMR (400 MHz, DMSO-d6) δ 7.03-6.97 (m, 3H), 5.03 (s, 1H), 4.49 (s, 2H), 2.68-2.67 (m, 4H), 1.73-1.70 (m, 4H).

[0286] Synthesis of Compounds 3-5 At 0°C, compound 3-4 (1.60 g, 9.87 mmol) was dissolved in toluene (20 mL), and then phosphorus tribromide (4 g, 14.78 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours. Water (50 mL) was added, and the reaction mixture was extracted with ethyl acetate (100 mL x 2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 49 / 1) to obtain compound 3-5. 1 H NMR (400 MHz, DMSO-d6) δ 7.15-7.10 (m, 2H), 7.02 (d, 1H), 4.63 (s, 2H), 2.72-2.62 (m, 4H), 1.77-1.66 (m, 4H).

[0287] Synthesis of Compounds 3-6 At 0°C under a nitrogen atmosphere, 2-((diphenylmethylene)amino)acetonitrile (1.40 g, 6.26 mmol) was dissolved in N,N-dimethylformamide (20 mL), and sodium hydride (500 mg, 12.50 mmol, 60%) was added. The reaction mixture was stirred at 0°C for 0.5 hours. A solution of compound 3-5 (1.70 g, 7.58 mmol) in N,N-dimethylformamide (5 mL) 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, and the reaction mixture was extracted with ethyl acetate (100 mL x 2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate) to obtain compound 3-6. MS-ESI: m / z 365.2 [M+1] + .

[0288] Synthesis of Compounds 3-7 At 0°C, compound 3-6 (1.80 g, 4.94 mmol) was dissolved in dioxane (10 mL), 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, and the reaction mixture was extracted with ethyl acetate (50 mL). The mixture was adjusted to pH=8 with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane (50 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 3-7, which was used directly in the next step. MS-ESI: m / z 184.1 [M-17+1] + .

[0289] Synthesis of Compounds 3-8 At room temperature, crude compounds 3-7 (156 mg, 0.78 mmol) and 2-6 (160 mg, 0.65 mmol) were dissolved in N,N-dimethylformamide (5 mL), followed by the addition of O-benzotriazole-N,N,N',N'-tetramethyluronium 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 saturated sodium bicarbonate aqueous solution (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 3-8, which was used directly in the next step. MS-ESI: m / z 372.1 [M-56+1] + .

[0290] Synthesis of Compound 3 At room temperature, crude compound 3-8 (230 mg, 0.54 mmol) was 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 resulting residue was purified by preparative high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain the trifluoroacetate of compound 3. MS-ESI: m / z 328.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.12-8.85 (m, 3H), 7.02-6.89 (m, 3H), 4.94-4.85 (m, 1H), 4.47-4.33 (m, 1H), 3.99-3.87 (m, 1H), 3.83-3.68 (m, 1H), 3.63-3.49 (m, 1H), 3.37-3.29 (m, 1H), 3.19-2.93 (m, 4H), 2.68 (s, 4H), 2.06-1.93 (m, 2H), 1.74 (s, 4H).

[0291] (Example 4) 4-Amino-N-(1-Cyano-2-(5,6,7,8-Tetrahydronaphthalene-2-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0292] [ka]

[0293] Synthesis of Compound 4-1 At room temperature, crude 2-amino-3-(5,6,7,8-tetrahydronaphthalene-2-yl)propanenitrile (compound 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 O-benzotriazole-N,N,N',N'-tetramethyluronium 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 saturated sodium bicarbonate aqueous solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, dichloromethane / methanol = 10 / 1) to obtain compound 4-1. MS-ESI: m / z 328.2 [M-100+1] + .

[0294] Synthesis of Compound 4 At room temperature, compound 4-1 (100 mg, 0.23 mmol) was dissolved in acetonitrile (5 mL), followed by the successive addition of trimethylchlorosilane (76 mg, 0.70 mmol) and sodium iodide (105 mg, 0.70 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, methanol was added, and the reaction mixture was concentrated under reduced pressure. The resulting residue was poured into saturated sodium bicarbonate aqueous solution (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting 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 (400 MHz, DMSO-d6) δ 7.00-6.93 (m, 3H), 4.88 (t, 1H), 3.67-3.55 (m, 3H), 3.52-3.48 (m, 1H), 3.09-2.95 (m, 2H), 2.67 (brs, 4H), 1.95-1.84 (m, 1H), 1.82-1.74 (m, 1H), 1.70 (brs, 4H), 1.27-1.10 (m, 2H).

[0295] (Example 5) (2S)-N-(1-cyano-2-(2,3-dihydro-1H-inden-5-yl)ethyl)-1,4-oxazepan-2-carboxamide trifluoroacetate

[0296] [ka]

[0297] Synthesis of compound 5-2 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 x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 2) to obtain compound 5-2. 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.75 (d, 1H), 7.35 (d, 1H), 3.83 (s, 3H), 2.92-2.88 (m, 4H), 2.12-1.98 (m, 2H).

[0298] Synthesis of compound 5-3 At 0°C, under a nitrogen atmosphere, compound 5-2 (2.13 g, 12.10 mmol) was dissolved in tetrahydrofuran (20 mL), and then a solution of lithium aluminum hydride in tetrahydrofuran (11 mL, 33 mmol, 3.0 mol / L) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, sodium sulfate decahydrate was added, and the reaction mixture was stirred for 0.5 hours and filtered. The filtrate was concentrated under reduced pressure to obtain compound 5-3. 1 H NMR (400 MHz, DMSO-d6) δ 7.16-7.14 (m, 2H), 7.05-7.03 (m, 1H), 5.06 (t, 1H), 4.43 (d, 2H), 2.87-2.78 (m, 4H), 2.08-1.93 (m, 2H).

[0299] Synthesis of Compound 5-4 At 0°C, compound 5-3 (1.60 g, 10.80 mmol) was dissolved in toluene (10 mL), and then phosphorus tribromide (1.54 mL, 16.38 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours. Water (50 mL) was added, and the reaction mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined and washed sequentially with water (20 mL) and saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 5-4. 1 H NMR (400 MHz, DMSO-d6) δ 7.35-7.10 (m, 3H), 4.67 (s, 2H), 2.82 (t, 4H), 2.08-1.96 (m, 2H).

[0300] Synthesis of compound 5-5 At 0°C, 2-((diphenylmethylene)amino)acetonitrile (2.95 g, 13.40 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium hydride (1.07 g, 26.75 mmol, 60%) was added. The reaction mixture was stirred at 0°C for 30 minutes. Compound 5-4 (1.87 g, 8.90 mmol) was added, and the reaction mixture was stirred at 0°C for 2 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (50 mL) was added, and the reaction mixture was extracted with ethyl acetate (50 mL x 2). The mixture was then washed sequentially with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 5-5. MS-ESI: m / z 351.2 [M+1] + .

[0301] Synthesis of Compounds 5-6 At 0°C, compound 5-5 (1.05 g, 3.00 mmol) was dissolved in dioxane (10 mL), 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, and the reaction mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed sequentially with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 5-6. MS-ESI: m / z 187.2 [M+1] + .

[0302] Synthesis of Compounds 5-7 At room temperature, 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). Subsequently, O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (306 mg, 0.81 mmol) and N,N-diisopropylethylamine (139 mg, 1.08 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 5-7. MS-ESI: m / z 358.2 [M-56+1] + .

[0303] Synthesis of Compound 5 At room temperature, compound 5-7 (100 mg, 0.24 mmol) was dissolved in acetonitrile (10 mL), followed by the successive 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, and the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution (20 mL) was added to the resulting residue, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative high-performance liquid chromatography (column: SunFire Prep C18, 250 × 19 mm, 10 μm; mobile phase: water (0.1% trifluoroacetic acid), acetonitrile; gradient: 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 (400 MHz, DMSO-d6) δ 9.20-8.70 (m, 3H), 7.19-7.11 (m, 2H), 7.02 (d, 1H), 5.00-4.82 (m, 1H), 4.46-4.32 (m, 1H), 4.01-3.85 (m, 1H), 3.84-3.70 (m, 1H), 3.61-3.46 (m, 1H), 3.22-2.90 (m, 5H), 2.83-2.80 (m, 4H), 2.03-1.88 (m, 4H).

[0304] (Example 6) 4-Amino-N-(1-Cyano-2-(2,3-Dihydro-1H-Inden-5-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0305] [ka]

[0306] Synthesis of compound 6-1 At room temperature, 2-amino-3-(2,3-dihydro-1H-inden-5-yl)propanenitrile (compound 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). Subsequently, O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (458 mg, 1.21 mmol) and N,N-diisopropylethylamine (208 mg, 1.61 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 6-1. MS-ESI: m / z 414.2 [M+1] + .

[0307] Synthesis of Compound 6 At room temperature, compound 6-1 (180 mg, 0.44 mmol) was dissolved in acetonitrile (5 mL), followed by the successive 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, and the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution (20 mL) was added to the resulting residue, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / aqueous system) to obtain compound 6. MS-ESI: m / z 314.5 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 7.19-7.07 (m, 2H), 7.05-6.99 (m, 1H), 4.89 (t, 1H), 3.70-3.54 (m, 3H), 3.51-3.47 (m, 1H), 3.16-2.98 (m, 2H), 2.84-2.76 (m, 4H), 2.06-1.84 (m, 3H), 1.85-1.68 (m, 1H), 1.23-1.15 (m, 2H).

[0308] (Example 7) 4-Amino-N-(1-Cyano-2-(9,10-Dihydrophenanthrene-2-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0309] [ka]

[0310] Synthesis of compound 7-2 At room temperature, 9,10-dihydrophenanthrene (compound 7-1) (2.00 g, 11.11 mmol) was dissolved in anhydrous dichloromethane (60 mL), followed by the addition of acetyl chloride (1.20 g, 15.28 mmol). Aluminum trichloride (2.00 g, 15.00 mmol) was added in batches 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 x 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 7-2. MS-ESI: m / z 223.0 [M+1] + .

[0311] Synthesis of Compound 7-3 At 0°C, potassium hydroxide (3.30 g, 58.81 mmol) was dissolved in water (20 mL), followed by the sequential addition of liquid bromine (0.9 mL, 17.56 mmol) and a solution of compound 7-2 (1.00 g, 4.50 mmol) in 1,4-dioxane (10 mL). 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 mixture was adjusted to pH=1 with concentrated hydrochloric acid and extracted with dichloromethane (50 mL x 2). The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain compound 7-3. MS-ESI: m / z 225.2 [M+1] + .

[0312] Synthesis of compound 7-4 At 0°C, compound 7-3 (930 mg, 4.15 mmol) was dissolved in tetrahydrofuran (10 ml), and then carbonyldiimidazole (874 mg, 5.39 mmol) was added in batches. The reaction mixture was stirred at room temperature for 1 hour. Sodium borohydride (470 mg, 12.42 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water (50 mL) and extracted with dichloromethane (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to obtain an intermediate, which was used in the next step.

[0313] At 0°C, the intermediate obtained in the above step (600 mg, 2.86 mmol) was dissolved in dichloromethane (10 ml), and then N,N-diisopropylethylamine (738 mg, 5.72 mmol) and methanesulfonyl chloride (493 mg, 4.29 mmol) were added sequentially. 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 x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain the intermediate, which was used in the next step.

[0314] At 0°C, 2-((diphenylmethylene)amino)acetonitrile (462 mg, 2.10 mmol) was dissolved in N,N-dimethylformamide (3 mL), then sodium hydride (140 mg, 3.50 mmol, 60%) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. The intermediate obtained in the above 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, and the reaction mixture was extracted with dichloromethane (50 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 7-4, which was used directly in the next step. MS-ESI: m / z 413.1 [M+1] + .

[0315] Synthesis of Compound 7-5 At 0°C, crude compound 7-4 (720 mg, 1.75 mmol) was dissolved in dioxane (2 mL), followed by the addition of 4 M hydrochloric acid (1 mL). The reaction mixture was stirred at 0°C for 1 hour. After the reaction was complete, saturated sodium bicarbonate aqueous solution (20 mL) was added, and the reaction mixture was extracted with dichloromethane (50 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, dichloromethane / methanol = 19 / 1) to obtain compound 7-5 (150 mg). MS-ESI: m / z 232.2 [M-17+1] + .

[0316] Synthesis of Compounds 7-6 At room temperature, compound 7-5 (150 mg, 0.60 mmol) and 4-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (162 mg, 0.66 mmol) were dissolved in N,N-dimethylformamide (5 mL), followed by the addition of O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (341 mg, 0.9 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 saturated sodium bicarbonate aqueous solution (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, dichloromethane / methanol = 19 / 1) to obtain compound 7-6. MS-ESI: m / z 420.5 [M-56+1] + .

[0317] Synthesis of Compound 7 At room temperature, compound 7-6 (75 mg, 0.16 mmol) was dissolved in acetonitrile (5 mL), followed by the successive 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, and the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution (10 mL) was added to the resulting residue, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge C18, 250 × 19 mm, 10 μm; mobile phase: water (0.1% ammonium bicarbonate), acetonitrile; gradient: 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 (400 MHz, DMSO-d6) δ 7.80-7.76 (m, 2H), 7.32-7.22 (m, 4H), 7.18-7.17 (m, 1H), 4.99-4.96 (m, 1H), 3.64-3.53 (m, 3H), 3.48-3.45 (m, 1H), 3.19-3.04 (m, 2H), 2.80-2.76 (m, 4H), 1.93-1.86 (m, 1H), 1.80-1.71 (m, 1H), 1.22-1.13 (m, 2H).

[0318] (Example 8) (S)-N-((S)-1-cyano-2-(9,10-dihydrophenanthrene-2-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0319] [ka]

[0320] Synthesis of compound 8-1 At room temperature, compound 7-1 (2.50 g, 13.89 mol) was dissolved in acetonitrile (20 mL), 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, followed by the addition of saturated sodium bicarbonate aqueous solution (50 mL), and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether) to obtain compound 8-1. 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, 1H), 7.60 (d, 1H), 7.43-7.40 (m, 1H), 7.38 (d, 1H), 7.27-7.19 (m, 3H), 2.87-2.83 (m, 4H).

[0321] Synthesis of compound 8-2 This was prepared by referring to the synthesis of compounds 1-3. MS-ESI: m / z 282.2 [M-100+1] + .

[0322] Synthesis of compound 8-3 This was prepared by referring to the synthesis of compounds 1-4. MS-ESI: m / z 267.2 [M-100+1] + .

[0323] Synthesis of compound 8-4 This was prepared by referring to the synthesis of compounds 1-5. MS-ESI: m / z 349.2 [M+1] + .

[0324] Synthesis of compound 8-5 This was prepared by referring to the synthesis of compounds 1-6. MS-ESI: m / z 232.2 [M-17+1] + .

[0325] Synthesis of compound 8-6 This compound was prepared by referring to the synthesis of compounds 1-7, under similar conditions except that N,N-dimethylformamide was replaced with dichloromethane. MS-ESI: m / z 420.1 [M-56+1] + .

[0326] Synthesis of compound 8 This was prepared by referring to the synthesis of compound 1. MS-ESI: m / z 376.2 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 7.74-7.72 (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).

[0327] (Example 9) (S)-N-((S)-1-cyano-2-(2-methyl-1,2,3,4-tetrahydroisoquinoline-6-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0328] [ka]

[0329] Synthesis of compound 9-2 Compound 9-2 was prepared by referring to the synthesis of Compound 1-3. MS-ESI: m / z 331.2 [M+1] + .

[0330] Synthesis of compound 9-3 At room temperature, compound 9-2 (1.50 g, 4.44 mmol) was dissolved in tetrahydrofuran (20 mL), followed by the addition of iodomethane (2.97 g, 20.92 mmol). The reaction mixture was stirred at room temperature for 12 hours and concentrated under reduced pressure to obtain crude compound 9-3, which was used directly in the next step. MS-ESI: m / z 345.4 [M-127] + .

[0331] Synthesis of compound 9-4 At room temperature, crude compound 9-3 (1.70 g, 3.60 mmol) was dissolved in a 7 M solution of ammonia in methanol (30 mL). The reaction mixture was stirred at room temperature for 12 hours and concentrated under reduced pressure to obtain crude compound 9-4, which was used directly in the next step. MS-ESI: m / z 330.1 [M-127] + .

[0332] Synthesis of compound 9-5 At room temperature, crude compound 9-4 (1.20 g, 2.62 mmol) was dissolved in methanol (10 mL), followed by the addition of a small amount of platinum-carbon dioxide. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 12 hours and then filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, dichloromethane / methanol = 7 / 3) to obtain compound 9-5. MS-ESI: m / z 334.2 [M+1] + .

[0333] Synthesis of Compound 9-6 At room temperature, compound 9-5 (530 mg, 1.54 mmol) was dissolved in a solution of hydrogen chloride in dioxane (10 mL), and the reaction mixture was stirred at room temperature for 3 hours. 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 step. MS-ESI: m / z 234.2 [M+1] + .

[0334] Synthesis of Compound 9-7 This compound was prepared by referring to the synthesis of compounds 1-7, except that N,N-dimethylformamide was replaced with a mixed solvent of N,N-dimethylformamide and dichloromethane (1 / 3). MS-ESI: m / z 461.3 [M+1] + .

[0335] Synthesis of Compound 9-8 This was prepared by referring to the synthesis of compounds 1-5. MS-ESI: m / z 443.6 [M+1] + .

[0336] Synthesis of compound 9 This was prepared by referring to the synthesis of compound 1. MS-ESI: m / z 343.5 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (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).

[0337] (Example 10) (S)-4-amino-N-(2-(chroman-7-yl)-1-cyanoethyl)tetrahydro-2H-pyran-4-carboxamide

[0338] [ka]

[0339] Synthesis of compound 10-2 At room temperature, under a nitrogen atmosphere, 7-bromochroman-4-one (compound 10-1) (3.00 g, 13.21 mmol) was dissolved in trifluoroacetic acid (50 mL), followed by the addition of triethylsilane (4.61 g, 39.64 mmol). The reaction mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 10-2.

[0340] Synthesis of compound 10-3 This was prepared by referring to the synthesis of compounds 1-3. MS-ESI: m / z 236.1 [M-100+1] + .

[0341] Synthesis of compound 10-4 This was prepared by referring to the synthesis of compounds 1-4. MS-ESI: m / z 321.2 [M+1] + .

[0342] Synthesis of compound 10-5 This was prepared by referring to the synthesis of compounds 1-5. MS-ESI: m / z 247.4 [M-56+1] + .

[0343] Synthesis of compound 10-6 At room temperature, compound 10-5 (200 mg, 0.66 mmol) was dissolved in a 5 mL solution of hydrogen chloride in dioxane, 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 used directly in the next step. MS-ESI: m / z 203.5 [M+1] + .

[0344] Synthesis of compound 10-7 This compound was prepared by referring to the synthesis of compounds 1-7, except that N,N-dimethylformamide was replaced with a mixed solvent of N,N-dimethylformamide and dichloromethane (1 / 2). MS-ESI: m / z 448.3 [M+1] + .

[0345] Synthesis of compound 10 This was prepared by referring to the synthesis of compound 1. MS-ESI: m / z 330.4 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 6.97 (d, 1H), 6.71 (d, 1H), 6.66 (s, 1H), 4.88 (t, 1H), 4.16-4.06 (m, 2H), 3.65-3.56 (m, 3H), 3.52-3.44 (m, 1H), 3.07-2.94 (m, 2H), 2.69 (t, 2H), 1.94-1.82 (m, 3H), 1.80-1.73 (m, 1H), 1.22-1.14 (m, 2H).

[0346] (Example 11) (2S)-N-(1-cyano-2-(8-fluoro-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepan-2-carboxamideformate

[0347] [ka]

[0348] Synthesis of compound 11-2 At room temperature under a nitrogen atmosphere, 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(diphenylphosphino)ferrocene]palladium(II) 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 resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 2) to obtain compound 11-2. MS-ESI: m / z 259.1 [M-18+1]+ .

[0349] Synthesis of compound 11-3 At room temperature, compound 11-2 (800 mg, 2.90 mmol) and triphenylphosphine (0.900 g, 3.43 mmol) were dissolved in toluene (10 mL), and then diethyl azodicarboxylate (1.52 g, 8.73 mmol) was added dropwise. 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 resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 11-3. MS-ESI: m / z 259.2 [M-18+1] + .

[0350] Synthesis of compound 11-4 At 0°C, compound 11-3 (560 mg, 2.17 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of diisobutylaluminum hydride (3.62 mL, 5.43 mmol, 1.5 mol / L) in toluene. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, sodium sulfate decahydrate (10 g) was added, and the reaction mixture was stirred for 30 minutes and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3) to obtain compound 11-4. 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (dd, 1H), 7.80 (d, 1H), 7.27-7.13 (m, 2H), 7.02 (dd, 1H), 6.93 (s, 1H), 5.23 (t, 1H), 5.11 (s, 2H), 4.48 (d, 2H).

[0351] Synthesis of compound 11-5 This was prepared by referring to the synthesis of compounds 3-5. 1H NMR (400 MHz, CDCl3) δ 7.64-7.62 (m, 2H), 7.10-7.05 (m, 2H), 7.05-7.02 (m, 1H), 6.87 (dd, 1H), 5.09 (s, 2H), 4.47 (s, 2H).

[0352] Synthesis of Compound 11-6 This was prepared by referring to the synthesis of compounds 3-6. MS-ESI: m / z 433.1 [M+1] + .

[0353] Synthesis of Compound 11-7 This was prepared by referring to the synthesis of compounds 3-7. MS-ESI: m / z 252.1 [M-17+1] + .

[0354] Synthesis of Compound 11-8 This compound was prepared by referring to the synthesis of compound 3-8, 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] + .

[0355] Synthesis of compound 11 Compound 11 was prepared by referring to the synthesis of Compound 1. MS-ESI: m / z 396.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.65-8.63 (m, 1H), 8.20 (s, 1H), 7.88-7.84 (m, 1H), 7.79 (dd, 1H), 7.25-7.17 (m, 2H), 6.99 (d, 1H), 6.92 (s, 1H), 5.10-5.06 (m, 2H), 5.06-4.91 (m, 1H), 4.04-3.95 (m, 1H), 3.92-3.82 (m, 1H), 3.76-3.67 (m, 1H), 3.18-3.04 (m, 3H), 2.92-2.57 (m, 3H), 1.75-1.73 (m, 2H).

[0356] (Example 12) (2S)-N-(1-cyano-2-(2,8-difluoro-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0357] [ka]

[0358] Synthesis of compound 12-2 At room temperature, methyl 2-fluoro-5-hydroxybenzoate (4.80 g, 28.23 mmol), 1-bromo-2-(bromomethyl)-4-fluorobenzene (compound 12-1) (9.24 g, 34.75 mmol), and potassium carbonate (5.50 g, 39.79 mmol) were dissolved in N,N-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 x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3) to obtain compound 12-2. 1 H NMR (400 MHz, CDCl3) δ 7.57-7.50 (m, 2H), 7.33-7.27 (m, 1H), 7.16-7.06 (m, 2H), 6.97-6.90 (m, 1H), 5.08 (s, 2H), 3.94 (s, 3H).

[0359] Synthesis of compound 12-3 At room temperature, under a nitrogen atmosphere, 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). The reaction mixture was heated to 130 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, followed by the addition of water (200 mL), and extraction with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 12-3. 1 H NMR (400 MHz, CDCl3) δ 7.66-7.61 (m, 1H), 7.53 (d, 1H), 7.39 (d, 1H), 7.14-7.07 (m, 1H), 6.94-6.88 (m, 1H), 5.10 (s, 2H), 3.93 (s, 3H).

[0360] Synthesis of compound 12-4 At room temperature, compound 12-3 (2.40 g, 8.25 mmol) was dissolved in tetrahydrofuran (50 mL), followed by the addition of lithium aluminum hydride (0.31 g, 8.25 mmol) at 0°C. The reaction mixture was stirred at 0°C for 20 minutes. After the reaction was complete, water (50 mL) was added, the mixture was extracted with ethyl acetate (50 mL x 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 12-4. 1 H NMR (400 MHz, CDCl3) δ 7.56 (dd, 1H), 7.32 (d, 1H), 7.11-7.03 (m, 2H), 6.88 (dd, 1H), 5.06 (s, 2H), 4.73 (d, 2H).

[0361] Synthesis of compound 12-5 At room temperature, compound 12-4 (1.60 g, 6.12 mmol) was dissolved in dichloromethane (20 mL), and then phosphorus tribromide (1.66 g, 6.12 mmol) was added dropwise. 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 x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 12-5. 1 H NMR (300 MHz, CDCl3) δ 7.65-7.57 (m, 1H), 7.38 (d, 1H), 7.17-7.07 (m, 1H), 7.04 (d, 1H), 6.93 (d, 1H), 5.11 (s, 2H), 4.52 (s, 2H).

[0362] Synthesis of compound 12-6 At room temperature, N-(diphenylmethylene)aminoacetonitrile (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 x 2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3) to obtain compound 12-6. MS-ESI: m / z 451.1 [M+1] + .

[0363] Synthesis of Compound 12-7 At room temperature, compound 12-6 (1.50 mg, 2.97 mmol) was dissolved in tetrahydrofuran (10 mL), and then 1 M hydrochloric acid aqueous solution (4 mL) was added dropwise. 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 x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 12-7. MS-ESI: m / z 287.1 [M+1] + .

[0364] Synthesis of compound 12-8 At room temperature, 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)uronium hexafluorophosphate (256 mg, 0.68 mmol), and N,N-diisopropylethylamine (200 mg, 1.56 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was purified by preparative liquid chromatography (C18, acetonitrile / water system) to obtain compound 12-8. MS-ESI: m / z 458.1 [M-56+1] + .

[0365] Synthesis of compound 12 At room temperature, compound 12-8 (70 mg, 0.16 mmol) was dissolved in formic acid (2 ml), and the reaction mixture was heated to 30°C and stirred for 1 hour. After the reaction was complete, the reaction mixture was purified by preparative liquid chromatography (C18, ammonium bicarbonate / acetonitrile / water system) to obtain compound 12. MS-ESI: m / z 414.1 [M+1] + . 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, 1H), 7.36 (d, 1H), 7.11-7.06 (m, 1H), 6.96-6.87 (m, 2H), 5.20-5.09 (m, 1H), 5.07 (s, 2H), 4.09-4.00 (m, 2H), 3.81-3.73 (m, 1H), 3.40-3.26 (m, 1H), 3.20-3.11 (m, 2H), 3.07-2.95 (m, 1H), 2.93-2.84 (m, 2H), 1.96-1.80 (m, 2H).

[0366] (Example 13) (2S)-N-(1-cyano-2-(8-cyano-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0367] [ka]

[0368] Synthesis of compound 13-2 At room temperature, 4-bromo-3-methylbenzonitrile (compound 13-1) (10 g, 51.29 mmol), N-bromosuccinimide (22.70 g, 127.54 mmol), and dibenzoyl peroxide (1.24 g, 5.12 mmol) were dissolved in 1,2-dichloroethane (50 mL). The reaction mixture was heated to 100 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature, followed by the addition of saturated sodium bicarbonate aqueous solution (50 mL), and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3) to obtain compound 13-2. 1 H NMR (400 MHz, CDCl3) δ 7.77-7.69 (m, 2H), 7.47-7.41 (m, 1H), 4.57 (s, 2H).

[0369] Synthesis of compound 13-3 At room temperature, compound 13-2 (140 mg, 0.44 mmol) and methyl 3-hydroxybenzoate (0.09 mL, 0.65 mmol) were dissolved in acetonitrile (10 mL), 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, followed by the addition of water (50 mL), and extraction with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 13-3.

[0370] Synthesis of compound 13-4 This was prepared by referring to the synthesis of compound 12-3. 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (d, 1H), 8.09 (d, 1H), 7.90 (dd, 1H), 7.82 (d, 1H), 7.66 (dd, 1H), 7.49 (d, 1H), 5.24 (s, 2H), 3.87 (s, 3H).

[0371] Synthesis of compound 13-5 This was prepared by referring to the synthesis of compound 11-4. MS-ESI: m / z 220.2 [M-18+1] + .

[0372] Synthesis of compound 13-6 This was prepared by referring to the synthesis of compounds 3-5. 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (d, 1H), 7.97 (d, 1H), 7.87 (d, 1H), 7.80 (s, 1H), 7.20 (d, 1H), 7.12 (s, 1H), 5.21 (d, 2H), 4.71 (s, 2H).

[0373] Synthesis of compound 13-7 This was prepared by referring to the synthesis of compounds 3-6. MS-ESI: m / z 440.3 [M+1] + .

[0374] Synthesis of compound 13-8 This was prepared by referring to the synthesis of compounds 3-7. MS-ESI: m / z 259.2 [M-17+1] + .

[0375] Synthesis of Compound 13-9 This compound was prepared by referring to the synthesis of compounds 1-7, 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] + .

[0376] Synthesis of compound 13 This was prepared by referring to the synthesis of compound 1. MS-ESI: m / z 403.3 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 7.77-7.71 (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).

[0377] (Example 14) (S)-N-((S)-1-cyano-2-(8-cyano-2-fluoro-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0378] [ka]

[0379] Synthesis route A:

[0380] [ka]

[0381] Synthesis of compound 14-A1 At room temperature, methyl 2-fluoro-5-hydroxybenzoate (4.30 g, 25.29 mmol), 4-bromo-3-(bromomethyl)benzonitrile (compound 13-2) (7.72 g, 25.30 mmol), and potassium carbonate (6.99 g, 50.58 mmol) were dissolved in N,N-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 x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 14-A1. 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, 1H), 7.73 (d, 1H), 7.55-7.48 (m, 2H), 7.18-7.09 (m, 2H), 5.11 (s, 2H), 3.95 (s, 3H).

[0382] Synthesis of compound 14-A2 At room temperature, under a nitrogen atmosphere, 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). The reaction mixture was heated to 120 °C and stirred for 1.5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, followed by the addition of water (200 mL), and extraction with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to obtain compound 14-A2. 1 H NMR (400 MHz, CDCl3) δ 7.80-7.72 (m, 2H), 7.60 (d, 1H), 7.52-7.49 (m, 2H), 5.18 (s, 2H), 3.98 (s, 3H).

[0383] Synthesis of compound 14-A3 At room temperature, compound 14-A2 (1.20 g, 3.81 mmol) and lithium borohydride (0.25 g, 11.47 mmol) were dissolved in tetrahydrofuran (25 mL), and 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, followed by the addition of water (200 mL), and extraction with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 14-A3. 1 H NMR (400 MHz, CDCl3) δ 7.67 (s, 2H), 7.47 (s, 1H), 7.38 (d, 1H), 7.12 (d, 1H), 5.11 (s, 2H), 4.77 (s, 2H).

[0384] Synthesis of compound 14-A4 At room temperature, compound 14-A3 (450 mg, 1.59 mmol) was dissolved in dichloromethane (15 mL), and then phosphorus tribromide (520 mg, 1.92 mmol) was added dropwise. 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 x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 14-A4. 1 H NMR (300 MHz, CDCl3) δ 7.73 (s, 2H), 7.52 (s, 1H), 7.45 (d, 1H), 7.10 (d, 1H), 5.17 (s, 2H), 4.53 (s, 2H).

[0385] Synthesis of compound 14-A5 At room temperature, N-(diphenylmethylene)aminoacetonitrile (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 x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to obtain compound 14-A5. MS-ESI: m / z 458.4 [M+1] + .

[0386] Synthesis of compound 14-A6 At room temperature, compound 14-A5 (520 mg, 0.90 mmol) was dissolved in tetrahydrofuran (10 mL), and then 1 M hydrochloric acid aqueous solution (4 mL) was added dropwise. 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 x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 14-A6. MS-ESI: m / z 293.9 [M+1] + .

[0387] Synthesis of compound 14-A7 At room temperature, 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)uronium hexafluorophosphate (360 mg, 0.95 mmol), and N,N-diisopropylethylamine (250 mg, 1.93 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was purified by preparative liquid chromatography (C18, acetonitrile / water system) to obtain compound 14-A7. MS-ESI: m / z 465.1 [M-56+1] + .

[0388] Synthesis of compound 14-1 Compound 14-A7 (280 mg, 0.51 mmol) was subjected to chiral resolution (column: chiralpak IE, 250 × 25 mm, 5 μm; mobile phase: n-hexane, ethanol; gradient: 30% n-hexane phase; flow rate: 15 mL / min, column temperature: 30°C) to obtain compound 14-1 (a total of two diastereomer peaks, with compound 14-1 being the first elution peak). 1H NMR (300 MHz, DMSO-d6) δ 8.89 (d, 1H), 8.08 (d, 1H), 7.94-7.89 (m, 2H), 7.83 (s, 1H), 7.07 (d, 1H), 5.24-5.14 (m, 2H), 5.09-5.07 (m, 1H), 4.15-4.12 (m, 1H), 3.99-3.87 (m, 2H), 3.63-3.56 (m, 2H), 3.29-3.02 (m, 4H), 1.89-1.79 (m, 2H), 1.41-1.36 (m, 9H).

[0389] Synthesis of compound 14 At room temperature, compound 14-1 (85 mg, 0.16 mmol) was dissolved in formic acid (1 ml), and the reaction mixture was heated to 40°C and stirred for 1 hour. After the reaction was complete, the reaction mixture was purified by preparative liquid chromatography (C18, ammonium bicarbonate / acetonitrile / water system) to obtain compound 14. MS-ESI: m / z 421.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (d, 1H), 8.05 (d, 1H), 7.89-7.86 (m, 2H), 7.80 (s, 1H), 7.03 (d, 1H), 5.20-5.12 (m, 2H), 5.09-5.02 (m, 1H), 4.00-3.97 (m, 1H), 3.88-3.83 (m, 1H), 3.77-3.68 (m, 1H), 3.25-3.14 (m, 2H), 3.05-2.98 (m, 1H), 2.82-2.72 (m, 1H), 2.62-2.53 (m, 2H), 1.80-1.66 (m, 2H).

[0390] Synthesis pathway B:

[0391] [ka]

[0392] Synthesis of compound 14-B1 At room temperature under a nitrogen atmosphere, compound 13-1 (10.00 g, 51.01 mmol), bis(pinacolato)diborone (15.54 g, 61.21 mmol), potassium acetate (10.01 g, 102.02 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.75 g, 1.02 mmol) were dissolved in N,N-dimethylformamide (100 mL). The reaction mixture was heated to 100 °C and stirred for 18 hours. The reaction mixture was cooled to room temperature, followed by the addition of water (1.0 L), and extracted with ethyl acetate (500 mL x 2). The organic phases were combined, washed with saturated brine (500 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1) to obtain compound 14-B1. 1 H NMR (300 MHz, CDCl3): δ 7.82 (d, 1H), 7.46-7.39 (m, 2H), 2.55 (s, 3H), 1.35 (s, 12H).

[0393] Synthesis of compound 14-B2 At room temperature under a nitrogen atmosphere, 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(diphenylphosphino)ferrocene]palladium(II) dichloride (1.26 g, 1.73 mmol) were dissolved in a mixed solvent of 1,4-dioxane (120 mL) and water (20 mL). The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, followed by the addition of water (1.0 L), and extracted with ethyl acetate (500 mL x 2). The organic phases were combined, washed with saturated brine (500 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 14-B2. 1H NMR (300 MHz, CDCl3) δ 7.62-7.52 (m, 2H), 7.45-7.36 (m, 1H), 7.32-7.24 (m, 1H), 7.06-6.97 (m, 1H), 2.24 (s, 3H).

[0394] Synthesis of compound 14-B3 At room temperature, under a nitrogen atmosphere, compound 14-B2 (7.40 g, 24.02 mmol), N-bromosuccinimide (10.26 g, 57.64 mmol), and dibenzoyl peroxide (0.35 g, 1.44 mmol) were dissolved in carbon tetrachloride (80 mL). The reaction mixture was heated to 90 °C and stirred for 18 hours. The reaction mixture was cooled to room temperature, followed by the addition of water (200 mL), and extracted with dichloromethane (100 mL x 2). The organic phases were combined, washed with saturated brine (500 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 6 / 1) to obtain compound 14-B3. 1 H NMR (300 MHz, CDCl3): δ 8.41 (s, 1H), 7.72-7.62 (m, 1H), 7.54-7.46 (m, 1H), 7.31-7.26 (m, 1H), 7.15-7.06 (m, 1H), 6.41 (s, 1H).

[0395] Synthesis of compound 14-B4 At room temperature, compound 14-B3 (1.00 g, 2.15 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of a solution of silver nitrate (0.80 g, 4.72 mmol) in water (2 mL). The reaction mixture was heated to 90 °C and stirred for 18 hours. The reaction mixture was cooled to room temperature and filtered. Water (20 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (25 mL x 2). The organic phases were combined, washed with saturated brine (25 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 14-B4, which was used directly in the next step. 1H NMR (300 MHz, CDCl3): δ 9.92 (d, 1H), 8.32 (s, 1H), 7.96 (d, 1H), 7.57-7.43 (m, 2H), 7.17-7.10 (m, 1H).

[0396] Synthesis of compound 14-B5 At room temperature, crude compound 14-B4 (7.20 g, 22.35 mmol) was dissolved in a mixed solvent of tetrahydrofuran (40 mL) and methanol (40 mL), followed by batch addition of sodium borohydride (1.01 g, 26.82 mmol) in an ice bath. 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 1 / 3 of its original volume, slowly poured into 0.5 M hydrochloric acid (50 mL) under stirring, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3) to obtain compound 14-B5. 1 H NMR (300 MHz, CDCl3): δ 7.97 (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).

[0397] Synthesis of compound 14-B6 At room temperature, compound 14-B5 (6.50 g, 20.05 mmol) was dissolved in N,N-dimethylformamide (65 mL), followed by the addition of sodium hydride (0.48 g, 20.05 mmol, 60%) in a batch 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), stirred for 10 minutes, and filtered. The filtered cake was washed with water (50 mL x 5), and then with a mixed solvent of petroleum ether and ethyl acetate (9 / 1, 50 mL x 3). The filtered cake was dried under vacuum to a certain mass to obtain crude compound 14-B6, which was used directly in the next step. 1H NMR (300 MHz, DMSO-d6): δ 8.12-8.06 (m, 2H), 7.94-7.86 (m, 1H), 7.82 (s, 1H), 7.46-7.40 (m, 1H), 5.21 (s, 2H).

[0398] Synthesis of compound 14-B7 At room temperature, under a nitrogen atmosphere, 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 the addition of methyl(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (60.00 g, 182.30 mmol) from N,N-dimethylformamide (200 mL). The reaction mixture was heated to 50°C and stirred for 1 hour, and the supernatant was used as the zinc reagent.

[0399] At room temperature, under a nitrogen atmosphere, crude compound 14-B6 (20.00 g, 65.76 mmol) and bis(triphenylphosphine)palladium(II) dichloride (4.00 g, 0.13 mmol) were dissolved in N,N-dimethylformamide (100 mL) in a separate reaction flask. The zinc reagent was added, and the reaction mixture was heated to 70°C and stirred for 6 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, followed by the addition of water (800 mL) and extraction with ethyl acetate (250 mL x 3). The organic phases were combined, washed with water (100 mL x 3), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1), then ground in ethanol (50 mL) to obtain compound 14-B7. 1H NMR (400 MHz, CDCl3) δ 8.04-8.02 (m, 1H), 7.88-7.85 (m, 2H), 7.82-7.79 (m, 1H), 7.37-7.35 (m, 1H), 6.99-6.98 (m, 1H), 5.15 (s, 2H), 4.27-4.20 (m, 1H), 3.64 (s, 3H), 3.14-3.09 (m, 1H), 2.87-2.81 (m, 1H),1.31 (s, 9H).

[0400] Synthesis of compound 14-B8 At room temperature, compound 14-B7 (10.00 g, 23.45 mmol) was dissolved in tetrahydrofuran (100 mL), followed by the addition of an 8 M solution of ammonia in methanol (200 mL). The reaction mixture was sealed and heated to 40°C, stirring for 60 hours. 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 step. MS-ESI: m / z 356.0 [M-56+1] + .

[0401] Synthesis of compound 14-B9 At room temperature, crude compound 14-B8 (9.50 g, 23.09 mmol) and triethylamine (7.01 g, 69.27 mmol) were dissolved in tetrahydrofuran (100 mL). Trifluoroacetic anhydride (7.27 g, 34.64 mmol) was added dropwise at 0°C, and the reaction mixture was allowed to rise naturally to room temperature and stirred for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. Water (100 mL) was added to the resulting residue, and the mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1), then ground in ethanol (20 mL) to obtain compound 14-B9. MS-ESI: m / z 392.0 [M-1] - .

[0402] Synthesis of compound 14-B10 At room temperature, compound 14-B9 (7.80 g, 19.83 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of formic acid (50 mL). The reaction mixture was heated to 35°C and stirred for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (100 mL), slowly poured into 10% sodium carbonate aqueous solution (300 mL), stirred for 5 minutes, and extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 14-B10, which was used directly in the next step. MS-ESI: m / z 392.0 [M+1] + .

[0403] Synthesis of compound 14-1 At room temperature, crude compound 14-B10 (7.00 g, 23.87 mmol) and compound 2-6 (6.44 g, 26.25 mmol) were dissolved in N,N-dimethylformamide (100 mL). N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (10.89 g, 28.64 mmol) was added at 0°C, and the reaction mixture was stirred for 5 minutes. 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 30 minutes. After the reaction was complete, the reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed sequentially with water (50 mL x 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 14-1. MS-ESI: m / z 521.1 [M+1] + .

[0404] Synthesis of compound 14 At room temperature, compound 14-1 (10.50 g, 20.17 mmol) was dissolved in tetrahydrofuran (105 mL), followed by the addition of p-toluenesulfonic acid monohydrate (11.51 g, 60.51 mmol). The reaction mixture was heated to 35°C and stirred for 18 hours, then heated to 45°C and stirred for 5 hours. The reaction mixture was cooled to room temperature and poured into a solution of sodium carbonate (8.6 g, 4 equivalents) in water (200 mL), and extracted with a mixed solvent of dichloromethane and methanol (1 / 10, 100 mL x 2). The organic phases were combined, washed with water (50 mL), and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was ground in methanol (80 mL) and dried under reduced pressure to obtain compound 14. MS-ESI: m / z 421.2 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 8.68 (d, 2H), 7.47-7.42 (m, 2H), 7.27-7.25 (m, 1H), 7.00 (d, 1H), 5.22-5.16 (m, 1H), 5.11 (s, 2H), 4.10-4.07 (m, 1H), 4.04-3.99 (m, 1H), 3.80-3.73 (m, 1H), 3.29-3.25 (m, 1H), 3.22-3.12 (m, 2H), 3.01-2.93 (m, 2H), 2.89-2.83 (m, 1H), 1.93-1.77 (m, 2H). 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (d, 1H), 8.04 (d, 1H), 7.89-7.86 (m, 2H), 7.80 (s, 1H), 7.03 (d, 1H), 5.20-5.12 (m, 2H), 5.09-5.03 (m, 1H), 4.00-3.97 (m, 1H), 3.88-3.82 (m, 1H), 3.75-3.69 (m, 1H), 3.28-3.15 (m, 2H), 3.04-3.00 (m, 1H), 2.79-2.73 (m, 1H), 2.63-2.54 (m, 2H), 1.78-1.64 (m, 2H).

[0405] (Example 15) (2S)-N-(1-cyano-2-(3-fluoro-6H-benzo[c]chromen-8-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0406] [ka]

[0407] Synthesis of compound 15-2 At room temperature, methyl 4-bromo-3-methylbenzoate (compound 15-1) (11.30 g, 49.57 mmol) was dissolved in carbon tetrachloride (150 mL), followed by the addition of N-bromosuccinimide (13.20 g, 74.17 mmol) and azobisisobutyronitrile (4.10 g, 24.97 mmol). The reaction mixture was heated to 80°C and stirred for 12 hours. The reaction mixture was cooled to room temperature, followed by the addition of saturated sodium bicarbonate aqueous solution (150 mL), and extracted with dichloromethane (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3) to obtain compound 15-2 (12 g). 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (d, 1H), 7.85-7.79 (m, 2H), 4.83 (s, 2H), 3.87 (s, 3H).

[0408] Synthesis of compound 15-3 At room temperature, 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). 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 resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 2) to obtain 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).

[0409] Synthesis of compound 15-4 This was prepared by referring to the synthesis of compound 11-2. MS-ESI: m / z 275.1 [M-1] - .

[0410] Synthesis of compound 15-5 This was prepared by referring to the synthesis of compound 11-3. MS-ESI: m / z 259.1 [M+1] + .

[0411] Synthesis of Compound 15-6 This was prepared by referring to the synthesis of compound 11-4. MS-ESI: m / z 213.4 [M-18+1] + .

[0412] Synthesis of Compound 15-7 This was prepared by referring to the synthesis of compounds 3-5. 1 H NMR (400 MHz, CDCl3) δ 7.68-7.64 (m, 1H), 7.60 (d, 1H), 7.39 (dd, 1H), 7.19 (s, 1H), 6.80-6.75 (m, 1H), 6.73-6.70 (m, 1H), 5.11 (s, 2H), 4.51 (s, 2H).

[0413] Synthesis of compound 15-8 This was prepared by referring to the synthesis of compounds 3-6. MS-ESI: m / z 433.1 [M+1] + .

[0414] Synthesis of Compound 15-9 This was prepared by referring to the synthesis of compounds 3-7. MS-ESI: m / z 252.1 [M-17+1] + .

[0415] Synthesis of Compound 15-10 This compound was prepared by referring to the synthesis of compound 3-8, 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] + .

[0416] Synthesis of compound 15 This was prepared by referring to the synthesis of compound 1. MS-ESI: m / z 396.1 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 7.69-7.61 (m, 2H), 7.33-7.26 (m, 1H), 7.19-7.16 (m, 1H), 7.09 (d, 1H), 6.78 (td, 1H), 6.72 (dd, 1H), 5.19-5.09 (m, 3H), 4.10-4.07 (m, 1H), 4.03-3.96 (m, 1H), 3.80-3.72 (m, 1H), 3.38-3.28 (m, 1H), 3.17-3.01 (m, 3H), 2.96-2.87 (m, 2H), 1.88-1.78 (m, 2H).

[0417] (Example 16) (S)-N-((S)-1-cyano-2-(8,9-difluoro-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0418] [ka]

[0419] Synthesis of compound 16-2 At 0°C, (S)-2-amino-3-(3-hydroxyphenyl)propanoic acid (compound 16-1) (4.50 g, 24.84 mmol) was dissolved in methanol (50 mL), and then thionyl chloride (3.84 g, 32.29 mmol) was slowly added dropwise. 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 step. MS-ESI: m / z 196.2 [M+1] + .

[0420] Synthesis of compound 16-3 At 0°C, 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), followed by the addition of di-tert-butyl dicarbonate (7.38 g, 33.81 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, water (50 mL) was added, and the reaction mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 16-3. MS-ESI: m / z 196.2 [M-100+1] + .

[0421] Synthesis of compound 16-4 At room temperature, compound 16-3 (3.38 g, 11.45 mmol) was dissolved in N,N-dimethylformamide (50 mL), followed by the successive 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, followed by the addition of saturated sodium bicarbonate aqueous solution (50 mL), and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3) to obtain compound 16-4. MS-ESI: m / z 402.2 [M-100+1] + .

[0422] Synthesis of compound 16-5 At room temperature, compound 16-4 (1.00 g, 2.00 mmol) was dissolved in N,N-dimethylacetamide (50 mL), followed by the addition of sodium acetate (0.33 g, 4.00 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.78 g, 1.00 mmol). The reaction mixture was heated to 130°C by microwave and stirred for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, followed by the addition of saturated sodium bicarbonate aqueous solution (50 mL), and extraction with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3) to obtain compound 16-5. MS-ESI: m / z 320.3 [M-100+1] + .

[0423] Synthesis of compound 16-6 This was prepared by referring to the synthesis of compounds 1-4. MS-ESI: m / z 305.3 [M-100+1] + .

[0424] Synthesis of Compounds 16-7 This was prepared by referring to the synthesis of compounds 1-5, 1-6, and 3-8. MS-ESI: m / z 414.2 [M-100+1] + .

[0425] Synthesis of compound 16 This was prepared by referring to the synthesis of compound 1. MS-ESI: m / z 414.2 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ 7.72-7.64 (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).

[0426] (Example 17) (S)-4-amino-N-(1-cyano-2-(8,9-difluoro-6H-benzo[c]chromen-3-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0427] [ka]

[0428] Synthesis of Compound 17-1 This was prepared by referring to the synthesis of compounds 1-7. MS-ESI: m / z 414.2 [M-100+1] + .

[0429] Synthesis of Compound 17 This was prepared by referring to the synthesis of compound 1. MS-ESI: m / z 414.2 [M+1] + . 1H NMR (400 MHz, CD3OD) δ 7.73-7.64 (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).

[0430] (Example 18) (2S)-N-(1-cyano-2-(3-cyano-9-fluoro-5H-chromeno[4,3-c]pyridine-8-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0431] [ka]

[0432] Synthesis of compound 18-2 At room temperature, compound 18-1 (4.50 g, 17.97 mmol) was dissolved in a mixed solvent of tetrahydrofuran (40 mL) and methanol (5 mL), followed by the addition of lithium borohydride (0.78 g, 35.93 mmol) at 0°C. 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 x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 18-2. MS-ESI: m / z 221.9 [M+1] + .

[0433] Synthesis of compound 18-3 At room temperature, 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). Diisopropyl azodicarboxylate (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 resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 18-3. MS-ESI: m / z 373.9 [M+1] + .

[0434] Synthesis of compound 18-4 At room temperature under a nitrogen atmosphere, 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). 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, followed by the addition of water (100 mL), and extraction with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 18-4. MS-ESI: m / z 293.9 [M+1] + .

[0435] Synthesis of compound 18-5 At room temperature, under a nitrogen atmosphere, compound 18-4 (1.10 g, 3.63 mmol), zinc cyanide (0.64 g, 5.45 mmol), and tetrakis(triphenylphosphine)palladium (0.63 g, 0.55 mmol) were dissolved in N,N-dimethylformamide (15 mL). The reaction mixture was heated to 90 °C and stirred for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, followed by the addition of water (100 mL), and extraction with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 18-5. MS-ESI: m / z 284.9 [M+1] + .

[0436] Synthesis of compound 18-6 This was prepared by referring to the synthesis of compound 17-5. 1 H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 7.43 (s, 1H), 7.39 (d, 1H), 7.09 (d, 1H), 5.07 (s, 2H), 4.72 (s, 2H).

[0437] Synthesis of compound 18-7 At room temperature, 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), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to obtain compound 18-7. 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 7.52-7.47 (m, 2H), 7.08 (d, 1H), 5.15 (s, 2H), 4.48 (s, 2H).

[0438] Synthesis of compound 18-8 This was prepared by referring to the synthesis of compound 14-A5. MS-ESI: m / z 459.2 [M+1] + .

[0439] Synthesis of compound 18-9 This was prepared by referring to the synthesis of compound 14-A6. MS-ESI: m / z 295.0 [M+1] + .

[0440] Synthesis of compound 18-10 This was prepared by referring to the synthesis of compound 14-A7. MS-ESI: m / z 422.1 [M-100+1] + .

[0441] Synthesis of compound 18 This was prepared by referring to the synthesis of compound 14. MS-ESI: m / z 422.1 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 9.24 (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).

[0442] (Example 19) (S)-N-((S)-1-cyano-2-(3-cyano-9-fluoro-5H-chromeno[4,3-c]pyridine-8-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0443] [ka]

[0444] Synthesis of compound 19 Compound 18 (50 mg, 0.312 mmol) was subjected to chiral resolution (column: chiralpak IC, 250 × 30 mm, 5 μm; mobile phase: acetonitrile, isopropanol (0.2% diethylamine); gradient: acetonitrile phase 60%; flow rate: 15 mL / min, column temperature: 30 °C) to obtain compound 19 (a total of two diastereomer peaks, with compound 19 being the second elution peak). MS-ESI: m / z 422.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.69 (d, 1H), 8.02 (d, 1H), 7.98 (s, 1H), 7.06 (d, 1H), 5.29-5.21 (m, 2H), 5.11-5.01 (m, 1H), 4.01-3.95 (m, 1H), 3.89-3.81 (m, 1H), 3.77-3.68 (m, 1H), 3.30-3.20 (m, 2H), 3.02 (dd, 1H), 2.80-2.72 (m, 1H), 2.62-2.50 (m, 2H), 1.81-1.62 (m, 2H).

[0445] (Example 20) (S)-N-((S)-1-cyano-2-(2,8-difluoro-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0446] [ka]

[0447] Synthesis of compound 20-1 Tert-butyl(2S)-2-((1-cyano-2-(2,8-difluoro-6H-benzo[c]chromen-3-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (compound 12-8) (160 mg, 0.31 mmol) was subjected to chiral resolution (column: chiralpak IC, 250 × 30 mm, 5 μm; mobile phase: n-hexane, ethanol; gradient: 50% n-hexane phase; flow rate: 15 mL / min, column temperature: 30 °C) to obtain compound 20-1 (a total of two diastereomer peaks, with compound 20-1 being the first elution peak).

[0448] Synthesis of compound 20 This was prepared by referring to the synthesis of compound 14. MS-ESI: m / z 414.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (d, 1H), 7.93-7.88 (m, 1H), 7.74 (d, 1H), 7.28-7.17 (m, 2H), 6.98 (d, 1H), 5.15-5.08 (m, 2H), 5.07-4.99 (m, 1H), 4.02-3.96 (m, 1H), 3.89-3.82 (m, 1H), 3.77-3.69 (m, 1H), 3.26-3.11 (m, 2H), 3.07-2.99 (m, 1H), 2.81-2.73 (m, 1H), 2.64-2.52 (m, 2H), 1.80-1.65 (m, 2H).

[0449] (Example 21) (S)-N-((S)-2-(2-chloro-8-cyano-6H-benzo[c]chromen-3-yl)-1-cyanoethyl)-1,4-oxazepan-2-carboxamide

[0450] [ka]

[0451] Synthesis of compound 21-2 Compound 21-2 was prepared by referring to the synthesis of compound 14-A1 under similar conditions, except that potassium carbonate was replaced with cesium carbonate. 1 H NMR (400 MHz, DMSO-d6) δ 8.10 (d, 1H), 7.93 (d, 1H), 7.80 (dd, 1H), 7.52 (d, 1H), 7.49 (d, 1H), 7.30 (dd, 1H), 5.19 (s, 2H), 3.87 (s, 3H).

[0452] Synthesis of compound 21-3 At room temperature under a nitrogen atmosphere, compound 21-2 (13.30 g, 34.90 mmol) was dissolved in anhydrous N,N-dimethylacetamide (150 mL), followed by the addition of bis(triphenylphosphine)palladium(II) dichloride (2.45 g, 3.50 mmol) and anhydrous potassium acetate (10.30 g, 104.95 mmol). The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with saturated brine (100 mL x 3). The aqueous phase was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was ground in ethyl acetate (50 mL) to obtain compound 21-3. 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.19 (d, 1H), 7.91 (dd, 1H), 7.84 (s, 1H), 7.42 (s, 1H), 5.26 (s, 2H), 3.86 (s, 3H).

[0453] Synthesis of compound 21-4 This was prepared by referring to the synthesis of compound 14-A3. 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (d, 1H), 8.02 (s, 1H), 7.85 (dd, 1H), 7.79 (s, 1H), 7.16 (s, 1H), 5.50 (t, 1H), 5.20 (s, 2H), 4.54 (d, 2H).

[0454] Synthesis of compound 21-5 This was prepared by referring to the synthesis of compound 14-A4. 1 H NMR (400 MHz, DMSO-d6) δ 8.16-8.11 (m, 2H), 7.88 (dd, 1H), 7.81 (s, 1H), 7.32 (s, 1H), 5.22 (s, 2H), 4.71 (s, 2H).

[0455] Synthesis of compound 21-6 At room temperature, under a nitrogen atmosphere, sodium hydride (167 mg, 4.18 mmol, 60%) was added to anhydrous tetrahydrofuran (10 mL). A solution of N-(diphenylmethylene)aminoacetonitrile (1.84 g, 8.37 mmol) in tetrahydrofuran (10 mL) was added at -10°C, and the reaction mixture was stirred at -10°C for 10 minutes. A solution of compound 21-5 (700 mg, 2.09 mmol) in tetrahydrofuran (8 mL) was added, and the reaction mixture was stirred at -10°C for 20 minutes. A solution of crude compound 21-6 in tetrahydrofuran was obtained and used directly in the next step. MS-ESI: m / z 474.1 [M+1] + .

[0456] Synthesis of Compound 21-7 At room temperature, a solution of crude compound 21-6 in tetrahydrofuran (1.27 g, 2.69 mmol) was added to anhydrous tetrahydrofuran (10 mL). The reaction mixture was adjusted to pH 5-6 with 1 M hydrochloric acid (10 mL) and stirred at room temperature for 16 hours. Water (30 mL) was added, and the reaction mixture was washed with ethyl acetate (50 mL x 2). The aqueous phase was adjusted to pH 7-8 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 21-7, which was used directly in the next step. MS-ESI: m / z 310.1 [M+1] + .

[0457] Synthesis of compound 21-8 At room temperature, crude compounds 21-7 (500 mg, 1.26 mmol) and 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). Subsequently, O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (955 mg, 2.52 mmol) and N,N-diisopropylethylamine (407 mg, 3.15 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. Saturated sodium bicarbonate aqueous solution (30 mL) was added, and the reaction mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, ethyl acetate). This was then further purified by preparative liquid chromatography (column: Phenomenex Luna C18, 150 × 40 mm, 15 μm; mobile phase: water (0.225% formic acid), acetonitrile; gradient: acetonitrile phase 52-82%; flow rate: 60 mL / min; column temperature: room temperature) to obtain compound 21-8. MS-ESI: m / z 481.1 [M-56+1] + .

[0458] Synthesis of Compound 21-9 Compound 21-8 (390 mg, 0.73 mmol) was separated by preparative SFC (column: DAIEL CHIRALCEL OJ, 250 × 30 mm, 10 μm; mobile phase: supercritical carbon dioxide, methanol (0.1% ammonia monohydrate); gradient: 55% carbon dioxide phase; flow rate: 70 mL / min; column temperature: room temperature) to obtain compound 21-9 (a total of two diastereomer peaks, with compound 21-9 being the second elution peak).

[0459] Synthesis of Compound 21 This was prepared by referring to the synthesis of compound 14. MS-ESI: m / z 437.2 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, 1H), 8.14-8.09 (m, 2H), 7.87 (dd, 1H), 7.80 (d, 1H), 7.07 (s, 1H), 5.25-5.15 (m, 2H), 5.07-4.99 (m, 1H), 3.94-3.85 (m, 2H), 3.74-3.66 (m, 1H), 3.32-3.20 (m, 2H), 3.12 (dd, 1H), 2.84-2.76 (m, 1H), 2.74-2.62 (m, 2H), 1.84-1.64 (m, 2H).

[0460] (Example 22) 4-amino-N-(1-cyano-2-(8-fluoro-6H-benzo[c]chromen-3-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide formate

[0461] [ka]

[0462] Synthesis of compound 22-1 This compound was prepared by referring to the synthesis of compounds 1-7, 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] + .

[0463] Synthesis of compound 22 This was prepared by referring to the synthesis of compound 1. MS-ESI: m / z 396.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ: 8.25 (d, 1H), 8.00, (s, 1H), 7.66-7.63 (m, 2H), 7.07 (td, 1H), 6.99-6.96 (m, 1H), 6.89-6.87 (m, 2H), 5.13-5.08 (m, 3H), 3.93-3.83 (m, 2H), 3.65-3.56 (m, 2H), 3.08 (d, 2H), 2.33-2.16 (m, 2H), 1.32-1.22 (m, 2H).

[0464] (Example 23) 4-amino-N-(1-cyano-2-(3-fluoro-6H-benzo[c]chromen-8-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0465] [ka]

[0466] Synthesis of Compound 23-1 This compound was prepared by referring to the synthesis of compounds 1-7, 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] + .

[0467] Synthesis of compound 23 This was prepared by referring to the synthesis of compound 1. MS-ESI: m / z 396.1 [M+H] + . 1H NMR (400 MHz, 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).

[0468] (Example 24) 4-Amino-N-(1-Cyano-2-(2,8-Difluoro-6H-Benzo[c]Cromen-3-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0469] [ka]

[0470] Synthesis of compound 24-1 This was prepared by referring to the synthesis of compounds 1-7. MS-ESI: m / z 458.1 [M-56+1] + .

[0471] Synthesis of Compound 24 This compound was prepared by referring to the synthesis of compound 14, under similar conditions except that the reaction temperature was changed from 40°C to 30°C. MS-ESI: m / z 414.2 [M+1] + . 1H NMR (400 MHz, CDCl3) δ 8.29 (d, 1H), 7.59-7.54 (m, 1H), 7.35 (d, 1H), 7.12-7.05 (m, 1H), 6.91-6.86 (m, 1H), 5.16-5.08 (m, 1H), 5.06 (s, 2H), 3.94-3.81 (m, 2H), 3.65-3.55 (m, 2H), 3.24-3.17 (m, 1H), 3.13-3.06 (m, 1H), 2.32-2.22 (m, 1H), 2.21-2.11 (m, 1H), 1.32-1.26 (m, 1H), 1.23-1.17 (m, 1H).

[0472] (Example 25) 4-amino-N-(1-cyano-2-(8-cyano-6H-benzo[c]chromen-3-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0473] [ka]

[0474] Synthesis of compound 25-1 This was prepared by referring to the synthesis of compound 21-8. MS-ESI: m / z 403.3 [M-100+1] + .

[0475] Synthesis of Compound 25 This was prepared by referring to the synthesis of compound 1. MS-ESI: m / z 403.3 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 8.28 (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).

[0476] (Example 26) (2S,3aS,6aS)-N-((S)-1-cyano-2-(8-cyano-2-fluoro-6H-benzo[c]chromen-3-yl)ethyl)octahydrocyclopenta[b]pyrrole-2-carboxamide

[0477] [ka]

[0478] Synthesis of compound 26-2 At room temperature, (2S,3aS,6aS)-1-(tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid (compound 26-1) (174 mg, 0.68 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (259 mg, 0.68 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred for 10 minutes. 3-(2-amino-2-cyanoethyl)-2-fluoro-6H-benzo[c]chromen-8-carbonitrile (compound 14-A6) (200 mg, 0.68 mmol) and triethylamine (0.19 mL, 1.36 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, (10 mL) was added, and the reaction mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified 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] - .

[0479] Synthesis of compound 26-3 Compound 26-2 (300 mg, 0.57 mmol) was subjected to chiral resolution (column: chiralpak IE, 250 × 30 mm, 5 μm; mobile phase: n-hexane, ethanol; gradient: 50% n-hexane phase; flow rate: 25 mL / min, column temperature: 30 °C) to obtain compound 26-3 (a total of two diastereomer peaks, with compound 26-3 being the second elution peak).

[0480] Synthesis of Compound 26 This compound was prepared by referring to the synthesis of compound 14, under similar conditions except that the temperature was changed to 50°C. MS-ESI: m / z 431.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, 1H), 8.04 (d, 1H), 7.91-7.83 (m, 2H), 7.79 (s, 1H), 7.03 (d, 2H), 5.20-5.11 (m, 2H), 5.10-5.04 (m, 1H), 3.57 (t, 1H), 3.42-3.36 (m, 1H), 3.26-3.21 (m, 2H), 2.43-2.37 (m, 1H), 2.09-2.00 (m, 1H), 1.62-1.49 (m, 2H), 1.45-1.35 (m, 3H), 1.24-1.14 (m, 1H), 1.02-0.93 (m, 1H).

[0481] (Example 27) (S)-N-((S)-1-cyano-2-(8-cyano-2-fluoro-6,6-dimethyl-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0482] [ka]

[0483] Synthesis of compound 27-2 At room temperature, under a nitrogen atmosphere, 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), followed by the addition of dichloromethyl methyl ether (13.9 mL, 153.68 mmol) 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) and extracted with ethyl acetate (25 mL x 3). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1) to obtain compound 27-2. 1 H NMR (300 MHz, CDCl3) δ 10.31 (s, 1H), 7.45 (d, 1H), 7.31 (d, 1H), 3.93 (s, 3H).

[0484] Synthesis of compound 27-3 At room temperature, compound 27-2 (7.00 g, 30.18 mmol) was dissolved in methanol (60 mL), followed by the addition of sodium borohydride (1.14 g, 30.14 mmol) at 0°C. The reaction mixture was slowly warmed 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 x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 27-3. 1 H NMR (400 MHz, CDCl3) δ 7.25 (d, 1H), 6.98 (d, 1H), 4.71 (s, 2H), 3.88 (s, 3H).

[0485] Synthesis of compound 27-4 At room temperature, compound 27-3 (4.20 g, 17.86 mmol) was dissolved in dichloromethane (60 mL), 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 x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 70 / 1) to obtain compound 27-4. 1 H NMR (400 MHz, CDCl3) δ 7.70-7.64 (m, 4H), 7.46-7.34 (m, 6H), 7.25-7.15 (m, 2H), 4.79 (s, 2H), 3.86 (s, 3H), 1.12 (s, 9H).

[0486] Synthesis of compound 27-5 At room temperature under a nitrogen atmosphere, compound 27-4 (5.00 g, 10.88 mmol), bis(pinacolato)diborone (3.59 g, 14.14 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.80 g, 1.08 mmol), and potassium acetate (3.20 g, 32.64 mmol) were dissolved in 1,4-dioxane (80 mL). The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, followed by the addition of water (50 mL), and extracted with ethyl acetate (25 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 70 / 1) to obtain compound 27-5. 1H NMR (400 MHz, CDCl3) δ 7.71-7.64 (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).

[0487] Synthesis of compound 27-6 At room temperature under a nitrogen atmosphere, compound 27-5 (6.00 g, 11.53 mmol), methyl 5-bromo-2-iodobenzoate (4.72 g, 13.83 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (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). 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, followed by the addition of water (30 mL) and extraction with ethyl acetate (25 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1) to obtain compound 27-6. 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, 1H), 7.74-7.67 (m, 4H), 7.66 (dd, 1H), 7.46-7.35 (m, 6H), 7.16 (d, 2H), 6.87 (d, 1H), 4.88 (s, 2H), 3.69 (s, 3H), 3.67 (s, 3H), 1.12 (s, 9H).

[0488] Synthesis of compound 27-7 At room temperature, under a nitrogen atmosphere, compound 27-6 (4.20 g, 6.91 mmol) was dissolved in tetrahydrofuran (80 mL). Methyllithium (9.9 mL, 19.80 mmol, 2.0 mol / L) was added dropwise at 0°C, and the reaction mixture was slowly warmed to room temperature and stirred for 2 hours. After the reaction was complete, water (20 mL) was added, and the reaction mixture was extracted with dichloromethane (25 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain compound 27-7. 1 H NMR (300 MHz, CDCl3) δ 7.79 (s, 1H), 7.71 (d, 4H), 7.43-7.34 (m, 7H), 7.25-7.16 (m, 1H), 6.87 (d, 1H), 6.76 (d, 1H), 4.89 (s, 2H), 3.71 (s, 3H), 1.49 (s, 3H), 1.35 (s, 3H), 1.13 (s, 9H).

[0489] Synthesis of Compound 27-8 At room temperature, compound 27-7 (2.00 g, 3.29 mmol) was dissolved in acetonitrile (30 mL). Hydroiodic acid (7.5 mL, 55% aqueous solution) was added dropwise, and 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 x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain compound 27-8. 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (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).

[0490] Synthesis of compound 27-9 At room temperature, under a nitrogen atmosphere, compound 27-8 (100 mg, 0.29 mmol) and zinc cyanide (42 mg, 0.35 mmol) were dissolved in N,N-dimethylformamide (3 mL), followed by the addition of tetrakis(triphenylphosphine)palladium (34.3 mg, 0.031 mmol). The reaction mixture was sealed and heated to 140°C, stirring for 16 hours. The reaction mixture was cooled to room temperature, followed by the addition of saturated sodium bicarbonate aqueous solution (20 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 27-9. 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (d, 1H), 7.90-7.78 (m, 3H), 7.02 (d, 1H), 5.36 (t, 1H), 4.53 (d, 2H), 1.59 (s, 6H).

[0491] Synthesis of compound 27-10 This was prepared by referring to the synthesis of compound 18-7. 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (d, 1H), 7.96-7.83 (m, 3H), 7.15 (d, 1H), 4.68 (s, 2H), 1.60 (s, 6H).

[0492] Synthesis of compound 27-11 This compound was prepared by referring to the synthesis of compound 14-A5, under similar conditions except that benzyltrimethylammonium chloride was replaced with benzyltriethylammonium chloride. 1H NMR (300 MHz, CDCl3) δ 7.67-7.57 (m, 4H), 7.53-7.40 (m, 5H), 7.40-7.30 (m, 3H), 7.05-6.94 (m, 2H), 6.90 (d, 1H), 4.51 (t, 1H), 3.38-3.22 (m, 2H), 1.66 (s, 3H), 1.56 (s, 3H).

[0493] Synthesis of compound 27-12 This was prepared by referring to the synthesis of compound 14-A6. 1 H NMR (300 MHz, CDCl3) δ 7.71-7.60 (m, 2H), 7.52 (s, 1H), 7.42 (d, 1H), 6.91 (d, 1H), 4.01 (s, 1H), 3.10-3.05 (m, 2H), 1.71 (s, 3H), 1.64 (s, 3H).

[0494] Synthesis of compound 27-13 This compound was prepared by referring to the synthesis of compound 14-A7 under similar conditions, except that N,N-diisopropylethylamine was replaced with triethylamine. MS-ESI: m / z 547.2 [M-1] - .

[0495] Synthesis of compound 27-14 Compound 27-13 (230 mg, 0.42 mmol) was subjected to chiral resolution (column: chiralpak IC, 250 × 30 mm, 5 μm; mobile phase: n-hexane, ethanol; gradient: 50% n-hexane phase; flow rate: 25 mL / min, column temperature: 30°C) to obtain crude compound 27-14 (a total of 3 diastereomer peaks, with compound 27-14 being the first elution peak). The crude compound was further subjected to chiral resolution (column: chiralpak IG, 250 × 30 mm, 5 μm; mobile phase: n-hexane, ethanol; gradient: 60% n-hexane phase; flow rate: 25 mL / min, column temperature: 30°C) to obtain compound 27-14 (a total of 2 diastereomer peaks, with compound 27-14 being the first elution peak).

[0496] Synthesis of Compound 27 This was prepared by referring to the synthesis of compound 14. MS-ESI: m / z 449.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (d, 1H), 8.06 (d, 1H), 7.90-81 (m, 3H), 6.95 (d, 1H), 5.11-5.02 (m, 1H), 4.01-3.94 (m, 1H), 3.88-3.80 (m, 1H), 3.76-3.67 (m, 1H), 3.24-3.16 (m, 2H), 3.00 (dd, 1H), 2.80-2.71 (m, 1H), 2.62-2.52 (m, 2H), 1.77-1.67 (m, 2H), 1.58 (s, 6H).

[0497] (Example 28) (2S)-N-(1-cyano-2-(9-(oxetan-3-yl)-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0498] [ka]

[0499] Synthesis of compound 28-2 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 batches at 0°C, and the reaction mixture was stirred at 0°C for 5 minutes. Bromomethyl methyl ether (2.98 g, 23.88 mmol) was added dropwise, and the reaction 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 (50 mL x 2). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain compound 28-2. 1 H NMR (400 MHz, CDCl3) δ 10.24 (d, 1H), 7.88 (d, 1H), 7.30 (d, 1H), 7.10-7.03 (m., 1H), 5.23 (s, 2H), 3.49 (s, 3H).

[0500] Synthesis of compound 28-3 At room temperature, compound 28-2 (4.40 g, 17.95 mmol) was dissolved in methanol (50 mL), followed by the addition of sodium borohydride (1.36 g, 35.91 mmol) in a batch at 0°C. The reaction 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 x 3). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 28-3. 1 H NMR (300 MHz, CDCl3) δ 7.39-7.33 (m, 1H), 7.30-7.24 (m, 1H), 7.03-6.96 (m, 1H), 5.15 (s, 2H), 4.69 (s, 2H), 3.47 (s, 3H).

[0501] Synthesis of compound 28-4 At room temperature, crude compound 28-3 (5.00 g, 20.24 mmol) and triethylamine (6.14 g, 60.71 mmol) were dissolved in dichloromethane (50 mL). Methanesulfonyl chloride (3.48 g, 30.35 mmol) was added dropwise, and 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 x 2). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude intermediate.

[0502] At room temperature, m-hydroxybenzoic acid (2.34 g, 15.38 mmol) was dissolved in N,N-dimethylformamide (50 mL). Sodium hydride (0.80 g, 19.99 mmol, 60%) was added at 0°C, and the reaction mixture was stirred at 0°C for 5 minutes. The solution of the crude intermediate (5 g, 15.38 mmol) in N,N-dimethylformamide (10 mL) was added, and the reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed sequentially with water (25 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain compound 28-4. 1 H NMR (300 MHz, CDCl3) δ 7.69-7.64 (m, 2H), 7.47-7.30 (m, 3H), 7.20-7.14 (m, 1H), 7.05-6.97 (m, 1H), 5.30 (s, 2H), 5.17 (s, 2H), 3.92 (s, 3H), 3.48 (s, 3H).

[0503] Synthesis of compound 28-5 At room temperature, under a nitrogen atmosphere, compound 28-4 (4.90 g, 12.85 mmol), potassium carbonate (3.55 g, 25.71 mmol), tricyclohexylphosphine tetrafluoroborate (0.47 g, 1.28 mmol), and palladium acetate (0.29 g, 1.28 mmol) were dissolved in N,N-dimethylformamide (50 mL). The reaction mixture was heated to 120 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, poured into water (200 mL), and extracted with ethyl acetate (50 mL x 2). The organic phases were combined and washed sequentially with water (25 mL x 2) and saturated brine (25 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain compound 28-5. 1 H NMR (300 MHz, CDCl3) δ 7.77-7.70 (m, 2H), 7.69-7.62 (m, 1H), 7.43-7.38 (m, 1H), 7.13-7.07 (m, 1H), 7.06-6.98 (m, 1H), 5.23 (s, 2H), 5.10 (s, 2H), 3.92 (s, 3H), 3.51 (s, 3H).

[0504] Synthesis of compound 28-6 At room temperature, compound 28-5 (4.00 g, 13.33 mmol) was dissolved in tetrahydrofuran (40 mL), followed by the addition of concentrated hydrochloric acid (4 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was poured into water (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to obtain compound 28-6. 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.87 (d, 1H), 7.67-7.61 (m, 1H), 7.45 (s, 1H), 7.23 (d, 1H), 7.13 (d, 1H), 6.85-6.78 (m, 1H), 5.09 (s, 2H), 3.86 (s, 3H).

[0505] Synthesis of compound 28-7 At room temperature, compound 28-6 (1.20 g, 4.68 mmol) and triethylamine (1.40 g, 13.84 mmol) were dissolved in dichloromethane (30 mL), followed by the addition of N-phenylbis(trifluoromethanesulfonimide) (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 x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 28-7. 1 H NMR (400 MHz, CDCl3) δ 7.79-7.73 (m, 1H), 7.73-7.69 (m, 1H), 7.67 (d, 1H), 7.60 (d, 1H), 7.29-7.22 (m, 2H), 5.16 (s, 2H), 3.93 (s, 3H).

[0506] Synthesis of compound 28-8 At room temperature, under a nitrogen atmosphere, compound 28-7 (1.60 g, 4.12 mmol) and bis(pinacolato)diborone (1.20 g, 4.73 mmol) were dissolved in 1,4-dioxane (40 mL), followed by the addition of potassium acetate (1.20 g, 12.23 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (300 mg, 0.410 mmol). 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 x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to obtain compound 28-8. 1 H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.90 (d, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.63 (s, 1H), 7.18 (d, 1H), 5.16 (s, 2H), 3.92 (s, 3H),1.37 (s, 12H).

[0507] Synthesis of compound 28-9 At room temperature, compound 28-8 (1.50 g, 4.10 mmol) was dissolved in tetrahydrofuran (20 mL), 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 x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was ground in a mixed solvent of ethyl acetate and petroleum ether (50 mL) to obtain compound 28-9. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.23 ​​(s, 2H), 8.03 (d, 1H), 7.81 (d, 1H), 7.72-7.65 (m, 1H), 7.47 (d, 1H), 7.28 (d, 1H), 5.21 (s, 2H), 3.86 (s, 3H).

[0508] Synthesis of compound 28-10 At room temperature, under a nitrogen atmosphere, compound 28-9 (1.10 g, 3.87 mmol) and 3-iodooxetane (800 mg, 4.35 mmol) were dissolved in isopropanol (30 mL), followed by the addition of nickel iodide (300 mg, 0.96 mmol), 2-aminocyclohexanol hydrochloride (100 mg, 0.87 mmol), and a solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (8.0 mL, 8.00 mmol, 1.0 mol / L). 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 x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to obtain compound 28-10.

[0509] Synthesis of compound 28-11 This was prepared by referring to the synthesis of compound 12-4. MS-ESI: m / z 251.2 [M-18+1] + .

[0510] Synthesis of compound 28-12 This was prepared by referring to the synthesis of compound 18-7, under similar conditions except that dichloromethane was replaced with tetrahydrofuran. 1H NMR (400 MHz, CDCl3) δ 7.76-7.70 (m, 2H), 7.34 (d, 1H), 7.16 (d, 1H), 7.13-7.07 (m, 1H), 7.03 (s, 1H), 5.16-5.08 (m, 4H), 4.80 (t, 2H), 4.47 (s, 2H), 4.32-4.21 (m, 1H).

[0511] Synthesis of compound 28-13 At room temperature, N-(diphenylmethylene)aminoacetonitrile (135 mg, 0.61 mmol) was dissolved in tetrahydrofuran (5 mL). Sodium hydroxide (75 mg, 1.88 mmol) and water (3 mL) were added, and the reaction mixture was stirred at room temperature for 10 minutes. Compound 28-12 (200 mg, 0.604 mmol) was added, and 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 x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to obtain compound 28-13. MS-ESI: m / z 471.5 [M+1] + .

[0512] Synthesis of compound 28-14 This was prepared by referring to the synthesis of compound 14-A6. MS-ESI: m / z 329.1 [M+1] + .

[0513] Synthesis of compound 28-15 This compound was prepared by referring to the synthesis of compound 14-A7, under similar conditions except that N,N-diisopropylethylamine was replaced with triethylamine. MS-ESI: m / z 434.5 [M-100+1] + .

[0514] Synthesis of compound 28 This was prepared by referring to the synthesis of compound 14. MS-ESI: m / z 434.2 [M+1]+ . 1 H NMR (400 MHz, CD3OD) δ 7.83 (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).

[0515] (Example 29) (2S)-N-(1-cyano-2-(2-fluoro-8-(methylsulfonyl)-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0516] [ka]

[0517] Synthesis of compound 29-2 At room temperature, under a nitrogen atmosphere, 2-bromo-5-hydroxybenzaldehyde (compound 29-1) (13 g, 64.67 mmol) was dissolved in N,N-dimethylformamide (50 mL). At 0°C, sodium hydride (1.63 g, 67.90 mmol, 60%) was added in batches, and the mixture was stirred at 0°C for 10 minutes. Bromomethylmethyl ether (8.49 g, 67.90 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, water (100 mL) was added, and the reaction mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 29-2. 1H NMR (300 MHz, CDCl3) δ 10.31 (s, 1H), 7.60-7.51 (m, 2H), 7.15 (dd, 1H), 5.20 (s, 2H), 3.47 (s, 3H).

[0518] Synthesis of compound 29-3 At room temperature, compound 29-2 (9.60 g, 39.17 mmol) was dissolved in a mixed solvent of water (10 mL) and methanol (100 mL). At 0°C, sodium borohydride (2.22 g, 58.76 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, ethyl acetate (20 mL) was added, and the reaction mixture was concentrated under reduced pressure. Water (30 mL) was added to the resulting residue, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 29-3. 1 H NMR (300 MHz, CDCl3) δ 7.43 (d, 1H), 7.19(d, 1H), 6.86 (dd, 1H), 5.17 (s, 2H), 4.71 (s, 2H), 3.47 (s, 3H).

[0519] Synthesis of compound 29-4 This was prepared by referring to the synthesis of compound 18-3. 1 H NMR (300 MHz, CDCl3) δ 7.54-7.50 (m, 1H), 7.47(d, 1H), 7.23 (d, 1H), 7.18-7.01 (m, 2H), 6.86 (dd, 1H), 5.15 (s, 2H), 5.07 (s, 2H), 3.94 (s, 3H), 3.46 (s, 3H).

[0520] Synthesis of compound 29-5 This was prepared by referring to the synthesis of compound 18-4. MS-ESI: m / z 319.2 [M+1] + .

[0521] Synthesis of compound 29-6 At room temperature, compound 29-5 (3.50 g, 11.00 mmol) was dissolved in methanol (20 mL), followed by the addition of 6 M hydrochloric acid (20 mL). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, water (20 mL) was added, and the reaction mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was ground in ethyl acetate (30 mL) to obtain compound 29-6. MS-ESI: m / z 275.1 [M+1] + .

[0522] Synthesis of compound 29-7 At room temperature, compound 29-6 (2.40 g, 8.75 mmol) was dissolved in N,N-dimethylformamide (25 mL), followed by the addition of triethylamine (1.33 g, 13.13 mmol) and N-phenylbis(trifluoromethanesulfonimide) (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, and the reaction mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to obtain compound 29-7. 1 H NMR (300 MHz, CDCl3) δ 7.73 (d, 1H), 7.57 (d, 1H), 7.44 (d, 1H), 7.35-7.26 (m, 1H), 7.14 (d, 1H), 5.14 (s, 2H), 3.94 (s, 3H).

[0523] Synthesis of compound 29-8 At room temperature under a nitrogen atmosphere, compound 29-7 (1.00 g, 2.46 mmol), tris(dibenzylideneacetone)dipalladium (0.20 g, 0.25 mmol), potassium carbonate (0.68 g, 4.92 mmol), and 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (0.28 g, 0.49 mmol) were dissolved in 1,4-dioxane (10 mL), followed by the addition of 4-methoxybenzylthiol (0.42 g, 2.72 mmol). 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, followed by the addition of water (30 mL) and extraction with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 29-8. MS-ESI: m / z 411.3 [M+1] + .

[0524] Synthesis of compound 29-9 At room temperature, compound 29-8 (860 mg, 1.86 mmol) was dissolved in trifluoroacetic acid (9 mL), and the reaction mixture was heated to 70 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. Water (20 mL) was added to the resulting residue, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude intermediate, which was dissolved in N,N-dimethylformamide (6 mL). At 0 °C, sodium hydride (32.23 mg, 1.34 mmol) was added in batches, and the mixture was stirred 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 x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 29-9.1 H NMR (300 MHz, CDCl3) δ 7.98 (d, 1H), 7.83 (d, 1H), 7.79 (s, 1H), 7.58 (d, 1H), 7.52 (d, 1H), 5.20 (s, 2H), 3.95 (s, 3H), 3.10 (s, 3H).

[0525] Synthesis of compound 29-10 At room temperature, compound 29-9 (400 mg, 1.32 mmol) and m-chloroperoxybenzoic acid (22 mg, 0.13 mmol, 85%) were dissolved in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (20 mL) was added, and the reaction mixture was extracted with dichloromethane (25 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 29-10. 1 H NMR (300 MHz, CDCl3) δ 7.98 (d, 1H), 7.83 (d, 1H), 7.79 (s, 1H), 7.58 (d, 1H), 7.52 (d, 1H), 5.20 (s, 2H), 3.95 (s, 3H), 3.10 (s, 3H).

[0526] Synthesis of compound 29-11 This was prepared by referring to the synthesis of compound 14-A3. 1 H NMR (400 MHz, CDCl3) δ 8.10 (d, 1H), 7.91 (dd, 1H), 7.89 (s, 1H), 7.83 (d, 1H), 7.09 (d, 1H), 5.37 (t, 1H), 5.24 (s, 2H), 4.55 (d, 2H), 3.24 (s, 3H).

[0527] Synthesis of compound 29-12 This was prepared by referring to the synthesis of compound 14-A4. 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, 1H), 7.82-7.62 (d, 2H), 7.45 (d, 1H), 7.06 (d, 1H), 5.17 (s, 2H), 4.49 (s, 2H), 3.09 (s, 3H).

[0528] Synthesis of compound 29-13 This was prepared by referring to the synthesis of compound 14-A5. 1 H NMR (300 MHz, CDCl3) δ 7.93 (dd, 1H), 7.76-7.71 (m, 2H), 7.65-7.59 (m, 2H), 7.50-7.42 (m, 4H), 7.38-7.32 (m, 3H), 7.09-6.99 (m, 2H), 6.91 (d, 1H), 5.12 (s, 2H), 4.54 (t, 1H), 3.36-3.15 (m, 2H), 3.08 (s, 3H).

[0529] Synthesis of compound 29-14 This was prepared by referring to the synthesis of compound 14-A6.

[0530] Synthesis of compound 29-15 This was prepared by referring to the synthesis of compound 14-A7.

[0531] Synthesis of compound 29 This was prepared by referring to the synthesis of compound 14. MS-ESI: m / z 474.2 [M+1] + . 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 7.99-7.89 (m, 2H), 7.82 (s, 1H), 7.66 (d, 1H), 6.97 (d, 1H), 5.17 (s, 2H), 5.16-5.03 (m, 1H), 4.23-4.10 (m, 1H), 4.07-3.94 (m, 1H), 3.81-3.71 (m, 1H), 3.45-3.38 (m, 0.5H), 3.32-3.28 (m, 0.5H), 3.27-3.14 (m, 2H), 3.13 (s, 3H), 3.09-2.95 (m, 2H), 2.95-2.87 (m, 0.5H), 2.80-2.73 (m, 0.5H), 2.03-1.83 (m, 2H).

[0532] (Example 30) (S)-N-((S)-1-cyano-2-(2-fluoro-8-(methylsulfonyl)-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0533] [ka]

[0534] Synthesis of compound 30-1 Tert-butyl(2S)-2-((1-cyano-2-(2-fluoro-8-(methylsulfonyl)-6H-benzo[c]chromen-3-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (compound 29-15) (100 mg, 0.17 mmol) was subjected to chiral resolution (column: chiralpak IA, 250 × 25 mm, 5 μm; mobile phase: supercritical carbon dioxide, isopropanol; gradient: carbon dioxide phase 70%; flow rate: 60 mL / min, column temperature: 30 °C) to obtain compound 30-1 (a total of two diastereomer peaks, with compound 30-1 being the first elution peak).

[0535] Synthesis of compound 30 This was prepared by referring to the synthesis of compound 14. MS-ESI: m / z 474.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (d, 1H), 8.15-8.09 (m, 1H), 7.96-7.85 (m, 3H), 7.04 (d, 1H), 5.29-5.17 (m, 2H), 5.12-5.02 (m, 1H), 4.03-3.96 (m, 1H), 3.90-3.81 (m, 1H), 3.78-3.68 (m, 1H), 3.25 (s, 3H), 3.23-3.13 (m, 2H), 3.07-2.98 (m, 1H), 2.82-2.72 (m, 1H), 2.65-2.53 (m, 2H), 1.82-1.64 (m, 2H).

[0536] (Example 31)

[0537] [ka]

[0538] (2S)-N-(1-cyano-2-(9-cyano-2-fluoro-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0539] [ka]

[0540] Synthesis of compound 31-1 At room temperature, crude (2-bromo-4-(methoxymethoxy)phenyl)methanol (compound 28-3) (3.00 g, 12.14 mmol) and triethylamine (3.00 g, 29.65 mmol) were dissolved in dichloromethane (60 mL). Methanesulfonyl chloride (2.00 g, 1.35 mL, 17.46 mmol) was added dropwise, and 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 x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude intermediate.

[0541] 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 obtained 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 x 3). The organic phases were combined, washed with water (100 mL x 3), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 8 / 1) to obtain compound 31-1. 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, 1H), 7.49 (d, 1H), 7.38 (s, 1H), 7.22-7.07 (m, 3H), 5.29 (s, 2H), 5.14 (s, 2H), 4.00 (s, 3H), 3.57 (s, 3H).

[0542] Synthesis of compound 31-2 At room temperature, under a nitrogen atmosphere, 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), followed by the addition of potassium carbonate (0.50 g, 3.62 mmol) and tricyclohexylphosphine tetrafluoroborate (0.30 g, 0.63 mmol). 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 x 3). The organic phases were combined, washed with water (20 mL x 3), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 31-2. 1 H NMR (400 MHz, CDCl3) δ 7.56 (d, 1H), 7.46 (d, 1H), 7.36 (s, 1H), 7.18-7.08 (m, 2H), 5.27 (s, 2H), 5.12 (s, 2H), 3.97 (s, 3H), 3.55(s, 3H).

[0543] Synthesis of compound 31-3 At room temperature, compound 31-2 (5 g, 15.71 mmol) was dissolved in tetrahydrofuran (30 mL), 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, and the reaction mixture was separated into two phases. The organic phase was washed with saturated sodium bicarbonate aqueous solution (30 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was ground in ethyl acetate (20 mL) to obtain compound 31-3. 1 H NMR (400 MHz, DMSO-d6) δ 7.74 (d, 1H), 7.36 (d, 1H), 7.25 (s, 1H), 7.14 (d, 1H), 6.85 (dd, 1H), 5.07 (s, 2H), 3.85 (s, 3H).

[0544] Synthesis of Compound 31-4 Compound 31-3 (1.20 g, 3.94 mmol) and triethylamine (0.80 g, 7.88 mmol) were dissolved in N,N-dimethylformamide (10 mL), followed by the addition of N-phenylbis(trifluoromethanesulfonimide) (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, and the reaction mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 31-4. 1 H NMR (300 MHz, DMSO-d6) δ 8.26-8.21 (m, 1H), 8.12 (d, 1H), 7.64-7.52 (m, 2H), 7.48-7.42 (m, 1H), 5.28 (s, 2H), 3.90 (s, 3H).

[0545] Synthesis of Compound 31-5 At room temperature, under a nitrogen atmosphere, compound 31-4 (1.80 g, 3.54 mmol), zinc cyanide (0.62 g, 5.32 mmol), and tetrakis(triphenylphosphine)palladium (0.61 g, 0.53 mmol) were dissolved in N,N-dimethylformamide (20 mL). The reaction mixture was heated to 90 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, followed by the addition of water (100 mL), and extraction with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 31-5. 1 1H NMR (300 MHz, DMSO-d6) 1H NMR (300 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.09-8.05 (m, 1H), 7.91-7.89 (m, 1H), 7.56-7.53 (m, 1H), 7.42-7.40 (m, 1H), 5.28 (s, 2H), 3.86 (s, 3H).

[0546] Synthesis of Compound 31-6 This compound was prepared by referring to the synthesis of compound 14-A3, except that tetrahydrofuran was replaced with a mixed solvent of tetrahydrofuran and methanol (volume ratio 10 / 1). 1 H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.92-7.82 (m, 2H), 7.55-7.50 (m, 1H), 7.12-7.07 (m, 1H), 5.39 (s, 2H), 4.59-4.54 (m, 2H).

[0547] Synthesis of Compound 31-7 This was prepared by referring to the synthesis of compound 18-7. 1 H NMR (300 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.01-7.96 (m, 1H), 7.90-7.85 (m, 1H), 7.57-7.52 (m, 1H), 7.27-7.21 (m, 1H), 5.26 (s, 2H), 4.71 (s, 2H).

[0548] Synthesis of Compound 31-8 This was prepared by referring to the synthesis of compound 14-A5. MS-ESI: m / z 458.1 [M+1] + .

[0549] Synthesis of Compound 31-9 This was prepared by referring to the synthesis of compound 14-A6. MS-ESI: m / z 294.0 [M+1] + .

[0550] Synthesis of compound 31-10 This was prepared by referring to the synthesis of compound 14-A7. MS-ESI: m / z 538.2 [M+18] + .

[0551] Synthesis of compound 31 This was prepared by referring to the synthesis of compound 14. MS-ESI: m / z 421.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.72-8.63 (m, 1H), 8.39 (s, 1H), 7.94-7.87 (m, 1H), 7.85-7.79 (m, 1H), 7.53-7.47 (m, 1H), 7.05-7.00 (m, 1H), 5.26-5.15 (m, 2H), 5.10-4.93 (m, 1H), 4.02-3.81 (m, 2H), 3.77-3.65 (m, 1H), 3.27-2.98 (m, 3H), 2.84-2.52 (m, 3H), 1.82-1.64 (m, 2H).

[0552] (Example 32) (S)-N-((S)-1-cyano-2-(9-cyano-2-fluoro-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0553] [ka]

[0554] Synthesis of compound 32-1 Tert-butyl(2S)-2-((1-cyano-2-(9-cyano-2-fluoro-6H-benzo[c]chromen-3-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (compound 31-10) (350 mg, 0.67 mmol) was subjected to chiral resolution (column: chiralpak IC, 250 × 30 mm, 5 μm; mobile phase: n-hexane, ethanol; gradient: 30% n-hexane phase; flow rate: 25 mL / min, column temperature: 30 °C) to obtain compound 32-1 (a total of two diastereomer peaks, with compound 32-1 being the second elution peak).

[0555] Synthesis of compound 32 This was prepared by referring to the synthesis of compound 14. MS-ESI: m / z 421.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (d, 1H), 8.39 (s, 1H), 7.91 (d, 1H), 7.82 (d, 1H), 7.50 (d, 1H), 7.02 (d, 1H), 5.26-5.14 (m, 2H), 5.10-5.00 (m, 1H), 4.02-3.95 (m, 1H), 3.89-3.82 (m, 1H), 3.77-3.69 (m, 1H), 3.28-3.12 (m, 2H), 3.05-2.98 (m, 1H), 2.81-2.72 (m, 1H), 2.63-2.51 (m, 2H), 1.81-1.64 (m, 2H).

[0556] (Example 33) (2S)-N-(1-cyano-2-(3-cyano-9-fluoro-5H-chromeno[4,3-b]pyridine-8-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0557] [ka]

[0558] Synthesis of compound 33-2 At room temperature, 2-fluoro-5-hydroxybenzoic acid (compound 33-1) (25.00 g, 146.93 mmol) was dissolved in chloroform (300 mL). At 0°C, a solution of bromine (76.70 g, 480.00 mmol) in acetic acid (300 mL) was slowly added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. At 0°C, saturated sodium thiosulfate aqueous solution (300 mL) was slowly added, and the reaction mixture was stirred for 15 minutes to separate it into two phases. The aqueous phase was extracted with ethyl acetate (300 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was ground in dichloromethane (50 mL) to obtain compound 33-2. 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.56 (d, 1H), 7.40 (d, 1H).

[0559] Synthesis of compound 33-3 At room temperature, compound 33-2 (22.60 g, 84.60 mmol) was dissolved in methanol (100 mL). Thionyl chloride (20.10 g, 177.36 mmol) was slowly added dropwise, and 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 resulting residue was diluted with ethyl acetate (150 mL), washed sequentially with water (50 mL) and saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 33-3. 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, 1H), 7.32 (d, 1H), 3.94 (s, 3H).

[0560] Synthesis of compound 33-4 At room temperature, 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). 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 x 4). The organic phases were combined and washed sequentially with water (200 mL) and saturated sodium chloride aqueous solution (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 33-4. 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, 1H), 7.42-7.37 (m, 3H), 6.96-6.92 (m, 2H), 5.09 (s, 2H), 3.94 (s, 3H), 3.83 (s, 3H).

[0561] Synthesis of compound 33-5 At room temperature under a nitrogen atmosphere, compound 33-4 (24.30 g, 45.40 mmol), bis(pinacolato)diborone (13.80 g, 54.34 mmol), potassium acetate (8.91 g, 90.78 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (3.32 g, 4.54 mmol) were dissolved in dioxane (100 mL). 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 x 3). The organic phases were combined, washed sequentially with water (100 mL) and saturated sodium chloride aqueous solution (80 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 33-5. MS-ESI: m / z 439.2 [M+23] + . 1H NMR (400 MHz, CDCl3) δ 7.53-7.40 (m, 4H), 6.91 (d, 2H), 5.06 (s, 2H), 3.94 (s, 3H), 3.83 (s, 3H), 1.36 (s, 12H).

[0562] Synthesis of compound 33-6 At room temperature under a nitrogen atmosphere, compound 33-5 (16.50 g, 31.70 mmol), 2,5-dibromopyridine-3-ylmethanol (10.80 g, 38.00 mmol), 1,1'-bis(diphenylphosphin)ferrocenepalladium(II) dichloride (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 x 3). The organic phases were combined, washed sequentially with water (200 mL) and saturated sodium chloride aqueous solution (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 33-6. MS-ESI: m / z 476.1 [M+1] + .

[0563] Synthesis of compound 33-7 At room temperature, compound 33-6 (6.80 g, 9.56 mmol) was dissolved in dichloromethane (10 mL), 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 resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 33-7. MS-ESI: m / z 355.9 [M+1] + . 1H NMR (400 MHz, CDCl3) δ 8.63 (d, 1H), 8.31 (d, 1H), 7.58 (d, 1H), 7.33 (d, 1H), 4.83 (s, 2H), 3.96 (s, 3H).

[0564] Synthesis of compound 33-8 At room temperature under a nitrogen atmosphere, compound 33-7 (3.70 g, 10.10 mmol) was dissolved in tetrahydrofuran (100 mL). Triphenylphosphine (3.45 g, 13.15 mmol) was added, and the mixture was stirred at 0°C for 30 minutes. Diisopropyl azodicarboxylic acid (2.66 g, 13.15 mmol) was slowly added dropwise, and 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 x 3). The organic phases were combined, washed sequentially with water (80 mL) and saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 33-8. MS-ESI: m / z 338.0 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.93 (d, 1H), 7.63 (s, 1H), 7.51 (d, 1H), 5.22 (s, 2H), 3.94 (s, 3H).

[0565] Synthesis of compound 33-9 At room temperature, compound 33-8 (2.60 g, 7.68 mmol) and cuprous cyanide (2.06 g, 23.00 mmol) were dissolved in N-methylpyrrolidone (20 mL). 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 x 3). The organic phases were combined and washed sequentially with water (30 mL) and saturated sodium chloride aqueous solution (30 mL). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, dichloromethane) to obtain compound 33-9. MS-ESI: m / z 285.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (d, 1H), 8.31-8.27 (m, 1H), 7.95 (d, 1H), 7.45 (d, 1H), 5.40 (s, 2H), 3.87 (s, 3H).

[0566] Synthesis of compound 33-10 This compound was prepared by referring to the synthesis of compound 14-A3, under similar conditions except that the temperature was changed to room temperature. MS-ESI: m / z 257.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (d, 1H), 8.22 (d, 1H), 7.77 (d, 1H), 7.11 (d, 1H), 5.45 (t, 1H), 5.33 (s, 2H), 4.57 (d, 2H).

[0567] Synthesis of compound 33-11 This compound was prepared by referring to the synthesis of compound 18-7, under similar conditions except that the temperature was changed to 0°C. MS-ESI: m / z 319.0 [M+1] + .

[0568] Synthesis of compound 33-12 At room temperature, N-(diphenylmethylene)aminoacetonitrile (221 mg, 1.00 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the slow addition of sodium hydride (20 mg, 0.50 mmol, 60%) at 0°C. After stirring at 0°C for 30 minutes, compound 33-11 (90 mg, 0.25 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The pH was adjusted to 2 by adding 1 M hydrochloric acid, and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with 1 M hydrochloric acid (10 mL) and washed with ethyl acetate (20 mL x 3). The aqueous phase was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed sequentially with water (20 mL) and saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 33-12. MS-ESI: m / z 295.0 [M+1] + .

[0569] Synthesis of compound 33-13 This compound was prepared by referring to the synthesis of compound 14-A7, except that N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate was replaced with O-benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate. MS-ESI: m / z 422.1 [M-100+1] + .

[0570] Synthesis of compound 33 This was prepared by referring to the synthesis of compound 14. MS-ESI: m / z 422.1 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, 1H), 8.67 (dd, 1H), 8.22 (s, 1H), 7.80 (dd, 1H), 7.07 (d, 1H), 5.39-5.27 (m, 2H), 5.12-4.96 (m, 1H), 4.00-3.90 (m, 1H), 3.89-3.81 (m, 1H), 3.77-3.66 (m, 1H), 3.27-3.17 (m, 2H), 3.14-2.98 (m, 1H), 2.84-2.66 (m, 2H), 2.64-2.54 (m, 1H), 1.82-1.63 (m, 2H).

[0571] (Example 34) 4-amino-N-(1-cyano-2-(9-(pyrrolidine-3-yl)-6H-benzo[c]chromen-3-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0572] [ka]

[0573] Synthesis of compound 34-3 At room temperature, under a nitrogen atmosphere, compound 34-1 (900 mg, 3.05 mmol) and compound 34-2 (957 mg, 3.24 mmol) were dissolved in a mixed solvent of toluene (50 mL) and water (5 mL). Subsequently, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (100 mg, 0.12 mmol) and potassium acetate (1.00 g, 10.19 mmol) were added. The reaction 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 x 3). The organic phases were combined, washed with water (10 mL x 3), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain compound 34-3. 1H NMR (300 MHz, CDCl3) δ 7.86-7.69 (m, 4H),7.43-7.37 (m, 1H), 7.21 (d, 1H), 6.27 (d, 1H), 5.20 (s, 2H), 4.66-4.52 (m, 2H), 4.50-4.32 (m, 4H), 1.59-1.50 (m, 9H), 1.45 (t, 3H).

[0574] Synthesis of compound 34-4 At room temperature, compound 34-3 (350 mg, 0.830 mmol) and palladium carbon (100 mg, 10%) were dissolved in methanol (20 mL). The reaction mixture was heated to 50°C in a hydrogen atmosphere (balloon) and stirred for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 34-4, which was used directly in the next step. 1 H NMR (300 MHz, CDCl3) δ 7.85-7.74 (m, 2H), 7.66 (d, 2H), 7.27-7.16 (m, 2H), 5.16 (s, 2H), 4.41 (q, 2H), 3.97-3.80 (m, 1H), 3.76-3.58 (m, 1H), 3.57-3.25 (m, 3H), 2.41-2.25 (m, 1H), 2.14-1.98 (m, 1H), 1.52 (s, 9H), 1.44(t, 3H).

[0575] Synthesis of Compound 34-5 This compound was prepared by referring to the synthesis of compound 14-A3, under the same conditions except that the temperature was changed from 55°C to room temperature. 1 H NMR (300 MHz, CDCl3) δ 7.76-7.69 (m, 1H),7.58 (s, 1H), 7.24-7.01 (m, 4H), 5.18 (s, 2H), 4.52 (s, 2H), 4.00-3.78 (m, 1H), 3.75-3.55 (m, 1H), 3.53-3.28 (m, 3H), 2.41-2.25 (m, 1H), 2.17-2.00 (m, 1H), 1.45 (s, 9H).

[0576] Synthesis of compound 34-6 This was prepared by referring to the synthesis of compound 18-7. 1 H NMR (400 MHz, CDCl3) δ 7.91-7.83 (m, 1H), 7.82-7.74 (m, 1H), 7.67-7.51 (m, 2H), 7.23-7.10 (m, 1H), 7.08-6.96 (m, 1H), 5.15 (s, 2H), 3.97-3.81 (m, 1H), 3.79-3.59 (m, 1H), 3.56-3.31 (m, 3H), 3.07 (d, 2H), 2.42-2.26 (m, 1H), 2.14-2.01 (m, 1H), 1.54 (s, 9H).

[0577] Synthesis of compound 34-7 This was prepared by referring to the synthesis of compounds 14-A5, 14-A6, and 14-A7. MS-ESI: m / z 491.2 [M-100-56+1] + .

[0578] Synthesis of compound 34 This was prepared by referring to the synthesis of compound 14. MS-ESI: m / z 447.3 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (d, 1H),7.73 (s, 1H), 7.25-7.18 (m, 2H), 6.99 (d, 1H), 6.91 (s, 1H), 5.07 (s, 2H), 4.98 (t, 1H), 3.78-3.69 (m, 1H), 3.64-3.55 (m, 3H), 3.54-3.40 (m, 3H), 3.30-3.20 (m, 2H), 3.15-3.10 (m, 2H), 2.27-2.17 (m, 1H), 2.08-1.97 (m, 1H), 1.94-1.83 (m, 1H), 1.78-1.68 (m, 1H), 1.25-1.08 (m, 2H).

[0579] (Example 35) (2S)-N-(2-(8-(azetidine-1-ylsulfonyl)-2-fluoro-6H-benzo[c]chromen-3-yl)-1-cyanoethyl)-1,4-oxazepan-2-carboxamide

[0580] [ka]

[0581] Synthesis of compound 35-1 This compound was prepared by referring to the synthesis of compound 29-8, under similar conditions except that the reaction temperature was changed from 70°C to 80°C. MS-ESI: m / z 437.1 [M+1] + .

[0582] Synthesis of compound 35-2 At room temperature, compound 35-1 (300 mg, 0.69 mmol) and acetic acid (0.5 mL) were dissolved in tetrahydrofuran (5 mL), followed by the addition of water (0.5 mL) and 1,3-dichloro-5,5-dimethylhydantoin (300 mg, 1.52 mmol) at 0°C. 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 x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude intermediate, which was dissolved in dichloromethane (5 mL). Azethidine (50 mg, 0.88 mmol) and triethylamine (170 mg, 1.68 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 (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, dichloromethane / methanol = 24 / 1) to obtain compound 35-2. MS-ESI: m / z 378.2 [M+1] + .

[0583] Synthesis of compound 35-3 This compound was prepared by referring to the synthesis of compound 12-4, under similar conditions except that the temperature was changed from 0°C to room temperature. MS-ESI: m / z 350.2 [M+1] + .

[0584] Synthesis of compound 35-4 This was prepared by referring to the synthesis of compound 14-A4. 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, 1H), 7.76-7.67 (m, 2H), 7.43 (d, 1H), 7.06 (d, 1H), 5.15 (s, 2H), 4.49 (s, 2H), 3.48-3.41 (m, 2H), 3.23-3.14 (m, 2H), 2.12-2.05 (m, 2H).

[0585] Synthesis of compound 35-5 N-(diphenylmethylene)aminoacetonitrile (90 mg, 0.49 mmol) was dissolved in tetrahydrofuran (5 mL). Sodium hydroxide (45 mg, 1.13 mmol) and water (2 mL) were added, and the reaction mixture was stirred at room temperature for 10 minutes. Compound 35-4 (150 mg, 0.36 mmol) was added, and 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 x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to obtain compound 35-5. MS-ESI: m / z 552.4 [M+1] + .

[0586] Synthesis of Compound 35-6 This was prepared by referring to the synthesis of compound 14-A6.

[0587] Synthesis of compound 35-7 This compound was prepared by referring to the synthesis of compound 14-A7, under similar conditions except that N,N-diisopropylethylamine was replaced with triethylamine. MS-ESI: m / z 515.4 [M-100+1] + .

[0588] Synthesis of Compound 35 This was prepared by referring to the synthesis of compound 14. MS-ESI: m / z 515.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.72-8.65 (m, 1H), 8.17-8.11 (m, 1H), 7.93-7.86 (m, 1H), 7.81-7.76 (m, 2H), 7.05 (d, 1H), 5.33-5.20 (m, 2H), 5.12-4.94 (m, 1H), 4.03-3.81 (m, 2H), 3.78-3.67 (m, 5H), 3.30-3.00 (m, 3H), 2.86-2.51 (m, 3H), 2.06-1.96 (m, 2H), 1.83-1.65 (m, 2H).

[0589] (Example 36) 4-amino-N-(1-cyano-2-(9-fluoro-6,7-dihydrodibenzo[b,d]oxepin-3-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0590] [ka]

[0591] Synthesis of compound 36-1 At room temperature, compound 11-1 (3.00 g, 12.99 mmol) was dissolved in tetrahydrofuran (25 mL). 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 minutes. Bromomethylmethyl ether (3.25 g, 25.97 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, water (100 mL) was added to quench the reaction, and the resulting solution was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1) to obtain compound 36-1. MS-ESI: m / z 274.9 [M+1] + .

[0592] Synthesis of compound 36-2 At room temperature under a nitrogen atmosphere, compound 36-1 (5.40 g, 19.63 mmol), bis(pinacolato)diborone (6.98 g, 27.48 mmol), potassium acetate (3.85 g, 39.26 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (1.44 g, 1.96 mmol) were dissolved in dioxane (50 mL). The reaction mixture was heated to 90 °C and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, followed by the addition of water (100 mL), and extraction with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain compound 36-2. MS-ESI: m / z 323.1 [M+1] + .

[0593] Synthesis of compound 36-3 At room temperature, 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). The reaction mixture was heated to 35°C and stirred for 3 hours. After the reaction was complete, water (100 mL) was added, and the reaction mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1) to obtain compound 36-3. 1 H NMR (400 MHz, CDCl3): δ 7.59-7.55 (m, 1H), 7.32-7.26 (m, 1H), 7.00-6.95 (m, 1H), 3.83 (s, 2H).

[0594] Synthesis of compound 36-4 At room temperature, compound 36-3 (3.60 g, 15.98 mmol) was dissolved in an 8 M solution of hydrogen chloride in methanol (20 mL). 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 concentrated under reduced pressure to remove the solvent. The resulting residue was adjusted to pH=7 with saturated sodium bicarbonate aqueous solution (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent and obtain crude compound 36-4. 1 H NMR (400 MHz, CDCl3): δ 7.54-7.50 (m, 1H), 7.06-7.03 (m, 1H), 6.91-6.86 (m, 1H), 3.77 (s, 2H), 3.73 (s, 3H).

[0595] Synthesis of compound 36-5 At room temperature, compound 36-4 (3 g, 10.93 mmol) was dissolved in tetrahydrofuran (30 mL). Lithium aluminum hydride (0.41 g, 10.93 mmol) was added at 0°C. The reaction solution was stirred at 0°C for 20 minutes. After the reaction was complete, water (100 mL) was added, and the reaction mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain compound 36-5. 1 H NMR (400 MHz, CDCl3): δ 7.57-7.52 (m, 1H), 7.09-7.05 (m, 1H), 6.91-6.85 (m, 1H), 3.93 (t, 2H), 3.04 (t, 2H).

[0596] Synthesis of compound 36-6 At room temperature, under a nitrogen atmosphere, compound 36-5 (2.40 g, 10.41 mmol), compound 36-2 (4.01 g, 11.45 mmol), 1,1-bis(diphenylphosphin)ferrocenepalladium(II) 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). 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, followed by the addition of water (100 mL), and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain 36-6. 1H NMR (300 MHz, CDCl3): δ 7.88 (s, 1H), 7.82-7.78 (m, 1H), 7.25 (d, 1H), 7.20-7.10 (m, 2H), 7.08-6.97 (m, 1H), 5.21-5.13 (m, 2H), 3.99 (s, 3H), 3.75-3.67 (m, 2H), 3.38 (s, 3H), 2.79-2.74 (m, 2H).

[0597] Synthesis of Compound 36-7 At room temperature, compound 36-6 (3.20 g, 8.61 mmol) was dissolved in 30 mL of an 8 M solution of hydrogen chloride in methanol, and the reaction mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The resulting residue was adjusted to pH=7 with 50 mL of saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 36-7, which was used directly in the next step. MS-ESI: m / z 289.0 [M-1] - .

[0598] Synthesis of compound 36-8 At room temperature, compound 36-7 (2.60 mg, 8.15 mmol) and triphenylphosphine (2.99 g, 11.41 mmol) were dissolved in tetrahydrofuran (150 mL). Diisopropyl azodicarboxylate (2.05 g, 9.781 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 12 hours. Water (200 mL) was added, and the reaction mixture was extracted with ethyl acetate (200 mL x 2), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1) to obtain compound 36-8. MS-ESI: m / z 273.1 [M+1] + .

[0599] Synthesis of compound 36-9 This was prepared by referring to the synthesis of compound 12-4.1 H NMR (300 MHz, CDCl3) δ7.44-7.32 (m, 2H), 7.25-7.16 (m, 2H), 7.12-6.98 (m, 2H), 4.73 (s,2H), 4.57 (t, 2H), 2.79 (t, 2H).

[0600] Synthesis of compound 36-10 This was prepared by referring to the synthesis of compound 14-A4. 1 H NMR (300 MHz, CDCl3) δ7.47-7.36 (m, 2H), 7.35-7.28 (m, 1H), 7.25-7.20 (m, 1H), 7.17-7.03 (m, 2H), 4.62 (t, 2H), 4.56 (s, 2H), 2.85 (t, 2H).

[0601] Synthesis of compound 36-11 This was prepared by referring to the synthesis of compound 14-A5. MS-ESI: m / z 447.1 [M+1] + .

[0602] Synthesis of compound 36-12 This was prepared by referring to the synthesis of compound 14-A6. MS-ESI: m / z 283.1 [M+1] + .

[0603] Synthesis of compound 36-13 This compound was prepared by referring to the synthesis of compound 14-A7, except that (S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-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] + .

[0604] Synthesis of Compound 36 This was prepared by referring to the synthesis of compound 14. MS-ESI: m / z 410.3 [M+1] + . 1H NMR (400 MHz, CDCl3) δ 8.23 ​​(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).

[0605] (Example 37) 4-amino-N-(1-cyano-2-(9-fluoro-5,7-dihydrodibenzo[c,e]oxepin-3-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0606] [ka]

[0607] Synthesis of compound 37-2 At room temperature, ethyl 4-hydroxybenzoate (compound 37-1) (3.00 g, 18.05 mmol) and triethylamine (15.1 mL, 108.32 mmol) were dissolved in 1,2-dichloroethane (100 mL). Anhydrous magnesium chloride (8.59 g, 90.27 mmol) was added, and the reaction mixture was heated to 40°C and stirred for 1 hour. Paraformaldehyde (6.2 mL, 180.53 mmol) was added, and the reaction mixture was heated to 80°C and stirred for 15 hours. The reaction mixture was cooled to room temperature, followed by the addition of water (100 mL) and concentrated hydrochloric acid (5 mL), and extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain product 37-2 as a white solid. 1H NMR (300 MHz, CDCl3) δ 11.39 (s, 1H), 9.96 (s, 1H), 8.35-8.30 (m, 1H), 8.24-8.17 (m, 1H), 7.04 (q, 1H), 4.39 (q, 2H), 1.41 (t, 3H).

[0608] Synthesis of compound 37-3 At room temperature, compound 37-2 (2.00 g, 10.30 mmol) and triethylamine (4.3 mL, 30.9 mmol) were dissolved in dichloromethane (30 mL), followed by the addition of N-phenylbis(trifluoromethanesulfonimide) (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 x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 37-3. 1 H NMR (300 MHz, CDCl3) δ 10.29 (s, 1H), 8.68-8.63 (d, 1H), 8.43-8.35 (m, 1H), 7.54-7.47 (m, 1H), 4.44 (q, 2H), 1.43 (t, 3H).

[0609] Synthesis of compound 37-4 This was prepared by referring to the synthesis of compound 36-6. 1 H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 9.75 (d, 1H), 8.68 (d, 1H), 8.36-8.30 (m, 1H), 7.78-7.71 (m, 1H), 7.45-7.37 (m, 2H), 7.35-7.30 (m, 1H), 4.46 (q, 2H), 1.45 (t, 3H).

[0610] Synthesis of compound 37-5 At room temperature, compound 37-4 (2.20 g, 7.33 mmol) was dissolved in a mixed solvent of tetrahydrofuran (20 mL) and ethanol (10 mL), followed by the addition of sodium borohydride (0.28 g, 7.33 mmol) in batches at 0°C. The reaction mixture was stirred at 0°C for 20 minutes. After the reaction was complete, the reaction mixture was poured into water (20 mL), the pH was adjusted to 6 with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 8 / 1) to obtain compound 37-5. 1 H NMR (400 MHz, CDCl3) δ 8.18 (d, 1H), 8.05-7.98 (m, 1H), 7.30-7.26 (m, 1H), 7.25-7.20 (m, 1H), 7.10-7.01 (m, 2H), 4.46-4.37 (m, 4H), 4.33-4.28 (m, 2H), 1.42 (t, 3H).

[0611] Synthesis of compound 37-6 At room temperature, compound 37-5 (2.15 g, 7.07 mmol) was dissolved in phosphoric acid (30 mL), and the reaction mixture was heated to 150 °C and stirred for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature, followed by the addition of water (100 mL), and extraction with ethyl acetate (25 mL x 3). The organic phases were combined, washed with water (10 mL x 2) and saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 37-6. 1 H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 8.12-8.06 (m, 2H), 7.76-7.68 (m, 2H), 7.51-7.40 (m, 1H), 4.33 (s, 2H), 4.26 (s, 2H).

[0612] Synthesis of compound 37-7 At 0°C, compound 37-6 (1.60 g, 6.20 mmol) was dissolved in tetrahydrofuran (40 mL). A solution of borane in tetrahydrofuran (9.29 mL, 9.29 mmol, 1.0 mol / L) was added dropwise, and the reaction mixture was heated to 50°C and stirred for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. Water (30 mL) was added to the resulting residue, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to obtain compound 37-7. MS-ESI: m / z 226.9 [M-18+1] + .

[0613] Synthesis of Compound 37-8 At room temperature, compound 37-7 (1.50 g, 6.14 mmol) was dissolved in chloroform (10 mL). Phosphorus tribromide (0.7 mL, 7.37 mmol) was added dropwise, and 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 resulting residue, and the mixture was adjusted to pH=7 with saturated sodium carbonate aqueous solution and extracted with a mixed solvent of petroleum ether and ethyl acetate (5 / 1, 25 mL x 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 37-8, which was used directly in the next step. 1 H NMR (300 MHz, CDCl3) δ 7.57-7.44 (m, 4H), 7.25-7.12 (m, 2H), 4.57 (s, 2H), 4.35 (s, 2H), 4.32 (s, 2H).

[0614] Synthesis of compound 37-9 This compound was prepared by referring to the synthesis of compound 14-A5, under similar conditions except that the temperature was changed from 35°C to room temperature. MS-ESI: m / z 447.3 [M+1] + .

[0615] Synthesis of compound 37-10 This was prepared by referring to the synthesis of compound 14-A6.

[0616] Synthesis of compound 37-11 This was prepared by referring to the synthesis of compound 14-A7, except that (S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2-carboxylic acid was replaced with 4-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylic acid. 1 H NMR (300 MHz, CDCl3) δ 7.54-7.46 (m, 2H), 7.46-7.41 (m, 1H), 7.35-7.27 (m, 1H), 7.24-7.13 (m, 2H), 5.20-5.09 (m, 1H), 4.37-4.29 (m, 4H), 3.84-3.61 (m, 4H), 3.17-3.15 (m, 2H), 2.28-2.17 (m, 2H), 2.05-1.80 (m, 2H), 1.44 (s, 9H).

[0617] Synthesis of Compound 37 This was prepared by referring to the synthesis of compound 14. MS-ESI: m / z 410.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.65-7.60 (m, 1H), 7.56-7.52 (m, 1H), 7.49-7.44 (m, 1H), 7.44-7.34 (m, 3H), 5.08-5.01 (m, 1H), 4.27-4.16 (m, 4H), 3.66-3.52 (m, 3H), 3.49-3.40 (m, 1H), 3.26-3.20 (m, 2H), 1.93-1.83 (m, 1H), 1.76-1.66 (m, 1H), 1.22-1.08 (m, 2H).

[0618] (Examples 38A and 38B) 38A: (S)-N-((S)-1-cyano-2-(2,8-difluoro-9-(oxetan-3-yl)-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepan-2-carboxamide 38B: (S)-N-((R)-1-cyano-2-(2,8-difluoro-9-(oxetan-3-yl)-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepan-2-carboxamide

[0619] [ka]

[0620] Synthesis of compound 38-2 At room temperature, 2-bromo-4,5-difluorobenzoic acid (compound 38-1) (15 g, 63.29 mmol) was dissolved in methanol (150 mL), followed by the addition of concentrated sulfuric acid (1.24 g, 12.66 mmol). The reaction mixture was heated to 80°C 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 resulting residue, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 38-2. 1 H NMR (300 MHz, CDCl3) δ 7.81-7.74 (m, 1H), 7.58-7.52 (m, 1H), 3.97 (s, 3H).

[0621] Synthesis of compound 38-3 At room temperature, benzyl alcohol (6.82 mL, 63.10 mmol) was dissolved in tetrahydrofuran (100 mL), followed by batch addition of sodium hydride (2.52 g, 63.10 mmol, 60%). The reaction mixture was stirred at room temperature for 10 minutes, then at 80°C for 2 hours. At 0°C, a solution of compound 38-2 (16 g, 57.36 mmol) in tetrahydrofuran (100 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 9 / 1) to obtain compound 38-3. 1 H NMR (300 MHz, CDCl3) δ 7.77-7.70 (m, 1H), 7.49-7.38 (m, 5H), 7.36-7.30 (m, 1H), 5.22 (s, 2H), 3.95 (s, 3H).

[0622] Synthesis of compound 38-4 At room temperature, compound 38-3 (17 g, 45.11 mmol) was dissolved in dichloromethane (50 mL). At 0°C, a solution of boron tribromide (49.62 mL, 49.62 mmol, 1.0 M) in dichloromethane was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was poured into water (200 mL) and extracted with dichloromethane (200 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 5 / 1) to obtain compound 38-4. MS-ESI: m / z 246.9 [M-1] - .

[0623] Synthesis of compound 38-5 At room temperature, compound 38-4 (19 g, 68.67 mmol) was dissolved in tetrahydrofuran (200 mL). Sodium hydride (3.57 g, 89.27 mmol, 60%) was added in batches, and the reaction mixture was stirred at room temperature for 1 hour. At 0°C, chloromethyl methyl ether (11.16 g, 89.27 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (300 mL) was added, and the reaction mixture was extracted with ethyl acetate (100 mL x 2), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 10 / 1) to obtain compound 38-5. 1 H NMR (300 MHz, CDCl3) δ 7.72 (d, 1H), 7.54 (d, 1H), 5.31 (s, 2H), 3.95 (s, 3H), 3.57 (s, 3H).

[0624] Synthesis of compound 38-6 At room temperature, compound 38-5 (17 g, 52.20 mmol) was dissolved in a mixed solvent of tetrahydrofuran (180 mL) and methanol (45 mL), followed by the addition of lithium borohydride (4.55 g, 208.81 mmol) in batches. 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, followed by the addition of water (400 mL) and extraction with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 3 / 1) to obtain compound 38-6. 1 H NMR (300 MHz, DMSO-d6) δ 7.50 (d, 1H), 7.36 (d, 1H), 5.55-5.51 (m, 1H), 5.29 (s, 2H), 4.48-4.43 (m, 2H), 3.44 (s, 3H).

[0625] Synthesis of compound 38-7 At room temperature, compound 6 (13 g, 49.04 mmol) was dissolved in dichloromethane (130 mL), followed by the addition of triethylamine (10.2 mL, 73.56 mmol). At 0°C, methanesulfonyl chloride (6.74 g, 58.85 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (100 mL) was added, and the reaction mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated brine (250 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude intermediate, which was used directly in the next step.

[0626] At room temperature, methyl 2-fluoro-5-hydroxybenzoate (14.72 g, 86.55 mmol) was dissolved in N,N-dimethylformamide (165 mL). At 0°C, sodium hydride (1.50 g, 62.51 mmol, 60%) was slowly added, and the reaction mixture was stirred at room temperature for 30 minutes. The solution of the crude intermediate (16.5 g, 48.08 mmol) in N,N-dimethylformamide (30 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, water (500 mL) was added, and the mixture was extracted with ethyl acetate (250 mL × 3). The organic phases were combined, washed with saturated brine (250 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was ground in a mixed solvent of petroleum ether and ethyl acetate (10 / 1) to obtain compound 38-7. 1 H NMR (400 MHz, CDCl3): δ 7.51-7.43 (m, 2H), 7.29 (d, 1H), 7.15-7.07 (m, 2H), 5.21 (s, 2H), 5.03 (s, 2H), 3.94 (s, 3H), 3.53 (s, 3H).

[0627] Synthesis of compound 38-8 At room temperature, under a nitrogen atmosphere, 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). The reaction mixture was heated to 115 °C and stirred for 2 hours. After the reaction was complete, water (600 mL) was added, and the reaction mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 5 / 1) to obtain compound 38-8. 1 H NMR (300 MHz, CDCl3): δ 7.56-7.44 (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).

[0628] Synthesis of compound 38-9 At room temperature, compound 38-8 (7.50 g, 22.30 mmol) and hydrochloric acid (20 mL) were dissolved in methanol (70 mL), 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 resulting residue was ground in a mixed solvent of petroleum ether and ethyl acetate (2 / 1) to obtain compound 38-9. MS-ESI: m / z 293.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6): δ 10.13 (s, 1H), 7.70 (dd, 1H), 7.44 (d, 1H), 7.36 (dd, 1H), 7.18 (d, 1H), 5.06 (s, 2H), 3.85 (s, 3H).

[0629] [ka]

[0630] Synthesis of compound 38-10 At room temperature, methyl 2,8-difluoro-9-hydroxy-6H-benzo[c]chromen-3-carboxylate (compound 38-9) (5.30 g, 18.10 mmol) and pyridine (5.73 g, 72.50 mmol) were dissolved in dichloromethane (30 mL). At 0°C, trifluoromethanesulfonic anhydride (7.67 g, 27.18 mmol) was added dropwise, and 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) and extracted with ethyl acetate (80 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 1 / 1) to obtain compound 38-10. MS-ESI: m / z 425.0 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 7.58 (t, 2H), 7.37 (d, 1H), 7.14 (d, 1H), 5.12 (s, 2H), 3.95 (s, 3H).

[0631] Synthesis of compound 38-11 At room temperature under a nitrogen atmosphere, compound 38-10 (3.40 g, 8.01 mmol), bis(pinacolato)diborone (4.07 g, 16.03 mmol), potassium acetate (2.36 g, 24.04 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (586 mg, 0.80 mmol) were dissolved in dioxane (20 mL). 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 x 3). The organic phases were combined, washed sequentially with water (80 mL) and saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 1 / 1) to obtain the crude product. This crude product was then ground in methyl tert-butyl ether (10 mL) to obtain compound 38-11. MS-ESI: m / z 403.2 [M+1] + .

[0632] Synthesis of compound 38-12 At room temperature, compound 38-11 (5.70 g, 14.10 mmol) was dissolved in methanol (170 mL), followed by the addition of aqueous copper bromide 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, concentrated under reduced pressure, and the resulting residue was extracted with (80 mL × 3) solutions. The organic phases were combined and washed sequentially with water (50 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 2 / 1) to obtain compound 38-12. MS-ESI: m / z 355.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (d, 1H), 8.00 (d, 1H), 7.39 (m, 2H), 5.15 (s, 2H), 3.85 (s, 3H).

[0633] Synthesis of compound 38-13 At room temperature, under a nitrogen atmosphere, 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,N 1' Bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate (58.3 mg, 0.05 mmol), sodium carbonate (1.09 g, 10.28 mmol), [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride (10.2 mg, 0.03 mmol), and tris(trimethylsilyl)silane (1.29 g, 5.18 mmol) were dissolved in ethylene glycol dimethyl ether (80 mL). The reaction mixture was stirred at room temperature for 14 hours under irradiation with a 34 W blue LED lamp. The reaction mixture was diluted with water (50 mL x 3) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed sequentially with water (50 mL) and saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 1 / 1) to obtain compound 38-13. MS-ESI: m / z 333.1 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 7.75 (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).

[0634] Synthesis of compound 38-14 At room temperature, under a nitrogen atmosphere, compound 38-13 (1.80 g, 4.71 mmol) was dissolved in tetrahydrofuran (15 mL). At 0°C, a solution of lithium aluminum hydride in tetrahydrofuran (5.2 mL, 5.20 mmol, 1 mol / L) was slowly added dropwise, and the reaction mixture was stirred at room temperature for 20 minutes. After the reaction was complete, the reaction mixture was quenched in an ice bath with saturated potassium sodium tartrate aqueous solution (10 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed sequentially with water (80 mL) and saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 1 / 1) to obtain compound 38-14. MS-ESI: m / z 287.1 [M-18+1] + . 1 H NMR (400 MHz, CDCl3) δ 7.69 (d, 1H), 7.41 (d, 1H), 7.08 (d, 1H), 6.88 (d, 1H), 5.12 (dd, 2H), 5.06 (s, 2H), 4.88 (t, 2H), 4.76 (s, 2H), 4.61-4.52 (m, 1H).

[0635] Synthesis of compound 38-15 At room temperature, compound 38-14 (1.10 g, 3.61 mmol) and diisopropylethylamine (1.87 g, 14.47 mmol) were dissolved in dichloromethane (20 mL), followed by the slow addition of methanesulfonic anhydride (1.26 g, 7.23 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. After the reaction was complete, water (20 mL) was added, and the reaction mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude intermediate, which was used directly in the next step.

[0636] 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 and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 5 / 1) to obtain compound 38-15. 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, 1H), 7.42 (d, 1H), 7.02 (d, 1H), 6.88 (d, 1H), 5.12 (dd, 2H), 5.07 (s, 2H), 4.88 (t, 2H), 4.62-4.51 (m, 1H), 4.50 (s, 2H).

[0637] Synthesis of compound 38-16 At room temperature, N-(diphenylmethylene)aminoacetonitrile (2.64 g, 12.56 mmol) was dissolved in tetrahydrofuran (50 mL). At 0°C, sodium hydride (263 mg, 6.59 mmol, 60%) was added, and the reaction mixture was stirred at 0°C for 30 minutes. Compound 38-15 (1.10 g, 2.99 mmol) was added, and the reaction mixture was stirred 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) and washed with ethyl acetate (50 mL x 3). The aqueous phase was adjusted to pH=8 with solid sodium bicarbonate and extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed sequentially with water (50 mL) and saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 38-16, which was used directly in the next step. MS-ESI: m / z 343.2 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, 1H), 7.91 (d, 1H), 7.17 (d, 1H), 7.01 (d, 1H), 5.09 (s, 2H), 4.96-4.89 (m, 2H), 4.88-4.82 (m, 2H), 4.59-4.47 (m, 1H), 4.02-3.94 (m, 1H), 2.94 (dd, 2H).

[0638] Synthesis of compound 38-17 At room temperature, crude compound 38-16 (700 mg, 2.04 mmol), compound 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 O-benzotriazole-N,N,N,N-tetramethyluronium 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 x 3). The organic phases were combined and washed sequentially with water (20 mL) and saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 1 / 2) to obtain compound 38-17.

[0639] Synthesis of Compound 38-18A and Compound 38-18B Compound 38-17 (730 mg, 1.19 mmol) was separated by preparative SFC (column: DAIEL CHIRALCEL OJ, 250 × 30 mm, 10 μm; mobile phase: supercritical carbon dioxide, methanol (0.1% ammonia monohydrate); gradient: 65% carbon dioxide phase; flow rate: 65 mL / min; column temperature: room temperature) to obtain compounds 38-18A and 38-18B (a total of two diastereomer peaks, with compound 38-18A being the second elution peak and compound 38-18B being the first elution peak).

[0640] Synthesis of compound 38A This compound was prepared by referring to the synthesis of compound 14, under similar conditions except that the temperature was changed to 50°C. MS-ESI: m / z 468.2 [M-1] - . 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (d, 1H), 7.98-7.87 (m, 2H), 7.17 (d, 1H), 6.97 (d, 1H), 5.13-4.98 (m, 3H), 4.94-4.88 (m, 2H), 4.84 (t, 2H), 4.57-4.48 (m, 1H), 3.99 (dd, 1H), 3.90-3.81 (m, 1H), 3.77-3.67 (m, 1H), 3.26-3.20 (m, 1H), 3.18-3.12 (m, 1H), 3.02 (dd, 1H), 2.82-2.73 (m, 1H), 2.63-2.53 (m, 2H), 1.81-1.62 (m, 2H).

[0641] Synthesis of compound 38B This compound was prepared by referring to the synthesis of compound 14, under similar conditions except that the temperature was changed to 50°C. MS-ESI: m / z 470.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, 1H), 8.01-7.89 (m, 2H), 7.17 (d, 1H), 6.98 (d, 1H), 5.09 (s, 2H), 4.99-4.94 (m, 1H), 4.92 (dd, 2H), 4.84 (t, 2H), 4.57-4.47 (m, 1H), 3.94-3.86 (m, 2H), 3.72-3.68 (m, 1H), 3.26-3.18 (m, 2H), 3.16-3.08 (m, 1H), 2.83-2.77 (m, 1H), 2.73-2.66 (m, 2H), 1.81-1.66 (m, 2H).

[0642] (Example 39) 4-Amino-N-(1-Cyano-2-(3-Fluoro-6,7-Dihydrodibenzo[b,d]oxepin-9-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0643] [ka]

[0644] Synthesis of compound 39-2 At room temperature, under a nitrogen atmosphere, 2-bromo-5-fluorophenol (compound 39-1) (10.00 g, 52.65 mmol) was dissolved in tetrahydrofuran (50 mL). At 0°C, sodium hydride (3.10 g, 77.50 mmol, 60%) was added, and the reaction mixture was stirred at 0°C for 1 hour. 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) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 39-2. 1 H NMR (400 MHz, CDCl3) δ 7.50-7.44 (m, 1H), 6.93 (dd, 1H), 6.68-6.60 (m, 1H), 5.23 (s, 2H), 3.51 (s, 3H).

[0645] Synthesis of compound 39-4 At room temperature, 2-(3-methoxyphenyl)ethane-1-ol (compound 39-3) (10.00 g, 65.75 mmol) was dissolved in acetonitrile (80 mL), followed by the addition of N-bromosuccinimide (11.70 g, 65.74 mmol). 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 x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 39-4. 1 H NMR (400 MHz, CDCl3) δ 7.41 (d, 1H), 6.82 (d, 1H), 6.68-6.61 (m, 1H), 3.88-3.78 (m, 2H), 3.76 (s, 3H), 3.00-2.92 (m, 2H), 2.05-1.96 (m, 1H).

[0646] Synthesis of compound 39-5 At room temperature, compound 39-4 (12.50 g, 54.10 mmol) was dissolved in dichloromethane (150 mL), followed by the addition of tert-butyldimethylsilyl chloride (10.00 g, 66.40 mmol) and imidazole (6.00 g, 88.10 mmol). 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 x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 19 / 1) to obtain compound 39-5. 1 H NMR (400 MHz, CDCl3) δ 7.40 (d, 1H), 6.83 (d, 1H), 6.68-6.62 (m, 1H), 3.87-3.80 (m, 2H), 3.78 (s, 3H), 2.98-2.90 (m, 2H), 0.88 (s, 9H), 0.01 (s, 6H).

[0647] Synthesis of compound 39-6 At room temperature, under a nitrogen atmosphere, compound 39-5 (15.00 g, 43.40 mmol) and bis(pinacolato)diborone (15.00 g, 59.07 mmol) were dissolved in 1,4-dioxane (200 mL), followed by the addition of potassium acetate (13.00 g, 132.46 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (2.00 g, 2.73 mmol). 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 x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 19 / 1) to obtain compound 39-6. 1 H NMR (400 MHz, CDCl3) δ 7.80-7.73 (m, 1H), 6.84-6.72 (m, 2H), 3.86-3.76 (m, 5H), 3.14 (t, 2H), 1.34 (s, 12H), 0.89 (s, 9H), 0.01 (s, 6H).

[0648] Synthesis of compound 39-7 This compound was prepared by referring to the synthesis of compound 36-6, under similar conditions except that the temperature was changed from 80°C to 95°C. 1 H NMR (300 MHz, CDCl3) δ 7.19-7.8 (m, 2H), 7.06-6.99 (m, 1H), 6.97-6.92 (m, 1H), 6.90-6.77 (m, 2H), 5.16-5.08 (m, 2H), 3.90 (s, 3H), 3.70-3.61 (m, 2H), 3.42 (s, 3H), 2.80-2.70 (m, 2H), 0.88 (s, 9H), 0.00 (s, 6H).

[0649] Synthesis of compound 39-8 At room temperature, compound 39-7 (5.80 g, 13.80 mmol) was dissolved in tetrahydrofuran (30 mL), 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 x 3). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 39-8. 1 H NMR (400 MHz, CDCl3) δ 7.13-7.08 (m, 1H), 7.03-6.97 (m, 1H), 6.93-6.88 (m, 1H), 6.87-6.83 (m, 1H), 6.70-6.61 (m, 2H), 3.83 (s, 3H), 3.76-3.71 (m, 2H), 2.76-2.60 (m, 2H).

[0650] Synthesis of compound 39-9 This was prepared by referring to the synthesis of compound 36-9. 1 H NMR (400 MHz, CDCl3) δ 7.35-7.28 (m, 2H), 6.97-6.89 (m, 2H), 6.88-6.83 (m, 2H), 4.56 (t, 2H), 3.85 (s, 3H), 2.78 (t, 2H).

[0651] Synthesis of compound 39-10 At room temperature under a nitrogen atmosphere, compound 39-9 (2.00 g, 8.19 mmol) was dissolved in dichloromethane (20 mL). Boron tribromide (12.0 mL, 12.00 mmol, 1.0 mol / L in dichloromethane) was added dropwise, and 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 x 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 39-10. 1 H NMR (400 MHz, CDCl3) δ 7.34-7.27 (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).

[0652] Synthesis of compound 39-11 At room temperature, compound 39-10 (500 mg, 2.17 mmol) and triethylamine (0.7 mL, 4.94 mmol) were dissolved in dichloromethane (10 mL), followed by the addition of N-phenylbis(trifluoromethanesulfonimide) (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 x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 39-11. 1 H NMR (400 MHz, CDCl3) δ 7.47-7.41 (m, 1H), 7.39-7.27 (m, 2H), 7.24-7.18 (m, 1H), 7.02-6.95 (m, 1H), 6.93-6.87 (m, 1H), 4.58 (t, 2H), 2.84 (t, 2H).

[0653] Synthesis of compound 39-12 At room temperature, compound 39-11 (450 mg, 1.24 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (200 mg, 0.27 mmol) were dissolved in methanol (10 mL), followed by the addition of triethylamine (0.52 mL, 3.76 mmol). The reaction mixture was heated to 100 °C under a carbon monoxide atmosphere (5 MPa) and stirred for 18 hours. The reaction mixture was cooled to room temperature, poured into water (30 mL), and extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 39-12 (220 mg). 1 H NMR (400 MHz, CDCl3) δ 8.07-8.02 (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).

[0654] Synthesis of compound 39-13 This compound was prepared by referring to the synthesis of compound 12-4, under similar conditions except that the temperature was changed from 0°C to room temperature. MS-ESI: m / z 227.1 [M-18+1] + .

[0655] Synthesis of compound 39-14 This was prepared by referring to the synthesis of compound 14-A4. 1 H NMR (400 MHz, CDCl3) δ 7.43-7.30 (m, 4H), 6.99-6.92 (m, 1H), 6.90-6.84 (m, 1H), 4.57 (t, 2H), 4.54 (s, 2H), 2.81 (t, 2H).

[0656] Synthesis of compound 39-15 This compound was prepared by referring to the synthesis of compound 14-A5, under similar conditions except for the absence of benzyltrimethylammonium chloride. MS-ESI: m / z 447.3 [M+1] + .

[0657] Synthesis of compound 39-16 This was prepared by referring to the synthesis of compound 14-A6. MS-ESI: m / z 266.1 [M-17+1] + .

[0658] [ka]

[0659] Synthesis of compound 39-17 At room temperature, 2-amino-3-(3-fluoro-6,7-dihydrodibenzo[b,d]oxepin-9-yl)propanenitrile (compound 39-16) (40 mg, 0.14 mmol) and 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-azabenzotriazole-1-yl)uronium hexafluorophosphate (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 x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 39-17. MS-ESI: m / z 410.3 [M-100+1] + .

[0660] Synthesis of compound 39 This compound was prepared by referring to the synthesis of compound 14, under similar conditions except that the temperature was changed from 40°C to 50°C. MS-ESI: m / z 410.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.50-7.42 (m, 1H), 7.39-7.35 (m, 1H), 7.33-7.29 (m, 1H), 7.26 (s, 1H), 7.15-7.08 (m, 1H), 7.03-6.97 (m, 1H), 5.03-4.97 (m, 1H), 4.52-4.45 (m, 2H), 3.68-3.54 (m, 3H), 3.52-3.44 (m, 1H), 3.23-3.12 (m, 2H), 2.78-2.70 (m, 2H), 1.93-1.85 (m, 1H), 1.80-1.70 (m, 1H), 1.24-1.10 (m, 2H).

[0661] (Example 40) (S)-4-amino-N-(1-cyano-2-(9-fluoro-6-methyl-5-oxo-6,7-dihydro-5H-dibenzo[c,e]azepine-3-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0662] [ka]

[0663] Synthesis of compound 40-2 At room temperature, (2-bromo-5-fluorophenyl)methaneamine (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 resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 40-2. MS-ESI: m / z 248.1 [M-56+1] + .

[0664] Synthesis of compound 40-3 At room temperature under a nitrogen atmosphere, compound 40-2 (11.00 g, 36.17 mmol), bis(pinacolato)diborone (18.37 g, 72.33 mmol), and potassium acetate (7.10 g, 72.33 mmol) were dissolved in dioxane (50 mL), followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (2.95 g, 3.62 mmol). 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, poured into saturated sodium bicarbonate aqueous solution (200 mL), and extracted with dichloromethane (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 40-3. MS-ESI: m / z 252.3 [M-100+1] + . 1 H NMR (400 MHz, CDCl3) δ 7.85-7.78 (m, 1H), 7.12-7.07 (m, 1H), 6.98-6.90 (m, 1H), 5.39 (s, 1H), 4.44 (s, 2H), 1.43 (s, 9H), 1.53 (s, 12H).

[0665] Synthesis of compound 40-4 At room temperature under a nitrogen atmosphere, 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), followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.93 g, 1.14 mmol). 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, poured into saturated sodium bicarbonate aqueous solution (200 mL), and extracted with dichloromethane (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound 40-4. MS-ESI: m / z 340.1 [M-100+1] + .

[0666] Synthesis of compound 40-5 At 0°C, compound 40-4 (1.32 g, 3.01 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of trifluoroacetic acid (4 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution (10 mL) was added to the resulting residue, and the mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 40-5, which was used directly in the next step. MS-ESI: m / z 340.1 [M+1] + .

[0667] Synthesis of compound 40-6 At room temperature, crude compound 40-5 (1.00 g, 2.96 mmol) was dissolved in toluene (20 mL). The reaction mixture was heated to 120 °C and stirred for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 40-6. MS-ESI: m / z 306.1 [M+1] + .

[0668] Synthesis of compound 40-7 At room temperature, compound 40-6 (800 mg, 2.60 mmol) was dissolved in N,N-dimethylformamide (200 mL). At 0°C, sodium hydride (156 mg, 3.89 mmol, 60%) was added in batches, and the reaction mixture was stirred at 0°C for 1 hour. Iodomethane (1.11 g, 7.79 mmol) was added, and the reaction mixture was stirred at 0°C for 2 hours. After the reaction was complete, water (150 mL) was added, and the reaction mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 40-7. MS-ESI: m / z 320.1 [M+1] + .

[0669] Synthesis of compound 40-8 This compound was prepared by referring to the synthesis of compounds 1-3, under similar conditions except that the temperature was changed from 60°C to 70°C. MS-ESI: m / z 443.4 [M+1] + .

[0670] Synthesis of compound 40-9 This was prepared by referring to the synthesis of compounds 1-4. MS-ESI: m / z 428.6 [M+1] + .

[0671] Synthesis of compound 40-10 This was prepared by referring to the synthesis of compounds 1-5. MS-ESI: m / z 410.1 [M+1]+ .

[0672] Synthesis of compound 40-11 This was prepared by referring to the synthesis of compounds 1-6. MS-ESI: m / z 310.1 [M+1] + .

[0673] Synthesis of compound 40-12 This compound was prepared by referring to the synthesis of compounds 1-7, under similar conditions except that N,N-dimethylformamide was replaced with dichloromethane. MS-ESI: m / z 537.2 [M+1] + .

[0674] Synthesis of compound 40 This was prepared by referring to the synthesis of compound 1. MS-ESI: m / z 437.3 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.73-7.66 (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).

[0675] (Example 41) (S)-N-((S)-1-Cyano-2-(9-Cyano-2-Fluoro-6-methyl-5-oxo-6,7-dihydro-5H-dibenzo[c,e]azepine-3-yl)ethyl)-1,4-Oxazepan-2-carboxamide

[0676] [ka]

[0677] Synthesis of compound 41-2 At room temperature, 2-amino-5-bromo-4-fluorobenzoic acid (compound 41-1) (5.00 g, 21.40 mmol) was added to a solution of concentrated hydrochloric acid (17.8 mL, 214.00 mmol) in water (10 mL). At 0°C, a solution of sodium nitrite (1.77 g, 25.65 mmol) in water (10 mL) was slowly added, and the reaction mixture was stirred at 0°C for 30 minutes. A solution of potassium iodide (5.32 g, 32.00 mmol) in water (10 mL) was slowly added, and the reaction mixture was stirred at 0°C for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted with methyl tert-butyl ether (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 41-2, which was used directly in the next step. 1 H NMR (400 MHz, DMSO-d6) δ 13.61 (br s, 1H), 8.09-8.01 (m, 2H).

[0678] Synthesis of compound 41-3 At room temperature, compound 41-2 (6.50 g, 18.80 mmol) was dissolved in methanol (100 mL), followed by the slow addition of concentrated sulfuric acid (3.77 g, 37.70 mmol). The reaction 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 saturated sodium bicarbonate aqueous solution (300 mL) (pH of the system = 9), and extracted with methyl tert-butyl ether (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to obtain compound 41-3. 1 H NMR (400 MHz, CDCl3) δ 8.09 (d, 1H), 7.76 (d, 1H), 3.94 (s, 3H).

[0679] Synthesis of compound 41-4 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 batches. 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) and filtered. The filtered cake was washed with ice water (100 mL) to obtain crude compound 41-4, which was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, 1H), 7.79 (dd, 1H), 7.62 (d, 1H), 4.47 (s, 2H), 3.87 (s, 3H).

[0680] Synthesis of Compounds 41-5 At room temperature, crude compound 41-4 (18.60 g, 68.90 mmol) was dissolved in a mixed solvent of water (15 mL) and tetrahydrofuran (200 mL), followed by batch addition of triphenylphosphine (21.70 g, 82.73 mmol). The react...

Claims

1. Compounds of formula VI or pharmaceutically acceptable salts thereof 【Chemistry 1】 (In the formula, X1 is an oxygen atom, X 2 is -C(R 3b ) 2-; Ring C is selected from the group consisting of phenyl and 5- to 8-membered heteroaryls containing 1 to 3 heteroatoms, where each of the phenyl and 5- to 8-membered heteroaryls containing 1 to 3 heteroatoms independently comprises 1 to 3 R 3b It is replaced by choice; Ring A is selected from the group consisting of heterocycloalkyl groups, and the heterocycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, cyano, nitro, amino, acyl, amide, oxo, alkyl, and alkoxy groups, and each alkyl and alkoxy group is independently substituted with one or more R groups. 3a It is replaced by choice; Each R 3a is independently selected from the group consisting of hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1～6 alkyl, C 1～6 alkoxy, C 2～6 alkenyloxy, C 2～6 alkynyloxy, 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, each independently optionally substituted by one or more substituents selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro and cyano; 1～6 alkyl, C 1～6 alkoxy, C 2～6 alkenyloxy, C 2～6 alkynyloxy, 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 are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro and cyano; Each R 3b These are hydrogen, halogens, deuterium, hydroxyl, oxo, nitro, cyano, amino, acyl, amide, and C. 1～6 Alkyl, C 1～6 Alkoxy, C 2～6 Alkenyloxy, C 2～6 Alkynyloxy, C 3～6 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl, C 3～6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3～8 Cycloalkenyloxy, 5- to 6-membered aryls, 3- to 6-membered heteroaryls, methanesulfonyls and 【Chemistry 2】 Independently selected from the group consisting of C 1～6 Alkyl, C 1～6 Alkoxy, C 2～6 Alkenyloxy, C 2～6 Alkynyloxy, C 3～6 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl, C 3～6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3～8 Cycloalkenyloxys, 5- to 6-membered aryls, and 3- to 6-membered heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, deuterium, hydroxy, oxo, nitro, and cyano; Each R 1 This is independently selected from the group consisting of halogen, hydroxy, oxo, nitro, cyano, alkyl, cycloalkyl, amino, amide, acyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkoxy; n is an integer selected from the group consisting of 0 to 3.

2. The compound of formula VI, 【Transformation 3】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following: (In the formula, ring C is selected from the group consisting of phenyl and 5- to 8-membered heteroaryls containing 1 to 3 heteroatoms, where each of the phenyl and 5- to 8-membered heteroaryls containing 1 to 3 heteroatoms independently contains 1 to 3 R 3b It is replaced by choice; R 1 , n, ring A and R 3b (As defined in claim 1).

3. Ring A is a 3- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms, wherein the 3- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms is composed of deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, and C 1～6 Alkyl and C 1～6 It is optionally substituted with one or more substituents selected from the group consisting of alkoxys, C 1～6 Alkyl and C 1～6 Each alkoxy independently contains one to three R 3a It is replaced by choice, R 3a The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, as defined in claim 1.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the heteroatom is selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms.

5. Ring A is deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1～6 Alkyl and C 1～6 It is optionally substituted with one or more substituents selected from the group consisting of alkoxys. 【Chemistry 4】 Selected from the group consisting of; C 1～6 Alkyl and C 1～6 Each alkoxy independently contains one to three R 3a It is replaced by choice, R 3a The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, as defined in claim 1.

6. Ring A is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C1-6 alkyl, and C1-6 alkoxy. 【Transformation 5】 Selected from the group consisting of; The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein each C1-6 alkyl and C1-6 alkoxy is independently optionally substituted by one to three R3a, where R3a is as defined in claim 1.

7. Ring A is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C1-6 alkyl, and C1-6 alkoxy. 【Transformation 6】 and; The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein each C1-6 alkyl and C1-6 alkoxy is independently optionally substituted by one to three R3a, where R3a is as defined in claim 1.

8. Ring A is 【Transformation 7】 The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

9. The compound of formula VI, 【Transformation 8】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following: (In the formula, Each R 2 These are independently selected from the group consisting of halogen, nitro, cyano, amino, oxo, and hydroxy; m is an integer selected from the group consisting of 0 to 3; R 1 , n, ring C and R 3b (As defined in claim 1).

10. The compound of formula VI, 【Chemistry 9】 A compound according to claim 2 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following: (In the formula, Each R 2 These are independently selected from the group consisting of halogen, nitro, cyano, amino, oxo, and hydroxy; m is an integer selected from the group consisting of 0 to 3; R 1 , n, ring C and R 3b (As defined in claim 2).

11. R1 is a halogen, hydroxyl, C 1～6 Alkyl and C 3～6 A compound according to any one of claims 1 to 10, selected from the group consisting of cycloalkyls, or a pharmaceutically acceptable salt thereof.

12. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R1 is fluorine.

13. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from the group consisting of 1 to 2.

14. Ring C is phenyl, 【Chemistry 10】 Selected from the group consisting of phenyl, 【Chemistry 11】 Each of these independently generates one to three R's. 3b It is replaced by choice, R 3b The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, as defined in claim 1.

15. The carbon ring is phenyl, and phenyl has one to three R groups. 3b It is replaced by choice, R 3b The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, as defined in claim 1.

16. Each R 3a a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, and amino.

17. Each R 3a The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, which is independently selected from the group consisting of hydrogen, fluorine, chlorine, deuterium, oxo(=O), hydroxy, amino, methoxy, cyclopropoxy, cyclopropyl, cyclopentyl, pyridinyl, piperidinyl, and phenyl.

18. The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein each R 3a is hydrogen or amino.

19. Each R 3b However, hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, amide, C 1～6 Alkyl, C 1～6 Alkoxy, C 2～6 Alkenyloxy, C 2～6 Alkynyloxy, C 3～6 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl, C 3～6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3～8 A cycloalkenyloxy is independently selected from the group consisting of 5- to 6-membered aryls and 3- to 6-membered heteroaryls, C 1～6 Alkyl, C 1～6 Alkoxy, C 2～6 Alkenyloxy, C 2～6 Alkynyloxy, C 3～6 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl, C 3～6 Cycloalkoxys, 3-membered to 6-membered heterocycloalkoxys, C 3～8 The compounds according to any one of claims 1 to 18 or pharmaceutically acceptable salts thereof, wherein each cycloalkenyloxy, 5- to 6-membered aryl, and 3- to 6-membered heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro, and cyano.

20. Each R 3b The compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, acyl, and amide.

21. Each R 3b The compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, wherein, independently, hydrogen and a 3- to 6-membered heterocycloalkyl group are independently selected from the group consisting of 3- to 6-membered heterocycloalkyl groups, and the 3- to 6-membered heterocycloalkyl group is optionally substituted with one to three substituents selected from the group consisting of halogens, cyanos, and hydroxyls.

22. Each R 3b However, hydrogen, halogens, deuterium, cyano, 3- to 6-membered heterocycloalkyls, methanesulfonyl and 【Chemistry 12】 A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of the above.

23. A 3- to 6-membered heterocycloalkyl is 【Chemistry 13】 A compound according to claim 21 or 22, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

24. Each R 3b However, hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, amide, acetyl, methanesulfonyl, 【Chemistry 14】 A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of the above.

25. Each R 3b However, hydrogen, cyano, methanesulfonyl and 【Chemistry 15】 A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of the above.

26. The compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, wherein each R 3b is hydrogen or cyano.

27. The compound of formula VI, 【Chemical Engineering 16A】 【Chemical 16B】 [Chemical 16C] [16D] A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

28. An isotope-substituted compound of any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms in any one of the compounds or pharmaceutically acceptable salts described in claims 1 to 27 are substituted with deuterium atoms.

29. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound described in any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, or an isotope substitution described in claim 28, and a pharmaceutically acceptable excipient.

30. Use of a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, or an isotope substitution according to claim 28, or a pharmaceutical composition according to claim 29, in the preparation of a pharmaceutical for preventing and / or treating cathepsin C-related disorders.

31. Use of a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, or an isotope substitution according to claim 28, or a pharmaceutical composition according to claim 29, in the preparation of a pharmaceutical for the prevention and / or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, alpha-1 antitrypsin deficiency, lupus nephritis, diabetes mellitus, inflammatory bowel disease, or rheumatoid arthritis.

32. Compounds of the following formula 【Chemistry 17】 (In the formula, R 1 , n, ring C and R 3b (As defined in claim 2).

33. Compounds of the following formula [Chemistry 18] (In the formula, R 1 , n, C and R 3b (As defined in claim 2).

Images