Nitrile derivatives acting as inhibitors of dipeptidyl peptidase 1 and uses thereof - Patent Application 20070229633

Abstract

Provided is a nitrile derivative compound represented by Formula (I), its stereoisomer, deuterated product, co-crystal, solvate, or pharmaceutically acceptable salt, wherein each group is as defined herein. The compound has dipeptidyl peptidase 1 inhibitory activity and can be used to prepare a medicament for treating obstructive airway disease, bronchiectasis, cystic fibrosis, asthma, emphysema, chronic obstructive pulmonary disease, and other diseases. [Formula 1] JPEG2023539101000163.jpg35160

Description

[Technical field]

[0001] The present invention relates to nitrile derivatives as dipeptidyl peptidase 1 inhibitors, or stereoisomers, deuterated products, cocrystals, solvates or pharma- ceutically acceptable salts thereof, and their use in the preparation of medicaments for the treatment of diseases mediated by dipeptidyl peptidase 1. [Background technology]

[0002] Dipeptidyl peptidase 1 (DPP1), also known as cathepsin C, is a lysosomal cysteine ​​protease capable of removing dipeptides from the amino terminus of protein substrates. DPP1 was first discovered by Gutman and Fruton in 1948 (J Biol Chem, 174, 851-858). However, the cDNA for human dipeptidyl peptidase 1 was first described in 1995 (FEBS Lett, 369, 326-330). DPP1 is the only member of the papain family that functions as a tetramer, consisting of four identical subunits. Each subunit is composed of an N-terminal fragment, a heavy chain, and a light chain (J Biol Chem, 270, 21626-21631).

[0003] DPP1 is highly expressed in many tissues, such as the lung, kidney, liver, and spleen (Hoppe Seyler, Biol. Chem. 373:367-373, 1992). Consistent with its role in the activation of serine proteases in hematopoietic stem cells, DPP1 is also relatively highly expressed in neutrophils, cytotoxic lymphocytes, natural killer cells, alveolar macrophages, and mast cells. Recent data suggest that in addition to being a key enzyme in lysosomal protein degradation, DPP1 also functions as a key enzyme in granule serine protease activation in the following cells: cytotoxic T lymphocytes and natural killer cells (granzymes A and B; Proc. Nat. Acad. Sci 96:8627-8632, 1999), mast cells (chymotrypsin and plasmin; J Biol. Chem. 276:18551-18556, 2001), and neutrophils (cathepsin G, elastase, and proteinase 3; J Clin. Invest. 109:363.371, 2002). Once activated, these proteases are capable of degrading various extracellular matrix components, leading to tissue damage and chronic inflammation. Due to its central role in activating these proteases, DPP1 is considered to be a potential therapeutic target (J Clin Invest, 2002, 109, 363-271; J Immunol, 2004, 173, 7277-7281).

[0004] Therefore, cathepsin C inhibitors may be potentially useful in the treatment of the following diseases: neutrophil-dominant inflammatory diseases, such as rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), emphysema, asthma, multiple sclerosis, and cystic fibrosis (Curr.Topics Med.Chem.10:708-716,2010; Expert Opin.Ther.Patents 20:497-506,2010). Considering the role of DPP1 in the activation of some inflammatory serine proteases, compounds that inhibit the activity of DPP1 and further inhibit the activity of downstream serine proteases have good prospects for clinical application. At present, relevant patents have reported the synthesis of DPP1 inhibitors. WO 2004 / 110988 relates to certain nitrile derivatives and their use as DPP1 inhibitors. WO 2009 / 074829 relates to peptidyl nitriles and their use as DPP1 inhibitors. WO 2010 / 128324 relates to α-aminoamidonitriles and their use as DPP1 inhibitors. WO 2012 / 119941 relates to peptidyl nitrile compounds and their use as DPP1 inhibitors. WO 2013 / 041497 relates to N-[1-cyano-2-(phenyl)ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamides and their use as DPP1 inhibitors. WO 2001 / 096285 and WO 2003 / 048123 relate to β-aminoamidonitriles with inhibitory activity against cysteine ​​proteases. However, since there have been no DPP1 inhibitors available on the market so far, there remains an unmet clinical need for DPP1 inhibitors with high inhibitory activity and low toxicity. Summary of the Invention [Means for solving the problem]

[0005] The present invention provides, for the first time, compounds of formula (I), (II), (III) or (IV) or stereoisomers, deuterated products, co-crystals, solvates or pharma- ceutically acceptable salts thereof, having high activity, high bioavailability, good pharmacokinetics, and low toxicity and side effects: [ka] In the formula, ring G is a 5- to 12-membered carbocyclic ring, a 5- to 12-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from N, S and O, or a ring represented by the formula (I-1): [ka] is a fused ring of L1 is bonded to ring G by replacing any hydrogen atom on a ring atom (e.g., a carbon atom on a 5- to 12-membered carbocyclic ring, a ring carbon atom or ring heteroatom on a 5- to 12-membered monocyclic heterocyclic ring, and a ring carbon atom or ring heteroatom on a fused ring of formula (I-1)), and the carbocyclic ring or monocyclic heterocyclic ring is bonded to ring G by replacing any hydrogen atom on the ring atom (e.g., a carbon atom on a 5- to 12-membered carbocyclic ring, a ring carbon atom or ring heteroatom on a fused ring of formula (I-1)), and the carbocyclic ring or the ... G optionally substituted with a group; Optionally, formula (I-1) has the structure [ka] and optionally, formula (I-1) has the structure [ka] has.

[0006] In some embodiments, ring G is a 5-9 membered monocyclic carbocycle, a 5-7 membered monocyclic heterocycle containing 1-3 heteroatoms selected from N, S and O, or a fused ring of formula (I-1), optionally, formula (I-1) has structure (I-11), and optionally, formula (I-1) has structure (I-12).

[0007] In one embodiment, ring G is selected from 1 to 3 R G cyclopentane, cyclohexane, cycloheptane, benzene rings, optionally substituted with groups; [ka] or ring G is [ka] and Optionally, formula (I-2) has the structure [ka] and optionally, formula (I-2) has the structure [ka] has.

[0008] In one embodiment, [ka] But the following structure: [ka] is selected from one of the following:

[0009] In one embodiment, ring G is selected from 1 to 2 R G a benzene ring, optionally substituted with a group; [ka] and; Each R G are independently deuterium, SF5, =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkyloxy, C 3~6 Cycloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COC 1~4 Alkyl, -COOC 1~4 Alkyl, -CONH2, -CONHC 1~4 Alkyl, -CONHC3~6 Cycloalkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 Alkyl, -NHCOC 3~6 Cycloalkyl, -P(O)(C 1~4 Alkyl)2, -S(O)C 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)C 3~6 Cycloalkyl, -S(O)NH2, -S(O)NHC 1~4 Alkyl, -S(O)N(C 1~4 R is selected from -S(O)NH, -S(O)-NH, and a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O; G But deuterium, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxy C 1~4 Alkyl, -CONH2, NH2, C 1~6 Optionally, the 5-7 membered heterocycle is further substituted with 1-3 groups selected from alkoxy, hydroxyl, -COOH, halogen, and a 5-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the 5-7 membered heterocycle is further substituted with ═O, halogen, cyano, C 1~4 Alkyl and haloC 1~4 It is optionally substituted with 1 to 2 groups selected from alkyl.

[0010] In some embodiments, each R G are independently deuterium, SF5, =O, halogen, cyano, hydroxyl, NH2, C 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COC 1~4 Alkyl, -CONH2, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 Alkyl, -P(O)(C 1~4alkyl)2, and a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O; R G But deuterium, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxy C 1~4 Alkyl, -CONH2, NH2, C 1~6 Optionally, the 5-7 membered heterocycle is further substituted with 1-3 groups selected from alkoxy, hydroxyl, halogen, and a 5-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the 5-7 membered heterocycle is further substituted with ═O, halogen, cyano, C 1~4 Alkyl and haloC 1~4 It is optionally substituted with 1 to 2 groups selected from alkyl.

[0011] In some embodiments, each R G are independently selected from F, Cl, Br, I, methyl, ethyl, propyl, SF5, and CN; methyl, ethyl, and propyl are optionally further substituted with 1 to 3 groups selected from deuterium, F, Cl, Br, and I; Cy is a 5-12 membered heterocycle containing 1-3 heteroatoms selected from N, S and O, and the heterocycle is preferably deuterium, ═O, halogen, cyano, hydroxyl, NH2, —COOH, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxy C 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkyloxy, C 1~6 Alkoxyalkyl, HaloC 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COC 1~4 Alkyl, -COOC 1~4 Alkyl, -CONH2, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)C 1~4Alkyl, -S(O)NH2, -S(O)NHC 1~4 Alkyl, -S(O)N(C 1~4 alkyl)2, -S(O)2NH2, -S(O)2NHC 1~4 Alkyl, and -S(O)2N(C 1~4 alkyl)2.

[0012] In certain embodiments, Cy is a 5-12 membered monocyclic heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the monocyclic heterocycle is selected from deuterium, ═O, halogen, cyano, hydroxyl, NH, —COOH, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxy C 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkoxy, C 1~6 Alkoxyalkyl, HaloC 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COC 1~4 Alkyl, -COOC 1~4 Alkyl, -CONH2, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)NH2, -S(O)NHC 1~4 Alkyl, -S(O)N(C 1~4 alkyl)2, -S(O)2NH2, -S(O)2NHC 1~4 Alkyl, and -S(O)2N(C 1~4 alkyl)2.

[0013] In certain embodiments, Cy is a 5-8 membered monocyclic heterocycle, a 7-10 membered spirocyclic heterocycle, a 6-9 membered bridged ring heterocycle, or a 6-10 membered fused heterocycle containing 1-3 heteroatoms selected from N, S, and O; Cy is ═O, halogen, cyano, hydroxyl, NH, —COOH, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxy C 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkoxy, C 1~6 Alkoxyalkyl, HaloC 1~4 Alkoxy, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COC 1~4 Alkyl, -CONH2, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)NH2, -S(O)NHC 1~4 Alkyl, -S(O)N(C 1~4 alkyl)2, -S(O)2NH2, -S(O)2NHC 1~4 Alkyl, and -S(O)2N(C 1~4 alkyl)2.

[0014] In certain embodiments, Cy is a 5-8 membered monocyclic heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the monocyclic heterocycle is selected from ═O, halogen, cyano, hydroxyl, NH, —COOH, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxy C 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkoxy, C 1~6 Alkoxyalkyl, HaloC 1~4 Alkoxy, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COC 1~4Alkyl, -CONH2, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)NH2, -S(O)NHC 1~4 Alkyl, -S(O)N(C 1~4 alkyl)2, -S(O)2NH2, -S(O)2NHC 1~4 Alkyl, and -S(O)2N(C 1~4 alkyl)2.

[0015] In certain embodiments, Cy is a 5-8 membered monocyclic heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the monocyclic heterocycle is selected from ═O, halogen, cyano, hydroxyl, NH, —COOH, C 1~4 Alkyl, haloC 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkoxy, HaloC 1~4 Alkoxy, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -CONH2, -CONHC 1~4 Alkyl, -CON(C 1~4 alkyl)2, -S(O)2NH2, -S(O)2NHC 1~4 Alkyl, and -S(O)2N(C 1~4 alkyl)2.

[0016] In certain embodiments, Cy is [ka] and In the formula, Rc is H, =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxy C 1~4 Alkyl, C 1~4 Alkoxy, C 1~6Alkoxyalkyl or haloC 1~4 It is an alkoxy.

[0017] In certain embodiments, Rc is H, halogen, C 1~2 Alkyl or C 1~2 is an alkoxy; W is C(=O), C(=S), C(=NR W ), S(=O) or S(=O)2, and R W is OH, CN or C 1~4 It is an alkyl.

[0018] In certain embodiments, W is C(=O); M is NR M or O, R M But, H, C 1~4 Alkyl or C 3~6 It is cycloalkyl.

[0019] In certain embodiments, M is NH; R1, R2, and R3 are each independently H, deuterium, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 cycloalkyl, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S and O, where the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are selected from halogen, C 1~4 optionally substituted with one to three groups selected from alkyl, cyano, hydroxyl, NH2, and -COOH; optionally, R1 and R2, together with the carbon atom to which they are attached, form a C 3~6 Form a cycloalkyl or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S and O, where the cycloalkyl or heterocycle is ═O, halogen, cyano, hydroxyl, NH2, —COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6Optionally substituted with 1 to 3 groups selected from cycloalkyl.

[0020] In certain embodiments, R, R, and R are each independently H, deuterium, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, and C 2~6 alkynyl, wherein alkyl, alkoxy, alkenyl, and alkynyl are selected from halogen, C 1~4 optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and COOH; Optionally, R and R together with the carbon atom to which they are attached form a C 3~6 A cycloalkyl or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S and O, wherein the cycloalkyl or heterocycle is selected from halogen, cyano, hydroxyl, NH2, COOH, and C 1~4 It is optionally substituted with 1 to 3 groups selected from alkyl.

[0021] In certain embodiments, R, R, and R are each independently H, deuterium, halogen, C 1~4 Alkyl, and C 1~4 alkoxy, wherein alkyl and alkoxy are selected from halogen, C 1~4 optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and COOH; Optionally, R and R together with the carbon atom to which they are attached form a C 3~6 Forms a cycloalkyl, where the cycloalkyl is halogen, cyano, hydroxyl, NH2, COOH, and C 1~4 It is optionally substituted with 1 to 3 groups selected from alkyl.

[0022] In certain embodiments, R1, R2, and R3 are each independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, methoxy, or ethoxy, wherein the methyl, ethyl, methoxy, or ethoxy is optionally substituted with 1-3 groups selected from F, Cl, Br, cyano, hydroxyl, and NH2; L1 is a bond, C 1~3 Alkylene, -NH-, -N(C 1~4 Alkyl)-, -O-, -S-, C 2~6 Alkenylene, C 2~6 alkynylene, -CO-, or -CONH-, where alkylene, alkenylene, or alkynylene is halogen, C 1~4 It is optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and -COOH.

[0023] In certain embodiments, L is a bond, C 1~3 Alkylene, -NH-, -O-, -S-, C 2~6 Alkenylene, C 2~6 Alkynylene, or -CO-, where the alkylene, alkenylene or alkynylene is optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, and NH2.

[0024] In certain embodiments, L is a bond, Each of Y1 and Y2 is independently selected from CR4 or N.

[0025] In certain embodiments, Y and Y are CH; Each R4 is independently H, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxyl, NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COOH, -COC 1~4 Alkyl, -COOC 1~4Alkyl, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 and alkyl, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S and O, where the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycle groups in the case of R4 are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2 and -COOH.

[0026] In certain embodiments, each R is independently H, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 R4 is selected from cycloalkyl, cyano, hydroxyl, and NH2, where the alkyl, alkenyl, alkynyl, and cycloalkyl in the case of R4 are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH.

[0027] In certain embodiments, R4 is H; X1, X2, X3, and X4 are each independently selected from a bond, NR5, O, CR6R7, S, S(O), and S(O)2, and no more than one of X1, X2, X3, and X4 is a bond; Each R5 is independently H, C 1~4 Alkyl, -COC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one to three groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH.

[0028] In certain embodiments, each R is independently H, C 1~4 Alkyl, -COC 1~4 Alkyl and C 3~6cycloalkyl, where alkyl and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH.

[0029] In certain embodiments, R5 is methyl; R6 and R7 are each independently H, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 cycloalkyl, cyano, hydroxyl, NH2, -COOH, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, and O, where the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH; optionally, R6 and R7 form =O; Optionally, two R5 on adjacent ring atoms, two R6 on adjacent ring atoms, or R5 and R6 on adjacent ring atoms in X1, X2, X3, and X4, together with the atoms to which they are attached, form a double bond; Optionally, R and R on the same carbon atom, together with the carbon atom to which they are attached, may be C 3~12 Form a carbocycle or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S and O, where the carbocycle or heterocycle is ═O, halogen, cyano, hydroxyl, NH2, —COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 Optionally substituted with 1 to 3 groups selected from cycloalkyl.

[0030] In certain embodiments, R and R are each independently H, deuterium, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6Alkynyl, and C 3~6 cycloalkyl, where alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH; optionally, R6 and R7 form =O; Optionally, two R5 on adjacent ring atoms, two R6 on adjacent ring atoms, or R5 and R6 on adjacent ring atoms in X1, X2, X3, and X4, together with the atoms to which they are attached, form a double bond; Optionally, R and R on the same carbon atom, together with the carbon atom to which they are attached, may be C 3~6 A cycloalkyl or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S and O, wherein the cycloalkyl or heterocycle is ═O, halogen, cyano, hydroxyl, NH2, COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 Optionally substituted with 1 to 3 groups selected from cycloalkyl.

[0031] In certain embodiments, R and R are each independently H, deuterium, halogen, C 1~4 Alkyl, and C 1~4 alkoxy, where alkyl and alkoxy are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH; optionally, R6 and R7 form =O; Optionally, two R5 on adjacent ring atoms, two R6 on adjacent ring atoms, or R5 and R6 on adjacent ring atoms in X1, X2, X3, and X4, together with the atoms to which they are attached, form a double bond; Z is CH or N.

[0032] The compounds of formulae (I) to (III) are required to fulfill one of the conditions (1) to (4): (1) A: [ka] , 6-membered heteroaryl, or 5-10 membered non-aromatic heterocycle, where the heteroaryl and non-aromatic heterocycle contain 1-3 heteroatoms selected from N, S and O, and A is optionally substituted with 1-3 R groups; * indicates a terminal end attached to an alkyl carbon atom; Ring B is C 3~12 a carbocycle or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S and O; Each R8 is independently H, ═O, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, -SC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxyl, NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COOH, -COC 1~4 Alkyl, -COOC 1~4 Alkyl, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 alkyl, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, and O; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle groups in the case of R8 are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH; Cy is substituted or unsubstituted [ka] In certain embodiments, A is not: [ka] , 6-membered heteroaryl, or 5-7 membered non-aromatic monocyclic heterocycle, where the heteroaryl and non-aromatic monocyclic heterocycle contain 1-3 heteroatoms selected from N, S and O, and A is optionally substituted with 1-3 R8 groups; * indicates a terminal end attached to an alkyl carbon atom; Ring B is C 4~6 a carbocycle or a 5-6 membered heterocycle containing 1-3 heteroatoms selected from N, S and O; Each R8 is independently H, ═O, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, -SC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, cyano, hydroxyl, -COOH, NH2, and C 3~6 cycloalkyl, where alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH; In other particular embodiments, A is [ka] wherein ring A is optionally substituted with 1 to 3 R groups; Each R8 is independently halogen, =O, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 cycloalkyl; * indicates a terminal end attached to an alkyl carbon atom; r is an integer from 1 to 3; E is selected from NH, S and O; In other particular embodiments, A is [ka] wherein ring A is optionally substituted with 1 to 3 R groups; and the substituents are located at any substitutable position on ring A, including any substitutable position on the carbon atoms of the benzene ring and on the carbon atoms or heteroatoms of any ring fused to the benzene ring; Each R8 is independently halogen, =O, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, C 1~4 Alkoxy, -SC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 cycloalkyl; * indicates a terminal end attached to an alkyl carbon atom; or (2) A is a 5-membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, and A is optionally substituted with 1-3 R groups; Each R8 is independently H, ═O, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, -SC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxyl, NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COOH, -COC 1~4 Alkyl, -COOC 1~4 Alkyl, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 alkyl, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, and O; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle groups in the case of R8 are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH; Cy is substituted or unsubstituted [ka] in certain embodiments, A is a 5-membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, and A is optionally substituted with 1-3 R groups; Each R8 is independently H, ═O, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, -SC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, cyano, hydroxyl, -COOH, NH2, and C 3~6 cycloalkyl; alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH; Cy is substituted or unsubstituted [ka] In certain embodiments, A is not: [ka] wherein A is optionally substituted with 1 to 3 R groups; Each R8 is independently halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 cycloalkyl; Z1 and Z2 are each independently CH or N; Z3 is S, O or NH; * indicates a terminal end attached to an alkyl carbon atom; In certain embodiments, A is [ka] A is halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, and C 3~6 optionally substituted with 1 to 3 groups selected from cycloalkyl; Cy, [ka] and * indicates a terminal end attached to an alkyl carbon atom; or (3) A: [ka] where: * indicates a terminal end attached to an alkyl carbon atom; R A1 , R A2 , R A3 , and R A4 are each independently R8, and R A1 , R A2 , R A3 , and R A4 but not simultaneously H; Each R8 is independently H, ═O, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, -SC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxyl, NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COOH, -COC 1~4 Alkyl, -COOC 1~4 Alkyl, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 alkyl, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, and O; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle groups in the case of R8 are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH; Cy is a 5-12 membered monocyclic heterocycle containing 1-3 heteroatoms selected from N, S and O, and the monocyclic heterocycle is preferably selected from deuterium, ═O, halogen, cyano, hydroxyl, NH, —COOH, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxy C 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkoxy, C 1~6 Alkoxyalkyl, HaloC 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COC 1~4 Alkyl, -COOC 1~4 Alkyl, -CONH2, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)NH2, -S(O)NHC 1~4 Alkyl, -S(O)N(C 1~4 alkyl)2, -S(O)2NH2, -S(O)2NHC 1~4 Alkyl, and -S(O)2N(C 1~4 alkyl)2; Cy is substituted or unsubstituted [ka] In certain embodiments, A is not: [ka] where: * indicates a terminal end attached to an alkyl carbon atom; R A1 , R A2 , R A3 , and R A4 are each independently R8, and R A1 , RA2 , R A3 , and R A4 but not simultaneously H; Each R8 is independently H, ═O, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, -SC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, cyano, hydroxyl, -COOH, NH2, and C 3~6 cycloalkyl; alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH; Cy is a 5-8 membered monocyclic heterocycle containing 1-3 heteroatoms selected from N, S and O, and the monocyclic heterocycle is selected from =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxy C 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkoxy, C 1~6 Alkoxyalkyl, HaloC 1~4 Alkoxy, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COC 1~4 Alkyl, -CONH2, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)NH2, -S(O)NHC 1~4 Alkyl, -S(O)N(C 1~4 alkyl)2, -S(O)2NH2, -S(O)2NHC 1~4 Alkyl, and -S(O)2N(C 1~4 alkyl)2; In certain embodiments, A is [ka] where: * indicates a terminal end attached to an alkyl carbon atom; R A1 , R A2 , R A3 , and R A4 are each independently R8, and R A1 , R A2 , R A3 , and R A4 but not simultaneously H; Each R8 is independently H, deuterium, halogen, or C 1~4 Alkyl, C 1~4 alkoxy, cyano, hydroxyl, NH2, and COOH, where the alkyl and alkoxy are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH; Cy, [ka] and; or (4) A: [ka] where: * indicates a terminal end attached to an alkyl carbon atom; R1, R2, and R3 are each independently H, deuterium, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 cycloalkyl, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S and O, where the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are selected from halogen, C 1~4 optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and -COOH, where R1, R2, and R3 are not simultaneously H; Optionally, R and R together with the carbon atom to which they are attached form a C 3~6 Form a cycloalkyl or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S and O, where the cycloalkyl or heterocycle is ═O, halogen, cyano, hydroxyl, NH2, —COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 optionally substituted with 1 to 3 groups selected from cycloalkyl; In certain embodiments, A is [ka] where: * indicates a terminal end attached to an alkyl carbon atom; R1, R2, and R3 are each independently H, deuterium, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, and C 2~6 alkynyl, wherein alkyl, alkoxy, alkenyl, and alkynyl are selected from halogen, C 1~4 optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and COOH, where R1, R2, and R3 are not simultaneously H; Optionally, R and R together with the carbon atom to which they are attached form a C 3~6 Forms a cycloalkyl, where the cycloalkyl is =O, halogen, cyano, hydroxyl, NH2, COOH, C 1~4 Alkyl, C 2~6 Alkenyl, and C 2~6 optionally substituted with 1 to 3 groups selected from alkynyl; In certain embodiments, A is [ka] where: * indicates a terminal end attached to an alkyl carbon atom; R1, R2, and R3 are each independently H, deuterium, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, and C 2~6 alkynyl, wherein alkyl, alkoxy, alkenyl, and alkynyl are selected from halogen, C 1~4 optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and COOH, where R1, R2, and R3 are not simultaneously H; Optionally, R and R together with the carbon atom to which they are attached form a C 3~6 It forms a cycloalkyl, which is optionally substituted with one to three groups selected from halogen, cyano, hydroxyl, NH2, and COOH.

[0033] In the present invention, [ka] indicates the binding site.

[0034] More specifically, as a first technical solution of the present invention, the present invention provides a compound of formula (I) or a stereoisomer, deuterated product, co-crystal, solvate or pharma- ceutically acceptable salt thereof: [ka] In the formula, ring G is a 5- to 12-membered carbocyclic ring, a 5- to 12-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from N, S and O, or a ring represented by the formula (I-1): [ka] is a fused ring of L1 is bonded to ring G by replacing any hydrogen atom on a ring atom (e.g., a carbon atom on a 5- to 12-membered carbocyclic ring, a ring carbon atom or ring heteroatom on a 5- to 12-membered monocyclic heterocyclic ring, and a ring carbon atom or ring heteroatom on a fused ring of formula (I-1)), and the carbocyclic ring or monocyclic heterocyclic ring is bonded to ring G by replacing any hydrogen atom on the ring atom (e.g., a carbon atom on a 5- to 12-membered carbocyclic ring, a ring carbon atom or ring heteroatom on a fused ring of formula (I-1)), and the carbocyclic ring or the ... G optionally substituted with a group; Optionally, formula (I-1) has the structure [ka] and optionally, formula (I-1) has the structure [ka] having Each R G are independently deuterium, SF5, =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, haloC 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkyloxy, C 3~6 Cycloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COC 1~4 Alkyl, -COOC 1~4 Alkyl, -CONH2, -CONHC 1~4 Alkyl, -CONHC 3~6 Cycloalkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 Alkyl, -NHCOC 3~6 Cycloalkyl, -P(O)(C 1~4 Alkyl)2, -S(O)C 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)C 3~6 Cycloalkyl, -S(O)NH2, -S(O)NHC 1~4 Alkyl, -S(O)N(C 1~4 R is selected from -S(O)NH, -S(O)-NH, and a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O; G But deuterium, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxy C 1~4 Alkyl, -CONH2, NH2, C 1~6Optionally, the 5-7 membered heterocycle is further substituted with 1-3 groups selected from alkoxy, hydroxyl, -COOH, halogen, and a 5-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the 5-7 membered heterocycle is further substituted with ═O, halogen, cyano, C 1~4 Alkyl and haloC 1~4 optionally substituted with 1 to 2 groups selected from alkyl; Cy is a 5-12 membered heterocycle containing 1-3 heteroatoms selected from N, S and O, and the heterocycle is preferably deuterium, ═O, halogen, cyano, hydroxyl, NH2, —COOH, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxy C 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkyloxy, C 1~6 Alkoxyalkyl, HaloC 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COC 1~4 Alkyl, -COOC 1~4 Alkyl, -CONH2, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)NH2, -S(O)NHC 1~4 Alkyl, -S(O)N(C 1~4 alkyl)2, -S(O)2NH2, -S(O)2NHC 1~4 Alkyl, and -S(O)2N(C 1~4 alkyl)2; W is C(=O), C(=S), C(=NR W ), S(=O) or S(=O)2; M is NR M or O; R W is OH, CN or C 1~4 is alkyl; R M But, H, C 1~4 Alkyl or C 3~6 is cycloalkyl; R1, R2, and R3 are each independently H, deuterium, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 cycloalkyl, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S and O, where the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are selected from halogen, C 1~4 optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and -COOH; Optionally, R and R together with the carbon atom to which they are attached form a C 3~6 Form a cycloalkyl or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S and O, where the cycloalkyl or heterocycle is ═O, halogen, cyano, hydroxyl, NH2, —COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 optionally substituted with 1 to 3 groups selected from cycloalkyl; L1 is a bond, C 1~3 Alkylene, -NH-, -N(C 1~4 Alkyl)-, -O-, -S-, C 2~6 Alkenylene, C 2~6 Alkynylene, -CO-, or -CONH-, wherein the alkylene, alkenylene, or alkynylene is halogen, C 1~4 optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and -COOH; Y1 and Y2 are each independently selected from CR4 and N; Each R4 is independently H, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxyl, NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COOH, -COC 1~4 Alkyl, -COOC 1~4 Alkyl, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 and alkyl, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S and O, where the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycle groups in the case of R4 are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2 and -COOH. X1, X2, X3, and X4 are each independently selected from a bond, NR5, O, CR6R7, S, S(O), and S(O)2, and no more than one of X1, X2, X3, and X4 is a bond; Each R5 is independently H, C 1~4 Alkyl, -COC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 cycloalkyl, where alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH; R6 and R7 are each independently H, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 cycloalkyl, cyano, hydroxyl, NH2, -COOH, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, and O, where the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH; optionally, R6 and R7 form =O; Optionally, two R5 on adjacent ring atoms, two R6 on adjacent ring atoms, or R5 and R6 on adjacent ring atoms in X1, X2, X3, and X4, together with the atoms to which they are attached, form a double bond; Optionally, R and R on the same carbon atom, together with the carbon atom to which they are attached, may be C 3~12 Form a carbocycle or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S and O, where the carbocycle or heterocycle is ═O, halogen, cyano, hydroxyl, NH2, —COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 cycloalkyl; however: (1) A: [ka] , 6-membered heteroaryl, or 5-10 membered non-aromatic heterocycle, A is optionally substituted with 1-3 R groups; * indicates a terminal end attached to an alkyl carbon atom; Ring B is C 3~12 A carbocycle or a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, wherein the carbocycle or heterocycle is ═O, halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, C 1~4 Alkoxy, -SC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 optionally substituted with 1 to 3 groups selected from cycloalkyl; Each R8 is independently H, ═O, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, -SC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6Cycloalkyl, cyano, hydroxyl, NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COOH, -COC 1~4 Alkyl, -COOC 1~4 Alkyl, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 alkyl, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, and O; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle groups in the case of R8 are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH; Cy is substituted or unsubstituted [ka] Not; or (2) A is a 5-membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, and A is optionally substituted with 1-3 R groups; Each R8 is independently H, ═O, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, -SC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxyl, NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COOH, -COC 1~4 Alkyl, -COOC 1~4 Alkyl, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4alkyl, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, and O; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle groups in the case of R8 are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH; Cy is substituted or unsubstituted [ka] Not; or (3) A: [ka] where: * indicates a terminal end attached to an alkyl carbon atom; R A1 , R A2 , R A3 , and R A4 are each independently R8, and R A1 , R A2 , R A3 , and R A4 but not simultaneously H; Each R8 is independently H, ═O, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, -SC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, cyano, hydroxyl, NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COOH, -COC 1~4 Alkyl, -COOC 1~4 Alkyl, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4alkyl, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, and O; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle groups in the case of R8 are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH; Cy is a 5-12 membered monocyclic heterocycle containing 1-3 heteroatoms selected from N, S and O, and the monocyclic heterocycle is preferably selected from deuterium, ═O, halogen, cyano, hydroxyl, NH, —COOH, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxy C 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkyloxy, C 1~6 Alkoxyalkyl, HaloC 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COC 1~4 Alkyl, -COOC 1~4 Alkyl, -CONH2, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)NH2, -S(O)NHC 1~4 Alkyl, -S(O)N(C 1~4 alkyl)2, -S(O)2NH2, -S(O)2NHC 1~4 Alkyl, and -S(O)2N(C 1~4 alkyl)2; Cy is substituted or unsubstituted [ka] Not; or (4) A: [ka] where: * indicates a terminal end attached to an alkyl carbon atom; R1, R2, and R3 are each independently H, deuterium, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 cycloalkyl, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S and O, where the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are selected from halogen, C 1~4 optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and -COOH, where R1, R2, and R3 are not simultaneously H; Optionally, R and R together with the carbon atom to which they are attached form a C 3~6 Form a cycloalkyl or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S and O, where the cycloalkyl or heterocycle is ═O, halogen, cyano, hydroxyl, NH2, —COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 Optionally substituted with 1 to 3 groups selected from cycloalkyl.

[0035] As a second technical solution of the present invention, the present invention provides a compound of formula (I) or its stereoisomer, deuterated product, co-crystal, solvate or pharma- ceutically acceptable salt, wherein the compound is represented by formula (II): [ka] and each group is as described in the first technical solution.

[0036] As a third technical solution of the present invention, the present invention provides a compound of formula (II) or a stereoisomer, deuterated product, co-crystal, solvate or pharma- ceutically acceptable salt thereof, wherein: Ring G is a 5- to 9-membered monocyclic carbocycle, a 5- to 7-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, S and O, or a ring represented by the formula (I-1) [ka] is a fused ring of L1 is bonded to ring G by replacing any hydrogen atom on the ring atom, and the monocyclic carbocyclic or monocyclic heterocyclic ring is joined to ring G by 1 to 3 R G optionally substituted with a group; Optionally, formula (I-1) has the structure [ka] and optionally, formula (I-1) has the structure [ka] having Each R G are independently deuterium, SF5, =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, haloC 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkyloxy, C 3~6 Cycloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COC 1~4 Alkyl, -COOC 1~4 Alkyl, -CONH2, -CONHC 1~4 Alkyl, -CONHC 3~6 Cycloalkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 Alkyl, -NHCOC 3~6 Cycloalkyl, -P(O)(C 1~4 Alkyl)2, -S(O)C 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)C 3~6 Cycloalkyl, -S(O)NH2, -S(O)NHC 1~4Alkyl, -S(O)N(C 1~4 R is selected from -S(O)NH, -S(O)-NH, and a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O; G But deuterium, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxy C 1~4 Alkyl, -CONH2, NH2, C 1~6 Optionally, the 5-7 membered heterocycle is further substituted with 1-3 groups selected from alkoxy, hydroxyl, -COOH, halogen, and a 5-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the 5-7 membered heterocycle is further substituted with ═O, halogen, cyano, C 1~4 Alkyl and haloC 1~4 optionally substituted with 1 to 2 groups selected from alkyl; Cy is a 5-8 membered monocyclic heterocycle, a 7-10 membered spirocyclic heterocycle, a 6-9 membered bridged heterocycle, or a 6-10 membered fused heterocycle containing 1-3 heteroatoms selected from N, S, and O, and Cy is ═O, halogen, cyano, hydroxyl, NH, —COOH, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxy C 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkyloxy, C 1~6 Alkoxyalkyl, HaloC 1~4 Alkoxy, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COC 1~4 Alkyl, -CONH2, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)NH2, -S(O)NHC 1~4 Alkyl, -S(O)N(C 1~4 alkyl)2, -S(O)2NH2, -S(O)2NHC 1~4 Alkyl, and -S(O)2N(C 1~4alkyl)2; R1, R2, and R3 are each independently H, deuterium, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, and C 2~6 alkynyl, wherein alkyl, alkoxy, alkenyl, and alkynyl are selected from halogen, C 1~4 optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and COOH; Optionally, R and R together with the carbon atom to which they are attached form a C 3~6 A cycloalkyl or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S and O, wherein the cycloalkyl or heterocycle is selected from halogen, cyano, hydroxyl, NH2, COOH, and C 1~4 optionally substituted with 1 to 3 groups selected from alkyl; Each R4 is independently H, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 cycloalkyl, cyano, hydroxyl, and NH2; alkyl, alkenyl, alkynyl, and cycloalkyl in the case of R4 are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH; R6 and R7 are each independently H, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 cycloalkyl, where alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH; optionally, R6 and R7 form =O; Optionally, two R5 on adjacent ring atoms, two R6 on adjacent ring atoms, or R5 and R6 on adjacent ring atoms in X1, X2, X3, and X4, together with the atoms to which they are attached, form a double bond; Optionally, R and R on the same carbon atom, together with the carbon atom to which they are attached, may be C 3~6 A cycloalkyl or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S and O, wherein the cycloalkyl or heterocycle is ═O, halogen, cyano, hydroxyl, NH2, COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 cycloalkyl; however: (1) A: [ka] , 6-membered heteroaryl, or 5-7 membered non-aromatic monocyclic heterocycle, where the heteroaryl and non-aromatic monocyclic heterocycle contain 1-3 heteroatoms selected from N, S and O, and A is optionally substituted with 1-3 R8 groups; * indicates a terminal end attached to an alkyl carbon atom; Ring B is C 4~6 A carbocycle or a 5-6 membered heterocycle containing 1-3 heteroatoms selected from N, S and O, wherein the carbocycle or heterocycle is ═O, halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, C 1~4 Alkoxy, -SC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 optionally substituted with 1 to 3 groups selected from cycloalkyl; Each R8 is independently H, ═O, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, -SC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, cyano, hydroxyl, -COOH, NH2, and C 3~6 cycloalkyl; alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH; Cy is substituted or unsubstituted [ka] Not; or (2) A is a 5-membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, and A is optionally substituted with 1-3 R groups; Each R8 is independently H, ═O, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, -SC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, cyano, hydroxyl, -COOH, NH2, and C 3~6 cycloalkyl; alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH; Cy is substituted or unsubstituted [ka] Not; or (3) A: [ka] where: * indicates a terminal end attached to an alkyl carbon atom; R A1 , R A2 , R A3 , and R A4 are each independently R8, and R A1 , R A2 , R A3 , and R A4but not simultaneously H; Each R8 is independently H, ═O, deuterium, halogen, or C 1~4 Alkyl, C 1~4 Alkoxy, -SC 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, cyano, hydroxyl, -COOH, NH2, and C 3~6 cycloalkyl; alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH; Cy is a 5-8 membered monocyclic heterocycle containing 1-3 heteroatoms selected from N, S and O, and the monocyclic heterocycle is selected from =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxy C 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkyloxy, C 1~6 Alkoxyalkyl, HaloC 1~4 Alkoxy, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COC 1~4 Alkyl, -CONH2, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)C 1~4 Alkyl, -S(O)NH2, -S(O)NHC 1~4 Alkyl, -S(O)N(C 1~4 alkyl)2, -S(O)2NH2, -S(O)2NHC 1~4 Alkyl, and -S(O)2N(C 1~4 alkyl)2; Cy is substituted or unsubstituted [ka] Not; or (4) A: [ka] where: * indicates a terminal end attached to an alkyl carbon atom; R1, R2, and R3 are each independently H, deuterium, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, and C 2~6 alkynyl, wherein alkyl, alkoxy, alkenyl, and alkynyl are selected from halogen, C 1~4 optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and COOH, where R1, R2, and R3 are not simultaneously H; Optionally, R and R together with the carbon atom to which they are attached form a C 3~6 Forms a cycloalkyl, where the cycloalkyl is =O, halogen, cyano, hydroxyl, NH2, COOH, C 1~4 Alkyl, C 2~6 Alkenyl, and C 2~6 optionally substituted with 1 to 3 groups selected from alkynyl; The undefined groups are as described in the second technical solution.

[0037] As a fourth technical solution of the present invention, the present invention provides a compound of formula (I) or formula (II), or a stereoisomer, deuterated product, co-crystal, solvate or pharma- ceutically acceptable salt thereof, wherein the compound is represented by formula (III): [ka] wherein Rc is H, =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxy C 1~4 Alkyl, C 1~4 Alkoxy, C 1~6 Alkoxyalkyl or haloC 1~4 is alkoxy; R1, R2, and R3 are each independently H, deuterium, halogen, C 1~4 Alkyl, and C 1~4 alkoxy, wherein alkyl and alkoxy are selected from halogen, C 1~4 optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and COOH; Optionally, R and R together with the carbon atom to which they are attached form a C 3~6 Forms a cycloalkyl, where the cycloalkyl is halogen, cyano, hydroxyl, NH2, COOH, and C 1~4 optionally substituted with 1 to 3 groups selected from alkyl; L1 is a bond, C 1~3 Alkylene, -NH-, -O-, -S-, C 2~6 Alkenylene, C 2~6 alkynylene, or -CO-, where the alkylene, alkenylene, or alkynylene is optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, and NH; Each R5 is independently H, C 1~4 Alkyl, and C 3~6 cycloalkyl, where alkyl and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH; R6 and R7 are each independently H, deuterium, halogen, C 1~4 Alkyl, and C 1~4 alkoxy, where alkyl and alkoxy are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH; optionally, R6 and R7 form =O; Optionally, two R5 on adjacent ring atoms, two R6 on adjacent ring atoms, or R5 and R6 on adjacent ring atoms in X1, X2, X3, and X4, together with the atom to which they are attached, form a double bond; however: (1) A: [ka] wherein ring A is optionally substituted with 1 to 3 R groups; and the substituents are located at any substitutable position on ring A, including any substitutable position on the carbon atoms of the benzene ring and on the carbon atoms or heteroatoms of any ring fused to the benzene ring; Each R8 is independently halogen, =O, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 cycloalkyl; * indicates a terminal end attached to an alkyl carbon atom; r is an integer from 1 to 3; E is selected from NH, S and O; or (2) A: [ka] wherein A is optionally substituted with 1 to 3 R groups; Each R8 is independently halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 cycloalkyl; Z1 and Z2 are each independently CH or N; Z3 is S, O or NH; * indicates a terminal end attached to an alkyl carbon atom; or (3) A: [ka] where: * indicates a terminal end attached to an alkyl carbon atom; R A1 , R A2 , R A3 , and R A4 are each independently R8, and R A1, R A2 , R A3 , and R A4 but not simultaneously H; Each R8 is independently H, deuterium, halogen, or C 1~4 Alkyl, C 1~4 alkoxy, cyano, hydroxyl, NH2, and COOH, where the alkyl and alkoxy are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH; or (4) A: [ka] where: * indicates a terminal end attached to an alkyl carbon atom; R1, R2, and R3 are each independently H, deuterium, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, and C 2~6 alkynyl, wherein alkyl, alkoxy, alkenyl, and alkynyl are selected from halogen, C 1~4 optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and COOH, where R1, R2, and R3 are not simultaneously H; Optionally, R and R together with the carbon atom to which they are attached form a C 3~6 forming a cycloalkyl, the cycloalkyl being optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH; The undefined groups are as described in the third technical solution.

[0038] As a fifth technical solution of the present invention, the present invention provides a compound of formula (III) or a stereoisomer, deuterated product, co-crystal, solvate or pharma- ceutically acceptable salt thereof, wherein: Ring G is 1 to 3 R G cyclopentane, cyclohexane, cycloheptane, benzene rings, optionally substituted with groups; [ka] or ring G is [ka] and Optionally, formula (I-2) has the structure [ka] and optionally, formula (I-2) has the structure [ka] having L1 is bonded to ring G by replacing any hydrogen atom on the ring atom; Each R G are independently deuterium, SF5, =O, halogen, cyano, hydroxyl, NH2, C 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -COC 1~4 Alkyl, -CONH2, -CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2, -NHCOC 1~4 Alkyl, -P(O)(C 1~4 alkyl)2, and a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O; R G But deuterium, C 1~4 Alkyl, haloC 1~4 Alkyl, Hydroxy C 1~4 Alkyl, -CONH2, NH2, C 1~6 Optionally, the 5-7 membered heterocycle is further substituted with 1-3 groups selected from alkoxy, hydroxyl, halogen, and a 5-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the 5-7 membered heterocycle is further substituted with ═O, halogen, cyano, C 1~4Alkyl and haloC 1~4 optionally substituted with 1 to 2 groups selected from alkyl, however: (1) A: [ka] wherein ring A is optionally substituted with 1 to 3 R groups; and the substituents are located at any substitutable position on ring A, including any substitutable position on the carbon atoms of the benzene ring and on the carbon atoms or heteroatoms of any ring fused to the benzene ring; Each R8 is independently =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 cycloalkyl; * represents a terminal bond to an alkyl carbon atom; or (2) A: [ka] A is halogen, cyano, hydroxyl, NH2, -COOH, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 3~6 optionally substituted with 1 to 3 groups selected from cycloalkyl; * indicates a terminal end attached to an alkyl carbon atom; or (3) A: [ka] where: * indicates a terminal end attached to an alkyl carbon atom; R A1 , R A2 , R A3 , and R A4 are each independently R8, and R A1 , R A2 , R A3, and R A4 but not simultaneously H; Each R8 is independently H, deuterium, halogen, or C 1~4 Alkyl, C 1~4 alkoxy, cyano, hydroxyl, NH2, and COOH, where the alkyl and alkoxy are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH; or (4) A: [ka] where: * indicates a terminal end attached to an alkyl carbon atom; R1, R2, and R3 are each independently H, deuterium, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 2~6 Alkenyl, and C 2~6 alkynyl, wherein alkyl, alkoxy, alkenyl, and alkynyl are selected from halogen, C 1~4 optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and COOH, where R1, R2, and R3 are not simultaneously H; Optionally, R and R together with the carbon atom to which they are attached form a C 3~6 forming a cycloalkyl, the cycloalkyl being optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH; The undefined groups are as described in the fourth technical solution.

[0039] As a sixth technical solution of the present invention, the present invention provides a compound of formula (III) or a stereoisomer, deuterated product, co-crystal, solvate or pharma- ceutically acceptable salt thereof, wherein: [ka] But the following structure: [ka] is selected from one of Undefined groups are as described in the fifth technical solution.

[0040] As a seventh technical solution of the present invention, the present invention provides a compound of formula (I) or its stereoisomer, deuterated product, co-crystal, solvate or pharma- ceutically acceptable salt, wherein the compound is represented by formula (IV): [ka] wherein Rc is H, halogen, C 1~2 Alkyl or C 1~2 is alkoxy; R1, R2, and R3 are each independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, methoxy, or ethoxy, wherein the methyl, ethyl, methoxy, or ethoxy is optionally substituted with 1 to 3 groups selected from F, Cl, Br, cyano, hydroxyl, and NH2; Z is CH or N; Ring G is 1 to 2 R G a benzene ring, optionally substituted with a group; [ka] and; Each R G is independently selected from F, Cl, Br, I, methyl, ethyl, propyl, SF5, and CN, where methyl, ethyl, or propyl is optionally further substituted with 1 to 3 groups selected from deuterium, F, Cl, Br, and I.

[0041] As an eighth technical solution of the present invention, the present invention provides a compound of formula (I) or a stereoisomer, deuterated product, co-crystal, solvate or pharma- ceutically acceptable salt thereof, wherein the compound has the following structure: [ka] [ka] is selected from one of the following:

[0042] As a ninth technical solution of the present invention, the present invention provides a compound of formula (I) or its stereoisomer, deuterated product, co-crystal, solvate or pharma- ceutically acceptable salt, wherein the compound has the following structure: [ka] [ka] is selected from one of the following:

[0043] As a tenth technical solution of the present invention, the present invention also provides a pharmaceutical composition comprising the compound according to any one of the first to ninth technical solutions, or a stereoisomer, deuterated product, cocrystal, solvate or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier and / or excipient.

[0044] The present invention also provides the use of the compound according to any one of the first to ninth technical solutions, or its stereoisomer, deuterated product, cocrystal, solvate or pharma- ceutically acceptable salt, or the composition according to the tenth technical solution, in the preparation of a medicament for treating a disease mediated by dipeptidyl peptidase 1.

[0045] Furthermore, the disease mediated by dipeptidyl peptidase 1 is selected from obstructive airways disease, bronchiectasis, cystic fibrosis, asthma, emphysema, chronic obstructive pulmonary disease and other diseases.

[0046] Synthetic Route Those skilled in the art can prepare the compounds of the present invention according to known organic synthesis techniques, in which the starting materials used are commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are obtained from legitimate commercial sources, such as Titan Technology Co., Ltd., Energy Chemical Co., Ltd., Shanghai Demo Co., Ltd., Chengdu Kelong Chemical Co., Ltd., Accela ChemBio Co., Ltd., PharmaBlock Sciences (Nanjing), Inc., WuXi Apptec Co., Ltd., J&K Scientific Co., Ltd., etc.

[0047] References and monographs in the art detail the synthesis of reactants that may be used to prepare the compounds described herein or point to papers describing the preparation methods for reference. References and monographs include “Synthetic Organic Chemistry”, John Wiley&Sons, Inc., New York; SRSandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; HOHouse, “Modern Synthetic Reactions”, 2nd Ed., WABenjamin, Inc. Menlo Park, Calif. 1972; TLGilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley&Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992; Fuhrhop, J. and Penzlin G. “Organic Synthesis:Concepts,Methods,Starting Materials”,Second,Revised and Enlarged Edition(1994)John Wiley&Sons ISBN:3-527-29074-5;Hoffman,RV“Organic Chemistry,An Intermediate Text”(1996)Oxford University Press,ISBN 0-19-509618-5;Larock,RC“Comprehensive Organic Transformations:A Guide to Functional Group Preparations”2nd Edition(1999)Wiley-VCH,ISBN:0-471-19031-4;March,J."Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992), John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor), "Modern Carbonyl Chemistry" (2000), Wiley-VCH, ISBN: 3-527-29871-1; Patai, S., "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992), Interscience, ISBN: 0-471-93022-9; Solomons, T.W.G., "Organic Chemistry" 7th Edition (2000), John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993), Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999), John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942 - 2000), John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups", John Wiley & Sons, in 73 volumes.

[0048] Specific and similar reactants can be selectively identified by the index of known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, which is available in most public or university libraries and online. Known but non-commercially available chemicals in the catalog are optionally prepared by special chemical synthesis plants, where many of the standard chemical supply plants (e.g., those listed above) offer special synthesis services. A reference for the preparation and selection of pharmaceutically acceptable salts of the compounds described herein is P.H. Stahl & C.G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0049] term Unless otherwise specified, the terms of the present invention have the following meanings.

[0050] All carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen contained in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen contained in the groups and compounds of the present invention are optionally further substituted with one or more of their corresponding isotopes, where the isotopes of carbon are 12 C. 13 C and 14 C; isotopes of hydrogen include protium (H), deuterium (also known as heavy hydrogen, D), and tritium (also known as superheavy hydrogen, T); isotopes of oxygen include 16 O. 17 O and 18 O, and the sulfur isotopes are 32 S, 33 S, 34 S and 36 Contains S, and the nitrogen isotopes are 14 N and 15 Contains N, and the fluorine isotopes are 19 Contains F, and the chlorine isotope is 35 Cl and37 The isotopes of bromine include Cl and 79 Br and 81 Contains Br.

[0051] The term "halogen" as used herein refers to F, Cl, Br, I, or an isotope thereof.

[0052] The term "halo" or "substituted with halogen" refers to substitution with one or more groups selected from F, Cl, Br, I, or isotopes thereof, where the upper limit of the number of halogen substituents is equal to the total number of hydrogens that can be replaced in the substituted group. Although not particularly limited, the number of halogen substituents is any integer between 1 and the upper limit, and when the number of halogen substituents is more than 1, the substituted group can be substituted with the same or different halogens. In general, it includes cases where 1 to 5 halogens, 1 to 3 halogens, 1 to 2 halogens, and 1 halogen are substituted.

[0053] The term "deuterium" refers to the deuterium isotope of hydrogen (H).

[0054] The term "deuterated" refers to when hydrogen atoms on alkyl, cycloalkyl, alkylene, aryl, heteroaryl, alkenyl, alkynyl, and other groups are replaced with at least one deuterium isotope, where the upper limit of the number of deuterium substituents is equal to the total number of hydrogen atoms that can be replaced in the group being substituted. Although not particularly limited, the number of deuterium substituents is any integer between 1 and the upper limit, and is preferably 1 to 20 deuterium atoms, more preferably 1 to 10 deuterium atoms, more preferably 1 to 6 deuterium atoms, and even more preferably 1 to 3 deuterium atoms.

[0055] Base “C” x~y " refers to a group containing x to y carbon atoms, e.g., "C 1~6 "Alkyl" refers to an alkyl containing 1 to 6 carbon atoms.

[0056] The term "alkyl" refers to a monovalent linear or branched saturated aliphatic hydrocarbon group. Unless otherwise specified, alkyl refers to an alkyl containing 1 to 20 carbon atoms, preferably an alkyl containing 1 to 8 carbon atoms, more preferably an alkyl containing 1 to 6 carbon atoms, and even more preferably an alkyl containing 1 to 4 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isoamyl, neopentyl, n-hexyl, and various branched isomers thereof.

[0057] The term "alkylene" refers to a divalent linear or branched saturated alkyl. Examples of alkylene include, but are not limited to, methylene, ethylidene, and the like.

[0058] The term "haloalkyl" refers to an alkyl group in which one or more hydrogens are replaced with one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine, or isotopes thereof), where the upper limit of the number of halogen substituents is equal to the total number of hydrogens that can be replaced in the alkyl group. Although not limited, the number of halogen substituents is any integer between 1 and the upper limit. In general, an alkyl group is substituted with 1-5 halogens, 1-3 halogens, 1-2 halogens, or 1 halogen; if the number of halogen substituents is more than 1, the substituted groups can be substituted with the same or different halogens; specific examples include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0059] The term "alkoxy" or "alkyloxy" refers to -O-alkyl, e.g., -OC 1~8 Alkyl, -OC 1~6 Alkyl, -OC 1~4 Alkyl or -OC 1~2Refers to alkyl. Non-limiting examples of alkoxy or alkyloxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropoxy, cyclobutoxy, etc. Alkoxy can be optionally substituted with a substituent.

[0060] The term "haloalkoxy" refers to -O-haloalkyl, e.g., -O-haloC 1~8 Alkyl, -O-HaloC 1~6 Alkyl, -O-HaloC 1~4 Alkyl or -O-haloC 1~2 It refers to alkyl; the upper limit of the number of halogen substituents is equal to the total number of hydrogens that can be substituted in the substituted group. Although not particularly limited, the number of halogen substituents is any integer between 1 and the upper limit, and preferably 1-5 halogens, 1-3 halogens, 1-2 halogens, and 1 halogen; if the number of halogen substituents is more than 1, the substituted group can be substituted with the same or different halogens; non-limiting examples of haloalkoxy include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, etc.

[0061] The term "alkylamino" or "alkamino" refers to amino substituted with one or two alkyls, also described as -N-(alkyl)2 or -NH-alkyl, the latter also known as monoalkylamino. Non-limiting examples of alkylamino or alkamino include dimethylamino, monomethylamino, diethylamino, monoethylamino, etc.

[0062] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing at least one carbon-carbon double bond (C=C) and generally contains 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and even further such as 2 to 4 carbon atoms. Examples of alkenyl include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, Examples include 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, 1,4-hexadiene, and the like; alkenyls can be optionally further substituted with substituents.

[0063] The term "alkenylene" refers to a straight or branched divalent unsaturated hydrocarbon group containing at least one carbon-carbon double bond (C=C). Unless otherwise specified, alkenylene contains 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and non-limiting examples of alkenylene include ethenylene. Alkenylene can be optionally substituted with substituents.

[0064] The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing at least one carbon-carbon triple bond (C≡C) and generally contains 2 to 18 carbon atoms; further, alkynyls contain 2 to 8 carbon atoms; further, alkynyls contain 2 to 6 carbon atoms, and even further, alkynyls contain 2 to 4 carbon atoms. Examples of alkynyls include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, and the like; alkynyls can be optionally substituted with substituents.

[0065] The term "alkynylene" refers to a straight or branched, divalent unsaturated hydrocarbon group containing a carbon-carbon triple bond (C≡C), generally containing 2 to 6 carbon atoms, and further containing 2 to 4 carbon atoms. Non-limiting examples of alkynylene include ethynylene, propynylene, and butynylene, where alkynylene may be optionally substituted with substituents. The term "cycloalkyl" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group that does not contain ring heteroatoms. Cycloalkyls may be monocyclic, bicyclic, or polycyclic, and bicyclic or polycyclic cycloalkyls may be in the form of fused, spiro, bridged, or combinations thereof, and may contain one or more aromatic rings, although the ring system as a whole is non-aromatic, and the attachment site may be on an aromatic or non-aromatic ring. Typically, cycloalkyls contain 3 to 20 carbon atoms; further, cycloalkyls contain 3 to 8 carbon atoms; further, cycloalkyls contain 3 to 6 carbon atoms; when cycloalkyls are monocyclic cycloalkyls, cycloalkyls contain 3 to 15 carbon atoms, or 3 to 10 carbon atoms, or 3 to 8 carbon atoms, or 3 to 6 carbon atoms; when cycloalkyls are bicyclic or polycyclic cycloalkyls, cycloalkyls contain 5 to 12 carbon atoms, or 5 to 11 carbon atoms, or 6 to 10 carbon atoms; non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl, [ka] and the like, where cycloalkyl can be optionally substituted with substituents. The term "cycloalkylene" refers to a divalent saturated, substituted or unsubstituted cycloalkyl. Non-limiting examples include: [ka] Examples include:

[0066] The term "carbocycle" or "carbocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated, and aromatic or non-aromatic carbocyclic group, including monocyclic carbocycles, bicyclic bridged rings, bicyclic fused rings, bicyclic spiro rings, polycyclic rings containing at least three rings, and the like, generally containing 3 to 14 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 6 to 8 carbon atoms or 3 to 6 carbon atoms. In non-limiting examples, monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl; bicyclic bridged rings include, [ka] and the like; bicyclic fused rings include, [ka] and the like; bicyclic spiro rings include [ka] and the like; tricyclic rings include [ka] etc.

[0067] The term "heterocycle" or "heterocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated aromatic ring or non-aromatic ring, and unless otherwise limited, contains 1 to 5 heteroatoms, preferably 1 to 4 heteroatoms, more preferably 1 to 3 heteroatoms, selected from N, O, or S, and includes monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, bicyclic spiro heterocycles, polycyclic heterocycles containing at least three rings, and the like, preferably 3- to 15-membered heterocycles, more preferably 4- to 14-membered heterocycles, more preferably 4- to 10-membered heterocycles and 5- to 12-membered heterocycles, and even more preferably 5- to 8-membered heterocycles and 5- to 6-membered heterocycles. The heterocycle is preferably a saturated heterocycle, for example, a 5- to 12-membered saturated heterocycle, more preferably a 5- to 8-membered saturated heterocycle, a 7-membered saturated heterocycle, or a 5- to 6-membered saturated heterocycle. The ring atoms N and S of a heterocyclyl can be oxidized to various oxidation states. A heterocyclyl can be attached to a heteroatom or a carbon atom, and non-limiting examples of heterocyclyls include epoxyethyl, azacyclopropyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, piperazinyl, azacycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazoly, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-diphenyl ether, ... thianyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, benzodihydrofuryl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl, [ka] etc.

[0068] The term "heterocyclene" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or nonaromatic, divalent heterocyclic group. Non-limiting examples of heterocyclenes include: [ka] etc.

[0069] The term "aryl" refers to aromatic groups including 5- and 6-membered monocyclic aromatic groups that may contain 0-4 heteroatoms (N, S, and O) and polycyclic systems with at least one aromatic ring. The concept of aryl includes aromatic carbocyclic and heteroaromatic rings, such as phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, etc. Polycyclic (tricyclic or bicyclic) aryls include naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxybenzene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, deazapurine, or indolizine, etc. These aryl groups with heteroatoms in the ring structure may also be called "aromatic heterocycles", "heteroaryls" or "heteroaromatic rings".

[0070] The term "spiro ring" refers to a polycyclic group sharing one carbon atom (called a spiro atom) between the rings, which may contain zero or at least one double or triple bond, and zero to five heteroatoms selected from N, O, S, P, Si and their oxidation states. In general, the spiro ring is a 6- to 14-membered ring, or a 6- to 12-membered ring, or a 6- to 10-membered ring. In general, the spiro ring is a spiro ring formed by a 3-membered ring and a 3-membered ring, a 3-membered ring and a 4-membered ring, a 3-membered ring and a 5-membered ring, a 3-membered ring and a 6-membered ring, a 4-membered ring and a 4-membered ring, a 4-membered ring and a 5-membered ring, a 4-membered ring and a 6-membered ring, a 5-membered ring and a 5-membered ring, or a 5-membered ring and a 6-membered ring. Non-limiting examples of spiro rings include: [ka] and the spiro ring may be optionally substituted with a substituent.

[0071] The term "fused ring" refers to a polycyclic group in which the ring shares two adjacent ring atoms and one chemical bond, and may contain one or more double or triple bonds, and the fused ring may contain 0-5 heteroatoms selected from N, S, O, P, Si and their oxidation states. In general, the fused ring is a 5-membered to 20-membered ring, or a 5-membered to 14-membered ring, or a 5-membered to 12-membered ring, or a 5-membered to 10-membered ring. In general, the fused ring is in the form of a 3-membered fused 4-membered ring (referring to a fused ring formed by a 3-membered ring and a 4-membered ring, either a 3-membered ring or a 4-membered ring may possibly be used as a basic ring according to IUPAC nomenclature; the same hereinafter), a 3-membered fused 5-membered ring, a 3-membered fused 6-membered ring, a 4-membered fused 4-membered ring, a 4-membered fused 5-membered ring, a 4-membered fused 6-membered ring, a 5-membered fused 5-membered ring, a 5-membered fused 6-membered ring, and a 6-membered fused 6-membered ring. Non-limiting examples of fused rings include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene, and [ka] and the fused ring can be optionally substituted with a substituent.

[0072] The term "bridged ring" refers to a ring system in which two non-adjacent ring atoms are shared between the two rings, and the bridged ring may contain one or more double or triple bonds. The bridged ring may contain 0-5 heteroatoms selected from N, S, O, P, Si and their oxidation states. Typically, the bridged ring has 5-20, 5-14, 5-12, or 5-10 ring atoms. Non-limiting examples of bridged rings include adamantane, [ka] Examples include:

[0073] Unless otherwise specified, the term "substituted" or "substituent" refers to any substitution in any position permitted by chemical theory, and the number of substituents is in accordance with the rules of chemical bonding. Exemplary substituents include, but are not limited to:1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Heteroalkyl, C 5~12 Aryl, 5-12 membered heteroaryl, hydroxyl, C 1~6 Alkoxy, C 5~12 Aryloxy, thiol, C 1~6 Alkylthio, cyano, halogen, C 1~6 Alkylthiocarbonyl, C 1~6 Alkylcarbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, amino, phosphonic acid, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 Alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -HC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -NHSO2(C 1~6 Alkyl), -SO2N(C 1~6 Alkyl)2, -SO2NH(C 1~6 Alkyl), -SO2NH2, -SO2C 1~6 Alkyl and the like.

[0074] The term "optional" or "optionally" refers to the fact that the subsequently described event or circumstance may, but does not necessarily, occur, and the description includes cases where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with F" means that the alkyl may, but does not necessarily, be substituted with F, and the description includes cases where the alkyl is substituted with F and cases where the alkyl is not substituted with F.

[0075] Where a substituent is optionally further substituted, groups which cannot be formed in accordance with common chemical knowledge are not included.

[0076] Where a given group is selected from an atom or group such as H or deuterium, and the group is optionally further substituted, it does not include cases where the H or deuterium atom is further substituted.

[0077] The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention which retain the biological effectiveness and properties of the free acids or free bases and which are obtained by reacting the free acids with non-toxic inorganic or organic bases, or by reacting the free bases with non-toxic inorganic or organic acids.

[0078] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or their stereoisomers, solvates, pharma- ceutically acceptable salts, or co-crystals, and other components, including physiologically / pharmaceutical acceptable carriers and / or excipients.

[0079] The term "carrier" refers to a system that does not cause significant irritation to the organism, does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body, the distribution of the drug in the body, control the release rate of the drug, and deliver the drug to the target organ. Non-limiting examples of carriers include microcapsules, microspheres, nanoparticles, liposomes, etc.

[0080] The term "excipient" refers to a substance that is not a therapeutic agent in itself, but is used as a diluent, adjuvant, adhesive and / or vehicle for addition to a pharmaceutical composition, thereby improving its disposal or storage characteristics, or allowing or facilitating the formation of a compound or pharmaceutical composition into a unit dosage form for administration. As known to those skilled in the art, pharma- ceutically acceptable excipients can serve a variety of functions and may be described as wetting agents, buffers, suspending agents, lubricants, emulsifying agents, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents and sweeteners. Examples of pharma- ceutically acceptable excipients include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and croscarmellose (such as croscarmellose sodium); (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter or suppository wax; and (9) oils, such as peanut oil, cottonseed oil, safflower oil, and the like. (10) diols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free distilled water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffers; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other non-toxic compatible materials used in pharmaceuticals.

[0081] The term "stereoisomer" refers to isomers produced as a result of different spatial arrangements of atoms in molecules, including cis-trans isomers, enantiomers, and conformational isomers.

[0082] The term "solvate" refers to a substance formed by a compound of the present invention or a salt thereof and a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces. When the solvent is water, the solvate is a hydrate.

[0083] The term "cocrystal" refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds. The pure states of the API and CCF are both solids at room temperature, and there is a fixed stoichiometric ratio between the various components. Cocrystals are multicomponent crystals, which include both binary cocrystals formed between two neutral solids and multicomponent cocrystals formed between a neutral solid and a salt or solvate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0084] The contents of the present invention will be described in detail by the following examples. If no specific conditions are shown in the examples, conventional conditions are used in the experimental methods. The examples listed are intended to better illustrate the contents of the present invention, but should not be construed as limiting the contents of the present invention. According to the above contents of the present invention, those skilled in the art can make insubstantial changes and adjustments to the embodiments, which still fall within the protection scope of the present invention.

[0085] Detection Method The structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are given in units of 10-6 (ppm). The NMR was determined on a Bruker Avance III 400 and a Bruker Avance 300; the solvents for the determination were deuterated dimethylsulfoxide (DMSO-d6), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD); the internal standard was tetramethylsilane (TMS); MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI); HPLC was determined by Agilent 1260DAD high performance liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM); Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate is used as thin layer chromatography silica plate, the silica gel plate for thin layer chromatography (TLC) has a size of 0.15mm-0.20mm, and the size for separating and purifying products by thin layer chromatography is 0.4mm-0.5mm.

[0086] For column chromatography, Yantai Huanghai silica gel, 200-300 mesh silica gel, is commonly used as the carrier.

[0087] Explanation of abbreviations: Burgess's Reagent: (Methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) X-Phos: 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl DMF: N,N'-dimethylformamide HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate DIPEA: N,N-diisopropylethylamine LDA: Lithium diisopropylamide PE: Petroleum ether EA: Ethyl acetate THF: tetrahydrofuran MeOH: Methanol DCM: dichloromethane TMSOTf: Trimethylsilyl trifluoromethanesulfonate

[0088] Intermediates INT-1: tert-butyl (S)-(1-cyano-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate [ka] Compound 1a (4.50 g, 12.1 mmol, prepared with reference to WO2013041497) was dissolved in 1,4-dioxane (45 ml), and pinacolborane (3.12 g, 24.2 mmol), triethylamine (3.67 g, 36.3 mmol), and Pd(dppf)Cl2 (877 mg, 1.2 mmol) were added. After the addition was completed, the mixture was reacted under microwave at 100 °C for 1 hour. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated. The obtained residue was separated and purified by silica gel column chromatography (eluent: PE:EA (v / v) = 1:0 to 10:1) to obtain INT-1 as a white solid (2.1 g, yield: 46.7%). LCMS m / z = 373.2 [M + 1] + . 1 H NMR (400MHz, CDCl3) δ 7.81(d,2H), 7.29(d,2H), 4.81(s,1H), 4.72(s,1H), 3.15-3.03(m,2H), 1.44(s,9H), 1.34(s,12H).

[0089] INT-2: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate [ka] Compound 2a (2.0 g, 5.8 mmol, prepared with reference to WO 2016016242) was dissolved in ethylene glycol dimethyl ether (40 ml), and bis(pinacolato)diboron (2.23 g, 8.7 mmol), potassium acetate (1.70 g, 17.4 mmol), and Pd(dppf)Cl2 (423.1 mg, 0.58 mmol) were added. After the addition was completed, the mixture was warmed to 90°C and reacted for 3 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated. The obtained residue was separated and purified by silica gel column chromatography (eluent: PE:EA (v / v) = 1:0 to 10:1) to obtain INT-2 as a white solid (2.1 g, yield: 92.1%). LCMS m / z = 335.2 [M + 1-56] + . 1 H NMR (400MHz, CDCl3) δ 7.56(d,1H), 7.50(d,1H), 7.29(d,1H), 4.99(d,1H), 4.82(s,1H), 3.18-3.16(m,2H), 1.42(s,9H), 1.34(s,12H). EXAMPLES

[0090] Example 1: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 1) [ka] Step 1: (S)-tert-butyl (1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate (1B) 1A (0.29 g, 0.85 mmol, synthesized with reference to WO2016016242 A1) was dissolved in 1,4-dioxane (10 mL) and water (0.4 mL), and intermediate 2a (0.35 g, 1.27 mmol), potassium carbonate (0.24 g, 1.70 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (70 mg, 0.09 mmol) were added. After the addition was completed, the mixture was reacted at 90° C. for 3 hours. The reaction solution was cooled to room temperature, and saturated aqueous sodium chloride solution (20 mL) was added. The resulting mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 4:1) to give the title compound 1B (white solid, 0.34 g, 99.0%). LC-MS (ESI): m / z = 412.1 [M + H] + .

[0091] Step 2: (S)-2-amino-3-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile (1C) 1B (0.34 g, 0.83 mmol) was dissolved in formic acid (5 mL) and after the addition was complete, the mixture was allowed to react at room temperature overnight. The reaction solution was concentrated to dryness and ethyl acetate (25 mL) was added. Saturated aqueous sodium bicarbonate was then added dropwise to adjust the pH to about 8. The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (25 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product of the title compound 1C (light yellow solid, 0.21 g, 69.5%). LC-MS (ESI): m / z = 312.1 [M + H] + .

[0092] Step 3: (S)-tert-butyl 2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (1D) 1C (0.21 g, 0.60 mmol) was dissolved in DMF (10 mL) and DIPEA (0.23 g, 1.80 mmol), HATU (0.34 g, 0.90 mmol), and INT-3 (0.22 g, 0.90 mmol, prepared with reference to WO2015110826) were added. After the addition was completed, the mixture was reacted at room temperature overnight. The reaction was quenched by dropwise addition of saturated aqueous ammonium chloride solution, and saturated aqueous sodium chloride solution (30 mL) was added. The resulting mixture was extracted with ethyl acetate (25 mL), and the organic phase was washed with saturated aqueous sodium chloride solution (25 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 1D (light yellow solid, 0.32 g, 99.0%), which was used directly in the next reaction. LC-MS (ESI): m / z = 483.1 [M-57 + H] + .

[0093] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 1) 1D (0.32 g, 0.59 mmol) was dissolved in formic acid (2.5 mL), and after the addition was completed, the mixture was reacted at 50° C. for 10 min. The reaction solution was concentrated to dryness, and ethyl acetate (20 mL) was added. Then, saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to about 8. The organic layer was separated, and the remaining aqueous layer was extracted with ethyl acetate (25 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=20:1) to give the title compound 1 (0.15 g, 58.0%). LC-MS (ESI): m / z=439.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.43-7.22(m,5H), 7.12(d,1H), 5.19(dd,1H), 4.18-4.04(m,1H), 4.05-3.95(m,1 H), 3.78(m,1H), 3.46(s,3H), 3.41-3.17(m,3H), 3.03-2.87(m,3H), 1.88(m,2H).

[0094] Example 2: N-((S)-1-cyano-2-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 2) [ka] Step 1: 4-Bromo-1-(bromomethyl)-2-methoxybenzene (2B) (2A) (4 g, 18.43 mmol) was dissolved in DCM (60 mL) and CBr4 (9.09 g, 27.64 mmol) was added. Then, PPh3 (7.24 g, 27.64 mmol) was slowly added and the mixture was reacted at room temperature for 1 h. PE / EA (v / v=5:1, 12 mL) was added to the reaction solution. The resulting mixture was stirred and filtered off by suction, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (PE:EA (v / v)=30:1-20:1) to obtain the title compound (2B) as a white solid (3.9 g, yield: 76%).

[0095] Step 2: (2S,5R)-2-(4-bromo-2-methoxybenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (2C) (R)-2-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1 g, 5.43 mmol) was dissolved in THF (20 mL). The mixture was subjected to nitrogen purge, cooled to -78 °C, and n-butyllithium (6.5 mmol, 2.5 M in toluene, 2.6 mL) was added. The resulting mixture was reacted for 1 h, followed by the addition of a solution of 2B (1.67 g, 5.97 mmol) in THF (8 mL). The reaction was continued at -78 °C for 2 h. The reaction was quenched with saturated NH4Cl solution, and the system was extracted with EA (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was passed through a silica gel column (EA / PE (v / v) = 0%-6%) to give the title compound (2C) as a colorless oil (1.82 g, yield: 87%). LCMS m / z=383.3[M+1] +

[0096] Step 3: Methyl (S)-2-amino-3-(4-bromo-2-methoxyphenyl)propanoate (2D) 2C (1.82 g, 4.75 mmol) was dissolved in acetonitrile (15 mL) and 1 M HCl (5 mL) was added. The mixture was reacted at room temperature overnight, and the system was subjected to rotary evaporation. Saturated aqueous sodium bicarbonate was added to neutralize the system to a weakly basic pH, and EA (15 mL x 3) was added for extraction and liquid-liquid separation was performed. The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (DCM:MeOH (v / v) = 20:1 to 10:1) to give 2D (1.34 g, yield: 97%). LCMS m / z = 288.1 [M+1] +

[0097] Step 4: Methyl (S)-3-(4-bromo-2-methoxyphenyl)-2-((tert-butoxycarbonyl)amino)propanoate (2E) 2D (1.34 g, 4.69 mmol) was dissolved in DCM (20 mL), and triethylamine (1.3 mL) and di-tert-butyl dicarbonate (1.23 g, 5.63 mmol) were added. The mixture was reacted at room temperature for 3 h. Water was added to the system for extraction, and liquid-liquid separation was performed. The organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (DCM:MeOH (v / v) = 20:1 to 10:1) to obtain 2E as a colorless oil (0.7 g, yield: 31%). LCMS m / z = 288.1 [M-boc+1] +

[0098] Step 5: (S)-3-(4-bromo-2-methoxyphenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (2F) 2E (0.7 g, 1.87 mmol) was dissolved in methanol (10 mL) and water (6 mL), then NaOH (1.50 g, 3.74 mmol) was added. The mixture was reacted at room temperature for 2 h, and methanol was removed by rotary evaporation. Dilute hydrochloric acid was added to adjust the solution to a weakly acidic pH. EA (10 mL x 3) was added for extraction, and liquid-liquid separation was performed. The organic phase was subjected to rotary evaporation to give the crude product (2F) (0.65 g). LCMS m / z = 274.2 [M-boc+1] +

[0099] Step 6: tert-Butyl (S)-(1-amino-3-(4-bromo-2-methoxyphenyl)-1-oxopropan-2-yl)carbamate (2G) 2F (0.65 g, 1.73 mmol), NH4Cl (0.74 g), and HATU (0.66 g, 1.73 mmol) were dissolved in DMF (15 mL), and then DIPEA (1.15 mL) was added. The mixture was reacted at room temperature overnight. Water and EA were added for extraction, liquid-liquid separation was performed, and the organic phase was dried over anhydrous Na2SO4 and concentrated to give the crude product (2G) (0.62 g). LCMS m / z=273.1 [M-boc+1] +

[0100] Step 7: tert-Butyl (S)-(2-(4-bromo-2-methoxyphenyl)-1-cyanoethyl)carbamate (2H) 2G (0.62 g, 1.66 mmol) was dissolved in DCM (10 mL), and then Burgess reagent (0.79 g, 3.32 mmol) was added. The mixture was reacted at room temperature overnight. The system was concentrated and subjected to rotary evaporation, and the crude product was separated and purified by silica gel column chromatography (EA / PE (v / v) = 0% to 25%) to obtain 2H (0.5 g, yield: 85%). LCMS m / z = 355.1 [M+1] +

[0101] Step 8: tert-Butyl (S)-(1-cyano-2-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate (2I) 2H (0.5 g, 1.41 mmol), 1B (0.11 g, 1.41 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (115 mg, 0.14 mmol), and potassium carbonate (390 mg, 2.82 mmol) were dissolved in 1,4-dioxane (20 mL), the system was placed under the protection of nitrogen substitution, and the mixture was reacted at 90 °C for 3 hours. The reaction solution was concentrated and subjected to rotary evaporation, then dissolved in DCM, filtered through Celite by suction, and the filtrate was subjected to rotary evaporation. The crude product was separated by silica gel column chromatography (EA / PE (v / v) = 0% ~ 40%) to obtain 2I as a pale yellow solid (550 mg, yield: 92%). LCMS m / z = 424.2 [M + 1] +

[0102] Step 9: (S)-2-amino-3-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile (2J) 2I (135 mg, 0.32 mmol) was dissolved in formic acid (8 mL) and the mixture was stirred at room temperature overnight. The system was diluted with DCM and saturated sodium bicarbonate solution was added to adjust the system to a weakly basic pH. Liquid-liquid separation was performed using DCM and water, and the organic phase was dried, concentrated and subjected to rotary evaporation to obtain the crude product (2J) (90 mg), which was used directly in the next reaction. LCMS m / z=324.1 [M+1] +

[0103] Step 10: tert-Butyl (S)-2-(((S)-1-cyano-2-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (2K) 2J (90 mg, 0.28 mmol) and INT-3 (82 mg, 0.34 mmol) were dissolved in DMF (5 mL), then HATU (0.12 g, 0.31 mmol) and DIPEA (0.2 mL) were added. The mixture was reacted at room temperature overnight. Water and EA were added to the reaction system for extraction and liquid-liquid separation, and the organic phase was dried and concentrated to obtain the crude product as a pale yellow oil, which was purified by chromatography (MeOH / DCM (v / v) = 0-10%) to obtain 2K (90 mg). LCMS m / z = 549.1 [M+1] +

[0104] Step 11: (S)-N-((S)-1-cyano-2-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 2) 2K (90 mg, 0.16 mmol) was dissolved in formic acid (5 mL), and the mixture was reacted at room temperature for 4 hours. The system was diluted with DCM, and saturated sodium bicarbonate solution was added to adjust the system to a weakly basic pH. Liquid-liquid separation was performed using DCM and water, and the organic phase was dried, concentrated, and subjected to rotary evaporation to obtain a residue, which was separated and purified by silica gel column chromatography (DCM:MeOH (v / v) = 50:1 to 5:1) to obtain the title compound 2 (13 mg, yield: 18%). LC-MS m / z = 451.2 [M + 1] + 1 H NMR (400MHz, CDCl3)δ 7.49(d,1H), 7.32-7.28(m,2H), 7.14-7.12(m,2H), 7.05(d,1H), 5.13-5.06(m,1H), 4.18-4.14(m,1H), 4.07-4.01(m,1H), 3.96(s,3 H), 3.82-3.76(m,1H), 3.46(s,3H), 3.44-3.41(m,1H), 3.27-3.16(m,3H), 3.07-2.97(m,3H), 2.93-2.87(q,1H), 1.98-1.94(q,2H).

[0105] Example 3: (S)-N-((S)-1-cyano-2-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 3) [ka] Compound 3 was prepared from compound 3A by referring to the preparation method of compound 2. LC-MS m / z=439.2[M+1] + 1H NMR (400MHz, CDCl3)δ 7.43(t,1H), 7.31-7.27(m,2H), 7.21-7.17(m,2H), 7.14(d,1H), 5.21-5.15(m,1H), 4.30-4.27(m,1H), 4.08-4.02( m,1H), 3.84-3.77(m,1H), 3.53-3.49(m,1H), 3.44(s,3H), 3.23-3.04(m,5H), 2.04-2.00(m,3H), 1.26-1.22(m,1H). 19 F NMR (376MHz, CDCl3)δ -117.13.

[0106] Example 4: (S)-N-((S)-1-cyano-2-(5-(1-methyl-2-oxoindolin-6-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 4) [ka] Step 1: 6-Bromo-1-methylindolin-2-one (4B) 4A (5 g, 23.5 mmol) was dissolved in 200 mL of acetonitrile, then potassium carbonate (23 g, 94.32 mmol) and iodomethane (2.96 mL, 47.16 mmol) were added. The mixture was heated to 70° C. and stirred overnight. The reaction solution was concentrated, extracted with DCM and water, the organic phase was dried and concentrated, and the residue was separated by column chromatography (PE:EA=2:1 (v / v)) to give a brown solid 4B (1.8 g, 34%). LC-MS (ESI): m / z=226.1 [M+H] + .

[0107] Step 2: 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (4C) Compound 4B (1 g, 4.42 mmol), palladium acetate (200 mg, 0.88 mmol), potassium acetate (0.87 g, 8.84 mmol), 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (1.2 g, 2.65 mmol), and bis(pinacolato)diboron (1.35 g, 5.3 mmol) were mixed and dissolved in 50 mL of 1,4-dioxane, and the mixture was heated to 95 °C under N2 protection and reacted for 3 hours. After completion of the reaction detected by LCMS, the reaction solution was concentrated and separated by column chromatography (PE:EA (v / v) = 1:1) to obtain a pale yellow solid 4C (880 mg, 73%). LC-MS (ESI): m / z = 274.2 [M + H] + .

[0108] Step 3: tert-Butyl-(S)-(1-cyano-2-(5-(1-methyl-2-oxoindolin-6-yl)thiophen-2-yl)ethyl)carbamate (4D) Tert-butyl N-[(1S)-2-(5-bromothiophen-2-yl)-1-cyanoethyl]carbamate (480 mg, 1.45 mmol), 4C (475 mg, 1.74 mmol), potassium carbonate (400 mg, 2.9 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (21 mg, 0.29 mmol) were mixed and dissolved in 5 mL of 1,4-dioxane and 0.1 mL of water, and the mixture was heated to 120° C. under microwave and reacted for 1 h. After completion of the reaction detected by LCMS, the reaction solution was concentrated and separated by column chromatography (PE:EA (v / v)=1:1) to give a pale yellow solid 4D (175 mg, 33%). LC-MS (ESI): m / z=398.2 [M+H] + .

[0109] Step 4: (S)-2-amino-3-(5-(1-methyl-2-oxoindolin-6-yl)thiophen-2-yl)propanenitrile (4E) Formic acid (3 mL) was added to compound 4D (175 mg, 0.44 mmol) and the mixture was stirred at room temperature for 3 h. After completion of the reaction as detected by LCMS, saturated sodium carbonate solution was added to the reaction solution to adjust the pH to 10. The resulting mixture was extracted with DCM, and the organic phase was dried and concentrated to give product 4E (119 mg, 91%). LC-MS (ESI): m / z=298.1 [M+H] + .

[0110] Step 5: tert-Butyl-(S)-2-(((S)-1-cyano-2-(5-(1-methyl-2-oxoindolin-6-yl)thiophen-2-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (4F) Compound 4E (119 mg, 0.4 mmol), INT-3 (98 mg, 0.4 mmol), HATU (180 mg, 0.48 mmol), and DIEA (0.13 mL, 0.8 mmol) were mixed and dissolved in DMF, and the mixture was stirred at room temperature overnight. After completion of the reaction detected by LCMS, water and EA were added for extraction, the organic phase was dried and concentrated, and the residue was separated by column chromatography (PE:EA (v / v) = 1:1) to give a yellow solid 4F (165 mg, 78%). LC-MS (ESI): m / z = 525.2 [M + H] + .

[0111] Step 6: (S)-N-((S)-1-cyano-2-(5-(1-methyl-2-oxoindolin-6-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 4) Compound 4F (145 mg, 0.28 mmol) was dissolved in 3 mL of formic acid solution, and the mixture was reacted at room temperature for 3 h. After completion of the reaction detected by LCMS, the reaction solution was poured into saturated sodium carbonate solution to adjust the pH to 10. The resulting mixture was extracted with EA, the organic phase was dried and concentrated, and the residue was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 1:100 to 1:10) to obtain compound 4 (45 mg, 38%). LC-MS (ESI): m / z = 425.2 [M + H]+ . 1 H NMR (400MHz, DMSO-d6): 8.67-8.69(m,1H), 7.40-7.41(d,1H), 7.18-7.28(m,3H), 6.99-7.00(m,1H), 4.94-5.03(m,1H), 4.01-4.04 (m,1H), 3.71-3.77(m,1H), 3.55(s,2H), 3.33-3.46(m,3H), 3.16(s,3H), 3.07-3.12(m,1H), 2.61-2.81(m,4H), 1.69-1.78(m,2H).

[0112] Example 5: (S)-N-((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 5) [ka] Step 1: (S)-3-(5-bromothiophen-2-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (5B) 5A (10 g, 40.3 mmol) was dissolved in methanol (200 mL), and then triethylamine (12.2 g, 120.9 mmol) and di-tert-butyl dicarbonate (10.5 g, 48.36 mmol) were added. The mixture was reacted at room temperature for 2 hours and then concentrated. The pH was then adjusted to 6-7 using dilute hydrochloric acid (1N). The resulting mixture was extracted with dichloromethane, then concentrated, and the residue was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 1:100-1:10) to obtain the title compound (5B) as a yellow solid (14 g, yield: 99%). LCMS m / z = 350.23 [M + 1] +

[0113] Step 2: tert-Butyl (S)-(1-amino-3-(5-bromothiophen-2-yl)-1-oxopropan-2-yl)carbamate (5C) 5B (4 g, 11.5 mmol) was dissolved in DMF (50 mL), and then ammonium chloride (620 mg, 11.5 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate (4.4 mg, 13.8 mmol), and DIPEA (2.9 g, 23.0 mmol) were added. The mixture was reacted at room temperature overnight. Water (50 mL) was added, and the resulting mixture was extracted with ethyl acetate (50 mL x 3), washed three times with water (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 1:100 to 1:10) to obtain the title compound (5C) as a pale yellow solid (1.8 g, yield: 45%). LC-MS m / z = 349.01 [M+1] +

[0114] Step 3: tert-Butyl (S)-(2-(5-bromothiophen-2-yl)-1-cyanoethyl)carbamate (5D) 5C (1.8 g, 5.2 mmol) was dissolved in dichloromethane (50 mL), and Burgess reagent (1.6 g, 6.2 mmol) was added under ice bath. The mixture was reacted at room temperature for 2 hours. Water (50 mL) was added, and the resulting mixture was extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 1:10 to 1:5) to obtain the title compound (5D) as a pale yellow solid (1.4 g, yield: 81%). LCMS m / z = 331.23 [M + 1] +

[0115] Step 4: tert-Butyl (S)-(1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)carbamate (5E) 5D (700 mg, 2.1 mmol) was dissolved in dioxane (10 mL), then 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole-2(3H) (825 mg, 3.0 mmol), potassium carbonate (869 mg, 6.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (70 mg), and water (2 mL) were added. The mixture was reacted at 100° C. under microwave and nitrogen protection for 12 hours, then concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v)=1:5 to 1:1) to give the title compound (5E) as a yellow solid (290 mg, yield: 34%). LCMS m / z=400.13[M+1] +

[0116] Step 5: (S)-2-amino-3-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)propanenitrile (5F) 5E (290 mg, 0.73 mmol) was dissolved in formic acid (5 mL), the mixture was reacted at room temperature for 3 h, adjusted to pH=7-8 with saturated aqueous sodium carbonate solution, and then extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v)=1:100-1:10) to obtain the title compound (5F) as a yellow solid (150 mg, yield: 69%). LCMS m / z=300.07[M+1] +

[0117] Step 6: tert-Butyl (S)-2-(((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (5G) 5F (90 mg, 0.30 mmol) was dissolved in DMF (10 mL), and HATU (152 mg, 0.4 mmol), DIEA (116 mg, 0.9 mmol), and (S)-4-(tert-butoxycarbonyl)-1,4-oxaheptane-2-carboxylic acid (73 mg, 0.30 mmol) were added successively. The mixture was reacted at room temperature for 12 h. Water (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with water (30 mL x 2), then with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 1:100 to 1:10) to give the title compound (5G) as a yellow solid (100 mg, yield: 64%). LCMS m / z=527.19[M+1] +

[0118] Step 7: (S)-N-((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 5) 5G (100 mg, 0.19 mmol) was dissolved in formic acid (2 mL), the mixture was reacted at room temperature for 3 h, adjusted to pH=7-8 using saturated aqueous sodium carbonate solution, and then extracted with dichloromethane (30 mL×3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v)=1:100-1:10) to obtain the title compound 5 (25 mg, yield: 31%). LCMS M / Z (ESI): m / z=427.14[M+1] + 1H NMR (400MHz, DMSO-d6)δ 8.72(d,1H), 7.52-7.44(m,1H), 7.40-7.29(m,3H), 7.01(d,1H), 5.04-4.88(m,1H), 4.11-3.98(m,1H), 3.98-3.84(m,1H), 3. 81-3.68(m,1H), 3.47-3.38(m,2H), 3.38(s,3H), 3.36-3.32(m,1H), 3.24-3.12(m,1H), 2.94-2.62(m,3H), 1.90-1.69(m,2H).

[0119] Example 6: (S)-N-((S)-2-(4-(7-acetamido-2,3-dihydro-1H-inden-4-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (compound 6) [ka] Step 1: tert-Butyl (S)-(2-(4-(7-acetamido-2,3-dihydro-1H-inden-4-yl)-2-fluorophenyl)-1-cyanoethyl)carbamate (6B) 6A (254.0 mg, 1.00 mmol, prepared with reference to Journal of Medicinal Chemistry, 2015, 58, 878-887), INT-2 (470.0 mg, 1.20 mmol), Pd(dppf)Cl2 (160.0 mg, 0.20 mmol), and potassium carbonate (280.0 mg, 2.00 mmol) were added to a one-neck flask, and then 1,4-dioxane (10 mL) and water (0.4 mL) were added. The mixture was subjected to nitrogen purge three times, and then reacted at 95 °C for 4 hours. The reaction solution was cooled to room temperature, then concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 2:1) to obtain the title compound 6B as a white solid (360.0 mg, 82.3%). LC-MS(ESI): m / z=381.1[M-57+H] + .

[0120] Step 2: (S)-N-(7-(4-(2-amino-2-cyanoethyl)-3-fluorophenyl)-2,3-dihydro-1H-inden-4-yl)acetamide (6C) 6B (360.0 mg, 0.82 mmol) was dissolved in formic acid (5 mL) and the mixture was reacted at 35° C. for 4 h. The reaction was adjusted to basic pH using saturated potassium carbonate solution, extracted with ethyl acetate (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 6C as a pale yellow oil (270.0 mg, 97.6%), which was used directly in the next reaction. LC-MS (ESI): m / z=338.2 [M+H] + .

[0121] Step 3: tert-Butyl (S)-2-(((S)-2-(4-(7-acetamido-2,3-dihydro-1H-inden-4-yl)-2-fluorophenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (6D) 6C (270 mg, 0.80 mmol) was dissolved in DMF (5 mL), then INT-3 (235.2 mg, 0.96 mmol), HATU (364.8 mg, 0.96 mmol), and DIPEA (309.6 mg, 2.40 mmol) were added. After the addition was completed, the mixture was reacted at room temperature overnight. Water (20 mL) was added to the system. The resulting mixture was extracted with ethyl acetate (30 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 2:1) to give the title compound 6D as a white solid (370.0 mg, 82.0%). LC-MS (ESI): m / z = 563.3 [MH] - .

[0122] Step 4: (S)-N-((S)-2-(4-(7-acetamido-2,3-dihydro-1H-inden-4-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (compound 6) 6D (370 mg, 0.66 mmol) was dissolved in formic acid (5 mL), and the mixture was reacted at 35° C. for 4 hours. The reaction system was adjusted to basic pH using saturated potassium carbonate solution, extracted with ethyl acetate (30 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=30:1) to give the title compound 6 (90.0 mg, 30.0%). 1 H NMR (400MHz, CDCl3)δ 7.85(d,1H), 7.34(t,1H), 7.19-7.13(m,3H), 6.98(s,1H), 5.21-5.15(m,1H), 4.09(q,1H), 4.03-3.97(m,1H), 3.79-3.73(m,1H), 3.2 9(dd,1H), 3.24-3.17(m,2H), 2.99(t,2H), 2.96-2.85(m,5H), 2.22(s,3H), 2.15-2.07(m,2H), 1.87-1.80(m,2H), 1.61-1.50(m,2H). LC-MS(ESI): m / z=465.2[M+H] + .

[0123] Example 7: (S)-N-((S)-1-cyano-2-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 7) [ka] Step 1: tert-Butyl (S)-(1-cyano-2-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-2-fluorophenyl)ethyl)carbamate (7B) 7A (0.200 g, 0.81 mmol, prepared with reference to EP 3342765), INT-2 (0.316 g, 0.81 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.066 g, 0.081 mmol), and potassium carbonate (0.33 g, 2.43 mmol) were dissolved in 1,4-dioxane (10 mL), water (2 mL) was added, and then the mixture was subjected to nitrogen purge three times and reacted at 90° C. under nitrogen atmosphere for 4 hours. The reaction solution was concentrated to dryness, dissolved in dichloromethane, the mixture was filtered and concentrated. The residue was separated and purified by silica gel column chromatography (PE:EA (v / v)=5:1) to obtain the title compound 7B as a white solid (0.25 g, 71.8%). LC-MS(ESI): m / z=431.1[M+H] + .

[0124] Step 2: (S)-2-amino-3-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-2-fluorophenyl)propanenitrile 4-methylbenzenesulfonate (7C) 7B (0.25 g, 0.58 mmol) was dissolved in acetonitrile (5 mL), and then p-toluenesulfonic acid (0.331 g, 1.74 mmol) was added. After the addition was completed, the mixture was reacted at room temperature for 16 hours and then filtered. The filter cake was rinsed once with acetonitrile (2 mL) and subjected to rotary evaporation to give the title compound 7C as a white solid (0.240 g, 82.2%), which was used directly in the next reaction.

[0125] Step 3: tert-Butyl (S)-2-(((S)-1-cyano-2-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-2-fluorophenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (7D) INT-3 (0.161 g, 0.66 mmol) was dissolved in dichloromethane (10 mL), then triethylamine (0.17 g, 1.32 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.25 g, 0.66 mmol) were added. After the addition was completed, the mixture was reacted at room temperature for 1 hour with stirring, then 7C (0.24 g, 0.477 mmol) was added. The resulting mixture was reacted at room temperature overnight. After the reaction was completed, the reaction solution was concentrated to give the crude product 7D, which was used directly in the next reaction. LC-MS (ESI): m / z=556.3 [MH] - .

[0126] Step 4: (S)-N-((S)-1-cyano-2-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 7) The crude product 7D was dissolved in acetonitrile (10 mL) and p-toluenesulfonic acid (0.331 g, 1.74 mmol) was added. After the addition was completed, the mixture was reacted at room temperature for 16 hours and then concentrated to dryness. Ethyl acetate (25 mL) was added and saturated aqueous sodium bicarbonate was added dropwise to adjust the pH to about 8. The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to give the title compound 7 (110 mg, two-step yield: 50.5%). 1H NMR (400MHz, CDCl3)δ 7.82(d,1H), 7.65(d,1H), 7.54(s,1H), 7.42(d,1H), 7.38(s,1H), 7.32(d,1H) , 7.25-7.19(m,1H), 5.22-5.11(m,1H), 4.14-4.10(m,1H), 4.09-4.00(m,1H), 3.82-3.76(m,,1H), 3.58-3.52(m,2H), 3.50-3.42(m,2H), 3.41-3.32(m,1H), 3.24(t,2H), 3.00-2.93(m,2H), 1.90(d,2H), 1.60-1.51(m,1H), 1.39(dd,1H). LC-MS(ESI):m / z=458.1[M+H] + .

[0127] Example 8: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 8) [ka] Step 1: tert-Butyl (S)-(1-cyano-2-(3-fluoro-4'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate (8A) INT-2 (0.69 g, 1.77 mmol) was dissolved in dioxane (30 mL), then (4-bromophenyl)sulfur pentafluoride (0.5 g, 1.77 mmol), potassium carbonate (0.24 mg, 1.77 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (260 mg, 0.35 mmol) and water (6 mL) were added. The mixture was reacted at 100°C under nitrogen protection for 4 hours, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 1:10 to 1:5) to give the title compound 8A (600 mg, yield: 80%). LCMS m / z = 467.11 [M+1] +

[0128] Step 2: (S)-2-amino-3-(3-fluoro-4'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)propanenitrile (8B) 8A (0.6 g, 1.29 mmol) was dissolved in acetonitrile (20 mL) and p-toluenesulfonic acid (0.67 g, 3.87 mmol) was added. The mixture was reacted at 30° C. for 2 h. Water (30 mL) was added and the resulting mixture was adjusted to pH=7-8 using saturated aqueous sodium carbonate solution, extracted with dichloromethane (50 mL×3), then washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, and concentrated to give the title compound 8B (0.4 g, yield: 84%). LCMS m / z=367.32[M+1] +

[0129] Step 3: tert-Butyl (S)-2-(((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (8C) 8B (200 mg, 0.55 mmol) was dissolved in DMF (10 mL), then HATU (250 mg, 0.66 mmol), DIPEA (260 mg, 2.02 mmol), and INT-3 (130 mg, 0.55 mmol) were added successively. The mixture was reacted at room temperature for 12 h. Water (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with water (30 mL x 2) and saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:dichloromethane (v / v) = 1:10 to 1:5) to give the title compound 8C (250 mg, yield: 76%). LCMS m / z = 594.18 [M + 1] +

[0130] Step 4: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 8) 8C (250 mg, 0.42 mmol) was dissolved in acetonitrile (20 mL) and p-toluenesulfonic acid (220 mg, 1.26 mmol) was added. The mixture was reacted at 30° C. for 3 hours, then adjusted to pH=7-8 using saturated aqueous sodium carbonate solution, and extracted with dichloromethane (40 mL×3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=0.01:1-0.1:1) to give the title compound 8 (80 mg, 38%). 1 H NMR (400MHz, DMSO-d6)δ 8.70(d,1H), 8.12-7.87(m,4H), 7.67-7.57(m,2H), 7.54-7.47(m,1H), 5.15-4.85(m,1H), 4.03-3.97(m,1H), 3.90-3.80(m,1H), 3. 76-3.69(m,1H), 3.35-3.28(m,2H), 3.26-3.19(m,1H), 3.12-3.01(m,1H), 2.88-2.72(m,1H), 2.67-2.52(m,2H), 1.81-1.62(m,2H). LCMS m / z(ESI): m / z=494.13[M+1] +

[0131] Example 9: (S)-N-((S)-1-cyano-2-(3-fluoro-3'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 9) [ka] Step 1: tert-Butyl (S)-(1-cyano-2-(3-fluoro-3'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate (9A) INT-2 (0.69 g, 1.77 mmol) was dissolved in dioxane (30 mL), then (3-bromophenyl)sulfur pentafluoride (0.5 g, 1.77 mmol), potassium carbonate (0.24 mg, 1.77 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (260 mg, 0.35 mmol), and water (6 mL) were added. The mixture was reacted at 100°C under nitrogen protection for 4 hours, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 1:10 to 1:5) to give the title compound 9A (600 mg, yield: 80%). LCMS m / z = 467.11 [M+1] +

[0132] Step 2: (S)-2-amino-3-(3-fluoro-4'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)propanenitrile (9B) 9A (0.6 g, 1.29 mmol) was dissolved in acetonitrile (20 mL) and p-toluenesulfonic acid (0.67 g, 3.87 mmol) was added. The mixture was reacted at 30° C. for 2 h. Water (30 mL) was added and the resulting mixture was adjusted to pH=7-8 using saturated aqueous sodium carbonate solution, extracted with dichloromethane (50 mL×3), then washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, and concentrated to give the title compound 9B (0.4 g, yield: 84%). LCMS m / z=367.32[M+1] +

[0133] Step 3: tert-Butyl (S)-2-(((S)-1-cyano-2-(3-fluoro-3'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (9C) 9B (200 mg, 0.55 mmol) was dissolved in DMF (10 mL), then HATU (250 mg, 0.66 mmol), DIEA (260 mg, 2.02 mmol), and INT-3 (130 mg, 0.55 mmol) were added successively. The mixture was reacted at room temperature for 12 h. Water (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with water (30 mL x 2) and saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:dichloromethane (v / v) = 1:10 to 1:5) to give the title compound 9C (250 mg, yield: 76%). LCMS m / z = 594.18 [M + 1] +

[0134] Step 4: (S)-N-((S)-1-cyano-2-(3-fluoro-3'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 9) 9C (250 mg, 0.42 mmol) was dissolved in acetonitrile (20 mL) and p-toluenesulfonic acid (220 mg, 1.26 mmol) was added. The mixture was reacted at 30° C. for 3 hours, then adjusted to pH=7-8 using saturated aqueous sodium carbonate solution, and extracted with dichloromethane (40 mL×3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=0.01:1-0.1:1) to give the title compound 9 (78 mg, 37%). 1H NMR (400MHz, DMSO-d6)δ 8.69(d,1H), 8.12(s,1H), 8.01(d,1H), 7.93(d,1H), 7.76-7.44(m,4H), 5.21-4.95(m,1H), 4.05-3.97(m,1H), 3.91-3.80(m,1H) , 3.77-3.63(m,1H), 3.32(d,2H), 3.26-3.18(m,1H), 3.10-3.00(m,1H), 2.83-2.73(m,1H), 2.66-2.54(m,2H), 1.81-1.61(m,2H). LCMS m / z(ESI): m / z=494.13[M+1] +

[0135] Example 10: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 10) [ka] Step 1: tert-Butyl (S)-(1-cyano-2-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)carbamate (10A) 4A (0.27 g, 1.2 mmol), INT-2 (0.36 g, 0.92 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (71 mg, 0.1 mmol), and potassium carbonate (0.28 g, 2.0 mmol) were added successively to 1,4-dioxane (15 mL) and water (3 mL), the system was subjected to nitrogen purge three times, and reacted at 100 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (50 mL) was added, and the resulting aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE:EA=3:1 to 1:1) to give 10A as a brown solid (0.32 g, yield: 84%). LCMS m / z=410.2[M+1] +.

[0136] Step 2: (S)-2-amino-3-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)propanenitrile (10B) 10A (0.32 g, 0.78 mmol) was dissolved in formic acid (5.0 mL) and after the addition was completed, the mixture was reacted at 50° C. for 10 min. The reaction solution was concentrated to dryness. Ethyl acetate (60 mL) was added, followed by dropwise addition of saturated aqueous sodium bicarbonate to adjust the pH to about 8. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (60 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 10B (0.24 g, yield: 100%). LCMS m / z=310.2[M+1] + .

[0137] Step 3: tert-Butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (10C) 10B (0.24 g, 0.78 mmol) was dissolved in DMF (10 mL), then INT-3 (0.25 g, 1.0 mmol), diisopropylethylamine (0.19 g, 1.5 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.38 g, 1 mmol) were added. After the addition was completed, the mixture was reacted at room temperature for 1 hour. Saturated aqueous sodium chloride solution (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (60 mL x 2). The organic phase was washed with saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography (PE:EA = 2:1 to 1:2) to give the title compound 10C as a pale yellow solid (0.25 g, yield: 60%).

[0138] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 10) 10C (0.25 g, 0.47 mmol) was dissolved in formic acid (5.0 mL), and the mixture was reacted at 50° C. for 10 min. The reaction solution was concentrated under reduced pressure, and ethyl acetate (60 mL) was added. Then, saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to about 8. The organic layer was separated, and the remaining aqueous layer was extracted with ethyl acetate (60 mL×5). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=4:1) to obtain compound 10 (0.12 g, yield: 59%). 1 H NMR (400MHz, DMSO-d6) δ 8.78(d,1H), 7.96-7.87(m,2H), 7.70-7.64(m,2H), 7.63-7.53(m,2H), 7 .47(t,1H), 5.11-5.01(m,1H), 4.13-4.06(m,1H), 3.92-3.82(m,1H), 3. 78-3.70(m,1H), 3.43-3.31(m,2H), 3.26-3.10(m,2H), 2.97(t,2H), 2.9 4-2.84(m,1H), 2.79-2.61(m,2H), 2.04-1.92(m,1H), 1.82-1.73(m,2H). LC-MS m / z=437.2[M+1] +

[0139] Example 11: (S)-N-((S)-1-cyano-2-(4-(cyclopentylethynyl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 11) [ka] Step 1: tert-Butyl (S)-(1-cyano-2-(4-(cyclopentylethynyl)-2-fluorophenyl)ethyl)carbamate (11B) 11A (66 mg, 0.70 mmol), INT-2 (200 mg, 0.58 mmol), Pd(dppf)Cl2 (115.0 mg, 0.14 mmol), and potassium carbonate (193.2 mg, 1.4 mmol) were added to a one-neck flask, followed by the addition of 1,4-dioxane (10 mL) and water (0.4 mL). The mixture was subjected to nitrogen purge three times, and then reacted at 95° C. for 4 hours. The reaction solution was cooled to room temperature, then concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v)=3:1) to obtain the title compound 11B as a white solid (172.0 mg, 83.5%). LC-MS (ESI): m / z=300.1 [M-57+H] + .

[0140] Step 2: (S)-2-amino-3-(4-(cyclopentylethynyl)-2-fluorophenyl)propanenitrile (11C) 11B (172 mg, 0.48 mmol) was dissolved in formic acid (5 mL) and the mixture was reacted at 35° C. for 4 h. The reaction was adjusted to basic pH using saturated potassium carbonate solution, extracted with ethyl acetate (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 11C as a pale yellow oil (130 mg, 100.0%), which was used directly in the next reaction. LC-MS (ESI): m / z=257.1 [M+H] + .

[0141] Step 3: tert-Butyl (S)-2-(((S)-1-cyano-2-(4-(cyclopentylethynyl)-2-fluorophenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (11D) 11C (130 mg, 0.51 mmol) was dissolved in DMF (5 mL), and then INT-3 (150 mg, 0.61 mmol), HATU (230 mg, 0.61 mmol), and DIPEA (200 mg, 1.53 mmol) were added. After the addition was completed, the mixture was reacted at room temperature overnight. Water (20 mL) was added to the system. The resulting mixture was extracted with ethyl acetate (30 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 2:1) to give the title compound 11D as a white solid (190.0 mg, 77.0%). LC-MS (ESI): m / z = 428.3 [M-57 + H] + .

[0142] Step 4: (S)-N-((S)-1-cyano-2-(4-(cyclopentylethynyl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 11) 11D (190 mg, 0.39 mmol) was dissolved in formic acid (5 mL), and the mixture was reacted at 35° C. for 4 hours. The reaction system was adjusted to basic pH using saturated potassium carbonate solution, extracted with ethyl acetate (30 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=30:1) to obtain compound 11 (50.0 mg, 33.0%). 1 H NMR (400MHz, CDCl3)δ 7.20-7.17(m,2H), 7.07(dd,1H), 7.02(dd,1H), 5.08-5.02(m,1H), 4.09(q,1H), 3.94-3.89(m,1H), 3.71-3.64(m,1H), 3.22 (dd,1H), 3.13-3.03(m,2H), 2.87-2.80(m,3H), 2.78-2.70(m,1H), 2.02-1.88(m,3H), 1.82-1.67(m,4H), 1.66-1.50(m,4H). LC-MS(ESI):m / z=384.2[M+H] + .

[0143] Example 12: (S)-N-((S)-1-cyano-2-(4-(5-cyano-4-methylthiazol-2-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 12) [ka] Step 1: 2-Bromo-4-methylthiazole-5-carboxamide (12B) 12A (1.20 g, 4.8 mmol) was dissolved in 30% aqueous ammonia (30 mL) and the mixture was reacted at 35° C. for 24 hours. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 12B as a yellow solid (0.80 g, 75.4%). LC-MS (ESI): m / z=221.0 [M+H] + .

[0144] Step 2: 2-Bromo-4-methylthiazole-5-carbonitrile (12C) 12B (0.55 g, 2.49 mmol) was dissolved in dichloromethane (25 mL), and then Burgess reagent (1.19 g, 4.98 mmol) was added. After the addition was completed, the mixture was reacted at room temperature overnight. After concentration, the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 5:1) to give the title compound 12C as a white solid (0.40 g, 80.1%). LC-MS (ESI): m / z = 203.0 [M + H] + .

[0145] Step 3: (S)-(1-cyano-2-(4-(5-cyano-4-methylthiazol-2-yl)-2-fluorophenyl)ethyl) tert-butylcarbamate (12D) 12C (199 mg, 0.98 mmol), INT-2 (458.9 mg, 1.18 mmol), Pd(dppf)Cl2 (160.5 mg, 0.20 mmol), and potassium carbonate (270.9 mg, 1.96 mmol) were added to a one-neck flask, followed by the addition of 1,4-dioxane (10 mL) and water (0.4 mL). The mixture was subjected to nitrogen purge three times, and then reacted at 95° C. for 4 hours. The reaction solution was cooled to room temperature, then concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 3:1) to obtain the title compound 12D as a yellow solid (172.0 mg, 45.5%). LC-MS (ESI): m / z = 331.0 [M-57 + H] + .

[0146] Step 4: (S)-2-(4-(2-amino-2-cyanoethyl)-3-fluorophenyl)-4-methylthiazole-5-carbonitrile (12E) 12D (172 mg, 0.45 mmol) was dissolved in formic acid (5 mL) and the mixture was reacted at 35° C. for 4 hours. The reaction was adjusted to basic pH using saturated potassium carbonate solution, extracted with ethyl acetate (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 12E as a pale yellow oil (120 mg, 96.0%), which was used directly in the next reaction. LC-MS (ESI): m / z=287.1 [M+H] + .

[0147] Step 5: tert-Butyl (S)-2-(((S)-1-cyano-2-(4-(5-cyano-4-methylthiazol-2-yl)-2-fluorophenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (12F) 12E (120 mg, 0.42 mmol) was dissolved in DMF (5 mL), then INT-3 (120 mg, 0.50 mmol), HATU (190 mg, 0.50 mmol), and DIPEA (160 mg, 1.26 mmol) were added. After the addition was completed, the mixture was reacted at room temperature overnight. Water (20 mL) was added to the system. The resulting mixture was extracted with ethyl acetate (30 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 2:1) to give the title compound 12F as a yellow solid (160.0 mg, 74.2%). LC-MS (ESI): m / z = 458.1 [M-57 + H] + .

[0148] Step 6: (S)-N-((S)-1-cyano-2-(4-(5-cyano-4-methylthiazol-2-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 12) 12F (160 mg, 0.31 mmol) was dissolved in formic acid (5 mL), and the mixture was reacted at 35° C. for 4 hours. The reaction system was adjusted to basic pH using saturated potassium carbonate solution, extracted with ethyl acetate (30 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=30:1) to give the title compound 12 (50.0 mg, 39.0%). 1 H NMR (400MHz, CDCl3)δ 7.72(dd,1H), 7.69(dd,1H), 7.44(t,1H), 5.22-5.16(m,1H), 4.09(q,1H), 4.05-3.99(m,1H), 3.80 -3.73(m,1H), 3.30(dd,1H), 3.26-3.23(m,2H), 2.97-2.90(m,3H), 2.67(s,3H), 1.19-1.82(m,4H). LC-MS(ESI):m / z=414.2[M+H] + .

[0149] Example 13: (S)-N-((S)-2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (compound 13) [ka] Step 1: tert-Butyl (S)-(1-cyano-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate (13B) INT-2 (5.00 g, 14.57 mmol) was dissolved in 1,4-dioxane (100 mL), and then bis(pinacolato)diboron (4.81 g, 18.94 mmol), potassium acetate (4.29 g, 43.71 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (2.39 g, 2.91 mmol) were added. After the addition was completed, the mixture was heated to 100° C. and reacted for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 6:1) to obtain the title compound 13B as a colorless liquid (5.00 g, 87.93%). LC-MS (ESI): m / z = 391.2 [M + H] + .

[0150] Step 2: tert-Butyl (S)-(2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)carbamate (13C) 13B (0.40 g, 1.02 mmol) was dissolved in 1,4-dioxane (10 mL) and water (0.4 mL), then 2-bromobenzothiazole (0.26 g, 1.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.17 g, 0.20 mmol), and potassium carbonate (0.28 g, 2.04 mmol) were added. After the addition was completed, the mixture was heated to 90° C. and reacted for 2 hours under nitrogen protection. The reaction solution was then reacted at room temperature overnight. The resulting reaction mixture was concentrated to dryness, and saturated aqueous ammonium chloride solution (50 mL) was added. The resulting mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 4:1) to give the title compound 13C as a pale yellow liquid (0.24 g, 59.20%). LC-MS (ESI): m / z = 398.1 [M + H] + .

[0151] Step 3: (S)-2-amino-3-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)propanenitrile (13D) 13C (0.32 g, 0.81 mmol) was dissolved in formic acid (5 mL) and after the addition was completed, the mixture was reacted at 30° C. for 3 h. Saturated aqueous sodium bicarbonate was added dropwise to adjust the pH to about 8, and the resulting mixture was extracted with ethyl acetate (25 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 13D as a colorless liquid (0.24 g, 99.65%), which was used directly in the next reaction. LC-MS (ESI): m / z=298.1 [M+H] + .

[0152] Step 4: tert-Butyl (S)-2-(((S)-2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (13E) 13D (0.24 g, 0.81 mmol) was dissolved in dichloromethane (10 mL), then INT-1 (0.26 g, 1.05 mmol), diisopropylethylamine (0.31 g, 2.43 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.46 g, 1.22 mmol) were added. After the addition was completed, the mixture was reacted at room temperature overnight. Saturated aqueous sodium chloride solution (30 mL) was added, and then the resulting mixture was extracted with ethyl acetate (25 mL). The organic phase was washed with saturated aqueous sodium chloride solution (25 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 4:1) to give the title compound 13E as a pale yellow solid (0.25 g, 58.83%). LC-MS(ESI): m / z=469.2[M-57+H] + .

[0153] Step 5: (S)-N-((S)-2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (compound 13) 13E (0.32 g, 0.59 mmol) was dissolved in formic acid (2.0 mL), and after the addition was completed, the mixture was reacted at 35° C. for 4 hours. The reaction solution was concentrated to dryness, and ethyl acetate (25 mL) was added. Then, saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to about 8. The organic layer was separated, and the remaining aqueous layer was extracted with ethyl acetate (25 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=20:1) to give the title compound 13 (30 mg, 14.72%). 1H NMR (400MHz, CDCl3)δ 8.08(d,1H), 7.94-7.78(m,3H), 7.47(m,3H), 5.21(dd,1H), 4.15-3.92(m,2H), 3.76(m,1H), 3.38-3.19(m,3H), 2.95(dt,3H), 1.87(d,2H). LC-MS(ESI):m / z=425.1[M+H] + .

[0154] Example 14: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 14) [ka] Step 1: tert-Butyl-(S)-(1-cyano-2-(3-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate (14B) 14A (2.54 g, 8.04 mmol), INT-2 (2.3 g, 6.70 mmol), potassium carbonate (1.85 g, 13.4 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.98 g, 1.34 mmol) were dissolved in 1,4-dioxane (100 ml) and water (10 ml). The system was subjected to nitrogen purge three times, heated to 95°C, refluxed for 3 hours, filtered, the filter cake was washed with ethyl acetate (100 ml), and the filtrate was dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 0% to 15%) to obtain the title compound 14B as a dark brown solid (3.00 g, 99.0%). LC-MS(ESI): m / z=453.3[M+H] + .

[0155] Step 2: (S)-2-amino-3-(3-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)propanenitrile (14C) 14B (3.26 g, 7.2 mmol) was dissolved in formic acid (40 ml) and the mixture was stirred at room temperature overnight. Water (40 ml) and dichloromethane (80 ml) were added. The resulting mixture was adjusted to basic pH with sodium bicarbonate, the organic phase was separated, and the aqueous phase was further extracted with dichloromethane (80 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the resulting residue was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 0%-10%) to give the title compound 14C as a dark brown oil (2.32 g, 91.3%). LC-MS (ESI): m / z = 353.3 [M+H] + .

[0156] Step 3: tert-Butyl-(S)-2-(((S)-1-cyano-2-(3-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (14D) 14C (500 mg, 1.42 mmol), INT-3 (348 mg, 1.42 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (648 mg, 1.70 mmol), and DIPEA (366 mg, 2.84 mmol) were dissolved in dichloromethane (15 ml), and the mixture was stirred at room temperature for 4 hours. The reaction solution was washed with saturated sodium bicarbonate solution (10 ml x 3), the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and the resulting residue was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 0% to 10%) to obtain the title compound 14D as a yellow solid (400 mg, 48.6%). LC-MS (ESI): m / z = 580.3 [M + H] + .

[0157] Step 4: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 14) 14D (400 mg, 0.69 mmol) and 2,6-dimethylpyridine (74 mg, 0.69 mmol) were dissolved in dichloromethane (20 ml), and the mixture was stirred under ice-water bath. Tert-butyldimethylsilyl trifluoromethanesulfonate (550 mg, 2.07 mmol) was added dropwise to the reaction flask. After completion of the dropwise addition, the ice-water bath was removed, and the mixture was stirred and reacted at room temperature for 2 hours. The reaction solution was washed with saturated sodium bicarbonate solution (20 ml x 2), the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and the obtained residue was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 0% ~ 15%) to give the title compound 14 (57 mg, 17.2%). LC-MS (ESI): m / z = 480.3 [M + H] + . 1 H NMR (400MHz, DMSO-d6)δ 8.69(d,1H), 7.64(d,2H), 7.54-7.46(m,2H), 7.43(t,1H), 7.37(d,2H), 5.04(dd,1H), 4.01(dd,1H), 3.90-3.82(m,1H), 3.73(ddd,1H), 3.48(s,2H), 3.19(dd,1H), 3.06(dd,1H), 2.83-2.74(m,1H), 2.68-2.61(m,1H), 2.58(dd,1H), 2.35(d,8H), 2.15(s,3H), 1.74(ddd,2H).

[0158] Example 15: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(4-methylthiazol-2-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 15) [ka] Step 1: tert-Butyl (S)-(1-cyano-2-(2-fluoro-4-(4-methylthiazol-2-yl)phenyl)ethyl)carbamate (15B) 15A (0.23 g, 1.28 mmol), INT-2 (0.50 g, 1.28 mmol), [1,1'-(diphenylphosphino)ferrocene]palladium dichloride (94 mg, 0.13 mmol), and potassium carbonate (0.53 g, 3.84 mmol) were dissolved in a mixed solvent of dioxane (27 mL) and water (3 mL), and the mixture was reacted at 90° C. under nitrogen protection for 5 hours. The reaction solution was cooled to room temperature, and 50 mL of water was added. The resulting mixture was extracted with ethyl acetate (20 mL×3). The organic layers were combined, washed successively with saturated sodium bicarbonate (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v)=2:1) ​​to give the title compound 15B (0.25 g, 53%). LC-MS(ESI): m / z=362.1[M+H] + .

[0159] Step 2: (S)-2-amino-3-(2-fluoro-4-(4-methylthiazol-2-yl)phenyl)propanenitrile (15C) 15B (0.25 mg, 0.68 mmol) was dissolved in anhydrous formic acid (4 mL), and the mixture was reacted at 50° C. for 20 min. The reaction solution was cooled to room temperature and concentrated to remove most of the solvent. Saturated sodium bicarbonate solution (20 mL) was added to the residue, and the resulting mixture was extracted with ethyl acetate (10 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=97:3) to give the title compound 15C (0.17 g, 96%). LC-MS (ESI): m / z=262.2 [M+H] + .

[0160] Step 3: tert-Butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(4-methylthiazol-2-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (15D) INT-3 (0.18 g, 0.73 mmol) was dissolved in DMF (5 mL), and then HATU (0.42 g, 1.09 mmol) and DIPEA (0.28 g, 2.19 mmol) were added under nitrogen protection. The mixture was stirred at room temperature for 20 minutes, and then 15C (0.19 g, 0.73 mmol) was added. The resulting mixture was reacted at room temperature for 1 hour. To the reaction solution, 30 mL of water was added. The resulting mixture was extracted with ethyl acetate (15 mL x 5). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 97:3) to give the title compound 15D (0.26 g, 73%). LC-MS (ESI): m / z = 489.1 [M + H] + .

[0161] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(4-methylthiazol-2-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 15) 15D (0.26 g, 0.53 mmol) was dissolved in formic acid (4.0 mL), and after the addition was completed, the mixture was reacted at 50° C. for 30 min. The reaction solution was concentrated to dryness, and ethyl acetate (25 mL) was added. Then, saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to about 8. The organic layer was separated, and the remaining aqueous layer was extracted with ethyl acetate (25 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v)=1:2) to give the title compound 15 (80 mg, 39%). 1H NMR (400MHz, DMSO-d6) δ 8.97(d,J=8.4Hz, 1H), 7.74-7.66(m,2H), 7.48(t,J=7.8Hz, 1H), 7.39(s ,1H), 5.05(m,1H), 4.31(d,J=9.4Hz, 1H), 3.90(m,1H), 3.76(m,1H), 3.36 -3.32(m,1H), 3.21(m,1H), 3.15-3.07(m,1H), 2.97(m,1H), 2.82(dd,J= 14.0, 9.4Hz, 1H), 2.43 (s, 3H), 1.92 (p, J=5.6Hz, 2H), 1.29-1.21 (m, 1H). LC-MS(ESI): m / z=389.1[M+H] + .

[0162] Example 16: (S)-N-((S)-2-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (compound 16) [ka] Step 1: tert-Butyl (S)-(2-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-1-cyanoethyl)carbamate (16B) 16A (0.200 g, 0.83 mmol), INT-2 (0.323 g, 0.83 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.067 g, 0.083 mmol), and potassium carbonate (0.343 g, 2.49 mmol) were dissolved in 1,4-dioxane (10 mL), water (2 mL) was added, and then the mixture was subjected to nitrogen purge three times and reacted at 90° C. under nitrogen atmosphere for 4 hours. The reaction solution was concentrated to dryness, dissolved in dichloromethane, and the mixture was filtered and concentrated. The residue was separated and purified by silica gel column chromatography (PE:EA (v / v)=5:1) to obtain the title compound 16B as a white solid (0.100 g, 28.4%). LC-MS(ESI): m / z=424.1[M+H] + .

[0163] Step 2: (S)-3-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-2-aminopropanenitrile 4-methylbenzenesulfonate (16C) 16B (0.100 g, 0.24 mmol) was dissolved in acetonitrile (2 mL) and then p-toluenesulfonic acid monohydrate (0.134 g, 0.71 mmol) was added. After the addition was completed, the mixture was reacted at room temperature for 16 hours and then filtered. The filter cake was rinsed once with acetonitrile (1 mL) and subjected to rotary evaporation to give the title compound 16C as a white solid (0.100 g, 85.5%), which was used directly in the next reaction.

[0164] Step 3: tert-Butyl (S)-2-(((S)-2-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (16D) INT-3 (0.074 g, 0.303 mmol) was dissolved in dichloromethane (5 mL), then triethylamine (0.061 g, 0.606 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.115 g, 0.303 mmol) were added. After the addition was completed, the mixture was reacted at room temperature for 1 hour with stirring, then 16C (0.100 g, 0.202 mmol) was added. The resulting mixture was reacted at room temperature overnight. After the reaction was completed, the reaction solution was concentrated to give the crude product 16D, which was used directly in the next reaction. LC-MS (ESI): m / z=549.2 [MH] - .

[0165] Step 4: (S)-N-((S)-2-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (compound 16) The crude product 16D was dissolved in acetonitrile (10 mL) and p-toluenesulfonic acid monohydrate (0.134 g, 0.71 mmol) was added. After the addition was completed, the mixture was reacted at room temperature for 16 hours and then concentrated to dryness. Ethyl acetate (25 mL) was added and saturated aqueous sodium bicarbonate was added dropwise to adjust the pH to about 8. The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to give the title compound 16 (27 mg, two-step yield: 29.7%). 1 H NMR(400MHz, CD3OD)δ 8.15(d,1H), 7.51(s,1H), 7.47-7.28(m,4H), 5.14(dd,1H), 4.23-4.09(m,3H), 4.05-3.96(m,1H), 3.82-3.74(m,1H), 3.34(s,1H), 3.30-3.17(m,5H), 3.05-2.95(m,1H), 2.93-2.82(m,1H), 2.72(dd,1H), 2.25(s,3H), 1.97-1.83(m,2H). LC-MS(ESI):m / z=451.2[M+H] + .

[0166] Example 17: (S)-N-((S)-1-cyano-2-(4'-cyano-3'-cyclopropyl-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 17) [ka] Step 1: tert-Butyl (S)-(1-cyano-2-(4'-cyano-3'-cyclopropyl-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamate (17B) 17A (0.300 g, 1.67 mmol), INT-2 (0.646 g, 1.67 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.134 g, 0.167 mmol), and potassium carbonate (0.686 g, 4.98 mmol) were dissolved in 1,4-dioxane (15 mL), water (3 mL) was added, and then the mixture was subjected to nitrogen purge three times and reacted at 100° C. under nitrogen atmosphere for 16 hours. The reaction solution was concentrated to dryness, dissolved in dichloromethane, and the mixture was filtered and concentrated. The residue was separated and purified by silica gel column chromatography (PE:EA (v / v)=5:1) to obtain the title compound 17B as a white solid (0.380 g, 55.4%). LC-MS(ESI): m / z=406.1[M+H] + .

[0167] Step 2: (S)-4'-(2-amino-2-cyanoethyl)-3-cyclopropyl-3'-fluoro-[1,1'-biphenyl]-4-carbonitrile 4-methylbenzenesulfonate (17C) 17B (0.380 g, 0.94 mmol) was dissolved in acetonitrile (5 mL) and then p-toluenesulfonic acid monohydrate (534 g, 2.81 mmol) was added. After the addition was completed, the mixture was reacted at room temperature for 16 hours and then filtered. The filter cake was rinsed once with acetonitrile (2 mL) and subjected to rotary evaporation to give the title compound 17C as a white solid (0.360 g, 80.5%), which was used directly in the next reaction.

[0168] Step 3: tert-Butyl (S)-2-(((S)-1-cyano-2-(4'-cyano-3'-cyclopropyl-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (17D) INT-3 (0.123 g, 0.503 mmol) was dissolved in dichloromethane (5 mL), then triethylamine (0.101 g, 1.00 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.193 g, 0.503 mmol) were added. After the addition was completed, the mixture was stirred at room temperature for 1 h, and then 17C (0.160 g, 0.335 mmol) was added. The resulting mixture was reacted at room temperature overnight. After the reaction was completed, the reaction solution was concentrated to give the crude product 17D, which was used directly in the next reaction. LC-MS (ESI): m / z=531.2 [MH] - .

[0169] Step 4: (S)-N-((S)-1-cyano-2-(4'-cyano-3'-cyclopropyl-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 17) The crude product 17D was dissolved in acetonitrile (10 mL) and p-toluenesulfonic acid monohydrate (0.190 g, 1.00 mmol) was added. After the addition was completed, the mixture was reacted at room temperature for 16 hours and then concentrated to dryness. Ethyl acetate (25 mL) was added and saturated aqueous sodium bicarbonate was added dropwise to adjust the pH to about 8. The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to give the title compound 17 (60 mg, two-step yield: 41.4%). 1H NMR (400MHz, CDCl3)δ 7.66(d,1H), 7.44-7.37(m,2H), 7.33(dd,1H), 7.28(d,2H), 7.10(s,1H), 5.15(dt,1H), 4.22(dt,1H), 4.12-3.99(m,1H), 3.85-3.73(m, 1H), 3.57-3.41(m,1H), 3.30-3.17(m,2H), 3.13-2.97(m,3H), 2.34(ddd,1H), 2.07-1.94(m,2H), 1.24-1.15(m,2H), 0.92-0.83(m,2H). LC-MS(ESI): m / z=433.2[M+H] + .

[0170] Example 18: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 18) [ka] Step 1: tert-Butyl (S)-(1-cyano-2-(3-fluoro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate (18B) 18A (0.50 g, 1.46 mmol), 2a (0.26 g, 1.46 mmol), [1,1'-(diphenylphosphino)ferrocene]palladium dichloride (0.11 mg, 0.15 mmol), and potassium carbonate (0.61 g, 4.38 mmol) were dissolved in a mixed solvent of dioxane (27 mL) and water (3 mL), and the mixture was reacted at 90 °C under nitrogen protection for 5 h. The reaction solution was cooled to room temperature, and 50 mL of water was added. The resulting mixture was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed successively with saturated sodium bicarbonate (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 2:1) to give the title compound 18B (0.34 g, 59%). LC-MS(ESI): m / z=398.2[M+H] + .

[0171] Step 2: (S)-4'-(2-amino-2-cyanoethyl)-3'-fluoro-N-methyl-[1,1'-biphenyl]-4-carboxamide (18C) 18B (0.34 mg, 0.86 mmol) was dissolved in anhydrous formic acid (4 mL), and the mixture was reacted at 50° C. for 20 min. The reaction solution was cooled to room temperature and concentrated to remove most of the solvent. Saturated sodium bicarbonate solution (20 mL) was added to the residue, and the resulting mixture was extracted with ethyl acetate (10 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=97:3) to give the title compound 18C (0.22 g, 87%). LC-MS (ESI): m / z=298.1 [M+H] + .

[0172] Step 3: tert-Butyl (S)-2-(((S)-1-cyano-2-(3-fluoro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (18D) INT-3 (0.23 g, 0.76 mmol) was dissolved in DMF (5 mL), and then HATU (0.43 g, 1.14 mmol) and DIPEA (0.29 g, 2.28 mmol) were added under nitrogen protection. The mixture was stirred at room temperature for 20 min, and then 18C (0.23 g, 0.76 mmol) was added. The resulting mixture was reacted at room temperature for 1 h. To the reaction solution, 30 mL of water was added. The resulting mixture was extracted with ethyl acetate (15 mL x 5). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 97:3) to give the title compound 18D (0.31 g, 77%). LC-MS (ESI): m / z = 469.2 [M-56 + H] + .

[0173] Step 4: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 18) 18D (0.31 g, 0.59 mmol) was dissolved in formic acid (4.0 mL), and after the addition was completed, the mixture was reacted at 50° C. for 30 min. The reaction solution was concentrated to dryness, and ethyl acetate (25 mL) was added. Then, saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to about 8. The organic layer was separated, and the remaining aqueous layer was extracted with ethyl acetate (25 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v)=1:2) to give the title compound 18 (50 mg, 20%). 1 H NMR (400MHz, DMSO-d6)δ 8.98(d,1H), 8.49(d,1H), 7.93(d,2H), 7.81(d,2H), 7.64-7.57(m,2H), 7.47(t,1H), 5.06(m,1H), 4.35-4.29(m,1H), 3.91(m,1H), 3.77(m,1H), 3.38(m,1H), 3.18(m,1H), 2.98(m,2H), 2.87(m,1H), 2.80(d,3H), 1.92(m,2H), 1.23(m,1H). LC-MS(ESI):m / z=425.2[M+H] + .

[0174] Example 19: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-methyl-1H-indol-2-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 19) [ka] Step 1: tert-Butyl (S)-(1-cyano-2-(2-fluoro-4-(1-methyl-1H-indol-2-yl)phenyl)ethyl)carbamate (19B) 2a (0.40 g, 1.17 mmol) was dissolved in 1,4-dioxane (10 mL) and water (0.4 mL), then 1-methyl-2-indole boronic acid pinacol ester (0.39 g, 1.52 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.19 g, 0.23 mmol), and potassium carbonate (0.32 g, 2.34 mmol) were added. After the addition was completed, the mixture was heated to 90° C. and reacted for 2 hours under nitrogen protection. The reaction solution was then reacted at room temperature overnight. The resulting reaction mixture was concentrated to dryness, and saturated aqueous ammonium chloride solution (50 mL) was added. The resulting mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 10:1, 4:1) to give the title compound 19B as a white solid (0.25 g, 54.31%). LC-MS (ESI): m / z = 394.2 [M+H] + .

[0175] Step 2: (S)-2-amino-3-(2-fluoro-4-(1-methyl-1H-indol-2-yl)phenyl)propanenitrile (19C) 19B (0.37 g, 0.94 mmol) was dissolved in acetonitrile (30 mL) and p-toluenesulfonic acid monohydrate (0.54 g, 2.82 mmol) was added. After the addition was completed, the mixture was reacted at room temperature for 4 h. The reaction solution was concentrated to dryness and ethyl acetate (25 mL) was added. Then, saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to about 8. The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 1:1) to give the title compound 19C as a pale yellow solid (0.25 g, 90.67%). LC-MS (ESI): m / z = 294.3 [M + H] + .

[0176] Step 3: tert-Butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(1-methyl-1H-indol-2-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (19D) 19C (0.25 g, 0.85 mmol) was dissolved in dichloromethane (10 mL), then INT-3 (0.21 g, 0.85 mmol), diisopropylethylamine (0.55 g, 4.25 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.32 g, 0.85 mmol) were added. After the addition was completed, the mixture was reacted at room temperature overnight. Saturated aqueous sodium chloride solution (30 mL) was added, and then the resulting mixture was extracted with ethyl acetate (25 mL). The organic phase was washed with saturated aqueous sodium chloride solution (25 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 2:1) to give the title compound 19D as a white solid (0.40 g, 90.39%). LC-MS(ESI): m / z=485.1[M-57+H] + .

[0177] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-methyl-1H-indol-2-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 19) 19D (0.40 g, 0.77 mmol) was dissolved in acetonitrile (30 mL) and p-toluenesulfonic acid monohydrate (0.44 g, 2.31 mmol) was added. After the addition was completed, the mixture was reacted at room temperature for 4 h. The reaction solution was concentrated to dryness and ethyl acetate (25 mL) was added. Then, saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to about 8. The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to give the title compound 19 as a pale yellow solid (0.15 g, 46.33%). 1 H NMR (400MHz, CDCl3)δ 7.64(d,1H), 7.46-7.03(m,6H), 6.59(s,1H), 5.25-5.09(m,1H), 4.15(dd,1H), 4.07-3.90( m,1H), 3.82-3.61(m,4H), 3.37(dd,1H), 3.25(t,2H), 3.12-2.86(m,3H), 1.93-1.75(m,2H). LC-MS(ESI):m / z=421.2[M+H] + .

[0178] Example 20: (S)-N-((S)-1-cyano-2-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 20) [ka] Step 1: tert-Butyl (S)-(1-cyano-2-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamate (20B) 20A (0.200 g, 1.29 mmol), INT-2 (0.502 g, 1.29 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.105 g, 0.129 mmol), and potassium carbonate (0.534 g, 3.87 mmol) were dissolved in 1,4-dioxane (15 mL), water (3 mL) was added, and then the mixture was subjected to nitrogen purge three times and reacted at 90° C. under nitrogen atmosphere for 4 hours. The reaction solution was concentrated to dryness, dissolved in dichloromethane, and the mixture was filtered and concentrated. The residue was separated and purified by silica gel column chromatography (PE:EA (v / v)=5:1) to obtain the title compound 20B as a white solid (0.420 g, 78.5%). LC-MS(ESI): m / z=417.2[M+H] + .

[0179] Step 2: (S)-2-amino-3-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)propanenitrile 4-methylbenzenesulfonate (20C) 20B (0.420 g, 1.01 mmol) was dissolved in acetonitrile (8 mL) and then p-toluenesulfonic acid monohydrate (0.575 g, 3.03 mmol) was added. After the addition was completed, the mixture was reacted at room temperature for 16 hours and then filtered. The filter cake was rinsed once with acetonitrile (2 mL) and subjected to rotary evaporation to give the title compound 20C as a white solid (0.500 g, 99.9%), which was used directly in the next reaction.

[0180] Step 3: tert-Butyl (S)-2-(((S)-1-cyano-2-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (20D) INT-3 (0.148 g, 0.605 mmol) was dissolved in dichloromethane (10 mL), then triethylamine (0.124 g, 1.23 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.230 g, 0.605 mmol) were added. After the addition was completed, the mixture was reacted at room temperature for 1 hour with stirring, then 20C (0.200 g, 0.41 mmol) was added. The resulting mixture was reacted at room temperature overnight. After the reaction was completed, the reaction solution was concentrated to give the crude product 20D, which was used directly in the next reaction. LC-MS (ESI): m / z=542.2 [MH] - .

[0181] Step 4: (S)-N-((S)-1-cyano-2-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 20) The crude product 20D was dissolved in acetonitrile (10 mL) and p-toluenesulfonic acid monohydrate (0.234 g, 1.23 mmol) was added. After the addition was completed, the mixture was reacted at room temperature for 16 hours and then concentrated to dryness. Ethyl acetate (25 mL) was added and saturated aqueous sodium bicarbonate was added dropwise to adjust the pH to about 8. The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to give the title compound 20 (60 mg, two-step yield: 33.1%). 1H NMR (400MHz, CDCl3)δ 7.83(d,1H), 7.81(d,1H), 7.69(dd,2H), 7.41(d,2H), 7.38-7.30(m,2H), 5.18(dd,1H), 4.20(dd,1H), 4.09-3.98(m,1H), 3. 84-3.74(m,1H), 3.41(dd,1H), 3.31-3.17(m,2H), 3.06-2.91(m,3H), 1.96(s,1H), 1.78(d,6H), 1.38(dd,1H), 1.22(dd,1H). LC-MS(ESI):m / z=444.3[M+H] + .

[0182] Example 21: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 21) [ka] Step 1: tert-Butyl (S)-(1-cyano-2-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)carbamate (21B) Reagent 21A (0.47 g, 2.0 mmol) and INT-2 (0.69 g, 2.0 mmol) were dissolved in 1,4-dioxane (50 ml), then potassium carbonate (0.83 g, 6.0 mmol) and Pd(dppf)Cl2 (0.15 g, 0.2 mmol) were added. The mixture was placed under nitrogen protection and reacted at 100°C. TLC and LC-MS showed that a small amount of starting material was still present. The reaction solution was concentrated and subjected to rotary evaporation, then dissolved in DCM and filtered through Celite by suction, the filtrate was subjected to rotary evaporation and passed through a column (EA / PE=0%-40%) to obtain the title compound 21B as a pale yellow solid (0.50 g, 67.3%). LC-MS (ESI): m / z=372.3 [M+H] + .

[0183] Step 2: (S)-2-amino-3-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)propanenitrile (21C) 21B (0.5 g 1.35 mmol) was dissolved in anhydrous formic acid (10 ml). After the mixture was reacted at 50 °C for 0.5 h, TLC detection showed complete reaction of the substrate. Formic acid was removed by rotary evaporation at low temperature, and saturated sodium bicarbonate solution was added to adjust the pH to 8-10. The resulting mixture was extracted with DCM (20 ml x 2), dried over anhydrous sodium sulfate, subjected to rotary evaporation, and passed through a column (DCM:CH3OH=10:1) to obtain the title compound 21C as a pale yellow liquid (0.35 g, 95.6%). LC-MS (ESI): m / z = 272.3 [M + H] + .

[0184] Step 3: tert-Butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (21D) INT-3 (0.32 g, 1.29 mmol), HATU (0.59 g, 1.55 mmol), and DIPEA (0.5 ml) were dissolved in dichloromethane (30 ml) at room temperature. After the mixture was stirred at room temperature for 10 min, 21C (0.35 g, 1.29 mmol) was added, and the resulting mixture was stirred at room temperature for 1 h. TLC detection showed that the reaction was complete. Water (10 ml) was added to quench the reaction, and the reaction solution was extracted with dichloromethane (15 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 1:1) to give the title compound 21D (0.4 g, 62%). LC-MS (ESI): m / z = 443.1 [M-56 + H] + .

[0185] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 21) 21D (0.4 g 0.8 mmol) was dissolved in anhydrous formic acid (10 ml). After the mixture was stirred at 50 °C for 0.5 h, TLC detection showed complete reaction of the substrate. Formic acid was removed by rotary evaporation at low temperature, and saturated sodium bicarbonate solution was added to adjust the pH to 8-10. The resulting mixture was extracted with dichloromethane (20 ml x 2), dried over anhydrous sodium sulfate, subjected to rotary evaporation, and passed through a column (DCM:CH3OH = 10:1) to obtain compound 21 (0.2 g, 62.7%). LC-MS (ESI): m / z = 399.1 [M + H] + . 1 H NMR (400MHz, DMSO-d6)δ 8.71-8.69(m,1H), 8.22(s,1H), 7.87-7.84(m,1H), 7.48-7.37(m,3H), 6.48-6.46(m,1H), 5.03-4.99(m,1H), 4.05-4.02(m,1H), 3.90-3.84(m,1H), 3.76-3.70(m,1H), 3.50(s,3H), 3.25-3.09(m,4H), 2.86-2.80(m,1H), 2.70-2.58(m,2H), 1.80-1.71(m,2H).

[0186] Example 22: (S)-N-((S)-1-cyano-2-(4-(1-ethyl-1H-pyrazol-4-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 22) [ka] Step 1: (S)-tert-butyl (1-cyano-2-(4-(1-ethyl-1H-pyrazol-4-yl)-2-fluorophenyl)ethyl)carbamate (22B) 2a (0.32 g, 1.46 mmol) was dissolved in DMF (10 mL) and intermediate 1 (0.5 g, 1.46 mmol), potassium carbonate (0.61 g, 4.38 mmol), and 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (0.11 g, 0.15 mmol) were added. After the addition was completed, the mixture was reacted at 100°C for 3 h. The reaction solution was cooled to room temperature and saturated aqueous sodium chloride solution (20 mL) was added. The resulting mixture was extracted with dichloromethane (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 2:1) to give the title compound 22B as a colorless liquid (0.44 g, 84.1%). LC-MS(ESI): m / z=359.1[M+H] + .

[0187] Step 2: (S)-2-amino-3-(4-(1-ethyl-1H-pyrazol-4-yl)-2-fluorophenyl)propanenitrile (22C) 22B (0.40 g, 1.12 mmol) was dissolved in formic acid (10 mL) and after the addition was completed, the mixture was reacted at 50° C. for 2 h. The reaction solution was concentrated to dryness and ethyl acetate (25 mL) was added. Saturated aqueous sodium bicarbonate was added dropwise to adjust the pH to about 8 and the organic layer was separated. The remaining aqueous layer was extracted with ethyl acetate (25 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 22C as a colorless liquid (0.29 g, 100%), which was used directly in the next reaction.

[0188] Step 3: (S)-tert-butyl 2-(((S)-1-cyano-2-(4-(1-ethyl-1H-pyrazol-4-yl)-2-fluorophenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (22D) 22C (0.30 g, 1.16 mmol) was dissolved in DMF (10 mL), then INT-3 (0.28 g, 1.16 mmol), diisopropylethylamine (0.45 g, 3.48 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.66 g, 1.74 mmol) were added. After the addition was completed, the mixture was reacted at room temperature overnight. Saturated aqueous sodium chloride solution (30 mL) was added. The resulting mixture was extracted with ethyl acetate (25 mL), and the organic phase was washed with saturated aqueous sodium chloride solution (25 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 22D as a pale yellow solid (0.30 g, 53.3%), which was used directly in the next reaction. LC-MS(ESI): m / z=430.1[M-57+H] + .

[0189] Step 4: (S)-N-((S)-1-cyano-2-(4-(1-ethyl-1H-pyrazol-4-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 22) 22D (0.15 g, 0.31 mmol) was dissolved in formic acid (2.0 mL), and after the addition was completed, the mixture was reacted at 35° C. for 4 h. The reaction solution was concentrated to dryness, and ethyl acetate (25 mL) was added. Then, saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to about 8. The organic layer was separated, and the remaining aqueous layer was extracted with ethyl acetate (25 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v)=1:2) to give the title compound 22 (80 mg, 66.9%). 1H NMR (400 MHz, CDCl3) δ 9.43(s,1H), 9.10-9.08(m,1H), 8.27(s,1H), 7.92(s,1H), 7.44-7.31(m ,3H), 5.03-4.96(m,1H), 4.51-4.48(m,1H), 4.17-4.11(m,2H), 3.96-3. 90(m,1H), 5.82-4.76(m,1H), 3.47-3.43(m,1H), 3.29-3.21(m,2H), 3.1 6-3.07(m,2H), 2.98-2.92(m,1H), 2.12-1.96(m,2H), 1.42-1.38(m,3H). LC-MS(ESI): m / z=386.1[M+H] + .

[0190] Example 23: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 23) [ka] Step 1: 5-chloro-3-(methyl-d3)benzo[d]oxazol-2(3H)-one (23B) 23A (5 g, 29.49 mmol) was dissolved in DMF (25 mL), then cesium carbonate (10.57 g, 32.44 mmol) and deuterated iodomethane (4.28 g, 29.52 mmol) were added. The mixture was reacted at 25° C. for 4 hours. After completion of the reaction, the reaction solution was poured into water (60 mL), filtered, the filter cake was collected, dissolved in dichloromethane, and washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 23B as a brown solid (5.4 g, yield: 98.1%). LCMS m / z=187.0[M+1] +

[0191] Step 2: 3-(methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (23C) Compound 23B (5.4 g, 28.94 mmol) was dissolved in 1,4-dioxane (54 ml), and then pinacolborane (12.49 g, 49.20 mmol), potassium acetate (8.52 g, 86.82 mmol), palladium acetate (652 mg, 2.89 mmol), and X-Phos (2.73 g, 5.79 mmol) were added. After the addition was completed, the mixture was warmed to 100° C. and reacted for 3 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated. The obtained residue was separated and purified by silica gel column chromatography (eluent: PE:EA (v / v) = 1:0 to 10:1) to give 23C as a white solid (7.2 g, yield: 89.8%). LC-MS m / z = 279.2 [M+1] +

[0192] Step 3: tert-Butyl (S)-(1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate (23D) Compound 23C (2.0 g, 7.19 mmol) was dissolved in a mixed solvent of 1,4-dioxane (20 ml) and water (4 ml), and then 2a (2.47 mg, 7.19 mmol) was added. Then, potassium carbonate (2.98 g, 21.57 mmol), palladium acetate (161 mg, 0.72 mmol), and X-Phos (686 mg, 1.44 mmol) were added successively. After the completion of the addition, the mixture was subjected to nitrogen purge three times, warmed to 100 °C, and reacted for 5 hours. After the completion of the reaction, the reaction solution was directly concentrated, and the obtained residue was separated and purified by silica gel column chromatography (eluent: PE:EA (v / v) = 1:0 to 5:1) to obtain compound 23D as a white solid (2.57 g, 86.2%). LCMS m / z = 415.3 [M + 1] +

[0193] Step 4: (S)-2-amino-3-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile (23E) Compound 23D (1 g, 2.41 mmol) was dissolved in anhydrous formic acid (10 ml) and the mixture was stirred at 25° C. for 5 h. After completion of the reaction, the reaction solution was slowly poured into saturated sodium bicarbonate solution (100 ml) until the pH was 7-8. The resulting mixture was then extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 23E as a pale yellow solid (710 mg, 93.5%). LCMS m / z=315.2[M+1] +

[0194] Step 5: tert-Butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (23F) Under nitrogen protection, compound 23E (656 mg, 2.07 mmol) was dissolved in DMF (7 ml), and then INT-3 (510 mg, 2.07 mmol), diisopropylethylamine (1.34 g, 10.35 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.18 g, 3.10 mmol) were added. After the addition was completed, the mixture was warmed to 25°C and reacted for 3 hours. After the reaction was completed, the reaction solution was poured into water (20 ml) and then extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was separated and purified by silica gel column chromatography (eluent: PE:EA (v / v) = 1:0 to 1:1) to give compound 23F as a yellow solid (837 mg, 74.7%). LCMS m / z = 486.3 [M-tBu+1] +

[0195] Step 6: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 23) Compound 23F (837 mg, 1.55 mmol) was dissolved in formic anhydride (3 ml), and the mixture was stirred at 25° C. for 3 h. After completion of the reaction, the reaction solution was slowly poured into saturated sodium bicarbonate solution (30 ml) until the pH was 7-8. Then, the resulting mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated and purified by preparative liquid chromatography column (conditions for preparative liquid chromatography: C18 reversed-phase preparative column, mobile phase: deionized water containing 0.1% trifluoroacetic acid (A) and acetonitrile containing 0.1% trifluoroacetic acid (B), gradient elution, mobile phase B content = 5% to 50%, elution time: 15 min, flow rate: 12 mL / min, and column temperature: 30 °C; and retention time: 3.7 min) to give compound 23 (300 mg, yield: 43.8%). 1 H NMR (400MHz, DMSO-d6)δ 8.76(d,1H), 7.65(d,J=1.8,1H), 7.62-7.50(m,2H), 7.49-7.42(m,2H), 7.38(m,1H), 5.05(m,1H), 4.13(m,1H), 3.99-3.82( m,1H), 3.74(m,1H), 3.65-3.52(m,1H), 3.30(m,2H), 3.16(m,2H), 3.00-2.80(m,1H), 2.74-2.58(m,1H), 1.88-1.68(m,2H). LCMS m / z=442.1[M+1] +

[0196] Example 24: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 24) [ka] Step 1: 6-Bromo-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (24B) 24A (0.57 g, 2.5 mmol) was dissolved in dry N-N-dimethylformamide (20 mL) and the mixture was cooled to 0° C. under nitrogen protection. Sodium hydride (0.12 g, 3.0 mmol, 60% wt) was added in portions. After the addition, the resulting mixture was reacted under these conditions for 20 minutes, and then iodomethane (0.51 g, 3.6 mmol) was added dropwise to the system. After the addition, the mixture was reacted at room temperature for 30 minutes. Water (100 mL) was added to quench the reaction, and the resulting mixture was extracted with ethyl acetate (100 mL×2). The organic phases were combined, washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE:EA=6:1) to give the target compound, i.e., 6-bromo-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (24B), as a yellow solid (0.48 g, yield: 79%).

[0197] Step 2: tert-Butyl (S)-(1-cyano-2-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)carbamate (24C) 24B (0.29 g, 1.2 mmol), INT-2 (0.39 g, 1.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (71 mg, 0.1 mmol), and potassium carbonate (0.28 g, 2.0 mmol) were added successively to 1,4-dioxane (15 mL) and water (3 mL), the system was subjected to nitrogen purge three times, and reacted at 100 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (50 mL) was added, and the resulting aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE:EA=3:1 to 2:1) to give 24C as a brown solid (0.35 g, yield: 83%). LCMS m / z=424.2[M+1] + .

[0198] Step 3: (S)-2-amino-3-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)propanenitrile (24D) 24C (0.35 g, 0.83 mmol) was dissolved in formic acid (6.0 mL), and after the addition was completed, the mixture was reacted at 50° C. for 10 min. The reaction solution was concentrated to dryness. Ethyl acetate (60 mL) was added, followed by dropwise addition of saturated aqueous sodium bicarbonate solution to adjust the pH to about 8. The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (60 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 24D (0.24 g, yield: 89%).

[0199] Step 4: tert-Butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (24E) 24D (0.24 g, 0.74 mmol) was dissolved in DMF (10 mL), then INT-3 (0.25 g, 1.0 mmol), diisopropylethylamine (0.19 g, 1.5 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.38 g, 1 mmol) were added. After the addition was completed, the mixture was reacted at room temperature for 1 h. Water (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (60 mL x 2). The organic phase was washed with saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography (PE:EA = 2:1 to 1:2) to give the title compound 24E as a pale yellow solid (0.28 g, yield: 69%).

[0200] Step 5: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 24) 24E (0.28 g, 0.51 mmol) was dissolved in formic acid (6.0 mL), and the mixture was reacted at 50° C. for 10 min. The reaction solution was concentrated under reduced pressure, and ethyl acetate (60 mL) was added. Then, saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to about 8. The organic layer was separated, and the remaining aqueous layer was extracted with ethyl acetate (60 mL×5). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=10:1) to obtain compound 24 (0.18 g, yield: 78%). 1H NMR (400MHz, DMSO-d6)δ 8.82(d,1H), 7.93(d,1H), 7.71-7.63(m,2H), 7.63-7.53(m,2H), 7.47(t,1H), 5.11-5.01(m,1H), 4.15(dd,1H), 3.94-3.84(m,1H) , 3.80-3.70(m,1H), 3.58(t,2H), 3.37-3.16(m,4H), 3.08-3.01(m,4H), 3.00-2.90(m,1H), 2.89-2.65(m,2H), 1.88-1.74(m,2H). LC-MS(ESI): m / z=451.3[M+H] + .

[0201] Example 25: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 25) [ka] Step 1: tert-Butyl (S)-(1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)carbamate (25B) 25A (0.27 g, 1.2 mmol), INT-2 (0.36 g, 0.92 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (71 mg, 0.1 mmol), and potassium carbonate (0.28 g, 2.0 mmol) were added successively to 1,4-dioxane (15 mL) and water (3 mL), the system was subjected to nitrogen purge three times, and reacted at 100 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (50 mL) was added, and the resulting aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE:EA=3:1 to 2:1) to give 25B as a brown solid (0.36 g, yield: 95%). LCMS m / z=410.1[M+1] + .

[0202] Step 2: (S)-2-amino-3-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)propanenitrile (25C) 25B (0.36 g, 0.88 mmol) was dissolved in formic acid (6.0 mL) and after the addition was completed, the mixture was reacted at 50° C. for 10 min. The reaction solution was concentrated to dryness. Ethyl acetate (60 mL) was added, followed by dropwise addition of saturated aqueous sodium bicarbonate to adjust the pH to about 8. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (60 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 25C (0.28 g, yield: 100%). LCMS m / z=310.1[M+1] + .

[0203] Step 3: tert-Butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (25D) 25C (0.28 g, 0.88 mmol) was dissolved in DMF (10 mL), then INT-3 (0.25 g, 1.0 mmol), diisopropylethylamine (0.19 g, 1.5 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.38 g, 1 mmol) were added. After the addition was completed, the mixture was reacted at room temperature for 1 hour. Saturated aqueous sodium chloride solution (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (60 mL x 2). The organic phase was washed with saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography (PE:EA = 2:1 to 1:2) to give the title compound 25D as a pale yellow solid (0.29 g, yield: 60%).

[0204] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 25) 25D (0.29 g, 0.55 mmol) was dissolved in formic acid (6.0 mL), and the mixture was reacted at 50° C. for 10 min. The reaction solution was concentrated under reduced pressure, and ethyl acetate (60 mL) was added. Then, saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to about 8. The organic layer was separated, and the remaining aqueous layer was extracted with ethyl acetate (60 mL×5). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=10:1) to obtain compound 25 (0.15 g, yield: 64%). 1 H NMR (400MHz, DMSO-d6) δ8.84(d,1H), 7.92(s,1H), 7.80(dd,1H), 7.73(d,1H), 7.64-7.55(m,2H), 7.48(t,1H), 5.07(q,1H), 4.51(s,2H), 4. 16(dd,1H), 3.94-3.84(m,1H), 3.80-3.70(m,1H), 3.45-3.13(m,3H), 3.10(s,3H), 3.02-2.91(m,1H), 2.86-2.67(m,2H), 1.90-1.74(m,2H). LC-MS m / z=437.2[M+1] +

[0205] Example 26: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 26) [ka] Step 1: 6-Fluorobenzo[d]oxazol-2(3H)-one (26B) 26A (10 g, 78.67 mmol) was dissolved in anhydrous DMF (130 mL), and a solution of N,N'-carbonyldiimidazole (15.31 g, 94.40 mmol) in DMF (100 mL) was added dropwise under ice bath, and after the addition, the mixture was reacted at 60 °C for 4 h. The reaction solution was cooled to room temperature, and 600 mL of water was added. The resulting mixture was extracted with EA (100 mL x 4). The organic layers were combined, backflushed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 3:1) to give the title compound 26B (11 g, 91%). LC-MS (ESI): m / z = 154.1 [M + H] + .

[0206] Step 2: 6-Fluoro-5-iodobenzo[d]oxazol-2(3H)-one (26C) 26B (3 g, 19.59 mmol) was dissolved in sulfuric acid (40 mL), and N-iodosuccinimide (5.29 g, 23.51 mmol) was added in portions. The mixture was reacted at 40° C. overnight. The reaction solution was cooled to room temperature, poured into 500 mL of water, and extracted with EA (50 mL×5). The organic layers were combined, backflushed with saturated aqueous sodium bicarbonate (200 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v)=4:1) to give the title compound 26C (1.1 g, 20%). LC-MS (ESI): m / z=280.0 [M+H] + .

[0207] Step 3: 6-Fluoro-5-iodo-3-methylbenzo[d]oxazol-2(3H)-one (26D) 26C (1 g, 3.58 mmol) was dissolved in acetonitrile (40 mL) and potassium carbonate (0.59 g, 4.30 mmol) was added. The mixture was stirred at 40° C. for 30 min and allowed to reach room temperature. Iodomethane (1.02 g, 7.16 mmol) was added dropwise and the resulting mixture was reacted at room temperature overnight. The insoluble material was removed by filtration. The resulting mixture was extracted with EA (50 mL×3). The organic layers were combined, backflushed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v)=5:1) to give the title compound 26D (0.92 g, 88%). LC-MS (ESI): m / z=294.0 [M+H] + .

[0208] Step 4: 6-Fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (26E) 26D (0.92 g, 3.14 mmol), bis(pinacolato)diboron (0.96 g, 3.77 mmol), [1,1'-(diphenylphosphino)ferrocene]palladium dichloride (0.23 g, 0.31 mmol), and potassium acetate (0.92 g, 9.42 mmol) were dissolved in dioxane (40 mL), and the mixture was reacted at 100° C. under nitrogen protection for 5 h. The reaction solution was cooled to room temperature, and 120 mL of water was added. The resulting mixture was extracted with EA (30 mL×3). The organic layers were combined, backflushed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v)=5:1) to give the title compound 26E (0.52 g, 56%). 1 H NMR (400MHz, CDCl3) δ 7.25 (d, J = 4.5 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 3.41 (s, 3H), 1.37 (s, 12H). LC-MS(ESI):m / z=294.1[M+H] + .

[0209] Step 5: tert-Butyl (S)-(1-cyano-2-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate (26F) 2a (0.62 g, 1.81 mmol), 26E (0.53 g, 1.81 mmol), [1,1'-(diphenylphosphino)ferrocene]palladium dichloride (0.13 g, 0.18 mmol), and potassium carbonate (0.75 g, 5.43 mmol) were dissolved in a mixed solvent of dioxane (27 mL) and water (3 mL), and the mixture was reacted at 90 °C under nitrogen protection for 5 h. The reaction solution was cooled to room temperature, and 50 mL of water was added. The resulting mixture was extracted with ethyl acetate (20 mL x 3). The organic layers were combined and washed successively with saturated sodium bicarbonate (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 2:1) to give the title compound 26F (0.6 g, 77%). LC-MS(ESI): m / z=430.1[M+H] + .

[0210] Step 6: (S)-2-amino-3-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile (26G) 26F (0.6 g, 1.40 mmol) was dissolved in anhydrous formic acid (3 mL), and the mixture was reacted at 50° C. for 20 min. The reaction solution was cooled to room temperature and concentrated to remove most of the solvent. Saturated sodium bicarbonate solution (20 mL) was added to the residue, and the resulting mixture was extracted with EA (10 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=97:3) to give the title compound 26G (0.36 g, 78%). LC-MS (ESI): m / z=330.0 [M+H] + .

[0211] Step 7: tert-Butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (Compound 26H) INT-3 (0.26 g, 1.06 mmol) was dissolved in DMF (5 mL), and then HATU (0.6 g, 1.59 mmol) and DIPEA (0.41 g, 3.18 mmol) were added under nitrogen protection. The mixture was stirred at room temperature for 20 min, and then 26G (0.35 g, 1.06 mmol) was added. The resulting mixture was reacted at room temperature for 1 h. To the reaction solution, 30 mL of water was added. The resulting mixture was extracted with EA (15 mL x 5). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 97:3) to give the title compound 26H (0.33 g, 56%). LC-MS (ESI): m / z = 501.1 [M + H] + .

[0212] Step 8: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 26) 26H (0.33 g, 0.59 mmol) was dissolved in anhydrous formic acid (3 mL), and the mixture was reacted at 50° C. for 1 h. The reaction solution was cooled to room temperature and concentrated to remove most of the solvent. Saturated sodium bicarbonate solution (25 mL) was added to the residue, and the resulting mixture was extracted with EA multiple times until almost no product remained in the aqueous layer. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=10:1) to give compound 26 (120 mg, 44%). 1H NMR(400MHz, CD3OD)δ 7.47-7.22(m,5H), 5.17(dd,J=8.8, 6.8Hz, 1H), 4.13(dd,J=8.8, 3.6Hz, 1H), 4.02-3.95(m,1H), 3.79(m,1H), 3.43(s,3H), 3.38-3. 34(m,1H), 3.27-3.18(m,2H), 2.99-2.91(m,1H), 2.87-2.78(m,1H), 2.67(dd,J=14.4, 8.6Hz, 1H), 2.22-2.15(m,1H), 2.03(m,1H). LC-MS(ESI): m / z=457.1[M+H] + .

[0213] Example 27: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide [ka] Step 1: 1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (27B) At -78°C, under nitrogen protection, LDA (2.6mL, 5.2mmol) was slowly added dropwise to 27A (400mg, 2.6mmol, prepared with reference to WO 2016 / 172496 A1) in THF (4.0mL). Stirring was continued at this temperature for 30 minutes, and then a solution of N,N-bis(trifluoromethylsulfonyl)aniline (1.40g, 3.9mmol) in THF (2.0mL) was added dropwise. The resulting mixture was allowed to warm to room temperature and react for 1 hour. Water (5mL) was added to quench the reaction, and the reaction solution was extracted with ethyl acetate (5mL x 3). The organic phases were combined, washed with water (5 ml x 1) and saturated sodium chloride (5 mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (DCM:MeOH = 50:1 to 20:1) to give 27B as a pale yellow liquid (240 mg, 32.4%). LC-MS (ESI): m / z = 288.1 [M+H]+ .

[0214] Step 2: tert-Butyl-(S)-(1-cyano-2-(2-fluoro-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)carbamate (27C) INT-2 (200 mg, 0.6 mmol), 27B (200 mg, 0.7 mmol), Pd(dppf)Cl2 (44 mg, 0.06 mmol), and sodium carbonate (190 mg, 1.8 mmol) were added to a mixed solvent of 1,4-dioxane (5 mL) and water (1 mL) at room temperature, and the mixture was subjected to nitrogen purge three times, warmed to 60 °C, and reacted for 2 h. The reaction solution was cooled to room temperature and subjected to rotary evaporation, and the residue was directly purified by column chromatography (DCM:MeOH = 50:1 to 20:1) to give the title compound 27C as a yellow solid (180 mg, 64%). LC-MS (ESI): m / z = 402.2 [M + H] + .

[0215] Step 3: (S)-2-amino-3-(2-fluoro-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)propanenitrile (27D) 27C (180 mg, 0.4 mmol) was added to anhydrous formic acid (3.0 mL) at room temperature, and the mixture was warmed to 50° C. and reacted for 20 min. Most of the formic acid was removed under reduced pressure, and saturated sodium bicarbonate was added to neutralize the solution to basic pH. The resulting solution was extracted with dichloromethane (10 mL×4), washed with saturated sodium chloride (5 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product of compound 27D as a yellow viscous material (200 mg). LC-MS (ESI): m / z=302.2 [M+H] + .

[0216] Step 4: tert-Butyl-(S)-2-(((S)-1-cyano-2-(2-fluoro-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (27E) The crude product of 27D (200 mg), INT-3 (170 mg, 0.7 mmol), and DIPEA (180 mg, 1.4 mmol) were added to dichloromethane at room temperature, then HATU (270 mg, 0.7 mmol) was added, and stirring was continued at room temperature for 1 h. The reaction solution was subjected to rotary evaporation, and the residue was directly purified by column chromatography (DCM:MeOH=50:1 to 20:1) to give 27E as a yellow solid (200 mg, 2 steps yield: 94%). LC-MS (ESI): m / z=529.3 [M+H] + .

[0217] Step 5: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 27) 27E (150 mg, 0.3 mmol) was added to anhydrous formic acid (3.0 mL) at room temperature, and the mixture was warmed to 50° C. and reacted for 30 min. Most of the formic acid was removed under reduced pressure, and saturated sodium bicarbonate was added to neutralize the solution to a basic pH. The resulting solution was extracted with dichloromethane (10 mL×4), washed with saturated sodium chloride (5 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 27 (40 mg, 33%). LC-MS (ESI): m / z=429.3 [M+H] + . 1H NMR (400MHz, CDCl3)δ 7.27-7.21(m,2H), 7.18-7.15(m,1H), 7.12-7.08(m,1H), 6.12-6.10(m,1H), 5.16-5.10(m,1H), 4.74-4.68(m,4H), 4.18-4.15(m,1H), 4.05-3.99(m,1H), 3.81-3.75(m,1H), 3.68-3.63(m,1H), 3.42-3.37(m,1H), 3.22-3.14(m,2H), 3.09-3.07(m,2H), 3.01-2.92(m,3H), 2.61-2.56(m,4H), 1.95-1.92(m,3H).

[0218] Example 28: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(7-methoxy-1-methyl-1H-indol-4-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 28) [ka] Step 1: 4-Bromo-7-methoxy-1-methyl-1H-indole (28B) 28A (0.50 g, 2.21 mmol) was dissolved in acetonitrile (5 mL), cesium carbonate (1.44 g, 4.22 mmol) and iodomethane (0.47 g, 3.31 mmol) were added, and after the completion of the addition, the mixture was reacted at room temperature overnight. Water (25 mL) was added. The resulting mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 4:1) to give the title compound 28B as a white solid (0.50 g, 94.23%). LC-MS (ESI): m / z = 240.1 [M + H] + .

[0219] Step 2: tert-Butyl (S)-(2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)carbamate (28C) 28B (0.40 g, 1.02 mmol) was dissolved in 1,4-dioxane (10 mL) and water (0.4 mL), then INT-2 (0.26 g, 1.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.17 g, 0.20 mmol), and potassium carbonate (0.28 g, 2.04 mmol) were added. After the addition was completed, the mixture was heated to 90° C. and reacted under nitrogen protection for 2 hours. The reaction solution was then reacted at room temperature overnight. The resulting reaction mixture was concentrated to dryness, and saturated aqueous ammonium chloride solution (50 mL) was added. The resulting mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 4:1) to give the title compound 28C as a pale yellow liquid (0.24 g, 59.20%). LC-MS (ESI): m / z = 398.1 [M + H] + .

[0220] Step 3: (S)-2-amino-3-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)propanenitrile (28D) 28C (0.32 g, 0.81 mmol) was dissolved in formic acid (5 mL) and after the addition was completed, the mixture was reacted at 30° C. for 3 h. Saturated aqueous sodium bicarbonate was added dropwise to adjust the pH to about 8, and the resulting mixture was extracted with ethyl acetate (25 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 28D as a colorless liquid (0.24 g, 99.65%), which was used directly in the next reaction. LC-MS (ESI): m / z=298.1 [M+H] + .

[0221] Step 4: tert-Butyl (S)-2-(((S)-2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (28E) 28D (0.24 g, 0.81 mmol) was dissolved in dichloromethane (10 mL), then INT-3 (0.26 g, 1.05 mmol), diisopropylethylamine (0.31 g, 2.43 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.46 g, 1.22 mmol) were added. After the addition was completed, the mixture was reacted at room temperature overnight. Saturated aqueous sodium chloride solution (30 mL) was added, and then the resulting mixture was extracted with ethyl acetate (25 mL). The organic phase was washed with saturated aqueous sodium chloride solution (25 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 4:1) to give the title compound 28E as a pale yellow solid (0.25 g, 58.83%). LC-MS(ESI): m / z=469.2[M-57+H] + .

[0222] Step 5: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(7-methoxy-1-methyl-1H-indol-4-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 28) 28E (0.32 g, 0.59 mmol) was dissolved in formic acid (2.0 mL), and after the addition was completed, the mixture was reacted at 35° C. for 4 h. The reaction solution was concentrated to dryness, and ethyl acetate (25 mL) was added. Then, saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to about 8. The organic layer was separated, and the remaining aqueous layer was extracted with ethyl acetate (25 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=20:1) to give the title compound 28 (30 mg, 14.72%). 1H NMR (400MHz, CDCl3)δ 7.49-7.28(m,3H), 7.04-6.88(m,2H), 6.67(d,1H), 6.54(d,1H), 5.32-5.04(m,1H), 4.12-4.0 5(m,4H), 4.01-3.89(m,4H), 3.75(m,1H), 3.26(qd, 3H), 2.97-2.82(m,3H), 1.90-1.68(m,2H). LC-MS(ESI):m / z=451.2[M+H] + .

[0223] Example 29: (S)-N-((S)-1-cyano-2-(4'-cyano-3-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 29) [ka] Step 1: tert-Butyl (S)-(1-cyano-2-(4'-cyano-3-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate (29B) 29A (300.0 mg, 1.00 mmol), INT-2 (470.0 mg, 1.20 mmol), Pd(dppf)Cl2 (160.0 mg, 0.20 mmol), and potassium carbonate (280.0 mg, 2.00 mmol) were added to a one-neck flask, followed by the addition of 1,4-dioxane (10 mL) and water (0.4 mL). The mixture was subjected to nitrogen purge three times, and then reacted at 95° C. for 4 hours. The reaction solution was cooled to room temperature, then concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v)=2:1) ​​to obtain the title compound 29B as a white solid (230.0 mg, 53.1%). LC-MS (ESI): m / z=377.1 [M-57+H] + .

[0224] Step 2: (S)-4'-(2-amino-2-cyanoethyl)-3'-fluoro-3-(trifluoromethyl)-[1,1'-biphenyl]-4-carbonitrile (29C) 29B (230.0 mg, 0.53 mmol) was dissolved in formic acid (5 mL) and the mixture was reacted at 35° C. for 4 h. The reaction was adjusted to basic pH using saturated potassium carbonate solution, extracted with ethyl acetate (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 29C as a pale yellow oil (180.0 mg, 100%), which was used directly in the next reaction. LC-MS (ESI): m / z=334.1 [M+H] + .

[0225] Step 3: tert-Butyl (S)-2-(((S)-1-cyano-2-(4'-cyano-3-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (29D) 29C (180 mg, 0.54 mmol) was dissolved in DMF (5 mL), then INT-3 (160 mg, 0.65 mmol), HATU (250 mg, 0.65 mmol), and DIPEA (210 mg, 1.62 mmol) were added. After the addition was completed, the mixture was reacted at room temperature overnight. Water (20 mL) was added to the system. The resulting mixture was extracted with ethyl acetate (30 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 2:1) to give the title compound 29D as a white solid (280 mg, 92.5%). LC-MS (ESI): m / z = 505.2 [M-57 + H] + .

[0226] Step 4: (S)-N-((S)-1-cyano-2-(4'-cyano-3-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 29) 29D (280 mg, 0.50 mmol) was dissolved in formic acid (5 mL), and the mixture was reacted at 35° C. for 4 hours. The reaction system was adjusted to basic pH using saturated potassium carbonate solution, extracted with ethyl acetate (30 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=30:1) to give the title compound 29 (100.0 mg, 43.4%). 1 H NMR (400MHz, CDCl3)δ 7.96-7.92(m,2H), 7.85(dd,1H), 7.49(t,1H), 7.40(dd,1H), 7.35(dd,1H), 5.23-5.17(m,1H), 4.09(q,1H), 4.05-4.00 (m,1H), 3.80-3.74(m,1H), 3.30(dd,1H), 3.29-3.20(m,2H), 2.98-2.86(m,3H), 1.93-1.80(m,2H), 1.61-1.50(m,2H). LC-MS(ESI):m / z=461.2[M+H] + .

[0227] Example 30: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 30) [ka] Step 1: tert-Butyl (S)-(1-cyano-2-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)ethyl)carbamate (30B) 30A (0.20 g, 0.95 mmol), INT-2 (0.31 g, 0.79 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.12 g, 0.16 mmol), and potassium carbonate (0.22 g, 1.58 mmol) were added successively to 1,4-dioxane (20 mL) and water (4 mL), the system was subjected to nitrogen purge three times, and reacted at 100 °C for 2.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (40 mL) was added, and the resulting aqueous phase was extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE:EA (v / v) = 3:1 to 2:1) to give 30B (0.26 g, yield: 83%). LCMS m / z = 396.1 [M+H] + .

[0228] Step 2: (S)-2-amino-3-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)propanenitrile (30C) 30B (0.26 g, 0.66 mmol) was dissolved in formic acid (5.0 mL) and after the addition was completed, the mixture was reacted at 50° C. for 10 min. The reaction solution was concentrated to dryness. Ethyl acetate (60 mL) was added, followed by dropwise addition of saturated aqueous sodium bicarbonate to adjust the pH to about 8. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (60 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 30C (0.15 g, yield: 77%). LCMS m / z=296.1 [M+H] + .

[0229] Step 3: tert-Butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (30D) 30C (0.15 g, 0.51 mmol) was dissolved in N,N'-dimethylformamide (10 mL), then INT-3 (0.13 g, 0.51 mmol), triethylamine (0.1 g, 1 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.23 g, 0.61 mmol) were added. After the addition was completed, the mixture was reacted at room temperature for 1 hour. Saturated aqueous sodium chloride solution (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (60 mL x 3). The organic phase was washed with saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography (PE:EA (v / v) = 2:1 to 1:5) to give the title compound 30D (0.14 g, yield: 53%).

[0230] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 30) 30D (0.14 g, 0.27 mmol) was dissolved in formic acid (6.0 mL), and the mixture was reacted at 50° C. for 10 min. The reaction solution was concentrated under reduced pressure, and ethyl acetate (60 mL) was added. Then, saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to about 8. The organic layer was separated, and the remaining aqueous layer was extracted with dichloromethane (60 mL×5). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=4:1) to obtain compound 30 (48 mg, yield: 42%). 1H NMR (400MHz, DMSO-d6)δ 8.93(d,1H), 8.62(s,1H), 7.98-7.92(m,2H), 7.71-7.55(m,3H), 7.47(t,1H), 5.06(q,1H), 4.42(s,2H), 4.27(dd,1H), 3.95-3.90 m, 1H), 3.80-3.72(m,1H), 3.28-3.15(m,3H), 3.12-3.02(m,1H), 2.95-2.87(m,1H), 2.81(dd,1H), 1.94-1.84(m,2H). LC-MS m / z=423.2[M+H] + .

[0231] Example 31: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 31) [ka] Step 1: 6-Bromo-2-methylisoindolin-1-one (31A) 30A (0.49 g, 2.3 mmol) was dissolved in dry N-N-dimethylformamide (20 mL) and the mixture was cooled to 0° C. under nitrogen protection. Sodium hydride (0.14 g, 3.45 mmol, 60% wt) was added in portions. After the addition, the resulting mixture was reacted under these conditions for 20 minutes, and then iodomethane (0.49 g, 3.45 mmol) was added dropwise to the system. After the addition, the mixture was reacted at room temperature for 30 minutes. Water (100 mL) was added to quench the reaction, and the resulting mixture was extracted with ethyl acetate (100 mL×2). The organic phases were combined, washed with saturated brine (100 mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE:EA=6:1) to obtain the target compound 31A (0.37 g, yield: 71%). 1 H NMR (400MHz, CDCl3) δ 7.97(d,1H), 7.64(dd,1H), 7.31(d,1H), 4.33(s,2H), 3.20(s,3H).

[0232] Step 2: tert-Butyl (S)-(1-cyano-2-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)carbamate (31B) 31A (0.18 g, 0.8 mmol), INT-2 (0.29 g, 0.74 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.11 g, 0.15 mmol), and potassium carbonate (0.2 g, 1.48 mmol) were added successively to 1,4-dioxane (20 mL) and water (4 mL), the system was subjected to nitrogen purge three times, and reacted at 100 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (40 mL) was added, and the resulting aqueous phase was extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE:EA (v / v) = 3:1 to 1:1) to give 31B (0.27 g, yield: 89%). LCMS m / z = 432.1 [M+Na] + .

[0233] Step 3: (S)-2-amino-3-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)propanenitrile (31C) 31B (0.27 g, 0.66 mmol) was dissolved in formic acid (6.0 mL) and after the addition was completed, the mixture was reacted at 50° C. for 10 min. The reaction solution was concentrated to dryness. Ethyl acetate (60 mL) was added, followed by dropwise addition of saturated aqueous sodium bicarbonate to adjust the pH to about 8. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (60 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 31C (0.16 g, yield: 78%). LCMS m / z=310.2 [M+H] + .

[0234] Step 4: tert-Butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (31D) 31C (0.16 g, 0.52 mmol) was dissolved in N,N'-dimethylformamide (10 mL), then INT-3 (0.13 g, 0.52 mmol), triethylamine (0.1 g, 1 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.24 g, 0.62 mmol) were added. After the addition was completed, the mixture was reacted at room temperature for 1 hour. Saturated aqueous sodium chloride solution (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (60 mL x 3). The organic phase was washed with saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography (PE:EA (v / v) = 2:1 to 1:3) to give the title compound 31D (0.21 g, yield: 75%). LCMS m / z=559.2[M+Na] + .

[0235] Step 5: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 31) 31D (0.21 g, 0.39 mmol) was dissolved in formic acid (6.0 mL), and the mixture was reacted at 50° C. for 10 min. The reaction solution was concentrated under reduced pressure, and ethyl acetate (60 mL) was added. Then, saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to about 8. The organic layer was separated, and the remaining aqueous layer was extracted with dichloromethane (60 mL×5). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=10:1) to obtain compound 31 (100 mg, yield: 59%). 1H NMR (400MHz, DMSO-d6)δ 8.85(d,1H), 7.94-7.90(m,2H), 7.68(d,1H), 7.65-7.56(m,2H), 7.46(t,1H), 5.11-5.01(m,1H), 4.51(s,2H), 4.18(dd,1H) ), 3.94-3.84(m,1H), 3.79-3.70(m,1H), 3.26-3.14(m,3H), 3.10(s,3H), 3.02-2.92(m,1H), 2.87-2.69(m,2H), 1.90-1.77 m, 2H). LC-MS m / z=437.2[M+H] + .

[0236] Example 32: (2S)—N-(1-cyano-2-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 32) [ka] Step 1: Methyl 5-bromo-3-fluorothiophene-2-carboxylate (32B) At room temperature, 32A (15 g, 93.7 mmol) was dissolved in chloroform (200 mL), bromine (120 g, 750 mmol) was added, and the mixture was heated to 80° C. and reacted for 3 hours. The reaction solution was poured into saturated sodium thiosulfate solution (500 mL), the organic phase was concentrated to dryness, and the residue was separated and purified by preparative chromatography to obtain the title compound 32B (10 g, yield: 45%).

[0237] Step 2: (5-bromo-3-fluorothiophen-2-yl)methanol (32C) At room temperature, 32B (5 g, 20.9 mmol) was dissolved in dichloromethane (120 mL), and then diisobutylaluminum hydride (42 mL, 62.8 mmol) was added dropwise. The mixture was reacted at room temperature for 3 hours, and water (100 mL) was added. The resulting mixture was filtered, and the organic phase was concentrated to dryness to give the title compound 32C (4 g, yield: 90%).

[0238] Step 3: 5-Bromo-2-(bromomethyl)-3-fluorothiophene (32D) At room temperature, 32C (4 g, 19.0 mmol) was dissolved in dichloromethane (60 mL), and carbon tetrabromide (7.5 g, 22.7 mmol) and triphenylphosphine (7.5 g, 28.4 mmol) were added. The mixture was reacted at room temperature for 2 hours, the reaction solution was concentrated to dryness, and the residue was directly purified by column chromatography (PE:EA (v:v) = 20:1 to 10:1) to give the title compound 32D (4 g, yield: 77%).

[0239] Step 4: 3-(5-bromo-3-fluorothiophen-2-yl)-2-((diphenylmethylene)amino)propanenitrile (32E) At room temperature, 32D (2 g, 7.3 mmol) was dissolved in dichloromethane (40 mL) and water (4 mL), sodium hydroxide (0.5 g, 13.1 mmol) and benzyltrimethylammonium chloride (140 mg, 0.73 mmol) were added, and the mixture was reacted at room temperature for 16 h. The reaction solution was washed with water (50 mL x 1), the organic phase was concentrated, and the residue was directly purified by column chromatography (PE:EA (v:v) = 20:1 to 10:1) to give the title compound 32E (1.2 g, yield: 40%). LC-MS (ESI): m / z = 413.1 [M + H] + .

[0240] Step 5: 2-((diphenylmethylene)amino)-3-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)propanenitrile (32F) At room temperature, 32E (1.2 g, 2.9 mmol) was dissolved in dioxane (30 mL) and water (3 mL), and 1A (1 g, 3.5 mmol), potassium carbonate (1 g, 7.3 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (0.28 g, 0.6 mmol), and palladium acetate (0.065 g, 0.29 mmol) were added successively. The mixture was reacted at 100 °C for 3 h, and the reaction solution was directly stirred with silica gel for purification by column chromatography (PE:EA (v:v) = 5:1 to 1:1) to give the title compound 32F (1.4 g, yield: 70%). LC-MS (ESI): m / z = 482.1 [M + H] + .

[0241] Step 6: 2-amino-3-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)propanenitrile (32G) At room temperature, 32F (1.4 g, 2.9 mmol) was dissolved in tetrahydrofuran (20 mL), 1N hydrochloric acid (40 mL) was added, and the mixture was reacted at room temperature for 1 h. The reaction solution was extracted with ethyl acetate (50 mL x 1) to remove impurities, and then the aqueous phase was adjusted to pH 8-9 using potassium carbonate and extracted with ethyl acetate (50 mL x 2) for the product. The organic phase was concentrated to give the title compound 32G (0.45 g, yield: 49%). LC-MS (ESI): m / z = 318.1 [M + H] + .

[0242] Step 7: (2S)-tert-butyl-2-((1-cyano-2-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (32H) At room temperature, 32G (0.45 g, 1.4 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.6 g, 1.6 mmol), INT-3 (0.4 g, 1.7 mmol), and diisopropylethylamine (0.5 g, 3.6 mmol) were added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was poured into water (200 mL) and then extracted with ethyl acetate (100 mL x 2). The organic phase was concentrated to dryness to give the title compound 32H (0.4 g, yield: 52%). LC-MS (ESI): m / z = 545.2 [M + H] +

[0243] Step 8: (2S)-N-(1-cyano-2-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 32) At room temperature, compound 32G (0.4 g, 0.73 mmol) was dissolved in acetonitrile (20 mL) and p-toluenesulfonic acid (0.5 g, 3.0 mmol) was added. The mixture was reacted at 50° C. for 1 hour, and the reaction solution was poured into saturated aqueous sodium bicarbonate solution (100 mL), and then extracted with ethyl acetate (100 mL×2). The organic phase was concentrated, and the residue was purified by column chromatography (DCM:MeOH (v:v)=50:1 to 20:1) to obtain compound 32 (0.24 g, 70%). 1 H NMR (400MHz, CDCl3) δ7.33-7.29(s,1H), 7.21-7.19(m,1H), 7.07-7.03(m,1H), 7.00(s,1H), 5.18-5.13(m,1H) , 4.14-4.00(m,2H), 3.81-3.71(m,1H), 3.41(s,3H), 3.36-3.23(m,3H), 3.04-2.90(m,3H), 1.91-1.81(m,2H). LC-MS(ESI):m / z=445.1[M+H] + .

[0244] Example 33 and Example 34: (S)-N-((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-2-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 33 and Compound 34) [ka] Step 1: 5-Bromo-2-(bromomethyl)pyridine (33B) 2-Methyl-5-bromopyridine 33A (5 g, 29.07 mmol) was dissolved in carbon tetrachloride (50 mL), N-bromosuccinimide (5.43 g, 30.52 mmol) and azodiisobutyronitrile (1.19 g, 7.27 mmol) were added, and the mixture was reacted at 90° C. for 2.5 hours. The reaction solution was cooled to room temperature and concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 10:1) to obtain the title compound 33B (4.42 g, 61%). LC-MS (ESI): m / z = 251.9 [M + H] + .

[0245] Step 2: 3-(5-bromopyridin-2-yl)-2-((diphenylmethylene)amino)propanenitrile (33C) 33B (4.42 g, 17.54 mmol) and N-(diphenylmethylene)aminoacetonitrile (3.86 g, 17.54 mmol) were dissolved in dichloromethane (50 mL) and benzyltrimethylammonium chloride (0.33 g, 1.75 mmol) was added. A solution of sodium hydroxide (1.40 g, 35.08 mmol) in water (5 mL) was added under vigorous stirring and the mixture was reacted at room temperature overnight. Water (100 mL) was added. The resulting mixture was extracted with dichloromethane (30 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 10:1) to give the title compound 33C (5.20 g, 76%). LC-MS (ESI): m / z = 390.0 [M + H] + .

[0246] Step 3: 2-((diphenylmethylene)amino)-3-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)propanenitrile (33D) 33C (1.73 g, 4.43 mmol), 1A (1.34 g, 4.87 mmol), [1,1'-(diphenylphosphino)ferrocene]palladium dichloride (0.33 g, 0.44 mmol), and potassium carbonate (1.22 g, 8.86 mmol) were dissolved in a mixed solvent of dioxane (50 mL) and water (5 mL), and the mixture was reacted at 90 °C under nitrogen protection for 5 hours. The reaction solution was cooled to room temperature, and 200 mL of water was added. The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed successively with saturated sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 3:1) to give the title compound 33D (2.03 g, 68.92%). LC-MS(ESI): m / z=459.1[M+H] + .

[0247] Step 4: 2-amino-3-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-2-yl)propanenitrile (33E) 33D (1.02 g, 2.19 mmol) was dissolved in tetrahydrofuran (50 mL) and water (5 mL), and 2.5 mL of 1 M HCl aqueous solution was added dropwise, and after the addition, the mixture was reacted at room temperature for 5 h. The reaction solution was extracted with ether (15 mL x 3), and the resulting organic layer was discarded. The aqueous layer was adjusted to a pH of about 12 using 2 M NaOH aqueous solution, and then extracted with DCM (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound 33E (crude product, 580 mg), which was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 295.0 [M + H] + .

[0248] Step 5: tert-Butyl (2S)-2-((1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-2-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (33F) 33E (0.4 g, 1.36 mmol) was dissolved in dichloromethane (10 mL), DIPEA (0.34 mg, 2.64 mmol), HATU (0.55 mg, 1.45 mmol), and intermediate INT-3 (0.36 g, 1.5 mmol) were added successively, and the mixture was reacted at room temperature for 1 h. After TLC detection showed complete reaction, water (20 mL) was poured into the reaction solution for layering. The organic phase was washed successively with water (20 mL) and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily crude product. The crude product was purified by flash column chromatography (DCM:MeOH (v / v) = 96:4) to obtain 33F as a white solid (0.4 g, yield: 56.4%). LC-MS (ESI): m / z = 522.2 [M + H] + .

[0249] Step 6: (2S)—N-(1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (33G) Compound 33F (0.3 g, 0.58 mmol) was dissolved in dichloromethane (10 mL) and TMSOTf (0.19 g, 0.87 mmol) was added. Under ice bath, 2,6-lutidine (0.12 g, 1.16 mmol) was added dropwise, and after the dropwise addition, the mixture was warmed to room temperature and reacted for 1 hour. The reaction solution was poured into 30 mL of saturated ammonium chloride solution, and the resulting mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oily crude product, which was purified and separated by flash column chromatography (DCM:MeOH = 95:5, v / v) to give compound 33G (0.14 g).

[0250] Compound 33G was subjected to SFC chiral preparative separation to give peak 1 (40 mg, ee%=100%, yield: 16.5%, retention time: 2.728 min, set to be compound 33) and peak 2 (50 mg, ee%=98.5%, yield: 20.6%, retention time: 3.987 min, set to be compound 34).

[0251] The purification conditions were as follows: (Instrument name: MG II preparative SFC (SFC-14); Chromatography column: ChiralPak AD, 250×30 mm inner diameter (ID), 10 μm; Mobile phase: Phase A: CO; Phase B: Isopropanol (0.1% NH.H0); Flow rate: 70 mL / min; Column pressure: 100 bar; Column temperature: 35° C.; Absorption wavelength: 220 nm; and Cycle time: approximately 7 min). Peak 1: LC-MS (ESI): m / z = 422.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ 8.79-8.78(m,1H), 8.50-8.48(m,1H), 7.88-7.85(m,1H), 7.37-7.31(m,3H), 7.14(s,1H), 5.37-5.35(m,1H), 4.28-4.25(m,1H), 4.12-4.0 8(m,1H), 3.85-3.69(m,1H), 3.52-3.51(m,1H), 3.47(s,3H), 3.37-3.35(m,2H), 3.13-3.05(m,2H), 2.02-2.01(m,2H), 1.26-1.20(m,2H). Peak 2: LC-MS (ESI): m / z = 422.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ 8.79-8.78(m,1H), 8.50-8.48(m,1H), 7.88-7.85(m,1H), 7.37-7.31(m,3H), 7.14(s,1H), 5.39-5.34(m,1H), 4.28-4.25(m,1H), 4.15-4.0 9(m,1H), 3.85-3.71(m,1H), 3.52-3.51(m,1H), 3.47(s,3H), 3.37-3.34(m,2H), 3.14-3.04(m,2H), 2.02-2.01(m,2H), 1.26-1.20(m,2H).

[0252] Example 35 and Example 36: (S)-N-((S)-1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 35 and Compound 36) [ka] Step 1: 2-Bromo-4-fluoro-5-methylpyridine (35B) Compound 35A, i.e., 2-bromo-4-amino-5-methylpyridine (1.87 g, 10 mmol) was dissolved in hydrogen fluoride pyridine (20 mL) and sodium nitrite (0.83 g, 12 mmol) was added portionwise at -10°C. After the addition, the mixture was allowed to warm to room temperature naturally and reacted overnight. After the reaction was completed, water (100 mL) was added and the pH was adjusted to 8 using saturated sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (100 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE:EA = 10:1, v / v) to give the target compound 35B (1.21 g, yield: 63.4%). 1 H NMR (400MHz, CDCl3) δ 8.20(d,1H), 7.19(d,1H), 2.23(s,3H). LC-MS m / z=190.0 / 192.0[M+1] +

[0253] Step 2: 2-Bromo-5-(bromomethyl)-4-fluoropyridine (35C) 35B (2.84 g, 15.0 mmol) was dissolved in carbon tetrachloride (50 mL), N-bromosuccinimide (2.93 g, 16.5 mmol) and azodiisobutyronitrile (0.49 g, 3.0 mmol) were added, and the mixture was reacted at 90° C. for 4 hours. The reaction solution was cooled to room temperature and concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v)=10:1) to obtain the title compound 35C (2.45 g, 61%). 1 H NMR (400MHz, CDCl3) δ 8.40(d,1H), 7.28(d,1H), 4.43(s,2H).

[0254] Step 3: 3-(6-bromo-4-fluoropyridin-3-yl)-2-((diphenylmethylene)amino)propanenitrile (35D) 35C (2.4 g, 8.9 mmol) and N-(diphenylmethylene)aminoacetonitrile (1.96 g, 8.9 mmol) were dissolved in dichloromethane (40 mL) and benzyltrimethylammonium chloride (0.17 g, 0.89 mmol) was added. A solution of sodium hydroxide (1.07 g, 26.8 mmol) in water (4 mL) was added under vigorous stirring and the mixture was reacted at room temperature overnight. Water (100 mL) was added. The resulting mixture was extracted with dichloromethane (60 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 10:1) to give the title compound 35D (2.23 g, 61%). LC-MS (ESI): m / z = 408.1 [M + H] + .

[0255] Step 4: 2-((diphenylmethylene)amino)-3-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)propanenitrile (35E) 35D (1.3 g, 3.18 mmol), 1A (0.87 g, 3.18 mmol), [1,1'-(diphenylphosphino)ferrocene]palladium dichloride (0.35 g, 0.48 mmol), and potassium carbonate (0.88 g, 6.36 mmol) were dissolved in a mixed solvent of dioxane (30 mL) and water (5 mL), and the mixture was reacted at 90 °C under nitrogen protection for 5 hours. The reaction solution was cooled to room temperature, and 80 mL of water was added. The resulting mixture was extracted with ethyl acetate (60 mL x 3). The organic layers were combined and washed successively with saturated sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 3:1) to give the title compound 35E (1.02 g, 67%). LC-MS(ESI): m / z=477.2[M+H] + .

[0256] Step 5: 2-amino-3-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)propanenitrile (35F) 35E (1.02 g, 2.14 mmol) was dissolved in tetrahydrofuran (25 mL) and water (5 mL), and 5 mL of 1 M HCl aqueous solution was added dropwise, and after the addition, the mixture was reacted at room temperature for 5 h. The reaction solution was extracted with ether (40 mL), and the resulting organic layer was discarded. The aqueous layer was adjusted to a pH of about 12 using 2 M NaOH aqueous solution, and then extracted with DCM (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound 35F (crude product, 0.64 g), which was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 313.1 [M + H] + .

[0257] Step 6: (2S)—N-(1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (35G) 35F (0.64 g, 2.05 mmol) was dissolved in dichloromethane (10 mL), and intermediate INT-3 (0.5 g, 2.05 mmol), DIPEA (0.53 mg, 4.1 mmol), and HATU (0.94 mg, 2.46 mmol) were added successively, and the mixture was reacted at room temperature for 1 h. After TLC detection showed complete reaction, water (20 mL) was poured into the reaction solution for layering. The organic phase was washed successively with water (20 mL) and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily crude product. The crude product was purified by flash column chromatography (DCM:MeOH (v / v) = 20:1) to obtain 35G (0.98 g, yield: 88.6%). LC-MS (ESI): m / z = 540.2 [M + H] + .

[0258] Step 7: (S)-N-((S)-1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 35 and Compound 36) Compound 35G (0.98 g, 1.82 mmol) was dissolved in formic acid (10 mL), and the mixture was reacted at 50° C. for 10 minutes. The reaction solution was concentrated under reduced pressure. Dichloromethane (40 mL) and saturated sodium bicarbonate (40 mL) were added, and the mixture was subjected to liquid-liquid separation. The aqueous phase was extracted with dichloromethane (50 mL×4), and the organic phase was combined, washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the target compound (0.76 g, yield: 95%). The target compound was subjected to preparative SFC to obtain two isomers: peak 1 (retention time: 2.47 min, set to be compound 35) and peak 2 (retention time: 3.69 min, set to be compound 36).

[0259] Preparation conditions: Instrument: MG II preparative SFC (SFC-14). Column: ChiralPak AD, 250 x 30 mm internal diameter (ID), 10 μm. Mobile phase: A: CO2 and B: methanol (0.1% NH3H2O). Gradient: B 40%. Flow rate: 80 mL / min. Back pressure: 100 bar. Column temperature: 38°C. Wavelength: 220 nm. Cycle time: about 10 min. Sample preparation: The sample was dissolved in 15 ml of methanol / dichloromethane. Injection: 3.5 ml / injection. Peak 1: LC-MS m / z=440.1[M+1] + . 1H NMR (400MHz, CDCl3)δ 8.60(d,1H), 7.72(d,1H), 7.67(dd,1H), 7.47(d,1H), 7.32-7.26(m,2H), 5.28-5.17(m,1H), 4.12-3. 99(m,2H), 3.81-3.73(m,1H), 3.48(s,3H), 3.34-3.16(m,3H), 3.01-2.80(m,3H), 1.97-1.75(m,2H). Peak 2: LC-MS m / z=440.1[M+1] + . 1 H NMR (400MHz, CDCl3)δ 8.58(d,1H), 7.73(d,1H), 7.67(dd,1H), 7.48(d,1H), 7.32(d,1H), 7.28(d,1H), 5.17(dt,1H), 4.13-4.01(m,2H), 3. 83-3.75(m,1H), 3.48(s,3H), 3.38(dd,1H), 3.33-3.19(m,2H), 3.07(dd,1H), 3.02-2.87(m,2H), 2.06-1.78(m,2H).

[0260] Example 37 and Example 38: (S)-N-((S)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 37 and Compound 38) [ka] Step 1: 2-Bromo-5-(bromomethyl)pyridine (37B) 37A (5 g, 29.07 mmol) was dissolved in carbon tetrachloride (50 mL), N-bromosuccinimide (5.43 g, 30.52 mmol) and azodiisobutyronitrile (1.19 g, 7.27 mmol) were added, and the mixture was reacted at 90° C. for 2.5 hours. The reaction solution was cooled to room temperature and concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 10:1) to obtain the title compound 37B (4.42 g, 61%). LC-MS (ESI): m / z = 251.9 [M + H] + .

[0261] Step 2: 3-(6-bromopyridin-3-yl)-2-((diphenylmethylene)amino)propanenitrile (37D) 37B (4.42 g, 17.54 mmol) and 37C (3.86 g, 17.54 mmol) were dissolved in dichloromethane (50 mL) and benzyltrimethylammonium chloride (0.33 g, 1.75 mmol) was added. A solution of sodium hydroxide (1.40 g, 35.08 mmol) in water (5 mL) was added under vigorous stirring and the mixture was reacted at room temperature overnight. Water (100 mL) was added. The resulting mixture was extracted with dichloromethane (30 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 10:1) to give the title compound 37D (5.20 g, 76%). 1 H NMR (400MHz, CDCl3)δ 8.16(s,1H), 7.64-7.57(m,2H), 7.50-7.32(m,8H), 6.96(q,J=2.4Hz, 2H), 4.40(t,J=6.5Hz, 1H), 3.17(d,J=6.5Hz, 2H). LC-MS(ESI):m / z=390.0[M+H] + .

[0262] Step 3: 2-((diphenylmethylene)amino)-3-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)propanenitrile (37E) 37D (1.5 g, 3.84 mmol), 1A (1.06 g, 3.84 mmol), [1,1'-(diphenylphosphino)ferrocene]palladium dichloride (0.28 g, 0.38 mmol), and potassium carbonate (1.59 g, 11.52 mmol) were dissolved in a mixed solvent of dioxane (50 mL) and water (5 mL), and the mixture was reacted at 90 °C under nitrogen protection for 5 hours. The reaction solution was cooled to room temperature, and 200 mL of water was added. The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed successively with saturated sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 3:1) to give the title compound 37E (1.02 g, 57%). LC-MS(ESI): m / z=459.1[M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.48(s,1H), 7.74(s,1H), 7.69-7.61(m,5H), 7.49-7.42(m,4H), 7.36(t,J=7.5Hz, 2H), 7. 28-7.24(m,1H), 6.98(d,J=7.7Hz, 2H), 4.50-4.42(m,1H), 3.47(s,3H), 3.29-3.24(m,2H).

[0263] Step 4: 2-amino-3-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)propanenitrile (Compound 37F) 37E (1.02 g, 2.19 mmol) was dissolved in tetrahydrofuran (50 mL) and water (5 mL), and 2.5 mL of 1 M HCl aqueous solution was added dropwise, and after the addition, the mixture was reacted at room temperature for 5 h. The reaction solution was extracted with ether (15 mL x 3), and the resulting organic layer was discarded. The aqueous layer was adjusted to a pH of about 12 using 2 M NaOH aqueous solution, and then extracted with DCM (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound 37F (crude product, 580 mg), which was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 295.1 [M + H] + .

[0264] Step 5: tert-Butyl (2S)-2-((1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (Compound 37G) INT-3 (0.36 g, 1.22 mmol) was dissolved in DMF (5 mL), and then HATU (0.6 g, 1.59 mmol) and N,N-diisopropylethylamine (0.47 g, 3.66 mmol) were added under nitrogen protection. The mixture was stirred at room temperature for 20 min, and then 37F (0.3 g, 1.22 mmol) was added. The resulting mixture was reacted at room temperature for 3 h. To the reaction solution, 30 mL of water was added. The resulting mixture was extracted with EA (15 mL x 5). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (DCM:MeOH (v / v) = 97:3) to give the title compound 37G (0.32 g, 51%). LC-MS (ESI): m / z = 522.2 [M + H] + .

[0265] Step 6: (S)-N-(1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 37H) 37G (0.32 g, 0.61 mmol) was dissolved in anhydrous formic acid (3 mL), and the mixture was reacted at 50° C. for 1 h. The reaction solution was cooled to room temperature and concentrated to remove most of the solvent. Saturated sodium bicarbonate solution (25 mL) was added to the residue, and the resulting mixture was extracted with EA multiple times until almost no product remained in the aqueous layer. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (DCM:MeOH (v / v)=10:1) to give compound 37H (140 mg, 55%).

[0266] Compound 37H was subjected to SFC chiral preparative separation to give peak 1 (63 mg, ee%=98.22%, yield: 24.8%, retention time: 2.120 min, set to be compound 37) and peak 2 (73 mg, ee%=100%, yield: 28.7%, retention time: 2.689 min, set to be compound 38).

[0267] The purification conditions were as follows: (Instrument name: MG II Preparative SFC (SFC-14); Chromatography column: ChiralPak AD, 250×30 mm inner diameter (ID), 10 μm; Mobile phase: Phase A: CO; Phase B: Methanol (0.1% NH.H0); Flow rate: 80 mL / min; Column pressure: 100 bar; Column temperature: 35° C.; Absorption wavelength: 220 nm; and Cycle time: approximately 16.9 min). Peak 1: LC-MS (ESI): m / z = 422.3 [M+H] + . 1H NMR(400MHz, CD3OD)δ 8.55(s,1H), 7.90-7.82(m,2H), 7.79(m,2H), 7.37-7.31(m,1H), 5.17(dd,J=9.0, 6.8Hz, 1H), 4.11(dd,J=8.6, 3.6Hz, 1H), 4.03-3.95(m,1 H), 3.78(m,1H), 3.47(s,3H), 3.34(m,1H), 3.27-3.14(m,2H), 2.90(m,1H), 2.78(m,1H), 2.62(dd,J=14.4, 8.6Hz, 1H), 1.96-1.78(m,2H). Peak 2: LC-MS (ESI): m / z = 422.3 [M+H] + . 1 H NMR(400MHz, CD3OD)δ 8.55(s,1H), 7.90-7.82(m,2H), 7.81-7.76(m,2H), 7.36-7.31(m,1H), 5.12(dd,J=8.6, 6.8Hz, 1H), 4.11(dd,J=8.6, 3.6Hz , 1H), 4.05(m,1H), 3.79(m,1H), 3.47(s,3H), 3.40-3.33(m,1H), 3.29-3.20(m,2H), 3.06-2.89(m,3H), 2.02-1.83(m,2H).

[0268] Example 39 and Example 40: (S)-N-((S)-1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 39 and Compound 40) [ka] Step 1: (2-chloropyrimidin-5-yl)methanol (39B) 39A (2 g, 10.72 mmol) was dissolved in anhydrous THF (20 ml), and then the mixture was cooled to 0° C. under nitrogen protection. Diisobutylaluminum hydride (21.5 ml) was slowly added dropwise to the reaction solution. The resulting mixture was stirred under ice bath for 0.5 h. TLC detection showed complete reaction of the starting material. Saturated ammonium chloride (10 ml) was added to quench the reaction, and the reaction solution was extracted with ethyl acetate (3×20 ml). The organic phases were combined and dried over anhydrous sodium sulfate. The residue was passed through a column (PE:EA=1:1) to give product 39B (1.2 g, 77.4%). LC-MS (ESI): m / z=145.1 [M+H] + .

[0269] Step 2: 5-(Bromomethyl)-2-chloropyrimidine (39C) 39B (1 g, 6.92 mmol) was dissolved in DCM (20 ml) at room temperature, the reaction solution was cooled to 0° C. under nitrogen protection, and triphenylphosphine (1.82 g, 6.92 mmol) and carbon tetrabromide (2.29 g, 6.92 mmol) were added at this temperature. After the mixture was stirred at 0° C. for 0.5 h, the reaction solution was warmed to room temperature and stirring was continued for 1.5 h. TLC detection showed that a small amount of substrate was still present. The reaction solution was subjected to rotary evaporation and passed through a column (PE:EA=5:1) to give 39C (1 g, 70%). LC-MS (ESI): m / z=207.1 [M+H] + .

[0270] Step 3: 3-(2-chloropyrimidin-5-yl)-2-((diphenylmethylene)amino)propanenitrile (39D) 39C (1 g, 4.82 mmol), diphenylmethyleneaminoacetonitrile (1.06 g, 4.82 mmol), and benzyltrimethylammonium chloride (0.18 g, 0.96 mmol) were dissolved in DCM (30 ml) at room temperature. NaOH (0.8 ml, 19 mol / L) was slowly added to the reaction solution, and the reaction solution was stirred at room temperature overnight. Water (20 ml) was added to quench the reaction. The resulting mixture was extracted with DCM (20 ml x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, subjected to rotary evaporation, and passed through a column (PE:EA = 3:1) to obtain product 39D (1.1 g, 65.8%). LC-MS (ESI): m / z = 347.1 [M + H] + .

[0271] Step 4: 2-((diphenylmethylene)amino)-3-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)propanenitrile (39E) Reagent 39D (1.1 g, 3.17 mmol) and 1A (0.96 g, 3.49 mmol) were dissolved in 1,4-dioxane (100 ml), then potassium carbonate (1.31 g, 9.51 mmol) and Pd(dppf)Cl2 (0.23 g, 0.32 mmol) were added. The mixture was placed under nitrogen protection and reacted at 100 °C. TLC and LC-MS showed that a small amount of starting material was still present. The reaction solution was concentrated and subjected to rotary evaporation, then dissolved in DCM and filtered through Celite by suction, the filtrate was subjected to rotary evaporation and passed through a column (EA / PE = 0% ~ 40%) to give a pale yellow solid 39E (1.1 g, 75.5%). LC-MS (ESI): m / z = 460.2 [M + H] + .

[0272] Step 5: 2-amino-3-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)propanenitrile (39F) Substrate 39E (1.1 g, 2.39 mmol) was dissolved in DCM (30 ml), 1 M HCl (7.2 ml) was added, and the mixture was stirred at room temperature for 3 h. TLC detection indicated complete reaction of the starting material. The solution was adjusted to a pH of 8-10, then extracted with EA (20 ml x 2), and the organic phase was dried over anhydrous sodium sulfate and subjected to rotary evaporation to give product 39F (0.6 g, 85%). LC-MS (ESI): m / z = 296.1 [M+H] + .

[0273] Step 6: (2S)-tert-butyl 2-(1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)ethylcarbamoyl)-1,4-oxazepane-4-carboxylate (39G) INT-3 (0.5 g, 2.03 mmol), HATU (0.85 g, 2.23 mmol), and DIPEA (0.7 ml) were dissolved in DCM (30 ml) at room temperature. After the mixture was stirred at room temperature for 10 min, 39F (0.6 g, 2.03 mmol) was added, and the resulting mixture was stirred at room temperature for 1 h. TLC detection showed that the reaction was complete. Water (10 ml) was added to quench the reaction, and the reaction solution was extracted with dichloromethane (15 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 1:1) to give product 39G (0.6 g, 56%). LC-MS (ESI): m / z = 523.2 [M + H] + .

[0274] Step 7: (2S)-N-(1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)ethyl)-1,4-oxazepane-2-carboxamide (39H) 39G (0.6 g, 1.15 mmol) was dissolved in anhydrous formic acid (20 ml), and the mixture was stirred at room temperature for 2 h, after which TLC detection indicated complete reaction of the substrate. Formic acid was removed by rotary evaporation at low temperature, and saturated sodium bicarbonate solution was added to adjust the pH to 8-10. The resulting mixture was extracted with DCM (20 ml x 2), dried over anhydrous sodium sulfate, subjected to rotary evaporation, and passed through a column (DCM:CH3OH=10:1) to obtain compound 39H (0.15 g, 31%). Compound 39H was subjected to SFC chiral preparative separation to obtain peak 1 (retention time: 1.528 min, set to be compound 39) and peak 2 (retention time: 2.387 min, set to be compound 40).

[0275] The dissolution method was as follows: (Instrument name: MG II preparative SFC (SFC-14); Chromatography column: ChiralPak AD, 250 × 30 mm inner diameter (ID), 10 μm; Mobile phase: Phase A: CO2; Phase B: Isopropanol (0.1% NH3·H2O); Flow rate: 80 mL / 3 min; Column pressure: 100 bar; Column temperature: 35 °C; Absorption wavelength: 220 nm; and Cycle time: 3 min). Peak 1: 1 H NMR (400MHz, DMSO-d6)δ 8.79-8.78(m,1H), 8.38-8.35(m,1H), 7.43-7.38(m,3H), 6.48-6.46(m,1H), 5.03-4.99(m,1H), 4.05-4.02(m,1H), 3.90- 3.84(m,1H), 3.76-3.70(m,1H), 3.50(s,3H), 3.25-3.09(m,4H), 2.86-2.80(m,1H), 2.70-2.58(m,2H), 1.80-1.71(m,2H). Peak 2: 1H NMR (400MHz, DMSO-d6)δ 8.79-8.78(m,1H), 8.38-8.35(m,1H), 7.43-7.38(m,3H), 6.48-6.46(m,1H), 5.03-4.99(m,1H), 4.05-4.02(m,1H), 3.90- 3.84(m,1H), 3.76-3.70(m,1H), 3.50(s,3H), 3.25-3.09(m,4H), 2.86-2.80(m,1H), 2.70-2.58(m,2H), 1.80-1.71(m,2H).

[0276] Examples 41 and 42: (S)-N-((S)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 41 and Compound 42) [ka] Step 1: 3-(Bromomethyl)-6-chloropyridazine (41B) 3-(Methyl)-6-chloropyridazine (12.8 g, 100 mmol) was dissolved in carbon tetrachloride (300 mL), N-bromosuccinimide (17.8 g, 100 mmol) and azodiisobutyronitrile (3.4 g, 20 mmol) were added, and the mixture was reacted at 70° C. overnight and filtered. The filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v)=1:10 to 1:5) to obtain the title compound 41B (4 g, yield: 20%). LCMS m / z=207.46[M+1] +

[0277] Step 2: Ethyl 3-(6-chloropyridazin-3-yl)-2-((diphenylmethylene)amino)propanoate (41C) Ethyl 2-((diphenylmethylene)amino)acetate (6.18 g, 23.14 mmol), tetrabutylammonium bromide (9.32 g, 28.92 mmol), and potassium hydroxide (3.25 g, 2.24 mmol) were dissolved in a mixed solvent of toluene (100 mL) and water (20 mL). 41B (4.0 g, 19.28 mmol) was added under ice bath, and the mixture was allowed to warm to room temperature naturally and react for 2 h. Water (50 mL) was added, and the resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed three times with water (50 mL x 3), then dried over anhydrous sodium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 1:10 to 1:5) to give the title compound 41C (3.4 g, yield: 45%). LCMS m / z=394.12[M+1] +

[0278] Step 3: 3-(6-chloropyridazin-3-yl)-2-((diphenylmethylene)amino)propanamide (41D) 41C (3.4 g, 8.7 mmol) was dissolved in ammonia methanol solution (7N, 50 mL) and the mixture was reacted in a sealed tube (120 mL) overnight at 80° C. After concentration, the reaction mixture was separated and purified by silica gel column chromatography (MeOH:DCM (v / v)=1:10) to give the title compound 41D (1.8 g, yield: 56%). LCMS m / z=365.11[M+1] +

[0279] Step 4: 3-(6-chloropyridazin-3-yl)-2-((diphenylmethylene)amino)propanenitrile (41E) 41D (1.8 g, 4.93 mmol) was dissolved in dichloromethane (30 mL), Burgess reagent (2.35 g, 9.86 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After concentration, the reaction mixture was separated and purified by silica gel column chromatography (PE:EA (v / v) = 1:5 to 5:5) to obtain the title compound 41E (1.4 g, yield: 82%). LCMS m / z = 347.13 [M+1] +

[0280] Step 5: 2-((diphenylmethylene)amino)-3-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)propanenitrile (41F) 41E (1.4 g, 4.04 mmol) was dissolved in dioxane (30 mL), 1A (2.22 g, 8.08 mmol), potassium carbonate (1.67 g, 12.12 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (590 mg, 0.81 mmol) and then water (6 mL) were added. The mixture was reacted in a microwave reactor at 120 °C under nitrogen protection for 2 h. After concentration, the reaction mixture was separated and purified by silica gel column chromatography (PE:EA (v / v) = 1:5 to 1:1) to give the title compound 41F (800 mg, yield: 43%). LCMS m / z = 460.17 [M + 1] +

[0281] Step 6: 2-amino-3-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)propanenitrile (41G) 41F (800 mg, 1.74 mmol) was dissolved in dioxane (20 mL), hydrochloric acid solution (0.5 N, 8 mL) was added, and the mixture was reacted at room temperature for 0.5 h. The pH was adjusted to 7-8 using saturated aqueous sodium carbonate solution. The resulting mixture was extracted with dichloromethane (30 mL x 3), the organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (MeOH:DCM (v / v) = 1:100 - 1:10) to give the title compound 41G (300 mg, yield: 58%). LCMS m / z = 296.11 [M + 1] +

[0282] Step 7: tert-Butyl (2S)-2-((1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (41H) 41G (300 mg, 1.02 mmol) was dissolved in DMF (20 mL), then HATU (390 mg, 1.02 mmol), DIPEA (260 mg, 2.02 mmol), and INT-3 (250 mg, 1.02 mmol) were added successively. The mixture was reacted at room temperature for 12 h. Water (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with water (30 mL x 2) and saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (MeOH:DCM (v / v) = 1:100 to 1:10) to give the title compound 41H (300 mg, yield: 56%). LCMS m / z = 523.22 [M + 1] +

[0283] Step 8: (S)-N-((S)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 41 and Compound 42) 41H (300 mg, 0.57 mmol) was dissolved in acetonitrile (20 mL) and p-toluenesulfonic acid (332 mg, 1.71 mmol) was added. The mixture was reacted at 30° C. for 3 hours, then adjusted to pH=7-8 using saturated aqueous sodium carbonate solution, and extracted with dichloromethane (40 mL×3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (DCM:MeOH (v / v)=0.01:1-0.1:1) to obtain the crude compound.

[0284] 150 mg of the crude compound was taken and subjected to chiral preparative separation to obtain two enantiomers: peak 1 (retention time: 2.088 min, 30 mg, ee=99%, set to be compound 41) and peak 2 (retention time: 2.955 min, 30 mg, ee=99%, set to be compound 42). Dissolution conditions: Instrument: MG II preparative SFC (SFC-14); Column: ChiralPak AD, 250×30 mm internal diameter (ID); Mobile phase: A: CO2, and B: Ethanol (0.05% NH3H2O); Gradient: B 40%; Flow rate: 70 mL / min; Back pressure: 100 bar; Column temperature: 38° C.; Wavelength: 220 nm; Cycle: 13 min; Sample preparation: Compound 1 was dissolved in methanol to obtain a concentration of 15 mg / ml; and Injection: 1.0 ml / injection. Peak 1: MS M / Z(ESI): m / z=423.17[M+1] + . 1 H NMR (400MHz, DMSO-d6)δ 8.73(d,1H), 8.27(d,1H), 8.08(d,1H), 8.00-7.90(m,1H), 7.78(d,1H), 7.50(d,1H), 5.41-5.32(m,1H), 4. 02-3.84(m,2H), 3.78-3.49(m,3H), 3.44(s,3H), 3.18-3.07(m,1H), 2.90-2.53(m,4H), 1.82-1.63(m,2H). Peak 2: MS M / Z(ESI): m / z=423.17[M+1] + . 1 H NMR (400MHz, DMSO-d6)δ 8.75(d,1H), 8.27(d,1H), 8.07(d,1H), 7.98-7.86(m,1H), 7.78(d,1H), 7.50(d,1H), 5.62-5.19(m,1H), 4.05-3.97(m,1H), 3.92-3.82( m,1H), 3.77-3.66(m,1H), 3.66-3.51(m,2H), 3.43(s,3H), 3.09-3.00(m,1H), 2.86-2.70(m,1H), 2.69-2.51(m,3H), 1.80-1.63(m,2H).

[0285] Example 43: N-((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide (compound 43) [ka] Step 1: (2S,6R)-2-((benzyloxy)methyl)-6-methoxy-4-tosyl-1,4-oxazepane (43B) 43A (0.5 g, 1.28 mmol, prepared with reference to literature: Eur. J. Org. Chem. 2007, 2107-2113 (DOI: 10.1002 / ejoc.200700011) was dissolved in tetrahydrofuran (20 mL), sodium hydride (0.26 g, 6.4 mmol) was added at 0 °C, the mixture was stirred for 30 min, and then iodomethane (0.91 g, 6.4 mmol) was added. The resulting mixture was reacted at room temperature for 3 h, and then water (30 mL) was added at 0 °C. Then, the mixture was extracted with EA (20 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give colorless oil 43B (0.4 g, yield: 77%).

[0286] Step 2: (2S,6R)-2-((benzyloxy)methyl)-6-methoxy-1,4-oxazepane (43C) 43B (0.3 g, 0.74 mmol) was dissolved in methanol (10 mL), magnesium turnings (2.36 g, 97.08 mmol) was added, and the mixture was subjected to ultrasonic treatment at 50° C. for 2 h, after which the mixture was reacted at room temperature for 16 h, then filtered and concentrated to give a white oil 43C (0.18 g, yield: 96%), which was used directly in the next step. LC-MS (ESI): m / z=252.3 [M+1] +

[0287] Step 3: (2S,6R)-tert-butyl 2-((benzyloxy)methyl)-6-methoxy-1,4-oxazepane-4-carboxylate (43D) 43C (0.18 g, 0.72 mmol) was dissolved in DCM (10 mL), triethylamine (0.087 g, 0.85 mmol) and TBSCl (0.37 g, 1.71 mmol) were added successively, and the mixture was reacted at room temperature under nitrogen protection for 2 h. After that, the reaction mixture was concentrated to dryness, and the residue was purified by column chromatography (PE:EA=10:1-4:1) to give colorless oil 43D (0.12 g, yield: 47%).

[0288] Step 4: (2S,6R)-tert-Butyl 2-(hydroxymethyl)-6-methoxy-1,4-oxazepane-4-carboxylate (43E) 43D (0.12 g, 0.34 mmol) was dissolved in methanol (10 mL), palladium on carbon (0.1 g, 10%) was added, and the mixture was reacted under hydrogen atmosphere for 24 hours. After that, the reaction mixture was filtered and then concentrated to dryness to give colorless oil 43E (0.08 g, yield: 86%).

[0289] Step 5: (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazepane-2-carboxylic acid (43F) 43E (0.095 g, 0.3 mmol) was dissolved in acetone (7 mL) and saturated sodium bicarbonate (3 mL), sodium bromide (0.025 g, 0.24 mmol), and TEMPO (0.004 g, 0.024 mmol) were added. Then, trichloroisocyanuric acid (0.25 g, 1.06 mmol) was added at 0° C. The mixture was reacted for 16 hours. Dilute hydrochloric acid was added to adjust the pH to 5-6, and water (30 mL) was added. The resulting mixture was extracted with dichloromethane (20 mL×3), and the organic phase was washed with water (30 mL) and saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to give a yellow oil 43F (0.046 g, yield: 44%).

[0290] Step 6: tert-Butyl-2-(((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-6-methoxy-1,4-oxazepane-4-carboxylate (43G) Compound 8B (400 mg, 1.1 mmol), 43F (300 mg, 1.1 mmol), HATU (458 mg, 1.65 mmol), and DIEA (0.54 mL, 3.3 mmol) were mixed and dissolved in DMF, and the mixture was stirred at room temperature overnight. After completion of the reaction detected by LCMS, water and EA were added for extraction, the organic phase was dried and concentrated, and the residue was separated by column chromatography (DCM:MeOH=10:1) to give the title compound 43G (512 mg, 75%). LC-MS (ESI): m / z=624.2 [M+H] + .

[0291] Step 7: N-((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide (compound 43) Compound 43 (512 mg, 0.82 mmol) was dissolved in 40 mL of acetonitrile, p-toluenesulfonic acid (706 mg, 2.46 mmol) was added, and the mixture was heated to 40° C. and reacted for 2 h. After completion of the reaction detected by LCMS, the reaction solution was concentrated, and EA and saturated aqueous sodium bicarbonate solution were added for extraction, and liquid-liquid separation was performed. The organic phase was dried and concentrated, and the residue was separated by column chromatography (DCM:MeOH=10:1) to obtain the title compound 43 (75 mg, 17%). LC-MS (ESI): m / z=524.2 [M+H] + . 1 HNMR (400MHz, DMSO-d6): 8.74(d,1H), 7.92-8.00(m,4H), 7.48-7.66(m,3H), 5.03-5.09(m,1H), 3.97- 4.01(m,2H), 3.56-3.59(m,1H), 3.28-3.30(m,1H), 3.24-3.25(m,6H), 2.78-2.89(m,3H), 1.91(s,1H).

[0292] Biological testing 1. In Vitro DPP1 Enzyme Activity Assay Recombinant human DPP1 enzyme (R&D Systems, Cat. No. 1071-CY) at a final concentration of 100 μg / mL was mixed with recombinant human cathepsin L (R&D Systems, Cat. No. 952-CY) at a final concentration of 20 μg / mL and incubated at room temperature for 1 hour to activate the DPP1 enzyme. The activated DPP1 enzyme was diluted 100-fold, and 5 μL of compounds at various concentrations and 5 μL of the diluted DPP1 enzyme were added to a 384-well plate and incubated at room temperature for 30 minutes. After adding 10 μL of the substrate Gly-Arg-AMC (bachem, Cat. No. I-1215) at a concentration of 20 μM, the incubation was continued at room temperature for 60 minutes, and the fluorescence intensity was detected using a microplate reader (excitation=380 nm and emission=460 nm). IC 50 Values ​​were calculated using the DosResp function of Origin2019 software.

[0293] Test results: The compounds of the present invention showed inhibitory activity against the DPP1 receptor. IC of the example compounds against the DPP1 receptor 50 The values ​​were in the range of less than 100 nM. The test results of some examples are shown in Table 1.

[0294] [Table 1]

[0295] Conclusion: The compounds of the present invention showed relatively high inhibitory activity against the DPP1 receptor.

[0296] 2. Pharmacokinetics in rats 1.1 Test animals: male SD rats, about 220g, 6-8 weeks old, 6 rats / compound. Rats were purchased from CHENGDU DOSSY EXPERIMENTAL ANIMALS CO.,LTD.

[0297] 1.2 Study design: On the day of the experiment, six SD rats were randomly divided into groups according to their body weight. The rats were fasted but allowed water for 12-14 hours one day before dosing and fed 4 hours after dosing.

[0298] [Table 2]

[0299] Vehicle for intravenous administration: 5% DMA+5% Solutol+90% saline; Vehicle for intragastric administration: 0.5% MC; and control compound INS1007, i.e., compound 2 in WO2015110826 A1, were prepared with reference to the method of this patent.

[0300] Before and after administration, 0.1 ml of blood was collected from the orbit of the rat under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. Blood was centrifuged at 5000 rpm and 4°C for 10 minutes to collect plasma. Blood collection time points for the intravenous administration group: 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours; and blood collection time points for the intragastric administration group: 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C before analysis and detection.

[0301] [Table 3]

[0302] Conclusion: The compounds of the present invention have relatively good bioavailability and pharmacokinetic properties.

[0303] 3. Toxicity study in rats after repeated oral administration for 14 days According to body weight, SD rats were randomly divided into the following groups: vehicle control group (0.5% MC), INS1007 (30, 100, and 300 mg / kg) group, and compound (30, 100, and 300 mg / kg) group. In the treatment group, 16 rats were included in each group, and in the vehicle control group, 10 rats were included, and each group contained the same number of male and female rats. The rats were orally administered the corresponding concentration of drug or vehicle by gavage every day for 14 consecutive days, and allowed to recover for 7 days. During the treatment period, the general symptoms were observed, and the body weight and food intake were measured for each group. At the end of the treatment period and the end of the recovery period, hematological examination, serum biochemistry examination, and gross anatomical examination were performed separately in the rats of each group.

[0304] Conclusion: The compounds of the present invention are less toxic than INS1007 and therefore safer at the same dose.

Claims

1. Formula (IV): 【Chemistry 1】 [During the ceremony, Rc is H, halogen, C 1~2 Alkyl or C 1~2 is alkoxy; R 1 , R 2 , and R 3 are each independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, methoxy, or ethoxy, wherein the methyl, ethyl, methoxy, or ethoxy is selected from F, Cl, Br, cyano, hydroxyl, and NH 2 optionally substituted with 1 to 3 groups selected from Z is CH or N; Ring G is 【Chemistry 2】 or a benzene ring, each of which is one to two R G optionally substituted with a group; Each R G are independently F, Cl, Br, I, methyl, ethyl, propyl, SF 5 and CN, wherein said methyl, ethyl or propyl is optionally further substituted with 1 to 3 groups selected from deuterium, F, Cl, Br, and I. or a stereoisomer, deuterated product, solvate or pharma- ceutically acceptable salt thereof.

2. (1) Z is CH, and / or (2) Ring G is one or two R G Optionally substituted with a group 【Chemistry 3】 and / or (3) Each R G is independently selected from methyl, ethyl, and propyl; 2. The compound of claim 1, or a stereoisomer, deuterated product, solvate or pharma- ceutically acceptable salt thereof.

3. The structure: 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 or a stereoisomer, deuterated product, solvate or pharma- ceutically acceptable salt thereof.

4. The structure: 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 or a stereoisomer, deuterated product, solvate or pharma- ceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a stereoisomer, deuterated product, solvate or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier and / or excipient.

6. Use of a compound according to any one of claims 1 to 4, or a stereoisomer, deuterated product, solvate or pharma- ceutically acceptable salt thereof, or a composition according to claim 5, in the preparation of a medicament for treating a disease mediated by dipeptidyl peptidase 1.

7. 7. The use according to claim 6, wherein the disease is selected from obstructive airways disease, bronchiectasis, cystic fibrosis, asthma, emphysema, and chronic obstructive pulmonary disease.

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