Nitrile derivatives acting as inhibitors of dipeptidyl peptidase 1 and uses thereof

Abstract

Nitrile derivative compounds represented by Chemical Formula I, stereoisomers thereof, deuteration products, cocrystals, solvates, or pharmaceutically acceptable salts are provided, wherein each group is defined as in the detailed description. The compounds have dipeptidyl peptidase 1 inhibitory activity and can be used to manufacture drugs for treating obstructive airway diseases, bronchiectasis, cystic fibrosis, asthma, emphysema, chronic obstructive pulmonary disease and other diseases. [Chemical Formula I]

Description

Technology Field

[0001] The present invention relates to nitrile derivatives as dipeptidyl peptidase 1 inhibitors, or stereoisomers thereof, deuterated products, cocrystals, solvates or pharmaceutically acceptable salts thereof, and their use in the manufacture of drugs 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 terms of protein substrates. DPP1 was first discovered in 1948 by Gutman and Fruton (J. Biol Chem, 174, 851-858). However, the cDNA of human dipeptidyl peptidase 1 was first described in 1995 (FEBS Lett, 369, 326-330). DPP1 is the only member of the papain family to function as a tetramer, consisting of four identical subunits. Each subunit consists 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 lungs, kidneys, 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 an important enzyme in lysosomal proteolysis, DPP1 also acts as a key enzyme in the activation of granulose proteases in the following cells: cytotoxic T lymphocytes and natural killer cells (granzyme 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 protease 3; J Clin. Invest. 109:363.371, 2002). Once activated, these proteases can degrade various extracellular matrix components, causing tissue damage and chronic inflammation. DPP1 is considered a potent therapeutic target due to its central role in activating these proteases (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 neutrophil-controlled 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). Given the role of DPP1 in the activation of some pro-inflammatory serine proteases, compounds that inhibit the activity of DPP1, and further inhibit the activity of serine proteases downstream, have good prospects for clinical application. Currently, relevant patents have reported the synthesis of DPP1 inhibitors. WO 2004 / 110988 relates to specific nitrile derivatives and their use as DPP1 inhibitors. WO 2009 / 074829 relates to peptidyl nitrile and its use as a DPP1 inhibitor. WO 2010 / 128324 relates to alpha-aminoamide nitrile and its use as a DPP1 inhibitor. WO 2012 / 119941 relates to peptidyl nitrile compounds and their use as a DPP1 inhibitor. WO 2013 / 041497 relates to N-[1-cyano-2-(phenyl)ethyl]-2-azabicyclo[2.2.1] heptane-3-carboxamide and its use as a DPP1 inhibitor. WO 2001 / 096285 and WO 2003 / 048123 relate to beta-aminoamide nitrile having inhibitory activity against cysteine ​​protease. However, there are currently no DPP1 inhibitors available on the market, and therefore there is still an unmet clinical need for DPP1 inhibitors with high inhibitory activity and low toxicity. means of solving the problem

[0005] The present invention first provides a compound of Formula I, Formula II, Formula III, or Formula IV, or a stereoisomer, deuteriumation product, cocrystal, solvate, or pharmaceutically acceptable salt thereof, having high activity, high bioavailability, good pharmacokinetics, and low toxicity and side effects:

[0006] [Chemical Formula I]

[0007] ,

[0008] [Chemical Formula II]

[0009] ,

[0010] [Chemical Formula III]

[0011] , and

[0012] [Chemical Formula IV]

[0013]

[0014] Here, ring G is a 5 to 12-membered carbocyclic ring, a 5 to 12-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, or formula I-1 It is a fused ring of (Formula I-1), where L1 is attached 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 heterocycle, and a ring carbon atom or ring heteroatom on a fused ring of Formula I-1), and the carbocyclic ring or monocyclic heterocycle consists of 1 to 3 R G Selectively substituted with the gi;

[0015] Optionally, chemical formula I-1 is the structural formula (Chemical formula I-11),

[0016] Optionally, chemical formula I-1 is the structural formula It has (chemical formula I-12).

[0017] In some embodiments, ring G is a 5 to 9-membered monocyclic carbocyclic ring, a 5 to 7-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, S and O, or a fused ring of formula I-1, optionally formula I-1 has structural formula I-11, and optionally formula I-1 has structural formula I-12.

[0018] In some embodiments, ring G is 1 to 3 R G Selectively substituted cyclic, cyclopentane, cyclohexane, cycloheptane, benzene ring, , , , , , , , , , , or Or, ring G is (Chemical Formula I-2) and,

[0019] Optionally, chemical formula I-2 is the structural formula (Chemical formula I-21),

[0020] Optionally, chemical formula I-2 is the following structural formula It has (chemical formula I-22).

[0021] In some implementations, (Chemical Formula I-2) is selected from one of the following structural formulas:

[0022]

[0023] In some embodiments, ring G is 1 to 2 R G A benzene ring or which is selectively substituted with a group And;

[0024] Each R G is deuterium, SF5, =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyloxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 alkinyl, -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)2C 1-4 Alkyl, -S(O)2C 3-6 Cycloalkyl, -S(O)NH2, -S(O)NHC 1-4 Alkyl, -S(O)N(C 1-4 Independently selected from 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from alkyl)2, -S(O)2NH2, and N, S, and O, and R G is deuterium, C 1-4 Alkyl, Halo C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, -CONH2, NH2, C 1-6 It is further optionally substituted with 1 to 3 groups selected from a 5 to 7-membered heterocycle containing 1 to 3 heteroatoms selected from alkoxy, hydroxyl, -COOH, halogen, and N, S, and O, and furthermore, the 5 to 7-membered heterocycle is =O, halogen, cyano, C 1-4 Alkyl, and halo C 1-4 It is optionally substituted with one to two groups selected from alkyl.

[0025] In some embodiments, each R G is deuterium, SF5, =O, halogen, cyano, hydroxyl, NH2, C1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 alkinyl, -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 Independently selected from 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from alkyl)2, and N, S, and O, and R G is deuterium, C 1-4 Alkyl, Halo C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, -CONH2, NH2, C 1-6 It is additionally optionally substituted with 1 to 3 groups selected from a 5 to 7-membered heterocycle containing 1 to 3 heteroatoms selected from alkoxy, hydroxyl, halogen, and N, S, and O, and furthermore, the 5 to 7-membered heterocycle is =O, halogen, cyano, C 1-4 Alkyl, and halo C 1-4 It is optionally substituted with one to two groups selected from alkyl.

[0026] In some embodiments, each R G is independently selected from F, Cl, Br, I, methyl, ethyl, propyl, SF5, and CN; methyl, ethyl, and propyl are additionally optionally substituted with 1 to 3 groups selected from deuterium, F, Cl, Br, and I;

[0027] Cy is a 5 to 12-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, and the heterocycle is deuterium, =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, Halo C1-4 Alkyl, Hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyloxy, C 1-6 Alkoxyalkyl, halo C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 alkinyl, -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)2C 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 It is optionally substituted with 1 to 3 groups selected from alkyl)2.

[0028] In some specific embodiments, Cy is a 5 to 12-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, and the monocyclic heterocycle is a deuterium, =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, Halo C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Alkoxyalkyl, halo C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 alkinyl, -NHC 1-4 alkyl, -N(C 1-4 Alkyl)2, -COC 1-4 Alkyl, -COOC 1-4 Alkyl, -CONH2, -CONHC1-4 Alkyl, -CON(C 1-4 Alkyl)2, -NHCOC 1-4 Alkyl, -S(O)C 1-4 Alkyl, -S(O)2C 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 It is optionally substituted with 1 to 3 groups selected from alkyl)2.

[0029] In some specific embodiments, Cy is a 5 to 8-membered monocyclic heterocycle, a 7 to 10-membered spirocyclic heterocycle, a 6 to 9-membered bridged-ring heterocycle, or a 6 to 10-membered fused heterocycle, which contains 1 to 3 heteroatoms selected from N, S, and O, and Cy is =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, Halo C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Alkoxyalkyl, halo C 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)2C 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 It is optionally substituted with 1 to 3 groups selected from alkyl)2.

[0030] In some specific embodiments, Cy is a 5 to 8-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, and the monocyclic heterocycle is =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, Halo C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Alkoxyalkyl, halo C 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)2C 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 It is optionally substituted with 1 to 3 groups selected from alkyl)2.

[0031] In some specific embodiments, Cy is a 5 to 8-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, and the monocyclic heterocycle is =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, Halo C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, Halo C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -CONH2, -CONHC 1-4 alkyl, -CON(C 1-4Alkyl)2, -S(O)2NH2, -S(O)2NHC 1-4 Alkyl, and -S(O)2N(C 1-4 It is optionally substituted with 1 to 3 groups selected from alkyl)2.

[0032] In some specific embodiments, Cy is is,

[0033] Here, Rc is H, =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, Halo C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, C 1-6 Alkoxyalkyl, or halo C 1-4 It is an alkoxy.

[0034] In some specific embodiments, Rc is H, halogen, C 1-2 alkyl or C 1-2 It is an alkoxy,

[0035] W is C(=O), C(=S), C(=NR) W ), S(=O) or S(=O)2 and R W OH, CN, or C 1-4 It is an alkyl.

[0036] In some specific implementations, W is C(=O), and

[0037] M is NR M or O and R M H, C 1-4 alkyl or C 3-6 It is a cycloalkyl.

[0038] In some specific embodiments, M is NH;

[0039] R1, R2, and R3 are H, deuterium, halogen, and C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-6Each is independently selected from cycloalkyl, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are halogens, C 1-4 Optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and -COOH; optionally, R1 and R2 together with the carbon atom to which they are attached C 3-6 It forms a 4 to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkyl or 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 It is optionally substituted with 1 to 3 groups selected from cycloalkyl.

[0040] In some specific embodiments, R1, R2, and R3 are H, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, and C 2-6 Each is independently selected from alkynyl, and alkyl, alkoxy, alkenyl, and alkynyl are halogens, C 1-4 Optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and COOH;

[0041] Optionally, R1 and R2 are C together with the carbon atoms to which they are attached. 3-6 Forming a 4 to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkyl or N, S, and O, and the cycloalkyl or heterocycle is a halogen, cyano, hydroxyl, NH2, COOH, and C 1-4 It is optionally substituted with 1 to 3 groups selected from alkyl.

[0042] In some specific embodiments, R1, R2, and R3 are H, deuterium, halogen, C 1-4 Alkyl, and C 1-4 Each is independently selected from alkoxy, and the alkyl and alkoxy groups are halogens, C 1-4 Optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and COOH;

[0043] Optionally, R1 and R2 are C together with the carbon atoms to which they are attached. 3-6 They form cycloalkyl groups, and the cycloalkyl group consists of halogens, cyano, hydroxyl, NH2, COOH, and C 1-4 It is optionally substituted with 1 to 3 groups selected from alkyl.

[0044] In some specific embodiments, R1, R2, and R3 are each independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, methoxy, or ethoxy, and methyl, ethyl, methoxy, or ethoxy are optionally substituted with one to three groups selected from F, Cl, Br, cyano, hydroxyl, and NH2;

[0045] L1 is binding, C 1-3 Alkylene, -NH-, -N(C 1-4 Alkyl)-, -O-, -S-, C 2-6 Alkenylene, C 2-6 It is alkynylene, -CO-, or -CONH-, where alkylene, alkenylene, or alkynylene is a halogen, C 1-4 It is optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and -COOH.

[0046] In some specific embodiments, L1 is combined, C 1-3 Alkylene, -NH-, -O-, -S-, C 2-6 Alkenylene, C 2-6Alkynylene or -CO-, and the alkylene, alkenylene or alkynylene is optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, and NH2.

[0047] In some specific embodiments, L1 is a combination, and

[0048] Y1 and Y2 are each independently selected from CR4 or N.

[0049] In some specific embodiments, Y1 and Y2 are CH;

[0050] Each R4 is H, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkinyl, 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 The alkyl, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S and O are independently selected, and in the case of R4, the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycle groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH.

[0051] In some specific embodiments, each R4 is H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-6Independently selected from cycloalkyl, cyano, hydroxyl, and NH2, and for R4, alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH.

[0052] In some specific embodiments, R4 is H;

[0053] X1, X2, X3, and X4 are each independently selected from bonds, NR5, O, CR6R7, S, S(O), and S(O)2, and at most one of X1, X2, X3, and X4 is a bond;

[0054] Each R5 is H, C 1-4 Alkyl, -COC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, and C 3-6 Independently selected from cycloalkyl; alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH.

[0055] In some specific embodiments, each R5 is H, C 1-4 Alkyl, -COC 1-4 Alkyl and C 3-6 It is independently selected from cycloalkyl, wherein the alkyl and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH.

[0056] In some specific embodiments, R5 is methyl;

[0057] R6 and R7 contain H, deuterium, halogen, and C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-6Each is independently selected from cycloalkyl, cyano, hydroxyl, NH2, -COOH, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0058] Optionally, R6 and R7 form =O;

[0059] Optionally, in X1, X2, X3, and X4, two R5s on adjacent ring atoms, two R6s on adjacent ring atoms, or R5s and R6s on adjacent ring atoms form double bonds with the atoms to which they are attached;

[0060] Optionally, on the same carbon atom, R6 and R7 together with the carbon atom to which they are attached, C 3-12 It forms a carbocyclic ring or a 4 to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, wherein the carbocyclic ring 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 It is optionally substituted with 1 to 3 groups selected from cycloalkyl.

[0061] In some specific embodiments, R6 and R7 are H, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, and C 3-6Each is independently selected from cycloalkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH;

[0062] Optionally, R6 and R7 form =O;

[0063] Optionally, in X1, X2, X3, and X4, two R5s on adjacent ring atoms, two R6s on adjacent ring atoms, or R5s and R6s on adjacent ring atoms form double bonds with the atoms to which they are attached;

[0064] Optionally, R6 and R7 on the same carbon atom are C together with the carbon atom to which they are attached. 3-6 It forms a 4 to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkyl or N, S, and O, and 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 It is optionally substituted with 1 to 3 groups selected from cycloalkyl.

[0065] In some specific embodiments, R6 and R7 are H, deuterium, halogen, C 1-4 Alkyl, and C 1-4 Each is independently selected from alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH;

[0066] Optionally, R6 and R7 form =O;

[0067] Optionally, in X1, X2, X3, and X4, two R5s on adjacent ring atoms, two R6s on adjacent ring atoms, or R5s and R6s on adjacent ring atoms form double bonds with the atoms to which they are attached;

[0068] Z is CH or N.

[0069] Compounds of formulas I to III are required to satisfy one of the following conditions (1) to (4):

[0070] (1) A is , is a 6-membered heteroaryl or a 5 to 10-membered non-aromatic heterocycle, wherein the heteroaryl and non-aromatic heterocycle contain 1 to 3 heteroatoms selected from N, S and O, and A is optionally substituted with 1 to 3 R8 groups;

[0071] * indicates a terminal connected to an alkyl carbon atom;

[0072] Ring B is C 3-12 It is a carbocyclic ring or a 4 to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O;

[0073] Each R8 is H, =O, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, 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 1-4Independently selected from alkyl, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, and O; in the case of R8, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0074] Cy is unsubstituted or unsubstituted And;

[0075] In some specific implementations, A is , is a 6-membered heteroaryl or a 5- to 7-membered non-aromatic monocyclic heterocycle, wherein the heteroaryl and non-aromatic monocyclic heterocycle contain 1 to 3 heteroatoms selected from N, S and O, and A is optionally substituted with 1 to 3 R8 groups;

[0076] * indicates a terminal connected to an alkyl carbon atom;

[0077] Ring B is C 4-6 It is a carbocyclic ring or a 5 to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O;

[0078] Each R8 is H, =O, deuterium, halogen, 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 Independently selected from cycloalkyl, and the alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0079] In another specific embodiment, A is , , , , or And, ring A is optionally substituted with 1 to 3 R8 groups;

[0080] Each R8 is a halogen, =O, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, and C 3-6 Independently selected from cycloalkyls;

[0081] * indicates a terminal connected to an alkyl carbon atom;

[0082] r is an integer from 1 to 3;

[0083] E is selected from NH, S and O;

[0084] In another specific embodiment, A is And,

[0085] Ring A is optionally substituted with 1 to 3 R8 groups; the substituents are located at any substitutable position on ring A, including any substitutable position on a carbon atom of the benzene ring and on a carbon atom or heteroatom of the ring fused to the benzene ring;

[0086] Each R8 is a 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 Independently selected from cycloalkyls;

[0087] * indicates a terminal connected to an alkyl carbon atom;

[0088] (2) A is a pentagonal heteroaryl containing 1 to 3 heteroatoms selected from N, S and O, and A is optionally substituted with 1 to 3 R8 groups;

[0089] Each R8 is H, =O, deuterium, halogen, C 1-4 alkyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, 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 Independently selected from alkyl, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, and O; in the case of R8, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0090] Cy is unsubstituted or unsubstituted And;

[0091] In some specific embodiments, A is a pentagonal heteroaryl containing 1 to 3 heteroatoms selected from N, S and O, and A is optionally substituted with 1 to 3 R8 groups;

[0092] Each R8 is H, =O, deuterium, halogen, 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 Independently selected from cycloalkyl; the alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0093] Cy is unsubstituted or unsubstituted And;

[0094] In some specific implementations, A is and, A is optionally substituted with 1 to 3 R8 groups;

[0095] Each R8 is a halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, and C 3-6 Independently selected from cycloalkyls;

[0096] Z1 and Z2 are each independently CH or N;

[0097] Z3 is S, O, or NH;

[0098] * indicates a terminal connected to an alkyl carbon atom;

[0099] In some specific implementations, A is And, A is a 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;

[0100] Cy is And,

[0101] * indicates a terminal connected to an alkyl carbon atom;

[0102] (3) A is and, where * indicates a terminal connected to an alkyl carbon atom;

[0103] R A1 , R A2 , R A3 , and R A4 are each independently R8, and R A1 , R A2 , R A3, and R A4 is not H at the same time;

[0104] Each R8 is H, =O, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, 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 Independently selected from alkyl, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, and O; in the case of R8, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0105] Cy is a 5 to 12-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, and the monocyclic heterocycle is deuterium, =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, Halo C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Alkoxyalkyl, halo C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 alkinyl, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -COC 1-4 Alkyl, -COOC 1-4 Alkyl, -CONH2, -CONHC1-4 Alkyl, -CON(C 1-4 Alkyl)2, -NHCOC 1-4 Alkyl, -S(O)C 1-4 Alkyl, -S(O)2C 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 Optionally substituted with 1 to 3 groups selected from alkyl)2;

[0106] Cy is unsubstituted or unsubstituted And;

[0107] In some specific embodiments, A is a chemical formula and, where * indicates a terminal connected to an alkyl carbon atom;

[0108] R A1 , R A2 , R A3 , and R A4 are each independently R8, and R A1 , R A2 , R A3 , and R A4 is not H at the same time;

[0109] Each R8 is H, =O, deuterium, halogen, 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 Independently selected from cycloalkyl; the alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0110] Cy is a 5 to 8-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, and the monocyclic heterocycle is =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, Halo C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Alkoxyalkyl, halo C 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)2C 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 Optionally substituted with 1 to 3 groups selected from alkyl)2;

[0111] In some specific implementations, A is and, where * indicates a terminal connected to an alkyl carbon atom;

[0112] R A1 , R A2 , R A3 , and R A4 are each independently R8, and R A1 , R A2 , R A3 , and R A4 is not H at the same time;

[0113] Each R8 is H, deuterium, halogen, C 1-4 Alkyl, C 1-4Independently selected from alkoxy, cyano, hydroxyl, NH2, and COOH, wherein the alkyl and alkoxy groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH;

[0114] Cy is This or;

[0115] (4) A is and, where * indicates a terminal connected to an alkyl carbon atom;

[0116] R1, R2, and R3 are H, deuterium, halogen, and C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-6 Each is independently selected from cycloalkyl, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are halogens, 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;

[0117] Optionally, R1 and R2 are C together with the carbon atoms to which they are attached. 3-6 It forms a 4 to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkyl or 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;

[0118] In some specific implementations, A is and, where * indicates a terminal connected to an alkyl carbon atom;

[0119] R1, R2, and R3 are H, deuterium, halogen, and C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, and C 2-6 Each is independently selected from alkynyl, and alkyl, alkoxy, alkenyl, and alkynyl are halogens, 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;

[0120] Optionally, R1 and R2 are C together with the carbon atoms to which they are attached. 3-6 It forms a cycloalkyl group, and the cycloalkyl group 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;

[0121] In some specific implementations, A is and, where * indicates a terminal connected to an alkyl carbon atom;

[0122] R1, R2, and R3 are H, deuterium, halogen, and C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, and C 2-6 Each is independently selected from alkynyl, and alkyl, alkoxy, alkenyl, and alkynyl are halogens, 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;

[0123] Optionally, R1 and R2 are C together with the carbon atoms to which they are attached. 3-6It forms a cycloalkyl group, and the cycloalkyl group is optionally substituted with one to three groups selected from halogen, cyano, hydroxyl, NH2, and COOH.

[0124] In the present invention, " " indicates the connection point.

[0125] More specifically, as a first technical solution of the present invention, the present invention provides a compound of Formula I, or a stereoisomer thereof, a deuteration product, a cocrystal, a solvate, or a pharmaceutically acceptable salt:

[0126] [Chemical Formula I]

[0127]

[0128] Here, ring G is a 5 to 12-membered carbocyclic ring, a 5 to 12-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, or formula I-1 It is a fused ring of (Formula I-1), where L1 is attached 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 heterocycle, and a ring carbon atom or ring heteroatom on a fused ring of Formula I-1), and the carbocyclic ring or monocyclic heterocycle consists of 1 to 3 R G Selectively substituted with the gi;

[0129] Optionally, chemical formula I-1 is the structural formula (Chemical formula I-11),

[0130] Optionally, chemical formula I-1 is the structural formula Having (chemical formula I-12);

[0131] Each R G is deuterium, SF5, =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4Alkyl, Halo C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyloxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 alkinyl, -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)2C 1-4 Alkyl, -S(O)2C 3-6 Cycloalkyl, -S(O)NH2, -S(O)NHC 1-4 Alkyl, -S(O)N(C 1-4 Independently selected from 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from alkyl)2, -S(O)2NH2, and N, S, and O, and R G is deuterium, C 1-4 Alkyl, Halo C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, -CONH2, NH2, C 1-6 It is further optionally substituted with 1 to 3 groups selected from a 5 to 7-membered heterocycle containing 1 to 3 heteroatoms selected from alkoxy, hydroxyl, -COOH, halogen, and N, S, and O, and furthermore, the 5 to 7-membered heterocycle is =O, halogen, cyano, C 1-4 Alkyl, and halo C 1-4 Optionally substituted with 1 to 2 groups selected from alkyl;

[0132] Cy is a 5 to 12-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, and the heterocycle is deuterium, =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, Halo C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyloxy, C 1-6 Alkoxyalkyl, halo C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 alkinyl, -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)2C 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 Optionally substituted with 1 to 3 groups selected from alkyl)2;

[0133] W is C(=O), C(=S), C(=NR) W ), S(=O) or S(=O)2 and;

[0134] M is NR M or O and;

[0135] R W is OH, CN, or C 1-4 It is alkyl;

[0136] R M H, C 1-4 alkyl or C 3-6 It is cycloalkyl;

[0137] R1, R2, and R3 are H, deuterium, halogen, and C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-6 Each is independently selected from cycloalkyl, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycles are halogens, C 1-4 Optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and -COOH;

[0138] Optionally, R1 and R2 are C together with the carbon atoms to which they are attached. 3-6 It forms a 4 to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkyl or N, S, and O, and 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;

[0139] L1 is binding, C 1-3 Alkylene, -NH-, -N(C 1-4 Alkyl)-, -O-, -S-, C 2-6 Alkenylene, C 2-6 Alkynylene, -CO-, or -CONH-, and alkylene, alkenylene, or alkynylene is a halogen, C 1-4 Optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and -COOH;

[0140] Y1 and Y2 are each independently selected from CR4 and N;

[0141] Each R4 is H, deuterium, halogen, C 1-4 Alkyl, C1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkinyl, 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 It is independently selected from alkyl, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S and O, wherein in the case of R4, the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycle groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH.

[0142] X1, X2, X3, and X4 are each independently selected from bonds, NR5, O, CR6R7, S, S(O), and S(O)2, and at most one of X1, X2, X3, and X4 is a bond;

[0143] Each R5 is H, C 1-4 Alkyl, -COC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, and C 3-6 Independently selected from cycloalkyl, wherein the alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH;

[0144] R6 and R7 contain H, deuterium, halogen, and C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-6Each is independently selected from cycloalkyl, cyano, hydroxyl, NH2, -COOH, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0145] Optionally, R6 and R7 form =O;

[0146] Optionally, in X1, X2, X3, and X4, two R5s on adjacent ring atoms, two R6s on adjacent ring atoms, or R5s and R6s on adjacent ring atoms form double bonds with the atoms to which they are attached;

[0147] Optionally, on the same carbon atom, R6 and R7 together with the carbon atom to which they are attached, C 3-12 It forms a carbocyclic ring or a 4 to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, wherein the carbocyclic ring 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, and

[0148] step,

[0149] (1) A is , is a 6-membered heteroaryl or a 5 to 10-membered non-aromatic heterocycle, wherein A is optionally substituted with 1 to 3 R8 groups;

[0150] * indicates a terminal connected to an alkyl carbon atom;

[0151] Ring B is C 3-12It is a carbocyclic ring or a 4 to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, wherein the carbocyclic ring 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;

[0152] Each R8 is H, =O, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, 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 Independently selected from alkyl, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, and O; in the case of R8, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0153] Cy is unsubstituted or unsubstituted This or;

[0154] (2) A is a pentagonal heteroaryl containing 1 to 3 heteroatoms selected from N, S and O, and A is optionally substituted with 1 to 3 R8 groups;

[0155] Each R8 is H, =O, deuterium, halogen, C 1-4 alkyl , C 1-4 Alkoxy, -SC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, 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 Independently selected from alkyl, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, and O; in the case of R8, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0156] Cy is unsubstituted or unsubstituted This or;

[0157] (3) A is and, where * indicates a terminal connected to an alkyl carbon atom;

[0158] R A1 , R A2 , R A3 , and R A4 are each independently R8, and R A1 , R A2 , R A3 , and R A4 is not H at the same time;

[0159] Each R8 is H, =O, deuterium, halogen, C 1-4 alkyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, C 2-6 Alkenyl, C2-6 Alkinyl, 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 Independently selected from alkyl, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, and O; in the case of R8, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0160] Cy is a 5 to 12-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, and the monocyclic heterocycle is a deuterium, =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, Halo C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyloxy, C 1-6 Alkoxyalkyl, halo C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 alkinyl, -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)2C 1-4 Alkyl, -S(O)NH2, -S(O)NHC 1-4 Alkyl, -S(O)N(C1-4 Alkyl)2, -S(O)2NH2, -S(O)2NHC 1-4 Alkyl, and -S(O)2N(C 1-4 Optionally substituted with 1 to 3 groups selected from alkyl)2;

[0161] Cy is unsubstituted or unsubstituted This or;

[0162] (4) A is and, where * indicates a terminal connected to an alkyl carbon atom;

[0163] R1, R2, and R3 are H, deuterium, halogen, and C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-6 Each is independently selected from cycloalkyl, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycles are halogens, 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;

[0164] Optionally, R1 and R2 are C together with the carbon atoms to which they are attached. 3-6 It forms a 4 to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkyl or 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 It is optionally substituted with 1 to 3 groups selected from cycloalkyl.

[0165] As a second technical solution of the present invention, the present invention provides a compound of Formula I, or a stereoisomer thereof, a deuteration product, a cocrystalline form, a solvate, or a pharmaceutically acceptable salt, wherein the compound has the structure of Formula II:

[0166] [Chemical Formula II]

[0167] ;

[0168] Each device is the same as that described in the first technical solution.

[0169] As a third technical solution of the present invention, the present invention provides a compound of Formula I, or a stereoisomer thereof, a deuteration product, a cocrystal, a solvate, or a pharmaceutically acceptable salt, wherein

[0170] Ring G is a 5 to 9-membered monocyclic carbocyclic ring, a 5 to 7-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, or formula I-1 It is a fused ring of (Chemical Formula I-1), where L1 is attached to ring G by replacing any hydrogen atom on the ring atoms, and the monocyclic carbocyclic ring or monocyclic heterocycle consists of 1 to 3 R G Selectively substituted with the gi;

[0171] Optionally, chemical formula I-1 is the structural formula (Chemical formula I-11),

[0172] Optionally, chemical formula I-1 is the structural formula Having (chemical formula I-12);

[0173] Each R G is deuterium, SF5, =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, Halo C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyloxy, C 3-6 Cycloalkyl, C2-6 Alkenyl, C 2-6 alkinyl, -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)2C 1-4 Alkyl, -S(O)2C 3-6 Cycloalkyl, -S(O)NH2, -S(O)NHC 1-4 Alkyl, -S(O)N(C 1-4 Independently selected from 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from alkyl)2, -S(O)2NH2, and N, S, and O, and R G is deuterium, C 1-4 Alkyl, Halo C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, -CONH2, NH2, C 1-6 It is further optionally substituted with 1 to 3 groups selected from a 5 to 7-membered heterocycle containing 1 to 3 heteroatoms selected from alkoxy, hydroxyl, -COOH, halogen, and N, S, and O, and furthermore, the 5 to 7-membered heterocycle is =O, halogen, cyano, C 1-4 Alkyl, and halo C 1-4 Optionally substituted with 1 to 2 groups selected from alkyl;

[0174] Cy is a 5 to 8-membered monocyclic heterocycle, a 7 to 10-membered spirocyclic heterocycle, a 6 to 9-membered bridged-ring heterocycle, or a 6 to 10-membered fused heterocycle, which contains 1 to 3 heteroatoms selected from N, S, and O, and Cy is =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, Halo C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyloxy, C 1-6 Alkoxyalkyl, halo C 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)2C 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 Optionally substituted with 1 to 3 groups selected from alkyl)2;

[0175] R1, R2, and R3 are H, deuterium, halogen, and C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, and C 2-6 Each is independently selected from alkynyl, and alkyl, alkoxy, alkenyl, and alkynyl are halogens, C 1-4 Optionally substituted with 1 to 3 groups selected from alkyl, cyano, hydroxyl, NH2, and COOH;

[0176] Optionally, R1 and R2 are C together with the carbon atoms to which they are attached. 3-6Forming a 4 to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkyl or N, S, and O, and the cycloalkyl or heterocycle is a halogen, cyano, hydroxyl, NH2, COOH, and C 1-4 Optionally substituted with 1 to 3 groups selected from alkyl;

[0177] Each R4 is H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-6 Independently selected from cycloalkyl, cyano, hydroxyl, and NH2; for R4, alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH;

[0178] R6 and R7 contain H, deuterium, halogen, and C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, and C 3-6 Each is independently selected from cycloalkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH;

[0179] Optionally, R6 and R7 form =O;

[0180] Optionally, in X1, X2, X3, and X4, two R5s on adjacent ring atoms, two R6s on adjacent ring atoms, or R5s and R6s on adjacent ring atoms form double bonds with the atoms to which they are attached;

[0181] Optionally, on the same carbon atom, R6 and R7 together with the carbon atom to which they are attached, C 3-6It forms a 4 to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkyl or N, S, and O, and 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, and

[0182] step,

[0183] (1) A is , is a 6-membered heteroaryl or a 5- to 7-membered non-aromatic monocyclic heterocycle, wherein the heteroaryl and non-aromatic monocyclic heterocycle contain 1 to 3 heteroatoms selected from N, S and O, and A is optionally substituted with 1 to 3 R8 groups;

[0184] * indicates a terminal connected to an alkyl carbon atom;

[0185] Ring B is C 4-6 It is a carbocyclic ring or a 5 to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, wherein the carbocyclic ring 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;

[0186] Each R8 is H, =O, deuterium, halogen, 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 3-6Independently selected from cycloalkyl; the alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0187] Cy is unsubstituted or unsubstituted This or;

[0188] (2) A is a pentagonal heteroaryl containing 1 to 3 heteroatoms selected from N, S and O, and A is optionally substituted with 1 to 3 R8 groups;

[0189] Each R8 is H, =O, deuterium, halogen, 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 Independently selected from cycloalkyl; the alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0190] Cy is unsubstituted or unsubstituted This or;

[0191] (3) A is and, where * indicates a terminal connected to an alkyl carbon atom;

[0192] R A1 , R A2 , R A3 , and R A4 are each independently R8, and R A1 , R A2 , R A3 , and R A4 is not H at the same time;

[0193] Each R8 is H, =O, deuterium, halogen, C 1-4Alkyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, cyano, hydroxyl, -COOH, NH2, and C 3-6 Independently selected from cycloalkyl; the alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0194] Cy is a 5 to 8-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, and the monocyclic heterocycle is =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, Halo C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyloxy, C 1-6 Alkoxyalkyl, halo C 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)2C 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 Optionally substituted with 1 to 3 groups selected from alkyl)2;

[0195] Cy is unsubstituted or unsubstituted This or;

[0196] (4) A is and, where * indicates a terminal connected to an alkyl carbon atom;

[0197] R1, R2, and R3 are H, deuterium, halogen, and C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, and C 2-6 Each is independently selected from alkynyl, and alkyl, alkoxy, alkenyl, and alkynyl are halogens, 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;

[0198] Optionally, R1 and R2 are C together with the carbon atoms to which they are attached. 3-6 It forms a cycloalkyl group, and the cycloalkyl group 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;

[0199] The undefined elements are as described in the second technical solution.

[0200] As a fourth technical solution of the present invention, the present invention provides a compound of Formula I or a compound of Formula II, or a stereoisomer thereof, a deuteration product, a cocrystalline form, a solvate, or a pharmaceutically acceptable salt, wherein the compound has the structure of Formula III:

[0201] [Chemical Formula III]

[0202]

[0203] Here, Rc is H, =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, Halo C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, C 1-6Alkoxyalkyl, or halo C 1-4 It is an alkoxy;

[0204] R1, R2, and R3 are H, deuterium, halogen, and C 1-4 Alkyl, and C 1-4 Each is independently selected from alkoxy, and the alkyl and alkoxy groups are halogens, C 1-4 Alkyl, cyano, Optionally substituted with 1 to 3 groups selected from hydroxyl, NH2, and COOH;

[0205] Optionally, R1 and R2 are C together with the carbon atoms to which they are attached. 3-6 They form cycloalkyl groups, and the cycloalkyl group consists of halogens, cyano, hydroxyl, NH2, COOH, and C 1-4 Optionally substituted with 1 to 3 groups selected from alkyl;

[0206] L1 is binding, C 1-3 Alkylene, -NH-, -O-, -S-, C 2-6 Alkenylene, C 2-6 Alkynylene, or -CO-, wherein the alkylene, alkenylene, or alkynylene is optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, and NH2;

[0207] Each R5 is H, C 1-4 Alkyl, and C 3-6 Independently selected from cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH;

[0208] R6 and R7 contain H, deuterium, halogen, and C 1-4 Alkyl, and C 1-4 Each is independently selected from alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH;

[0209] Optionally, R6 and R7 form =O;

[0210] Optionally, in X1, X2, X3, and X4, two R5s on adjacent ring atoms, two R6s on adjacent ring atoms, or R5s and R6s on adjacent ring atoms form double bonds with the atoms to which they are attached, and

[0211] step,

[0212] (1) A is And, ring A is optionally substituted with 1 to 3 R8 groups; the substituents are located at any substitutable position on ring A, including any substitutable position on a carbon atom of the benzene ring and on a carbon atom or heteroatom of the ring fused to the benzene ring;

[0213] Each R8 is a halogen, =O, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, and C 3-6 Independently selected from cycloalkyls;

[0214] * indicates a terminal connected to an alkyl carbon atom;

[0215] r is an integer from 1 to 3;

[0216] E is selected from NH, S and O;

[0217] (2) A is and, A is optionally substituted with 1 to 3 R8 groups;

[0218] Each R8 is a halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, and C 3-6 Independently selected from cycloalkyls;

[0219] Z1 and Z2 are each independently CH or N;

[0220] Z3 is S, O, or NH;

[0221] * indicates a terminal connected to an alkyl carbon atom;

[0222] (3) A is and, where * indicates a terminal connected to an alkyl carbon atom;

[0223] R A1 , R A2 , R A3 , and R A4 are each independently R8, and R A1 , R A2 , R A3 , and R A4 is not H at the same time;

[0224] Each R8 is H, deuterium, halogen, C 1-4 Alkyl, C 1-4 Independently selected from alkoxy, cyano, hydroxyl, NH2, and COOH, wherein the alkyl and alkoxy groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH;

[0225] (4) A is and, where * indicates a terminal connected to an alkyl carbon atom;

[0226] R1, R2, and R3 are H, deuterium, halogen, and C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, and C 2-6 Each is independently selected from alkynyl, and alkyl, alkoxy, alkenyl, and alkynyl are halogens, 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;

[0227] Optionally, R1 and R2 are C together with the carbon atoms to which they are attached. 3-6It forms a cycloalkyl group, wherein the cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH;

[0228] The undefined elements are as described in the third technical solution.

[0229] As a fifth technical solution of the present invention, the present invention provides a compound of Formula III, or a stereoisomer thereof, a deuteration product, a cocrystal, a solvate, or a pharmaceutically acceptable salt, wherein

[0230] Ring G consists of 1 to 3 R G Selectively substituted cyclic, cyclopentane, cyclohexane, cycloheptane, benzene ring, Or, ring G is (Chemical Formula I-2) and,

[0231] Optionally, chemical formula I-2 is the structural formula (Chemical formula I-21),

[0232] Optionally, chemical formula I-2 is the structural formula Having (chemical formula I-22);

[0233] L1 is attached to ring G by replacing any hydrogen atom on the ring atom, and

[0234] Each R G is 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 alkinyl, -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 1-4Independently selected from 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from alkyl)2, and N, S, and O, and R G is deuterium, C 1-4 Alkyl, Halo C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, -CONH2, NH2, C 1-6 It is further optionally substituted with 1 to 3 groups selected from a 5 to 7-membered heterocycle containing 1 to 3 heteroatoms selected from alkoxy, hydroxyl, halogen, and N, S, and O, and furthermore, the 5 to 7-membered heterocycle is =O, halogen, cyano, C 1-4 Alkyl, and halo C 1-4 Optionally substituted with 1 to 2 groups selected from alkyl, and

[0235] step,

[0236] (1) A is or And, ring A is optionally substituted with 1 to 3 R8 groups; the substituents are located at any substitutable position on ring A, including any substitutable position on a carbon atom of the benzene ring and on a carbon atom or heteroatom of the ring fused to the benzene ring;

[0237] Each R8 is =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, and C 3-6 Independently selected from cycloalkyls;

[0238] * indicates a terminal connected to an alkyl carbon atom;

[0239] (2) A is And, A is a halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, and C3-6 Optionally substituted with 1 to 3 groups selected from cycloalkyl;

[0240] * indicates a terminal connected to an alkyl carbon atom;

[0241] (3) A is and, where * indicates a terminal connected to an alkyl carbon atom;

[0242] R A1 , R A2 , R A3 , and R A4 are each independently R8, and R A1 , R A2 , R A3 , and R A4 is not H at the same time;

[0243] Each R8 is H, deuterium, halogen, C 1-4 Alkyl, C 1-4 Independently selected from alkoxy, cyano, hydroxyl, NH2, and COOH, wherein the alkyl and alkoxy groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH;

[0244] (4) A is and, where * indicates a terminal connected to an alkyl carbon atom;

[0245] R1, R2, and R3 are H, deuterium, halogen, and C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, and C 2-6 Each is independently selected from alkynyl, and alkyl, alkoxy, alkenyl, and alkynyl are halogens, 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;

[0246] Optionally, R1 and R2 are C together with the carbon atoms to which they are attached. 3-6It forms a cycloalkyl group, wherein the cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH;

[0247] The undefined elements are as described in the fourth technical solution.

[0248] As a sixth technical solution of the present invention, the present invention provides a compound of Formula III, or a stereoisomer thereof, a deuteration product, a cocrystal, a solvate, or a pharmaceutically acceptable salt, wherein (Chemical Formula I-2) is selected from one of the following structural formulas:

[0249]

[0250] The undefined elements are as described in the fifth technical solution.

[0251] As a seventh technical solution of the present invention, the present invention provides a compound of Formula I, or a stereoisomer thereof, a deuteration product, a cocrystalline form, a solvate, or a pharmaceutically acceptable salt, wherein the compound has the structural formula of Formula IV:

[0252] [Chemical Formula IV]

[0253]

[0254] Here, Rc is H, halogen, C 1-2 alkyl or C 1-2 It is an alkoxy;

[0255] R1, R2, and R3 are each independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, methoxy, or ethoxy, and methyl, ethyl, methoxy, or ethoxy are optionally substituted with 1 to 3 groups selected from F, Cl, Br, cyano, hydroxyl, and NH2;

[0256] Z is CH or N;

[0257] Ring G is a benzene ring or 1 to 2 RG Selectively substituted by the And;

[0258] Each R G is independently selected from F, Cl, Br, I, methyl, ethyl, propyl, SF5, and CN, wherein methyl, ethyl, or propyl is additionally optionally substituted with 1 to 3 groups selected from deuterium, F, Cl, Br, and I.

[0259] As an eighth technical solution of the present invention, the present invention provides a compound of Formula I, or a stereoisomer thereof, a deuteration product, a cocrystalline form, a solvate, or a pharmaceutically acceptable salt, wherein the compound is selected from one of the following structural formulas:

[0260]

[0261]

[0262] As a ninth technical solution of the present invention, the present invention provides a compound of Formula I, or a stereoisomer thereof, a deuteration product, a cocrystalline form, a solvate, or a pharmaceutically acceptable salt, wherein the compound is selected from one of the following structural formulas:

[0263]

[0264]

[0265] As a tenth technical solution of the present invention, the present invention provides a pharmaceutical composition comprising a compound according to any one of the first to ninth technical solutions, or a stereoisomer thereof, a deuteriumation product, a cocrystalline body, a solvate or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

[0266] The present invention further provides the use of a compound according to any one of the first to ninth technical solutions, or a stereoisomer thereof, a deuterated product, a cocrystalline form, a solvate, or a pharmaceutically acceptable salt, or a composition according to the tenth technical solution, in the manufacture of a drug for the treatment of a disease mediated by dipeptidyl peptidase 1.

[0267] Furthermore, diseases mediated by dipeptidyl peptidase 1 are selected from obstructive airway diseases, bronchiectasis, cystic fibrosis, asthma, emphysema, chronic obstructive pulmonary disease, and other diseases.

[0268] Synthesis path

[0269] Those skilled in the art may prepare the compounds of the present invention according to known organic synthesis techniques, and the starting materials used therein are commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include 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.

[0270] References and papers in the art provide detailed descriptions of the synthesis of reactants that can be used to prepare the compounds described herein, or provide papers describing preparation methods for reference. References and papers include: ["Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; HO House, "Modern Synthetic Reactions", 2nd Ed., WA Benjamin, Inc. Menlo Park, Calif. 1972; TL Gilchrist, "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, R.C."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 및 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; 및 "Chemistry of Functional Groups", John Wiley & Sons, in 73 volumes]을 포함한다.

[0271] Specific and similar reactants can be selectively identified by indexes of known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, which are available in most public or university libraries and online. Chemicals that are known but not commercially available in catalogs are selectively manufactured by custom chemical synthesis plants, where many standard chemical supply plants (e.g., those listed above) provide custom synthesis services. Reference for the preparation and selection of pharmaceutically acceptable salts of the compounds described herein is [PH Stahl & CG Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002].

[0272] terminology

[0273] Unless otherwise specified, the terms of the present invention have the following meanings.

[0274] The carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen contained in the group and compound of the present invention all include isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen contained in the group and compound of the present invention is additionally optionally substituted with one or more of their corresponding isotopes, wherein the isotope of carbon is 12 C, 13 C and 14 It contains C, and hydrogen isotopes include protium (H), deuterium (D, also known as deuterium), and tritium (T, also known as superdeuterium), and oxygen isotopes 16 O, 17 O and 18 It contains O, and sulfur isotopes 32 S, 33 S, 34 S and 36 It contains S, and nitrogen isotopes 14 N and15 Containing N, the isotope of fluorine is 19 It contains F, and the chlorine isotope is 35 Cl and 37 Containing Cl, the isotope of bromine is 79 Br and 81 Includes Br.

[0275] In this specification, the term "halogen" refers to F, Cl, Br, I, or isotopes thereof.

[0276] The terms “halo” or “halogen-substituted” refer to being substituted with one or more groups selected from F, Cl, Br, I, or their isotopes, wherein the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted within the substituted group. Without specific limitations, the number of halogen substituents is any number between 1 and the upper limit, and if the number of halogen substituents is greater than 1, the substituted group may be substituted with the same or different halogens. Generally, environments substituted with 1 to 5 halogens, 1 to 3 halogens, 1 to 2 halogens, and 1 halogen are included.

[0277] The term "deuterium" refers to deuterium, an isotope of hydrogen (H).

[0278] The term "deuterated" refers to the case where a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, alkenyl, alkynyl, or other group is substituted with at least one isotopic deuterium, wherein the upper limit of the number of deuterium substituents is equal to the sum of the number of hydrogens that can be substituted within the group to be substituted. Without particular limitation, the number of deuterium substituents is any integer between 1 and the upper limit, preferably 1 to 20 deuterium atoms, more preferably 1 to 10 deuterium atoms, more preferably 1 to 6 deuterium atoms, and more preferably 1 to 3 deuterium atoms.

[0279] Gi "C x-y" refers to a group containing x to y carbon atoms, for example, "C 1-6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms.

[0280] The term "alkyl" refers to a monovalent linear or branched saturated aliphatic hydrocarbon group. Unless otherwise specified, alkyl refers to alkyls containing 1 to 20 carbon atoms, preferably alkyls containing 1 to 8 carbon atoms, more preferably alkyls containing 1 to 6 carbon atoms, and more preferably alkyls containing 1 to 4 carbon atoms. Non-limiting examples of alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isoamyl, neopentyl, n-hexyl, and various branched isomers thereof. .

[0281] The term "alkylene" refers to a divalent linear or branched saturated alkyl group. Examples of alkylenes include, but are not limited to, methylene, ethylidene, etc.

[0282] The term "haloalkyl" refers to an alkyl group in which one or more hydrogens are substituted with one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine, or isotopes thereof), wherein the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted within the alkyl group. Without special limitation, the number of halogen substituents is any integer between 1 and the upper limit. Generally, the alkyl group is substituted with 1 to 5 halogens, 1 to 3 halogens, 1 to 2 halogens, or 1 halogen; where the number of halogen substituents is greater than 1, the group to be substituted may be substituted with the same or different halogens; specific examples include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0283] The terms "alkoxy" or "alkyloxy" refer to -O-alkyl, e.g., -OC 1-8 Alkyl, -OC 1-6 Alkyl, -OC 1-4 alkyl or -OC 1-2 It refers to an alkyl group. Non-limiting specific examples of alkoxy or alkyloxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropoxy, cyclobutoxy, etc. The alkoxy group may be optionally substituted with a substituent.

[0284] The term "haloalkoxy" refers to -O-haloalkyl, e.g., -O-halo C 1-8 Alkyl, -O-halo C 1-6 Alkyl, -O-halo C 1-4 Alkyl or -O-halo C 1-2 Refers to an alkyl group; the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted within the substituted group. Without special limitation, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1 to 5 halogens, 1 to 3 halogens, 1 to 2 halogens, and 1 halogen; where the number of halogen substituents is greater than 1, the group to be substituted may be substituted with the same or different halogens; non-limiting examples of haloalkoxy include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, etc.

[0285] The term "alkylamino" or "alkamino" refers to an amino substituted with one or two alkyl groups, 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.

[0286] The term “alkenyl” refers to a linear or branched hydrocarbon group containing at least one carbon-carbon double bond (C=C), and generally includes 2 to 18 carbon atoms, e.g., 2 to 8 carbon atoms, e.g., 2 to 6 carbon atoms, and further e.g., 2 to 4 carbon atoms. Examples of alkenyls are, 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, 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, It includes 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, 1,4-hexadiene, etc.; furthermore, the alkenyl can be selectively substituted with a substituent.

[0287] The term "alkenylene" refers to a linear 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 may be optionally substituted with a substituent.

[0288] The term "alkynyl" refers to at least one carbon-carbon triple bond ( It refers to a linear or branched hydrocarbon group containing ), generally comprising 2 to 18 carbon atoms; furthermore, the alkynyl comprises 2 to 8 carbon atoms; furthermore, the alkynyl comprises 2 to 6 carbon atoms, and furthermore, the alkynyl comprises 2 to 4 carbon atoms. Examples of alkynyl include, but are not limited to, ethinyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexinyl, 3-hexinyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octinyl, 3-noninyl, 4-decinyl, etc.; the alkynyl may be optionally substituted with a substituent.

[0289] The term "alkynylene" refers to a carbon-carbon triple bond ( It refers to a linear or branched divalent unsaturated hydrocarbon group containing ), generally comprising 2 to 6 carbon atoms, and further comprising 2 to 4 carbon atoms. Non-limiting examples of alkynylene include ethinylene, propynylene, and butynylene, and 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 cyclic heteroatoms. Cycloalkyl may be monocyclic, acyclic, or polycyclic, and acyclic or polycyclic cycloalkyl may be in the form of a fused ring, spiro ring, bridged ring, or a combination thereof, and may comprise one or more aromatic rings, but the ring system is entirely non-aromatic, and the linking sites may be on an aromatic ring or a non-aromatic ring. Generally, cycloalkyl contains 3 to 20 carbon atoms; Furthermore, the cycloalkyl contains 3 to 8 carbon atoms; furthermore, the cycloalkyl contains 3 to 6 carbon atoms; where the cycloalkyl is a monocyclic cycloalkyl, the cycloalkyl contains 3 to 15 carbon atoms, or 3 to 10 carbon atoms, or 3 to 8 carbon atoms, or 3 to 6 carbon atoms; where the cycloalkyl is a bicyclic or polycyclic cycloalkyl, the cycloalkyl contains 5 to 12 carbon atoms, or 5 to 11 carbon atoms, or 6 to 10 carbon atoms; non-limiting examples of the cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl, Includes, etc., and the cycloalkyl may be optionally substituted with a substituent. The term "cycloalkylene" refers to a divalent saturated, substituted, or unsubstituted cycloalkyl. Non-limiting examples are Includes

[0290] The terms “carbon ring” or “carbocyclile” refer to substituted or unsubstituted, saturated or unsaturated, and aromatic or non-aromatic carbocyclic groups, including monocyclic carbocyclic, acyclic bridged ring, acyclic fused ring, acyclic spiro ring, polycyclic ring containing at least three rings, etc., and generally contain 3 to 14 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 6 to 8 carbon atoms or 3 to 6 carbon atoms. In non-limiting examples, the monocyclic carbocyclic ring includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, etc.; and the acyclic bridged ring Includes the back; the non-cyclic fusion ring Includes the back; the acyclic spiro ring Includes the back; the three-ring system is Includes the back.

[0291] The term “heterocycle” or “heterocyclile” refers to a substituted or unsubstituted, saturated or unsaturated aromatic ring or a non-aromatic ring, and, although not particularly limited, contains 1 to 5 heteroatoms selected from N, S and O, preferably 1 to 4 heteroatoms, more preferably 1 to 3 heteroatoms, and includes monocyclic heterocycles, acyclic bridged heterocycles, acyclic fused heterocycles, acyclic spiro heterocycles, polycyclic heterocycles containing at least 3 rings, preferably 3 to 15 heterocycles, more preferably 4 to 14 heterocycles, more preferably 4 to 10 heterocycles and 5 to 12 heterocycles, more preferably 5 to 8 heterocycles and 5 to 6 heterocycles. The heterocycle is preferably a saturated heterocycle, e.g., 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 the heterocyclile can be oxidized to various oxidation states. Heterocycliles can be connected to heteroatoms or carbon atoms, and non-limiting examples of heterocycliles 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, imidazolyl, piperidyl, piperadinyl, morpholinyl, thiomophorinyl, 1,3-dithianyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuryl, titrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, Tetrahydrothiazolyl, tetrahydropyranil, 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,.

[0292] Includes the back.

[0293] The term "heterocyclene" refers to a divalent heterocyclyl group that is substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic. Non-limiting examples of heterocyclenes are Includes the back.

[0294] The term "aryl" refers to an aromatic group and includes pentagonal and hexagonal monocyclic aromatic groups that may contain 0 to 4 heteroatoms (N, S, and O), and polycyclic systems having at least one aromatic ring. The concept of aryl includes aromatic carbocyclic rings and heteroaromatic rings, such as phenyl, pyrrole, furan, thiophene, thiazole, isothiazol, imidazole, triazole, tetrazole, pyrazol, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, etc. Polycyclic (tricyclic or bicyclic) aryls include naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxybenzene, quinoline, isoquinoline, naphthiridine, indole, benzofuran, purine, deazpurine, or indolizine. An aryl group having a heteroatom within a ring structure may also be referred to as an "aromatic heterocycle," "heteroaryl," or "heteroaromatic ring."

[0295] The term "spiro ring" refers to a polycyclic group sharing one carbon atom (referred to as a spiro atom) between rings, which may not contain double or triple bonds, or may contain at least one double or triple bond, and may contain 0 to 5 heteroatoms selected from N, O, S, P, Si and their oxidation states. Generally, a spiro ring is a 6 to 14-membered ring, or a 6 to 12-membered ring, or a 6 to 10-membered ring. Generally, a spiro ring is a spiro ring formed by a ternary ring and a ternary ring, a ternary ring and a quaternary ring, a ternary ring and a quinary ring, a ternary ring and a 6-membered ring, a quaternary ring and a quaternary ring, a quaternary ring and a 5-membered ring, a quaternary 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 are

[0296]

[0297] It includes, and the spiro ring can be optionally substituted with a substituent.

[0298] The term "fusion 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 fusion ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. Generally, the fusion ring is a 5 to 20-membered ring, or a 5 to 14-membered ring, or a 5 to 12-membered ring, or a 5 to 10-membered ring. Generally, the fusion ring is in the form of a ternary ring fused with a quaternary ring (representing a fusion ring formed by a ternary ring and a quaternary ring, where either the ternary ring or the quaternary ring may possibly be used as a base ring according to IUPAC nomenclature; similarly hereinafter), a ternary ring fused with a pentary ring, a ternary ring fused with a hexagram, a quaternary ring fused with a quaternary ring, a quaternary ring fused with a pentary ring, a quaternary ring fused with a hexagram, a pentary ring fused with a pentary ring, a pentary ring fused with a hexagram, and a hexagram fused with a hexagram. Non-limiting examples of the fusion ring are purines, quinolines, isoquinolines, benzopyrans, benzofurans, benzothiophenes, and

[0299]

[0300] It includes; the fusion ring can be optionally substituted with a substituent.

[0301] The term "bridged ring" refers to a ring system in which two non-adjacent ring atoms are shared between two rings, and the bridged ring may contain one or more double or triple bonds. The bridged ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Generally, the bridged ring has 5 to 20, 5 to 14, 5 to 12, or 5 to 10 ring atoms. Non-limiting examples of bridged rings include adamantane,

[0302]

[0303] Includes

[0304] Unless otherwise specified, the terms "substitute" or "substituent" refer to any substitution at a position permitted by chemical theory, and the number of substituents follows the rules of chemical bonding. Exemplary substituents are not limited thereto, but C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-8 Heteroalkyl, C 5-12 Aryl, 5 to 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, halo C 1-6 Alkyl, Halo C 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 Includes alkyl, etc.

[0305] The terms “optional” or “optional” indicate that an event or situation described sequentially may occur but is not necessarily required to occur, and such description includes cases where the event or situation occurs or does not occur. For example, “alkyl optionally substituted with F” means that an alkyl may be substituted with F but is not necessarily substituted, and the description includes cases where the alkyl is substituted with F and cases where the alkyl is not substituted with F.

[0306] When additional substituents are optionally substituted, groups that cannot be formed according to general chemical knowledge are not included.

[0307] A given group is selected from atoms or groups such as H or deuterium, and when the group is additionally optionally substituted, cases where H or deuterium atoms are additionally substituted are not included.

[0308] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, and such salt retains biological effects and the properties of a free acid or free base and is obtained by the reaction of a free acid with a non-toxic inorganic base or organic base, or by the reaction of a free base with a non-toxic inorganic acid or organic acid.

[0309] The term “pharmaceutical composition” refers to a mixture of one or more compounds or stereoisomers thereof, solvates, pharmaceutically acceptable salts or cocrystalline bodies, and other components comprising physiologically / pharmaceutically acceptable carriers and / or excipients as described herein.

[0310] The term "carrier" refers to a system that does not cause significant irritation to an organism, does not eliminate the biological activity and properties of an administered compound, can alter the manner in which a drug is introduced into the human body and its distribution within the body, and can control the drug release rate and delivery to a targeted organ. Non-limiting examples of carriers include microcapsules, microspheres, nanoparticles, liposomes, etc.

[0311] The term “excipient” refers to a substance that is not the therapeutic agent itself but is added to a pharmaceutical composition and used as a diluent, adjuvant, adhesive, and / or excipient, thereby improving its processing or storage properties, or allowing or facilitating the formation into a unit dosage form for the administration of the compound or pharmaceutical composition. As is known to those skilled in the art, pharmaceutically acceptable excipients may provide various functions and may be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, coloring agents, flavoring agents, and sweeteners. Examples of pharmaceutically acceptable excipients include, but are not limited to: (1) sugars, e.g., lactose, glucose, and sucrose; (2) starches, e.g., corn starch and potato starch; (3) Cellulose and derivatives thereof, e.g., sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose and croscarmellose (e.g., sodium croscarmellose); (4) Tragacanth powder; (5) Malt; (6) Gelatin; (7) Talc; (8) Excipients, e.g., cocoa butter or suppository wax; (9) Oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) Diols, e.g., propylene glycol; (11) Polyols, e.g., glycerol, sorbitol, mannitol and polyethylene glycol; (12) Esters, e.g., ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers, e.g., magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) non-pyrogenic factor water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethanol; (20) pH buffer solution; (21) polyester, polycarbonate and / or polyanhydride; and (22) other non-toxic miscible components used in pharmaceutical formulations.

[0312] The term "stereoisomer" refers to an isomer produced as a result of different spatial arrangements of atoms within a molecule, including cis-trans isomers, enantiomers, and conformation isomers.

[0313] The term "solvent" 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 solvent is a hydrate.

[0314] The term "cocrystal" refers to a crystal formed by a combination of an active pharmaceutical ingredient (API) and a cocrystallizer (CCF) under the action of hydrogen bonding or other non-covalent bonding. In their pure states, both API and CCF are solids at room temperature, and there is a fixed stoichiometric ratio between the various components. Cocrystals are multicomponent crystals, including binary cocrystals formed between two neutral solids and multicomponent cocrystals formed between a neutral solid and a salt or solvate. Specific details for implementing the invention

[0315] The content of the present invention is described in detail in the following examples. Where specific conditions are not indicated in the examples, ordinary conditions are used in the experimental methods. The listed examples are intended to better illustrate the content of the present invention, but should not be construed as limiting the content of the present invention. In accordance with the foregoing description of the present invention, those skilled in the art may make minor modifications and adjustments to the embodiments, which will still fall within the scope of protection of the present invention.

[0316] Detection method

[0317] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is provided in units of 10 to 6 (ppm). NMR is determined using a Bruker Avance III 400 and a Bruker Avance 300; the solvents for determination are deuteride dimethyl sulfoxide (DMSO-d6), deuteride chloroform (CDCl3), and deuteride methanol (CD3OD); the internal standard is tetramethylsilane (TMS);

[0318] MS is measured using the Agilent 6120B (ESI) and Agilent 6120B (APCI);

[0319] HPLC is determined using Agilent 1260DAD high-pressure liquid chromatography (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

[0320] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used as thin film chromatography silica plates, and silica gel plates for thin film chromatography (TLC) have a specification of 0.15 mm to 0.20 mm, and when separating and purifying products by thin film chromatography, the specification is 0.4 mm to 0.5 mm.

[0321] For column chromatography, Yantai Huanghai silica gel 200 to 300 mesh silica gel is generally used as a carrier.

[0322] Explanation of the abbreviation:

[0323] Burgess reagent: (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt

[0324] Pd(dppf)Cl2: [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0325] X-Force: 2-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

[0326] DMF: N,N'-Dimethylformamide

[0327] HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0328] DIPEA: N,N-Diisopropylethylamine

[0329] LDA: Lithium diisopropylamide

[0330] PE: Petroleum ether

[0331] EA: Ethyl acetate

[0332] THF: Tetrahydrofuran

[0333] MeOH: methanol

[0334] DCM: Dichloromethane

[0335] TMSOTf: Trimethylsilyl trifluoromethanesulfonate

[0336] intermediate

[0337] INT-1: tert-butyl (S)-(1-cyano-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate

[0338]

[0339] Compound 1a (4.50 g, 12.1 mmol, prepared with reference to WO 2013041497) 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. Upon completion of addition, the mixture was 100 The reaction was carried out under microwaves for 1 hour. After the reaction was complete, 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 provide INT-1 as a white solid (2.1 g, yield: 46.7%). LCMS m / z = 373.2 [M + 1] + .

[0340] 1 H NMR (400 MHz, 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).

[0341] 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

[0342]

[0343] 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(pinacollato)diborone (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. Upon completion of addition, the mixture was 90 The temperature was raised to [value] and the reaction was carried out for 3 hours. After the reaction was complete, 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 provide INT-2 as a white solid (2.1 g, yield: 92.1%). LCMS m / z = 335.2 [M +1-56] + .

[0344] 1H NMR (400 MHz, 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).

[0345] Example 1: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 1)

[0346]

[0347] Step 1: (S)-tert-butyl (1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)carbamate(1B)

[0348] 1A (0.29 g, 0.85 mmol, synthesized with reference to WO 2016016242 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. Upon completion of addition, the mixture was 90 The reaction was carried out for 3 hours. The reaction solution was cooled to room temperature, and a saturated aqueous solution of sodium chloride (20 mL) was added. The resulting mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 4:1) to obtain the title compound 1B (white solid, 0.34 g, 99.0%). LC-MS (ESI): m / z = 412.1 [M+H] + .

[0349] Step 2: (S)-2-amino-3-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)propanenitrile(1C)

[0350] 1B (0.34 g, 0.83 mmol) was dissolved in formic acid (5 mL), and upon completion of addition, the mixture was reacted overnight at room temperature. The reaction solution was concentrated and dried, and ethyl acetate (25 mL) was added. Subsequently, a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the residual 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 obtain the crude product of the title compound 1C (pale yellow solid, 0.21 g, 69.5%). LC-MS (ESI): m / z = 312.1 [M+H] + .

[0351] Step 3: (S)-tert-butyl 2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(1D)

[0352] 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 according to WO 2015110826) were added. Upon completion of addition, the mixture was reacted overnight at room temperature. The reaction was quenched by adding a saturated aqueous ammonium chloride solution dropwise, and a saturated aqueous sodium chloride solution (30 mL) was added. The resulting mixture was extracted with ethyl acetate (25 mL), the organic phase was washed with a saturated aqueous sodium chloride solution (25 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 1D (pale yellow solid, 0.32 g, 99.0%), which was used directly in the following reaction. LC-MS (ESI): m / z =483.1 [M-57+H] + .

[0353] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide(compound 1)

[0354] Dissolve 1D (0.32 g, 0.59 mmol) in formic acid (2.5 mL), and upon completion of addition, 50 of the mixture The reaction was carried out for 10 minutes. The reaction solution was concentrated and dried, and ethyl acetate (20 mL) was added. Subsequently, a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the residual aqueous layer was extracted with ethyl acetate (25 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain Title Compound 1 (0.15 g, 58.0%). LC-MS (ESI): m / z = 439.1 [M+H] +.

[0355] 1 H NMR (400 MHz, 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, 1H), 3.78 (m, 1H), 3.46 (s, 3H), 3.41 - 3.17 (m, 3H), 3.03 - 2.87 (m, 3H), 1.88 (m, 2H).

[0356] Example 2: N-((S)-1-cyano-2-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide(Compound 2)

[0357]

[0358] Step 1: 4-bromo-1-(bromomethyl)-2-methoxybenzene(2B)

[0359] (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 hour. PE / EA (v / v = 5:1, 12 mL) was added to the reaction solution. The resulting mixture was stirred and filtered by suction, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 30:1 to 20:1) to obtain the title compound (2B) as a white solid (3.9 g, yield: 76%).

[0360] Step 2: (2S,5R)-2-(4-bromo-2-methoxybenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine(2C)

[0361] (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1 g, 5.43 mmol) was dissolved in THF (20 mL). Nitrogen was substituted into the mixture, and -78 Cooled to [amount], and n-butyllithium (6.5 mmol, 2.5 M in toluene, 2.6 mL) was added. The resulting mixture was reacted for 1 hour, and a solution of 2B (1.67 g, 5.97 mmol) in THF (8 mL) was added sequentially. -78 The reaction was allowed to continue for 2 hours. The reaction was quenched with a saturated solution of NH4Cl, 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 then concentrated. The crude product was passed through a silica gel column (EA / PE(v / v) = 0% to 6%) to obtain the title compound (2C) as a colorless oil (1.82 g, yield: 87%). LCMS m / z = 383.3 [M+1] +

[0362] Step 3: Methyl (S)-2-amino-3-(4-bromo-2-methoxyphenyl)propanoate(2D)

[0363] 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 overnight at room temperature, and the system was rotary evaporated. The system was neutralized to a weakly basic pH by adding a saturated aqueous sodium bicarbonate solution, 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 obtain 2D (1.34 g, yield: 97%). LCMS m / z = 288.1 [M+1] +

[0364] Step 4: Methyl (S)-3-(4-bromo-2-methoxyphenyl)-2-((tert-butoxycarbonyl)amino)propanoate(2E)

[0365] 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 hours. Water was added to the system 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 obtain 2E as a colorless oil (0.7 g, yield: 31%). LCMS m / z = 288.1 [M-boc+1] +

[0366] Step 5: (S)-3-(4-bromo-2-methoxyphenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid(2F)

[0367] 2E (0.7 g, 1.87 mmol) was dissolved in methanol (10 mL) and water (6 mL), and then NaOH (1.50 g, 3.74 mmol) was added. The mixture was reacted at room temperature for 2 hours, and the methanol was removed by rotary evaporation. Diluted hydrochloric acid was added to adjust the solution pH to a weakly acidic level. For extraction, EA (10 mL × 3) was added, and liquid-liquid separation was performed. The organic phase was rotary evaporated to obtain the crude product (2F) (0.65 g). LCMS m / z = 274.2 [M-boc+1] +

[0368] Step 6: tert-butyl (S)-(1-amino-3-(4-bromo-2-methoxyphenyl)-1-oxopropane-2-yl)carbamate(2G)

[0369] 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 overnight at room temperature. Water and EA were added for extraction, liquid-liquid separation was performed, the organic phase was dried over anhydrous Na2SO4, and then concentrated to obtain the crude product (2G) (0.62 g). LCMS m / z = 273.1 [M-boc+1] +

[0370] Step 7: tert-butyl (S)-(2-(4-bromo-2-methoxyphenyl)-1-cyanoethyl)carbamate(2H)

[0371] 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 overnight at room temperature. The system was concentrated and rotary evaporated, 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] +

[0372] Step 8: tert-butyl (S)-(1-cyano-2-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)carbamate(2I)

[0373] 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 nitrogen-substituted protection, and the mixture was 90 The reaction was carried out for 3 hours. The reaction solution was concentrated and rotary evaporated, dissolved in DCM, filtered by suction through Celite, and the filtrate was rotary evaporated. The crude product was separated by silica gel column chromatography (EA / PE(v / v) = 0% to 40%) to obtain 2I as a pale yellow solid (550 mg, yield: 92%). LCMS m / z = 424.2 [M+1] +

[0374] Step 9: (S)-2-amino-3-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)propanenitrile(2J)

[0375] 2I (135 mg, 0.32 mmol) was dissolved in formic acid (8 mL), and the mixture was stirred overnight at room temperature. The system was diluted with DCM, and a saturated sodium bicarbonate solution was added to adjust the system's pH to a weakly basic level. Liquid-liquid separation was performed using DCM and water, and the organic phase was dried, concentrated, and rotary evaporated to obtain a crude product (2J) (90 mg), which was used directly in the following reaction. LCMS m / z = 324.1 [M+1] +

[0376] Step 10: tert-butyl (S)-2-(((S)-1-cyano-2-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(2K)

[0377] 2J (90 mg, 0.28 mmol) and INT-3 (82 mg, 0.34 mmol) were dissolved in DMF (5 mL), and then HATU (0.12 g, 0.31 mmol) and DIPEA (0.2 mL) were added. The mixture was reacted overnight at room temperature. Water and EA were added to the reaction system for extraction and liquid-liquid separation; 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 to 10%) to obtain 2K (90 mg). LCMS m / z = 549.1 [M+1] +

[0378] Step 11: (S)-N-((S)-1-cyano-2-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide(compound 2)

[0379] 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 a saturated sodium bicarbonate solution was added to adjust the system's pH to a weakly basic level. Liquid-liquid separation was performed using DCM and water; the organic phase was dried, concentrated, and rotary evaporated to obtain the residue, which was then 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] +

[0380] 1H NMR (400 MHz, 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, 3H), 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).

[0381] Example 3: (S)-N-((S)-1-cyano-2-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 3)

[0382]

[0383] Compound 3 was prepared from Compound 3A by referring to the preparation method of Compound 2. LC-MS m / z = 439.2 [M+1] +

[0384] 1 H NMR (400 MHz, 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).

[0385] 19 F NMR (376 MHz, CDCl3) δ -117.13.

[0386] Example 4: (S)-N-((S)-1-cyano-2-(5-(1-methyl-2-oxoindolin-6-yl)thiophene-2-yl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 4)

[0387]

[0388] Step 1: 6-bromo-1-methylindolin-2-one(4B)

[0389] 4A (5 g, 23.5 mmol) was dissolved in 200 mL of acetonitrile, and then potassium carbonate (23 g, 94.32 mmol) and iodomethane (2.96 mL, 47.16 mmol) were added. The mixture was 70 The mixture was heated to [value] 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 obtain brown solid 4B (1.8 g, 34%). LC-MS (ESI): m / z = 226.1 [M+H] + .

[0390] Step 2: 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(4C)

[0391] 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-triisopropyl biphenyl (1.2 g, 2.65 mmol), and bis(pinacolato)diborone (1.35 g, 5.3 mmol) were mixed and dissolved in 50 mL of 1,4-dioxane, and this mixture was heated under N2 protection at 95°C The mixture was heated to [value] and reacted for 3 hours. After the completion of the reaction was 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] + .

[0392] Step 3: tert-butyl-(S)-(1-cyano-2-(5-(1-methyl-2-oxoindolin-6-yl)thiophene-2-yl)ethyl)carbamate(4D)

[0393] Tert-butyl N-[(1S)-2-(5-bromoteophene-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, dissolved in 5 mL of 1,4-dioxane and 0.1 mL of water, and the mixture was heated under a microwave at 120°C The mixture was heated to [value] and reacted for 1 hour. After the completion of the reaction was 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 4D (175 mg, 33%). LC-MS (ESI): m / z = 398.2 [M+H] + .

[0394] Step 4: (S)-2-amino-3-(5-(1-methyl-2-oxoindolin-6-yl)thiophene-2-yl)propanitrile(4E)

[0395] Formic acid (3 mL) was added to compound 4D (175 mg, 0.44 mmol), and the mixture was stirred at room temperature for 3 hours. After the completion of the reaction was detected by LCMS, a saturated sodium carbonate solution was added to the reaction solution to adjust the pH to 10. The resulting mixture was extracted with DCM, the organic phase was dried, and then concentrated to obtain product 4E (119 mg, 91%). LC-MS (ESI): m / z = 298.1 [M+H] + .

[0396] Step 5: tert-butyl-(S)-2-(((S)-1-cyano-2-(5-(1-methyl-2-oxoindolin-6-yl)thiophene-2-yl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(4F)

[0397] 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, dissolved in DMF, and the mixture was stirred overnight at room temperature. After the completion of the reaction was detected by LCMS, water and EA were added for extraction, the organic phase was dried and concentrated, and the residues were separated by column chromatography (PE : EA (v / v) = 1 : 1) to obtain the yellow solid 4F (165 mg, 78%). LC-MS (ESI): m / z = 525.2 [M+H] + .

[0398] Step 6: (S)-N-((S)-1-cyano-2-(5-(1-methyl-2-oxoindolin-6-yl)thiophene-2-yl)ethyl)-1,4-oxazepan-2-carboxamide(compound 4)

[0399] 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 hours. After the completion of the reaction was detected by LCMS, the reaction solution was poured into a 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] + .

[0400] 1 H NMR (400 MHz, 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).

[0401] Example 5: (S)-N-((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)thiophene-2-yl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 5)

[0402]

[0403] Step 1: (S)-3-(5-bromothiophene-2-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid(5B)

[0404] 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 to 7 using dilute hydrochloric acid (1 N). 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 to 1:10) to obtain the title compound (5B) as a yellow solid (14 g, yield: 99%). LCMS m / z = 350.23 [M+1] +

[0405] Step 2: tert-butyl (S)-(1-amino-3-(5-bromoteophene-2-yl)-1-oxopropane-2-yl)carbamate(5C)

[0406] 5B (4 g, 11.5 mmol) was dissolved in DMF (50 mL), and then ammonium chloride (620 mg, 11.5 mmol), 2-(1H-benzotriazole-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 overnight at room temperature. Water (50 mL) was added, 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 then 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] +

[0407] Step 3: tert-butyl (S)-(2-(5-bromoteophene-2-yl)-1-cyanoethyl)carbamate(5D)

[0408] 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 an 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 then 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] +

[0409] Step 4: tert-butyl (S)-(1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)thiophene-2-yl)ethyl)carbamate(5E)

[0410] 5D (700 mg, 2.1 mmol) was dissolved in dioxane (10 mL), and 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 heated under microwave and nitrogen protection at 100°C The mixture was reacted 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 obtain the title compound (5E) as a yellow solid (290 mg, yield: 34%). LCMS m / z = 400.13 [M+1] +

[0411] Step 5: (S)-2-amino-3-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)thiophene-2-yl)propanitrile(5F)

[0412] 5E (290 mg, 0.73 mmol) was dissolved in formic acid (5 mL), the mixture was reacted at room temperature for 3 hours, the pH was adjusted to 7 to 8 using a saturated aqueous solution of sodium carbonate, and then extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with a saturated aqueous solution of sodium chloride (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 to 1:10) to obtain the title compound (5F) as a yellow solid (150 mg, yield: 69%). LCMS m / z = 300.07 [M+1] +

[0413] Step 6: tert-butyl (S)-2-(((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)thiophene-2-yl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(5G)

[0414] 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 in succession. The mixture was reacted at room temperature for 12 hours. Water (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with water (30 mL x 2), then 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 (methanol:dichloromethane (v / v) = 1:100 to 1:10) to obtain the title compound (5G) as a yellow solid (100 mg, yield: 64%). LCMS m / z = 527.19 [M+1] +

[0415] Step 7: (S)-N-((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)thiophene-2-yl)ethyl)-1,4-oxazepan-2-carboxamide(compound 5)

[0416] 5G (100 mg, 0.19 mmol) was dissolved in formic acid (2 mL), the mixture was reacted at room temperature for 3 hours, the pH was adjusted to 7 to 8 using a saturated aqueous solution of sodium carbonate, and then extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with a saturated aqueous solution of sodium chloride (50 mL), 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 5 (25 mg, yield: 31%). LCMS M / Z (ESI): m / z = 427.14 [M+1] +

[0417] 1 H NMR (400 MHz, 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).

[0418] Example 6: (S)-N-((S)-2-(4-(7-acetamido-2,3-dihydro-1H-indene-4-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepan-2-carboxamide (Compound 6)

[0419]

[0420] Step 1: tert-butyl (S)-(2-(4-(7-acetamido-2,3-dihydro-1H-indene-4-yl)-2-fluorophenyl)-1-cyanoethyl)carbamate(6B)

[0421] 6A(254.0 mg, 1.00 mmol, literature [ Journal of Medicinal Chemistry [prepared by referring to y, 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 single-neck flask, and then 1,4-dioxane (10 mL) and water (0.4 mL) were added. Nitrogen was substituted into the mixture three times, and then 95 The reaction was carried out for 4 hours. After cooling the reaction solution to room temperature and concentrating it, 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] + .

[0422] Step 2: (S)-N-(7-(4-(2-amino-2-cyanoethyl)-3-fluorophenyl)-2,3-dihydro-1H-indene-4-yl)acetamide(6C)

[0423] Dissolve 6B (360.0 mg, 0.82 mmol) in formic acid (5 mL), and the mixture 35 The reaction was carried out for 4 hours. The reaction system was adjusted to a basic pH using a saturated potassium carbonate solution, extracted with ethyl acetate (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 6C as a pale yellow oil (270.0 mg, 97.6%), which was used directly in the following reaction. LC-MS (ESI): m / z = 338.2 [M+H] + .

[0424] Step 3: tert-butyl (S)-2-(((S)-2-(4-(7-acetamido-2,3-dihydro-1H-indene-4-yl)-2-fluorophenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(6D)

[0425] 6C (270 mg, 0.80 mmol) was dissolved in DMF (5 mL), after which 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. Upon completion of addition, the mixture was reacted overnight at room temperature. 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, and concentrated. The residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 2 : 1) to obtain the title compound 6D as a white solid (370.0 mg, 82.0%). LC-MS (ESI): m / z = 563.3 [MH] -.

[0426] Step 4: (S)-N-((S)-2-(4-(7-acetamido-2,3-dihydro-1H-indene-4-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepan-2-carboxamide(compound 6)

[0427] Dissolve 6D (370 mg, 0.66 mmol) in formic acid (5 mL), and the mixture 35 The reaction was carried out for 4 hours. The reaction system was adjusted to a basic pH using a saturated potassium carbonate solution, extracted with ethyl acetate (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane : methanol (v / v) = 30 : 1) to obtain the title compound 6 (90.0 mg, 30.0%).

[0428] 1H NMR (400 MHz, 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), 3.29 (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] + .

[0429] Example 7: (S)-N-((S)-1-cyano-2-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophene-5-yl)-2-fluorophenyl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 7)

[0430]

[0431] Step 1: tert-butyl (S)-(1-cyano-2-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophene-5-yl)-2-fluorophenyl)ethyl)carbamate(7B)

[0432] 7A (0.200 g, 0.81 mmol, prepared according 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, the mixture was nitrogen-substituted three times, and the mixture was subjected to 90°C under a nitrogen atmosphere. The reaction was carried out for 4 hours. The reaction solution was concentrated and dried, 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 7B as a white solid (0.25 g, 71.8%). LC-MS (ESI): m / z = 431.1 [M+H] + .

[0433] Step 2: (S)-2-amino-3-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophene-5-yl)-2-fluorophenyl)propanenitrile 4-methylbenzenesulfonate(7C)

[0434] 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. Upon completion of the addition, the mixture was reacted at room temperature for 16 hours and then filtered. The filter paper was rinsed once with acetonitrile (2 mL) and rotary evaporated to obtain the title compound 7C as a white solid (0.240 g, 82.2%), which was used directly in the following reaction.

[0435] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophene-5-yl)-2-fluorophenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(7D)

[0436] INT-3 (0.161 g, 0.66 mmol) was dissolved in dichloromethane (10 mL), and then triethylamine (0.17 g, 1.32 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uroronium hexafluorophosphate (0.25 g, 0.66 mmol) were added. Upon completion of addition, the mixture was reacted under stirring at room temperature for 1 hour, after which 7C (0.24 g, 0.477 mmol) was added. The resulting mixture was reacted overnight at room temperature. After the reaction was complete, the reaction solution was concentrated to obtain the crude product 7D, which was used directly in the next reaction. LC-MS (ESI): m / z = 556.3 [MH] - .

[0437] Step 4: (S)-N-((S)-1-cyano-2-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophene-5-yl)-2-fluorophenyl)ethyl)-1,4-oxazepan-2-carboxamide(compound 7)

[0438] The crude product 7D was dissolved in acetonitrile (10 mL), and p-toluenesulfonic acid (0.331 g, 1.74 mmol) was added. Upon completion of addition, the mixture was reacted at room temperature for 16 hours, then concentrated and dried. Ethyl acetate (25 mL) was added, and a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the residual aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain the title compound 7 (110 mg, 2-step yield: 50.5%).

[0439] 1H NMR (400 MHz, 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] + .

[0440] Example 8: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-l6-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 8)

[0441]

[0442] Step 1: tert-butyl (S)-(1-cyano-2-(3-fluoro-4'-(pentafluoro-l6-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate(8A)

[0443] After dissolving INT-2 (0.69 g, 1.77 mmol) in dioxane (30 mL), (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 placed under nitrogen protection at 100 The mixture was reacted for 4 hours, concentrated, and the residue separated and purified by silica gel column chromatography (PE : EA (v / v) = 1 : 10 to 1 : 5) to obtain the title compound 8A (600 mg, yield: 80%). LCMS m / z = 467.11 [M+1] +

[0444] Step 2: (S)-2-amino-3-(3-fluoro-4'-(pentafluoro-l6-sulfanyl)-[1,1'-biphenyl]-4-yl)propanenitrile(8B)

[0445] 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 30 The reaction was carried out for 2 hours. Water (30 mL) was added, and the resulting mixture was adjusted to pH = 7 to 8 using a saturated aqueous solution of sodium carbonate, extracted with dichloromethane (50 mL x 3), then washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 8B (0.4 g, yield: 84%). LCMS m / z = 367.32 [M+1] +

[0446] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-l6-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(8C)

[0447] 8B (200 mg, 0.55 mmol) was dissolved in DMF (10 mL), and then HATU (250 mg, 0.66 mmol), DIPEA (260 mg, 2.02 mmol), and INT-3 (130 mg, 0.55 mmol) were added in succession. The mixture was reacted at room temperature for 12 hours. 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 obtain the title compound 8C (250 mg, yield: 76%). LCMS m / z = 594.18 [M+1] +

[0448] Step 4: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-l6-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepan-2-carboxamide(compound 8)

[0449] 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 30 After reacting for 3 hours, the pH was adjusted to 7 to 8 using a saturated aqueous solution of sodium carbonate, and extracted with dichloromethane (40 mL x 3). The organic phases were combined, washed with a saturated aqueous solution of sodium chloride (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 to 0.1 : 1) to obtain the title compound 8 (80 mg, 38%).

[0450] 1H NMR (400 MHz, 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] +

[0451] Example 9: (S)-N-((S)-1-cyano-2-(3-fluoro-3'-(pentafluoro-l6-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 9)

[0452]

[0453] Step 1: tert-butyl (S)-(1-cyano-2-(3-fluoro-3'-(pentafluoro-l6-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate(9A)

[0454] INT-2 (0.69 g, 1.77 mmol) was dissolved in dioxane (30 mL), and 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 placed under nitrogen protection at 100 The mixture was reacted for 4 hours, concentrated, and the residue separated and purified by silica gel column chromatography (PE : EA (v / v) = 1 : 10 to 1 : 5) to obtain the title compound 9A (600 mg, yield: 80%). LCMS m / z = 467.11 [M+1] +

[0455] Step 2: (S)-2-amino-3-(3-fluoro-4'-(pentafluoro-l6-sulfanyl)-[1,1'-biphenyl]-4-yl)propanenitrile(9B)

[0456] 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 30 The reaction was carried out for 2 hours. Water (30 mL) was added, and the resulting mixture was adjusted to pH = 7 to 8 using a saturated aqueous solution of sodium carbonate, extracted with dichloromethane (50 mL x 3), then washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 9B (0.4 g, yield: 84%). LCMS m / z = 367.32 [M+1] +

[0457] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(3-fluoro-3'-(pentafluoro-l6-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(9C)

[0458] 9B (200 mg, 0.55 mmol) was dissolved in DMF (10 mL), and then HATU (250 mg, 0.66 mmol), DIEA (260 mg, 2.02 mmol), and INT-3 (130 mg, 0.55 mmol) were added in succession. The mixture was reacted at room temperature for 12 hours. 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 obtain the title compound 9C (250 mg, yield: 76%). LCMS m / z = 594.18 [M+1] +

[0459] Step 4: (S)-N-((S)-1-cyano-2-(3-fluoro-3'-(pentafluoro-l6-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepan-2-carboxamide(compound 9)

[0460] 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 30 After reacting for 3 hours, the pH was adjusted to 7 to 8 using a saturated aqueous solution of sodium carbonate, and extracted with dichloromethane (40 mL x 3). The organic phases were combined, washed with a saturated aqueous solution of sodium chloride (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 to 0.1 : 1) to obtain the title compound 9 (78 mg, 37%).

[0461] 1H NMR (400 MHz, 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] +

[0462] Example 10: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 10)

[0463]

[0464] Step 1: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)ethyl) carbamate(10A)

[0465] 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 sequentially to 1,4-dioxane (15 mL) and water (3 mL), nitrogen was substituted into the system 3 times, and 100 The reaction was carried out for 2 hours. After the reaction was complete, 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 a saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and then 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 obtain 10A as a brown solid (0.32 g, yield: 84%). LCMS m / z = 410.2 [M + 1] + .

[0466] Step 2: (S)-2-amino-3-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)propanenitrile(10B)

[0467] Dissolve 10A (0.32 g, 0.78 mmol) in formic acid (5.0 mL), and upon completion of addition, 50 of the mixture The reaction was carried out for 10 minutes. The reaction solution was concentrated and dried. After adding ethyl acetate (60 mL), a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (60 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the title compound 10B (0.24 g, yield: 100%). LCMS m / z = 310.2 [M + 1] + .

[0468] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(10C)

[0469] After dissolving 10B (0.24 g, 0.78 mmol) in DMF (10 mL), INT-3 (0.25 g, 1.0 mmol), diisopropylethylamine (0.19 g, 1.5 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uroronium hexafluorophosphate (0.38 g, 1 mmol) were added. Upon completion of addition, the mixture was reacted at room temperature for 1 hour. A 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 a saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography (PE : EA = 2 : 1 to 1 : 2) to obtain the title compound 10C as a pale yellow solid (0.25 g, yield: 60%).

[0470] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide(compound 10)

[0471] Dissolve 10C (0.25 g, 0.47 mmol) in formic acid (5.0 mL), and the mixture 50 The reaction was carried out for 10 minutes. The reaction solution was concentrated under reduced pressure, and ethyl acetate (60 mL) was added. Then, a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the residual aqueous layer was extracted with ethyl acetate (60 mL x 5). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and 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%).

[0472] 1 ¹H NMR (400 MHz, DMSO-d 6) 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), 2.94 - 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] +

[0473] Example 11: (S)-N-((S)-1-cyano-2-(4-(cyclopentylethynyl)-2-fluorophenyl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 11)

[0474]

[0475] Step 1: tert-butyl (S)-(1-cyano-2-(4-(cyclopentylethynyl)-2-fluorophenyl)ethyl)carbamate(11B)

[0476] 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 single-neck flask, after which 1,4-dioxane (10 mL) and water (0.4 mL) were added. After nitrogen purging the mixture three times, 95 The reaction was carried out for 4 hours. After cooling the reaction solution to room temperature and concentrating it, 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]+ .

[0477] Step 2: (S)-2-amino-3-(4-(cyclopentylethynyl)-2-fluorophenyl)propanenitrile(11C)

[0478] Dissolve 11B (172 mg, 0.48 mmol) in formic acid (5 mL), and the mixture 35 The reaction was carried out for 4 hours. The reaction system was adjusted to a basic pH using a saturated potassium carbonate solution, extracted with ethyl acetate (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 11C as a pale yellow oil (130 mg, 100.0%), which was used directly in the following reaction. LC-MS (ESI): m / z = 257.1 [M+H] + .

[0479] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(4-(cyclopentylethynyl)-2-fluorophenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(11D)

[0480] 11C (130 mg, 0.51 mmol) was dissolved in DMF (5 mL), after which INT-3 (150 mg, 0.61 mmol), HATU (230 mg, 0.61 mmol), and DIPEA (200 mg, 1.53 mmol) were added. Upon completion of addition, the mixture was reacted overnight at room temperature. 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, and concentrated. The residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 2 : 1) to obtain the title compound 11D as a white solid (190.0 mg, 77.0%). LC-MS (ESI): m / z = 428.3 [M-57+H] + .

[0481] Step 4: (S)-N-((S)-1-cyano-2-(4-(cyclopentylethynyl)-2-fluorophenyl)ethyl)-1,4-oxazepan-2-carboxamide(compound 11)

[0482] Dissolve 11D (190 mg, 0.39 mmol) in formic acid (5 mL), and the mixture 35 The reaction was carried out for 4 hours. The reaction system was adjusted to a basic pH using a saturated potassium carbonate solution, extracted with ethyl acetate (30 mL x 2), dried over anhydrous sodium sulfate, filtered and 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%).

[0483] 1 H NMR (400 MHz, 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] + .

[0484] Example 12: (S)-N-((S)-1-cyano-2-(4-(5-cyano-4-methylthiazole-2-yl)-2-fluorophenyl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 12)

[0485]

[0486] Step 1: 2-bromo-4-methylthiazole-5-carboxamide (12B)

[0487] Dissolve 12A (1.20 g, 4.8 mmol) in 30% ammonia water (30 mL), and the mixture is 35 The reaction was carried out for 24 hours. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 12B as a yellow solid (0.80 g, 75.4%). LC-MS (ESI): m / z = 221.0 [M+H] + .

[0488] Step 2: 2-bromo-4-methylthiazole-5-carbonitrile(12C)

[0489] 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. Upon completion of the addition, the mixture was reacted overnight at room temperature. After concentration, the residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 5 : 1) to obtain the title compound 12C as a white solid (0.40 g, 80.1%). LC-MS (ESI): m / z = 203.0 [M+H] + .

[0490] Step 3: (S)-(1-cyano-2-(4-(5-cyano-4-methylthiazole-2-yl)-2-fluorophenyl)ethyl) tert-butyl carbamate(12D)

[0491] After adding 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) to a single-neck flask, 1,4-dioxane (10 mL) and water (0.4 mL) were added. After nitrogen purging the mixture three times, 95 The reaction was carried out for 4 hours. After cooling the reaction solution to room temperature, it was 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] + .

[0492] Step 4: (S)-2-(4-(2-amino-2-cyanoethyl)-3-fluorophenyl)-4-methylthiazole-5-carbonitrile(12E)

[0493] Dissolve 12D (172 mg, 0.45 mmol) in formic acid (5 mL), and the mixture 35 The reaction was carried out for 4 hours. The reaction system was adjusted to a basic pH using a saturated potassium carbonate solution, extracted with ethyl acetate (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 12E as a pale yellow oil (120 mg, 96.0%), which was used directly in the following reaction. LC-MS (ESI): m / z = 287.1 [M+H] + .

[0494] Step 5: tert-butyl (S)-2-(((S)-1-cyano-2-(4-(5-cyano-4-methylthiazole-2-yl)-2-fluorophenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(12F)

[0495] After dissolving 12E (120 mg, 0.42 mmol) in DMF (5 mL), INT-3 (120 mg, 0.50 mmol), HATU (190 mg, 0.50 mmol), and DIPEA (160 mg, 1.26 mmol) were added. Upon completion of addition, the mixture was reacted overnight at room temperature. 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, and concentrated. The residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 2 : 1) to obtain the title compound 12F as a yellow solid (160.0 mg, 74.2%). LC-MS (ESI): m / z = 458.1 [M-57+H] + .

[0496] Step 6: (S)-N-((S)-1-cyano-2-(4-(5-cyano-4-methylthiazole-2-yl)-2-fluorophenyl)ethyl)-1,4-oxazepan-2-carboxamide(compound 12)

[0497] Dissolve 12F (160 mg, 0.31 mmol) in formic acid (5 mL), and the mixture 35 The reaction was carried out for 4 hours. The reaction system was adjusted to a basic pH using a saturated potassium carbonate solution, extracted with ethyl acetate (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane : methanol (v / v) = 30 : 1) to obtain the title compound 12 (50.0 mg, 39.0%).

[0498] 1H NMR (400 MHz, 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] + .

[0499] Example 13: (S)-N-((S)-2-(4-(benzo[d]thiazole-2-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepan-2-carboxamide (Compound 13)

[0500]

[0501] 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)

[0502] After dissolving INT-2 (5.00 g, 14.57 mmol) in 1,4-dioxane (100 mL), bis(pinacolato)diborone (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. Upon completion of addition, the mixture was 100 The mixture was heated to [value] and reacted for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and concentrated. 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] + .

[0503] Step 2: tert-butyl (S)-(2-(4-(benzo[d]thiazole-2-yl)-2-fluorophenyl)-1-cyanoethyl)carbamate(13C)

[0504] 13B (0.40 g, 1.02 mmol) was dissolved in 1,4-dioxane (10 mL), water (0.4 mL), and subsequently 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. Upon completion of addition, the mixture was 90 The mixture was heated to [value] and reacted for 2 hours under nitrogen protection. Afterward, the reaction solution was reacted overnight at room temperature. The resulting reaction mixture was concentrated and dried, and a saturated aqueous solution of ammonium chloride (50 mL) was added. The resulting mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 4 : 1) to obtain the title compound 13C as a pale yellow liquid (0.24 g, 59.20%). LC-MS (ESI): m / z = 398.1 [M+H] + .

[0505] Step 3: (S)-2-amino-3-(4-(benzo[d]thiazole-2-yl)-2-fluorophenyl)propanenitrile(13D)

[0506] Dissolve 13C (0.32 g, 0.81 mmol) in formic acid (5 mL), and upon completion of addition, 30 of the mixture The reaction was carried out for 3 hours. Saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8, and the resulting mixture was extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the title compound 13D as a colorless liquid (0.24 g, 99.65%), which was used directly in the following reaction. LC-MS (ESI): m / z = 298.1 [M+H] + .

[0507] Step 4: tert-butyl (S)-2-(((S)-2-(4-(benzo[d]thiazole-2-yl)-2-fluorophenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(13E)

[0508] After dissolving 13D (0.24 g, 0.81 mmol) in dichloromethane (10 mL), INT-1 (0.26 g, 1.05 mmol), diisopropylethylamine (0.31 g, 2.43 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uroronium hexafluorophosphate (0.46 g, 1.22 mmol) were added. Upon completion of addition, the mixture was reacted overnight at room temperature. After adding a saturated aqueous sodium chloride solution (30 mL), the resulting mixture was extracted with ethyl acetate (25 mL). The organic phase was washed with a saturated aqueous sodium chloride solution (25 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 4 : 1) to obtain the title compound 13E as a pale yellow solid (0.25 g, 58.83%). LC-MS (ESI): m / z = 469.2 [M-57+H] + .

[0509] Step 5: (S)-N-((S)-2-(4-(benzo[d]thiazole-2-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepan-2-carboxamide(compound 13)

[0510] Dissolve 13E (0.32 g, 0.59 mmol) in formic acid (2.0 mL), and upon completion of addition, 35 of the mixture The reaction was carried out for 4 hours. The reaction solution was concentrated and dried, and ethyl acetate (25 mL) was added. Then, a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the residual aqueous layer was extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane : methanol (v / v) = 20 : 1) to obtain the title compound 13 (30 mg, 14.72%).

[0511] 1 H NMR (400 MHz, 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] + .

[0512] Example 14: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-((4-methylpiperazine-1-yl)methyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 14)

[0513]

[0514] Step 1: tert-butyl-(S)-(1-cyano-2-(3-fluoro-4'-((4-methylpiperazine-1-yl)methyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate(14B)

[0515] 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). After nitrogen substitution in the system three times, 95 The mixture was heated to [value], re-refluxed and filtered for 3 hours, the filter paper was washed with ethyl acetate (100 ml), the filtrate was dried over anhydrous sodium sulfate, and then 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] + .

[0516] Step 2: (S)-2-amino-3-(3-fluoro-4'-((4-methylpiperazine-1-yl)methyl)-[1,1'-biphenyl]-4-yl)propanenitrile(14C)

[0517] 14B (3.26 g, 7.2 mmol) was dissolved in formic acid (40 ml), and the mixture was stirred overnight at room temperature. Water (40 ml) and dichloromethane (80 ml) were added. The resulting mixture was adjusted to a basic pH using sodium bicarbonate, the organic phase was separated, and the aqueous phase was further extracted with dichloromethane (80 ml x 2). The aqueous 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% to 10%) to obtain the title compound 14C as a dark brown oil (2.32 g, 91.3%). LC-MS (ESI): m / z = 353.3 [M+H] + .

[0518] Step 3: tert-butyl-(S)-2-(((S)-1-cyano-2-(3-fluoro-4'-((4-methylpiperazine-1-yl)methyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(14D)

[0519] 14C (500 mg, 1.42 mmol), INT-3 (348 mg, 1.42 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uroronium 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 a 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] + .

[0520] Step 4: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-((4-methylpiperazine-1-yl)methyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepan-2-carboxamide(compound 14)

[0521] 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 an ice bath. Tert-butyldimethylsilyl trifluoromethanesulfonate (550 mg, 2.07 mmol) was added dropwise to the reaction flask. Upon completion of the dropwise addition, the ice bath was removed, and the mixture was stirred and reacted at room temperature for 2 hours. The reaction solution was washed with a saturated sodium bicarbonate solution (20 ml x 2), 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 15%) to obtain the title compound 14 (57 mg, 17.2%). LC-MS (ESI): m / z = 480.3 [M+H] + .

[0522] 1 H NMR (400 MHz, 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).

[0523] Example 15: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(4-methylthiazole-2-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 15)

[0524]

[0525] Step 1: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(4-methylthiazole-2-yl)phenyl)ethyl)carbamate(15B)

[0526] 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 heated under nitrogen protection at 90°C The reaction was carried out 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 x 3). The organic phases were combined, washed sequentially 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 obtain the title compound 15B (0.25 g, 53%). LC-MS (ESI): m / z = 362.1 [M+H] + .

[0527] Step 2: (S)-2-amino-3-(2-fluoro-4-(4-methylthiazole-2-yl)phenyl)propanenitrile(15C)

[0528] Dissolve 15B (0.25 mg, 0.68 mmol) in anhydrous formic acid (4 mL), and the mixture 50 The reaction was carried out for 20 minutes. The reaction solution was cooled to room temperature and concentrated to remove most of the solvent. A saturated sodium bicarbonate solution (20 mL) was added to the residue, and the resulting mixture was extracted with ethyl acetate (10 ml x 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 obtain the title compound 15C (0.17 g, 96%). LC-MS (ESI): m / z = 262.2 [M+H] + .

[0529] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(4-methylthiazole-2-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(15D)

[0530] INT-3 (0.18 g, 0.73 mmol) was dissolved in DMF (5 mL), after which 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, after which 15C (0.19 g, 0.73 mmol) was added. The resulting mixture was reacted at room temperature for 1 hour. 30 mL of water was added to the reaction solution. The resulting mixture was extracted with ethyl acetate (15 ml x 5). The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 97:3) to obtain the title compound 15D (0.26 g, 73%). LC-MS (ESI): m / z = 489.1 [M+H] + .

[0531] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(4-methylthiazole-2-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 15)

[0532] Dissolve 15D (0.26 g, 0.53 mmol) in formic acid (4.0 mL), and upon completion of addition, 50 of the mixture The reaction was carried out for 30 minutes. The reaction solution was concentrated and dried, and ethyl acetate (25 mL) was added. Then, a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the residual aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 1 : 2) to obtain the title compound 15 (80 mg, 39%).

[0533] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.97 (d, J = 8.4 Hz, 1H), 7.74 - 7.66 (m, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.39 (s, 1H), 5.05 (m, 1H), 4.31 (d, J = 9.4 Hz, 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, 9.4 Hz, 1H), 2.43 (s, 3H), 1.92 (p, J = 5.6 Hz, 2H), 1.29 - 1.21 (m, 1H). LC-MS (ESI): m / z =389.1 [M+H] + .

[0534] Example 16: (S)-N-((S)-2-(4-(1-acetylindoline-5-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepan-2-carboxamide (Compound 16)

[0535]

[0536] Step 1: tert-butyl (S)-(2-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-1-cyanoethyl)carbamate(16B)

[0537] 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, the mixture was nitrogen-substituted three times, and the mixture was heated under a nitrogen atmosphere at 90°C The reaction was carried out for 4 hours. The reaction solution was concentrated and dried, 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] + .

[0538] Step 2: (S)-3-(4-(1-acetylindoline-5-yl)-2-fluorophenyl)-2-aminopropanenitrile 4-methylbenzenesulfonate(16C)

[0539] 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. Upon completion of the addition, the mixture was reacted at room temperature for 16 hours and then filtered. The filter paper was rinsed with acetonitrile (1 mL) and rotary evaporated to obtain the title compound 16C as a white solid (0.100 g, 85.5%), which was used directly in the following reaction.

[0540] Step 3: tert-butyl (S)-2-(((S)-2-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(16D)

[0541] INT-3 (0.074 g, 0.303 mmol) was dissolved in dichloromethane (5 mL), after which triethylamine (0.061 g, 0.606 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uroronium hexafluorophosphate (0.115 g, 0.303 mmol) were added. Upon completion of addition, the mixture was reacted under stirring at room temperature for 1 hour, after which 16C (0.100 g, 0.202 mmol) was added. The resulting mixture was reacted overnight at room temperature. After the reaction was complete, the reaction solution was concentrated to obtain the crude product 16D, which was used directly in the next reaction. LC-MS (ESI): m / z = 549.2 [MH] - .

[0542] Step 4: (S)-N-((S)-2-(4-(1-acetylindoline-5-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepan-2-carboxamide(compound 16)

[0543] The crude product 16D was dissolved in acetonitrile (10 mL), and p-toluenesulfonic acid monohydrate (0.134 g, 0.71 mmol) was added. Upon completion of addition, the mixture was reacted at room temperature for 16 hours, then concentrated and dried. Ethyl acetate (25 mL) was added, and a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the residual aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane : methanol (v / v) = 20 : 1) to obtain the title compound 16 (27 mg, 2-step yield: 29.7%).

[0544] 1 H NMR (400 MHz, 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] + .

[0545] Example 17: (S)-N-((S)-1-cyano-2-(4'-cyano-3'-cyclopropyl-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 17)

[0546]

[0547] Step 1: tert-butyl (S)-(1-cyano-2-(4'-cyano-3'-cyclopropyl-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamate(17B)

[0548] 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, nitrogen was substituted into the mixture three times, and 100 under a nitrogen atmosphere The reaction was carried out for 16 hours. The reaction solution was concentrated and dried, then 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] + .

[0549] Step 2: (S)-4'-(2-amino-2-cyanoethyl)-3-cyclopropyl-3'-fluoro-[1,1'-biphenyl]-4-carbonitrile 4-methylbenzenesulfonate(17C)

[0550] 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. Upon completion of the addition, the mixture was reacted at room temperature for 16 hours and then filtered. The filter paper was rinsed once with acetonitrile (2 mL) and rotary evaporated to obtain the title compound 17C as a white solid (0.360 g, 80.5%), which was used directly in the following reaction.

[0551] 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-oxazepan-4-carboxylate(17D)

[0552] INT-3 (0.123 g, 0.503 mmol) was dissolved in dichloromethane (5 mL), after which triethylamine (0.101 g, 1.00 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uroronium hexafluorophosphate (0.193 g, 0.503 mmol) were added. Upon completion of addition, the mixture was stirred at room temperature for 1 hour, after which 17C (0.160 g, 0.335 mmol) was added. The resulting mixture was reacted overnight at room temperature. After the reaction was complete, the reaction solution was concentrated to obtain the crude product 17D, which was used directly in the next reaction. LC-MS (ESI): m / z = 531.2 [MH] - .

[0553] Step 4: (S)-N-((S)-1-cyano-2-(4'-cyano-3'-cyclopropyl-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 17)

[0554] The crude product 17D was dissolved in acetonitrile (10 mL), and p-toluenesulfonic acid monohydrate (0.190 g, 1.00 mmol) was added. Upon completion of addition, the mixture was reacted at room temperature for 16 hours, then concentrated and dried. Ethyl acetate (25 mL) was added, and a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the residual aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain the title compound 17 (60 mg, 2-step yield: 41.4%).

[0555] 1H NMR (400 MHz, 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] + .

[0556] Example 18: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 18)

[0557]

[0558] Step 1: tert-butyl (S)-(1-cyano-2-(3-fluoro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethyl) carbamate (18B)

[0559] 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 heated under nitrogen protection at 90°C The reaction was carried out 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 x 3). The organic layers were combined, washed sequentially 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 obtain the title compound 18B (0.34 g, 59%). LC-MS (ESI): m / z = 398.2 [M+H] + .

[0560] Step 2: (S)-4'-(2-amino-2-cyanoethyl)-3'-fluoro-N-methyl-[1,1'-biphenyl]-4-carboxamide(18C)

[0561] Dissolve 18B (0.34 mg, 0.86 mmol) in anhydrous formic acid (4 mL), and the mixture 50 The reaction was carried out for 20 minutes. The reaction solution was cooled to room temperature and concentrated to remove most of the solvent. A saturated sodium bicarbonate solution (20 mL) was added to the residue, and the resulting mixture was extracted with ethyl acetate (10 ml x 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 obtain the title compound 18C (0.22 g, 87%). LC-MS (ESI): m / z = 298.1 [M+H] + .

[0562] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(3-fluoro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(18D)

[0563] INT-3 (0.23 g, 0.76 mmol) was dissolved in DMF (5 mL), after which 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 minutes, after which 18C (0.23 g, 0.76 mmol) was added. The resulting mixture was reacted at room temperature for 1 hour. 30 mL of water was added to the reaction solution. The resulting mixture was extracted with ethyl acetate (15 ml x 5). The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 97:3) to obtain the title compound 18D (0.31 g, 77%). LC-MS (ESI): m / z =469.2 [M-56+H] + .

[0564] Step 4: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepan-2-carboxamide (compound 18)

[0565] Dissolve 18D (0.31 g, 0.59 mmol) in formic acid (4.0 mL), and upon completion of addition, 50 of the mixture The reaction was carried out for 30 minutes. The reaction solution was concentrated and dried, and then ethyl acetate (25 mL) was added. Afterward, a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the residual aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 1 : 2) to obtain the title compound 18 (50 mg, 20%).

[0566] 1 ¹H NMR (400 MHz, 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] + .

[0567] Example 19: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-methyl-1H-indole-2-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 19)

[0568]

[0569] Step 1: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(1-methyl-1H-indole-2-yl)phenyl)ethyl)carbamate(19B)

[0570] After dissolving 2a (0.40 g, 1.17 mmol) in 1,4-dioxane (10 mL) and water (0.4 mL), 1-methyl-2-indoleboronic 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. Upon completion of addition, the mixture was 90 The mixture was heated to [value] and reacted for 2 hours under nitrogen protection. Afterward, the reaction solution was reacted overnight at room temperature. The resulting reaction solution was concentrated and dried, and then a saturated aqueous ammonium chloride solution (50 mL) was added. The resulting mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 10 : 1, 4 : 1) to obtain the title compound 19B as a white solid (0.25 g, 54.31%). LC-MS (ESI): m / z = 394.2 [M+H] + .

[0571] Step 2: (S)-2-amino-3-(2-fluoro-4-(1-methyl-1H-indole-2-yl)phenyl)propanenitrile(19C)

[0572] 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. Upon completion of the addition, the mixture was reacted at room temperature for 4 hours. The reaction solution was concentrated and dried, and then ethyl acetate (25 mL) was added. Subsequently, a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the residual aqueous layer was extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 1 : 1) to obtain the title compound 19C as a pale yellow solid (0.25 g, 90.67%). LC-MS (ESI): m / z = 294.3 [M+H] + .

[0573] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(1-methyl-1H-indole-2-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(19D)

[0574] After dissolving 19C (0.25 g, 0.85 mmol) in dichloromethane (10 mL), INT-3 (0.21 g, 0.85 mmol), diisopropylethylamine (0.55 g, 4.25 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uroronium hexafluorophosphate (0.32 g, 0.85 mmol) were added. Upon completion of addition, the mixture was reacted overnight at room temperature. After adding a saturated aqueous sodium chloride solution (30 mL), the resulting mixture was extracted with ethyl acetate (25 mL). The organic phase was washed with a saturated aqueous sodium chloride solution (25 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 2 : 1) to obtain the title compound 19D as a white solid (0.40 g, 90.39%). LC-MS (ESI): m / z = 485.1 [M-57+H] + .

[0575] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-methyl-1H-indole-2-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide (compound 19)

[0576] 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. Upon completion of the addition, the mixture was reacted at room temperature for 4 hours. The reaction solution was concentrated and dried, and then ethyl acetate (25 mL) was added. Subsequently, a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the residual aqueous layer was extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane : methanol (v / v) = 20 : 1) to obtain the title compound 19 as a pale yellow solid (0.15 g, 46.33%).

[0577] 1 H NMR (400 MHz, 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] + .

[0578] Example 20: (S)-N-((S)-1-cyano-2-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 20)

[0579]

[0580] Step 1: tert-butyl (S)-(1-cyano-2-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamate(20B)

[0581] 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, then nitrogen was substituted into the mixture three times, and 90°C was subjected to nitrogen atmosphere. The reaction was carried out for 4 hours. The reaction solution was concentrated and dried, then 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] + .

[0582] Step 2: (S)-2-amino-3-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)propanenitrile 4-methylbenzenesulfonate(20C)

[0583] 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. Upon completion of the addition, the mixture was reacted at room temperature for 16 hours and then filtered. The filter paper was rinsed once with acetonitrile (2 mL) and rotary evaporated to obtain the title compound 20C as a white solid (0.500 g, 99.9%), which was used directly in the following reaction.

[0584] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(20D)

[0585] INT-3 (0.148 g, 0.605 mmol) was dissolved in dichloromethane (10 mL), after which triethylamine (0.124 g, 1.23 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uroronium hexafluorophosphate (0.230 g, 0.605 mmol) were added. Upon completion of addition, the mixture was reacted under stirring at room temperature for 1 hour, after which 20C (0.200 g, 0.41 mmol) was added. The resulting mixture was reacted overnight at room temperature. After the reaction was complete, the reaction solution was concentrated to obtain the crude product 20D, which was used directly in the next reaction. LC-MS (ESI): m / z = 542.2 [MH] - .

[0586] Step 4: (S)-N-((S)-1-cyano-2-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepan-2-carboxamide(compound 20)

[0587] The crude product 20D was dissolved in acetonitrile (10 mL), and p-toluenesulfonic acid monohydrate (0.234 g, 1.23 mmol) was added. Upon completion of addition, the mixture was reacted at room temperature for 16 hours, then concentrated and dried. Ethyl acetate (25 mL) was added, and a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the residual aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane : methanol (v / v) = 20 : 1) to obtain the title compound 20 (60 mg, 2-step yield: 33.1%).

[0588] 1H NMR (400 MHz, 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] + .

[0589] Example 21: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 21)

[0590]

[0591] Step 1: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-yl)phenyl)ethyl)carbamate(21B)

[0592] Reactant 21A (0.47 g, 2.0 mmol) and INT-2 (0.69 g, 2.0 mmol) were dissolved in 1,4-dioxane (50 ml), after which 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-substituted protection, and 100 The reaction was carried out in [location]. TLC and LC-MS showed that small amounts of starting material were still present. The reaction solution was concentrated and rotary evaporated, then dissolved in DCM, filtered by suction through Celite, the filtrate was rotary evaporated, and passed through a column (EA / PE = 0% to 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] + .

[0593] Step 2: (S)-2-amino-3-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-yl)phenyl)propanenitrile(21C)

[0594] 21B (0.5 g 1.35 mmol) was dissolved in anhydrous formic acid (10 ml). The mixture was 50 After reacting for 0.5 hours, TLC detection indicated a complete reaction of the substrate. Formic acid was removed by rotary evaporation at low temperature, and the pH was adjusted to 8 to 10 by adding a saturated sodium bicarbonate solution. The resulting mixture was extracted with DCM (20 ml x 2), dried over anhydrous sodium sulfate, rotary evaporated, 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] + .

[0595] Step 3: tert-butyl(S)-2-(((S)-1-cyano-2-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(21D)

[0596] 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 stirring the mixture at room temperature for 10 minutes, 21C (0.35 g, 1.29 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. TLC detection indicated 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 obtain the title compound 21D (0.4 g, 62%). LC-MS (ESI): m / z = 443.1 [M-56+H] + .

[0597] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide(compound 21)

[0598] 21D (0.4 g 0.8 mmol) was dissolved in anhydrous formic acid (10 ml). The mixture was 50 After stirring for 0.5 hours, TLC showed a complete reaction of the substrate. Formic acid was removed by rotary evaporation at low temperature, and the pH was adjusted to 8 to 10 by adding a saturated sodium bicarbonate solution. The resulting mixture was extracted with dichloromethane (20 ml x 2), dried over anhydrous sodium sulfate, rotary evaporated, 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] + .

[0599] 1H NMR (400 MHz, 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),.

[0600] Example 22: (S)-N-((S)-1-cyano-2-(4-(1-ethyl-1H-pyrazole-4-yl)-2-fluorophenyl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 22)

[0601]

[0602] Step 1: (S)-tert-butyl (1-cyano-2-(4-(1-ethyl-1H-pyrazole-4-yl)-2-fluorophenyl)ethyl)carbamate(22B)

[0603] 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. Upon completion of addition, the mixture was 100 The reaction was carried out for 3 hours. The reaction solution was cooled to room temperature, and a saturated aqueous solution of sodium chloride (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, and concentrated, and the residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 2 : 1) to obtain the title compound 22B as a colorless liquid (0.44 g, 84.1%). LC-MS (ESI): m / z = 359.1 [M+H] + .

[0604] Step 2: (S)-2-amino-3-(4-(1-ethyl-1H-pyrazole-4-yl)-2-fluorophenyl)propanenitrile(22C)

[0605] Dissolve 22B (0.40 g, 1.12 mmol) in formic acid (10 mL), and upon completion of addition, 50 of the mixture The reaction was carried out for 2 hours. The reaction solution was concentrated and dried, and then ethyl acetate (25 mL) was added. A saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to about 8, and the organic layer was separated. The residual aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the title compound 22C as a colorless liquid (0.29 g, 100%), which was used directly in the following reaction.

[0606] Step 3: (S)-tert-butyl 2-(((S)-1-cyano-2-(4-(1-ethyl-1H-pyrazole-4-yl)-2-fluorophenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(22D)

[0607] After dissolving 22C (0.30 g, 1.16 mmol) in DMF (10 mL), INT-3 (0.28 g, 1.16 mmol), diisopropylethylamine (0.45 g, 3.48 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uroronium hexafluorophosphate (0.66 g, 1.74 mmol) were added. Upon completion of addition, the mixture was reacted overnight at room temperature. A saturated aqueous solution of sodium chloride (30 mL) was added. The resulting mixture was extracted with ethyl acetate (25 mL), the organic phase was washed with a saturated aqueous solution of sodium chloride (25 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 22D as a pale yellow solid (0.30 g, 53.3%), which was used directly in the following reaction. LC-MS (ESI): m / z =430.1 [M-57+H] + .

[0608] Step 4: (S)-N-((S)-1-cyano-2-(4-(1-ethyl-1H-pyrazole-4-yl)-2-fluorophenyl)ethyl)-1,4-oxazepan-2-carboxamide(compound 22)

[0609] Dissolve 22D (0.15 g, 0.31 mmol) in formic acid (2.0 mL), and upon completion of addition, 35 of the mixture The reaction was carried out for 4 hours. The reaction solution was concentrated and dried, and then ethyl acetate (25 mL) was added. Subsequently, a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the residual aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 1 : 2) to obtain the title compound 22 (80 mg, 66.9%).

[0610] 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), 3.16 - 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] + .

[0611] Example 23: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 23)

[0612]

[0613] Step 1: 5-chloro-3-(methyl-d3)benzo[d]oxazole-2(3H)-one(23B)

[0614] After dissolving 23A (5 g, 29.49 mmol) in DMF (25 mL), cesium carbonate (10.57 g, 32.44 mmol) and deuterated iodomethane (4.28 g, 29.52 mmol) were added. The mixture was 25 The reaction was carried out for 4 hours. After the reaction was complete, the reaction solution was poured into water (60 mL) and filtered; the filter paper was collected, dissolved in dichloromethane, and washed with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain Compound 23B as a brown solid (5.4 g, yield: 98.1%). LCMS m / z = 187.0 [M+1]+

[0615] Step 2: 3-(methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole-2(3H)-one(23C)

[0616] Compound 23B (5.4 g, 28.94 mmol) was dissolved in 1,4-dioxane (54 ml), after which pinacolborane (12.49 g, 49.20 mmol), potassium acetate (8.52 g, 86.82 mmol), palladium acetate (652 mg, 2.89 mmol), and X-phosph (2.73 g, 5.79 mmol) were added. Upon completion of addition, the mixture was 100 The temperature was raised to [value] and the reaction was carried out for 3 hours. After the reaction was complete, 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 23C as a white solid (7.2 g, yield: 89.8%). LC-MS m / z = 279.2 [M+1] +

[0617] Step 3: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)carbamate(23D)

[0618] Compound 23C (2.0 g, 7.19 mmol) was dissolved in a mixed solvent of 1,4-dioxane (20 ml) and water (4 ml), after which 2a (2.47 mg, 7.19 mmol) was added. Subsequently, potassium carbonate (2.98 g, 21.57 mmol), palladium acetate (161 mg, 0.72 mmol), and X-phosph (686 mg, 1.44 mmol) were added in succession. Upon completion of addition, the mixture was nitrogen-substituted three times, and 100 The temperature was raised to [value] and the reaction was carried out for 5 hours. After the reaction was complete, the reaction solution was concentrated directly, and the resulting 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] +

[0619] Step 4: (S)-2-amino-3-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)propanitrile(23E)

[0620] Dissolve compound 23D (1 g, 2.41 mmol) in anhydrous formic acid (10 ml), and the mixture 25 The mixture was stirred for 5 hours. After the reaction was complete, the reaction solution was slowly poured into a saturated sodium bicarbonate solution (100 ml) to a pH of 7 to 8. Subsequently, the resulting mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain Compound 23E as a pale yellow solid (710 mg, 93.5%). LCMS m / z = 315.2 [M + 1] +

[0621] Step 5: tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(23F)

[0622] 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-azabezotriazole)-N,N,N',N'-tetramethyluroronium hexafluorophosphate (1.18 g, 3.10 mmol) were added. Upon completion of addition, the mixture was 25 The temperature was raised to [value] and the reaction was carried out for 3 hours. After the reaction was complete, the reaction solution was poured into water (20 ml) and 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, the filtrate concentrated, and the resulting residue was separated and purified by silica gel column chromatography (eluent: PE : EA (v / v) = 1 : 0 to 1 : 1) to obtain compound 23F as a yellow solid (837 mg, 74.7%). LCMS m / z = 486.3 [M-tBu+1] +

[0623] Step 6: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide(compound 23)

[0624] Dissolve compound 23F (837 mg, 1.55 mmol) in anhydrous formic acid (3 ml), and the mixture 25 The mixture was stirred for 3 hours. After the reaction was complete, the reaction solution was slowly poured into a saturated sodium bicarbonate solution (30 ml) to a pH of 7 to 8. Then, the resulting mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The residue was separated and purified using a preparative liquid chromatography column (preparative liquid chromatography conditions: C18 reverse-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 obtain Compound 23 (300 mg, yield: 43.8%).

[0625] 1 H NMR (400 MHz, 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] +

[0626] Example 24: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 24)

[0627]

[0628] Step 1: 6-bromo-2-methyl-3,4-dihydroisoquinoline-1(2H)-one(24B)

[0629] 24A (0.57 g, 2.5 mmol) was dissolved in dry NN-dimethylformamide (20 mL), and the mixture was 0 under nitrogen protection Cooled to [amount]. Sodium hydride (0.12 g, 3.0 mmol, 60 wt%) was added in portions. After addition, the resulting mixture was reacted under such conditions for 20 minutes, and then iodomethane (0.51 g, 3.6 mmol) was added dropwise to the system. After addition, the mixture was reacted at room temperature for 30 minutes. Water (100 mL) was added to quench the reaction, and the resulting solution was extracted with ethyl acetate (100 mL x 2). The organic phase was combined and washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue separated by silica gel column chromatography (PE:EA = 6:1) to obtain the target compound, namely 6-bromo-2-methyl-3,4-dihydroisoquinoline-1(2H)-one (24B), as a yellow solid (0.48 g, yield: 79%).

[0630] Step 2: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)ethyl)carbamate(24C)

[0631] 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 sequentially to 1,4-dioxane (15 mL) and water (3 mL), the system was subjected to nitrogen purging three times, and 100 The reaction was carried out for 2 hours. After the reaction was complete, 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 a saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and then 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 obtain 24C as a brown solid (0.35 g, yield: 83%). LCMS m / z = 424.2 [M + 1] + .

[0632] Step 3: (S)-2-amino-3-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)propanenitrile(24D)

[0633] Dissolve 24C (0.35 g, 0.83 mmol) in formic acid (6.0 mL), and upon completion of addition, 50 of the mixture The reaction was carried out for 10 minutes. The reaction solution was concentrated and dried. After adding ethyl acetate (60 mL), a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (60 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the title compound 24D (0.24 g, yield: 89%).

[0634] Step 4: tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(24E)

[0635] After dissolving 24D (0.24 g, 0.74 mmol) in DMF (10 mL), INT-3 (0.25 g, 1.0 mmol), diisopropylethylamine (0.19 g, 1.5 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uroronium hexafluorophosphate (0.38 g, 1 mmol) were added. Upon completion of addition, the mixture was reacted at room temperature for 1 hour. Water (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (60 mL x 2). The organic phase was washed with a saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography (PE : EA = 2 : 1 to 1 : 2) to obtain the title compound 24E as a pale yellow solid (0.28 g, yield: 69%).

[0636] Step 5: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide(compound 24)

[0637] Dissolve 24E (0.28 g, 0.51 mmol) in formic acid (6.0 mL), and 50 of the mixture The reaction was carried out for 10 minutes. The solution was concentrated under reduced pressure, and ethyl acetate (60 mL) was added. Then, a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the residual aqueous layer was extracted with ethyl acetate (60 mL x 5). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and 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%).

[0638] 1 ¹H NMR (400 MHz, DMSO-d 6) 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] + .

[0639] Example 25: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 25)

[0640]

[0641] Step 1: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)carbamate(25B)

[0642] 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 sequentially to 1,4-dioxane (15 mL) and water (3 mL), nitrogen was substituted into the system 3 times, and 100 The reaction was carried out for 2 hours. After the reaction was complete, 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 a saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and then 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 obtain 25B as a brown solid (0.36 g, yield: 95%). LCMS m / z = 410.1 [M + 1] + .

[0643] Step 2: (S)-2-amino-3-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)propanenitrile(25C)

[0644] Dissolve 25B (0.36 g, 0.88 mmol) in formic acid (6.0 mL), and upon completion of addition, 50 of the mixture The reaction was carried out for 10 minutes. The reaction solution was concentrated and dried. After adding ethyl acetate (60 mL), a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (60 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the title compound 25C (0.28 g, yield: 100%). LCMS m / z = 310.1 [M + 1] + .

[0645] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(25D)

[0646] After dissolving 25C (0.28 g, 0.88 mmol) in DMF (10 mL), INT-3 (0.25 g, 1.0 mmol), diisopropylethylamine (0.19 g, 1.5 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uroronium hexafluorophosphate (0.38 g, 1 mmol) were added. Upon completion of addition, the mixture was reacted at room temperature for 1 hour. A saturated aqueous solution of sodium chloride (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (60 mL x 2). The organic phase was washed with a saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by silica gel column chromatography (PE : EA = 2 : 1 to 1 : 2) to obtain the title compound 25D as a pale yellow solid (0.29 g, yield: 60%).

[0647] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide(compound 25)

[0648] Dissolve 25D (0.29 g, 0.55 mmol) in formic acid (6.0 mL), and 50 The reaction was carried out for 10 minutes. The reaction solution was concentrated under reduced pressure, and ethyl acetate (60 mL) was added. Then, a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the residual aqueous layer was extracted with ethyl acetate (60 mL x 5). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and 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%).

[0649] 1 ¹H NMR (400 MHz, DMSO-d 6) 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] +

[0650] Example 26: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 26)

[0651]

[0652] Step 1: 6-fluorobenzo[d]oxazole-2(3H)-one(26B)

[0653] Dissolve 26A (10 g, 78.67 mmol) in anhydrous DMF (130 mL), add a solution of N,N'-carbonyldiimidazole (15.31 g, 94.40 mmol) in DMF (100 mL) dropwise under an ice bath, and then 60 The reaction was carried out for 4 hours. 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, back-flushed 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 obtain the title compound 26B (11 g, 91%). LC-MS (ESI): m / z = 154.1 [M+H] +.

[0654] Step 2: 6-fluoro-5-iodobenzo[d]oxazole-2(3H)-one(26C)

[0655] 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 40 The reaction was carried out overnight. The reaction solution was cooled to room temperature, poured into 500 mL of water, and extracted with EA (50 ml x 5). The organic layers were combined, back-flushed with a saturated aqueous solution of sodium bicarbonate (200 mL), dried over anhydrous sodium sulfate, concentrated, and the residue separated and purified by silica gel column chromatography (PE : EA (v / v) = 4 : 1) to obtain the title compound 26C (1.1 g, 20%). LC-MS (ESI): m / z = 280.0 [M+H] + .

[0656] Step 3: 6-fluoro-5-iodo-3-methylbenzo[d]oxazole-2(3H)-one(26D)

[0657] 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 40 The mixture was stirred for 30 minutes and transferred to room temperature. Iodomethane (1.02 g, 7.16 mmol) was added dropwise, and the resulting mixture was reacted overnight at room temperature. Insoluble substances were removed by filtration. The resulting mixture was extracted with EA (50 ml x 3). The organic layers were combined, back-flushed 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 obtain the title compound 26D (0.92 g, 88%). LC-MS (ESI): m / z = 294.0 [M+H] + .

[0658] Step 4: 6-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole-2(3H)-one(26E)

[0659] 26D (0.92 g, 3.14 mmol), bis(pinacollato)diborone (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 heated under nitrogen protection for 100 The reaction was carried out for 5 hours. The reaction solution was cooled to room temperature, and 120 mL of water was added. The resulting mixture was extracted with EA (30 ml x 3). The organic layers were combined, back-flushed 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 obtain compound 26E (0.52 g, 56%).

[0660] 1 H NMR (400 MHz, 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] + .

[0661] Step 5: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)carbamate(26F)

[0662] 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 heated under nitrogen protection at 90°C The reaction was carried out 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 x 3). The organic layers were combined, washed sequentially 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 obtain the title compound 26F (0.6 g, 77%). LC-MS (ESI): m / z = 430.1 [M+H] + .

[0663] Step 6: (S)-2-amino-3-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)propanenitrile(26G)

[0664] Dissolve 26F (0.6 g, 1.40 mmol) in anhydrous formic acid (3 mL), and the mixture 50 The reaction was carried out for 20 minutes. The reaction solution was cooled to room temperature and concentrated to remove most of the solvent. A saturated sodium bicarbonate solution (20 mL) was added to the residue, and the resulting mixture was extracted with EA (10 ml x 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 obtain the title compound 26G (0.36 g, 78%). LC-MS (ESI): m / z = 330.0 [M+H] + .

[0665] Step 7: tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(compound 26H)

[0666] INT-3 (0.26 g, 1.06 mmol) was dissolved in DMF (5 mL), after which 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 minutes, after which 26G (0.35 g, 1.06 mmol) was added. The resulting mixture was reacted at room temperature for 1 hour. 30 mL of water was added to the reaction solution. The resulting mixture was extracted with EA (15 ml x 5). The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 97:3) to obtain the title compound 26H (0.33 g, 56%). LC-MS (ESI): m / z = 501.1 [M+H] + .

[0667] Step 8: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide(compound 26)

[0668] Dissolve 26H (0.33 g, 0.59 mmol) in anhydrous formic acid (3 mL), and the mixture 50 The reaction was carried out for 1 hour. The reaction solution was cooled to room temperature and concentrated to remove most of the solvent. A saturated sodium bicarbonate solution (25 mL) was added to the residue, and the resulting mixture was extracted multiple times with EA 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 obtain compound 26 (120 mg, 44%).

[0669] 1 H NMR (400 MHz, CD3OD) δ 7.47 - 7.22 (m, 5H), 5.17 (dd, J = 8.8, 6.8 Hz, 1H), 4.13 (dd, J = 8.8, 3.6 Hz, 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, 8.6 Hz, 1H), 2.22 - 2.15 (m, 1H), 2.03 (m, 1H). LC-MS (ESI): m / z =457.1 [M+H] + .

[0670] Example 27: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-(oxetane-3-yl)-1,2,3,6-tetrahydropyridine-4-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide

[0671]

[0672] Step 1: 1-(oxetane-3-yl)-1,2,3,6-tetrahydropyridine-4-yl trifluoromethanesulfonate (27B)

[0673] -78 Under nitrogen protection, LDA (2.6 mL, 5.2 mmol) was slowly added dropwise to 27A (400 mg, 2.6 mmol, prepared by reference WO 2016 / 172496 A1) in THF (4.0 mL). After stirring was continued at this temperature for 30 minutes, N,N-bis(trifluoromethylsulfonyl)aniline solution (1.40 g, 3.9 mmol) in THF (2.0 mL) was added dropwise. The resulting mixture was allowed to naturally warm to room temperature and reacted for 1 hour. Water (5 mL) was added to quench the reaction, and the reaction solution was extracted with ethyl acetate (5 mL 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 and concentrated under reduced pressure, and the residue was subjected to column chromatography (DCM : MeOH = 50 : 1 to 20 : 1) to obtain 27B as a pale yellow liquid (240 mg, 32.4%). LC-MS (ESI): m / z = 288.1 [M+H] + .

[0674] Step 2: tert-butyl-(S)-(1-cyano-2-(2-fluoro-4-(1-(oxetane-3-yl)-1,2,3,6-tetrahydropyridine-4-yl)phenyl)ethyl)carbamate(27C)

[0675] 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, nitrogen was substituted into the mixture three times, and 60 The temperature was raised to [value] and the reaction was carried out for 2 hours. The reaction solution was cooled to room temperature, rotary evaporated, and the residue was directly purified by column chromatography (DCM : MeOH = 50 : 1 to 20 : 1) to obtain the title compound 27C as a yellow solid (180 mg, 64%). LC-MS (ESI): m / z = 402.2 [M+H] + .

[0676] Step 3: (S)-2-amino-3-(2-fluoro-4-(1-(oxetane-3-yl)-1,2,3,6-tetrahydropyridine-4-yl)phenyl)propanenitrile(27D)

[0677] Add 27C (180 mg, 0.4 mmol) to anhydrous formic acid (3.0 mL) at room temperature, and the mixture 50 The temperature was raised to [value] and the reaction was carried out for 20 minutes. Most of the formic acid was removed under reduced pressure, and the solution was neutralized to a basic pH by adding saturated sodium bicarbonate. The resulting solution was extracted with dichloromethane (10 mL x 4), washed with saturated sodium chloride (5 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of compound 27D as a yellow viscous substance (200 mg). LC-MS (ESI): m / z = 302.2 [M+H] + .

[0678] Step 4: tert-butyl-(S)-2-(((S)-1-cyano-2-(2-fluoro-4-(1-(oxetane-3-yl)-1,2,3,6-tetrahydropyridine-4-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(27E)

[0679] The crude products 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, followed by the addition of HATU (270 mg, 0.7 mmol), and stirring was continued at room temperature for 1 hour. The reaction solution was rotary evaporated, and the residue was directly purified by column chromatography (DCM:MeOH = 50:1 to 20:1) to obtain 27E as a yellow solid (200 mg, 2-step yield: 94%). LC-MS (ESI): m / z = 529.3 [M+H] + .

[0680] Step 5: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-(oxetane-3-yl)-1,2,3,6-tetrahydropyridine-4-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide(compound 27)

[0681] Add 27E (150 mg, 0.3 mmol) to anhydrous formic acid (3.0 mL) at room temperature, and the mixture 50 The temperature was raised to [value] and reacted for 30 minutes. Most of the formic acid was removed under reduced pressure, and the solution was neutralized to a basic pH by adding saturated sodium bicarbonate. The resulting solution was extracted with dichloromethane (10 mL x 4), washed with saturated sodium chloride (5 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 27 (40 mg, 33%). LC-MS (ESI): m / z = 429.3 [M+H] + .

[0682] 1H NMR (400 MHz, 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).

[0683] Example 28: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(7-methoxy-1-methyl-1H-indole-4-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 28)

[0684]

[0685] Step 1: 4-bromo-7-methoxy-1-methyl-1H-indole(28B)

[0686] 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 upon completion of addition, the mixture was reacted overnight at room temperature. 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, and concentrated. The residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 4 : 1) to obtain the title compound 28B as a white solid. LC-MS (ESI): m / z = 240.1 [M+H] + .

[0687] Step 2: tert-butyl (S)-(2-(4-(benzo[d]thiazole-2-yl)-2-fluorophenyl)-1-cyanoethyl)carbamate(28C)

[0688] 28B (0.40 g, 1.02 mmol) was dissolved in 1,4-dioxane (10 mL) and water (0.4 mL), and 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. Upon completion of addition, the mixture was 90 The mixture was heated to [value] and reacted for 2 hours under nitrogen protection. Subsequently, the reaction solution was reacted overnight at room temperature. The resulting reaction mixture was concentrated and dried, after which a saturated aqueous solution of ammonium chloride (50 mL) was added. The resulting mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 4 : 1) to obtain the title compound 28C as a pale yellow liquid (0.24 g, 59.20%). LC-MS (ESI): m / z = 398.1 [M+H] + .

[0689] Step 3: (S)-2-amino-3-(4-(benzo[d]thiazole-2-yl)-2-fluorophenyl)propanenitrile(28D)

[0690] Dissolve 28C (0.32 g, 0.81 mmol) in formic acid (5 mL), and upon completion of addition, 30 of the mixture The reaction was carried out for 3 hours. Saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8, and the resulting mixture was extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the title compound 28D as a colorless liquid (0.24 g, 99.65%), which was used directly in the following reaction. LC-MS (ESI): m / z = 298.1 [M+H] + .

[0691] Step 4: tert-butyl (S)-2-(((S)-2-(4-(benzo[d]thiazole-2-yl)-2-fluorophenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(28E)

[0692] After dissolving 28D (0.24 g, 0.81 mmol) in dichloromethane (10 mL), INT-3 (0.26 g, 1.05 mmol), diisopropylethylamine (0.31 g, 2.43 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uroronium hexafluorophosphate (0.46 g, 1.22 mmol) were added. Upon completion of addition, the mixture was reacted overnight at room temperature. After adding a saturated aqueous sodium chloride solution (30 mL), the resulting mixture was extracted with ethyl acetate (25 mL). The organic phase was washed with a saturated aqueous sodium chloride solution (25 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 4 : 1) to obtain the title compound 28E as a pale yellow solid (0.25 g, 58.83%). LC-MS (ESI): m / z = 469.2 [M-57+H] + .

[0693] Step 5: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(7-methoxy-1-methyl-1H-indole-4-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 28)

[0694] Dissolve 28E (0.32 g, 0.59 mmol) in formic acid (2.0 mL), and upon completion of addition, 35 of the mixture The reaction was carried out for 4 hours. The reaction solution was concentrated and dried, and then ethyl acetate (25 mL) was added. Subsequently, a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic phase was separated, and the residual aqueous layer was extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane : methanol (v / v) = 20 : 1) to obtain the title compound 28 (30 mg, 14.72%).

[0695] 1 H NMR (400 MHz, 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 - 4.05 (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] + .

[0696] Example 29: (S)-N-((S)-1-cyano-2-(4'-cyano-3-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 29)

[0697]

[0698] Step 1: tert-butyl (S)-(1-cyano-2-(4'-cyano-3-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate(29B)

[0699] After adding 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) to a single-neck flask, 1,4-dioxane (10 mL) and water (0.4 mL) were added. After nitrogen purging the mixture three times, 95 The reaction was carried out for 4 hours. After cooling the reaction solution to room temperature and concentrating it, 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] + .

[0700] Step 2: (S)-4'-(2-amino-2-cyanoethyl)-3'-fluoro-3-(trifluoromethyl)-[1,1'-biphenyl]-4-carbonitrile(29C)

[0701] Dissolve 29B (230.0 mg, 0.53 mmol) in formic acid (5 mL), and the mixture 35 The reaction was carried out for 4 hours. The reaction system was adjusted to a basic pH using a saturated potassium carbonate solution, extracted with ethyl acetate (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 29C as a pale yellow oil (180.0 mg, 100%), which was used directly in the following reaction. LC-MS (ESI): m / z = 334.1 [M+H] + .

[0702] 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-oxazepan-4-carboxylate(29D)

[0703] After dissolving 29C (180 mg, 0.54 mmol) in DMF (5 mL), INT-3 (160 mg, 0.65 mmol), HATU (250 mg, 0.65 mmol), and DIPEA (210 mg, 1.62 mmol) were added. Upon completion of addition, the mixture was reacted overnight at room temperature. 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, and concentrated. The residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 2 : 1) to obtain the title compound 29D as a white solid (280 mg, 92.5%). LC-MS (ESI): m / z = 505.2 [M-57+H] + .

[0704] Step 4: (S)-N-((S)-1-cyano-2-(4'-cyano-3-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 29)

[0705] Dissolve 29D (280 mg, 0.50 mmol) in formic acid (5 mL), and the mixture 35 The reaction was carried out for 4 hours. The reaction system was adjusted to a basic pH using a saturated potassium carbonate solution, extracted with ethyl acetate (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane : methanol (v / v) = 30 : 1) to obtain the title compound 29 (100.0 mg, 43.4%).

[0706] 1H NMR (400 MHz, 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] + .

[0707] Example 30: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide(compound 30 )

[0708]

[0709] Step 1: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)ethyl)carbamate( 30B )

[0710] 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 sequentially to 1,4-dioxane (20 mL) and water (4 mL), nitrogen was substituted into the system 3 times, and 100 The reaction was carried out for 2.5 hours. After the reaction was complete, 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 a saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and then 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 obtain 30B (0.26 g, yield: 83%). LCMS m / z = 396.1 [M + H] + .

[0711] Step 2: (S)-2-amino-3-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)propanenitrile( 30C )

[0712] 30B( 0.26 g (0.66 mmol) is dissolved in formic acid (5.0 mL), and upon completion of addition, the mixture is 50 The reaction was carried out for 10 minutes. The reaction solution was concentrated and dried. After adding ethyl acetate (60 mL), a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (60 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the title compound. 30C was obtained (0.15 g, yield: 77%). LCMS m / z = 296.1[M + H] + .

[0713] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate( 30D )

[0714] 30C( After dissolving 0.15 g (0.51 mmol) in N,N'-dimethylformamide (10 mL), INT-3( 0.13 g (0.51 mmol), triethylamine (0.1 g, 1 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uroronium hexafluorophosphate (0.23 g, 0.61 mmol) were added. Upon completion of addition, the mixture was reacted at room temperature for 1 hour. A 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 a saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography (PE : EA (v / v) = 2 : 1 to 1 : 5) to obtain the title compound 30D (0.14 g, yield: 53%).

[0715] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide(compound 30 )

[0716] 30D( 0.14 g (0.27 mmol) was dissolved in formic acid (6.0 mL), and the mixture was 50 The reaction was carried out for 10 minutes. The reaction solution was concentrated under reduced pressure, and ethyl acetate (60 mL) was added. Subsequently, a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the residual aqueous layer was extracted with dichloromethane (60 mL x 5). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane : methanol (v / v) = 4 : 1). Compound 30 was obtained (48 mg, yield: 42%).

[0717] 1 ¹H NMR (400 MHz, 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] + .

[0718] Example 31: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide(compound 31 )

[0719]

[0720] Step 1: 6-bromo-2-methylisoindolin-1-one ( 31A )

[0721] 30A (0.49 g, 2.3 mmol) was dissolved in anhydrous NN-dimethylformamide (20 mL), and the mixture was 0 under nitrogen protection Cooled to [amount]. Sodium hydride (0.14 g, 3.45 mmol, 60 wt%) was added in portions. After addition, the resulting mixture was reacted under such conditions for 20 minutes, after which iodomethane (0.49 g, 3.45 mmol) was added dropwise to the system. After 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 x 2). The organic phases were combined, washed with saturated brine (100 mL x 1), dried and filtered over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE:EA = 6:1) to extract the target compound. 31A 0.37 g was obtained (yield: 71%).

[0722] 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, 1H), 7.64 (dd, 1H), 7.31 (d, 1H), 4.33 (s, 2H), 3.20 (s, 3H).

[0723] Step 2: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)carbamate( 31B )

[0724] 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 sequentially to 1,4-dioxane (20 mL) and water (4 mL), nitrogen was substituted into the system 3 times, and 100 The reaction was carried out for 2 hours. After the reaction was complete, 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 a saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and then 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). 31B was obtained (0.27 g, yield: 89%). LCMS m / z = 432.1 [M + Na] + .

[0725] Step 3: (S)-2-amino-3-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)propanenitrile( 31C )

[0726] 31B( 0.27 g (0.66 mmol) is dissolved in formic acid (6.0 mL), and upon completion of addition, the mixture is 50 The reaction was carried out for 10 minutes. The reaction solution was concentrated and dried. After adding ethyl acetate (60 mL), a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (60 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the title compound. 31C was obtained (0.16 g, yield: 78%). LCMS m / z = 310.2[M + H] + .

[0727] Step 4: tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate( 31D )

[0728] 31C(After dissolving 0.16 g (0.52 mmol) in N,N'-dimethylformamide (10 mL), INT-3( 0.13 g (0.52 mmol), triethylamine (0.1 g, 1 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uroronium hexafluorophosphate (0.24 g, 0.62 mmol) were added. Upon completion of addition, the mixture was reacted at room temperature for 1 hour. A 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 a saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography (PE : EA (v / v) = 2 : 1 to 1 : 3) to obtain the title compound 31D was obtained (0.21 g, yield: 75%). LCMS m / z = 559.2 [M + Na] + .

[0729] Step 5: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide(compound 31 )

[0730] 31D( 0.21 g (0.39 mmol) was dissolved in formic acid (6.0 mL), and the mixture was 50 The reaction was carried out for 10 minutes. The reaction solution was concentrated under reduced pressure, and ethyl acetate (60 mL) was added. Subsequently, a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the residual aqueous layer was extracted with dichloromethane (60 mL x 5). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane : methanol (v / v) = 10 : 1). Compound 31was obtained (100 mg, yield: 59%).

[0731] 1 ¹H NMR (400 MHz, DMSO- d 6) 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] + .

[0732] Example 32: (2S)-N-(1-cyano-2-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)thiophene-2-yl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 32)

[0733]

[0734] Step 1: Methyl 5-bromo-3-fluorothiophene-2-carboxylate (32B)

[0735] 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 80 The mixture was heated to [amount] and reacted for 3 hours. The reaction solution was poured into a saturated sodium thiosulfate solution (500 mL), the organic phase was concentrated and dried, and the residue was separated and purified by preparative chromatography to obtain the title compound 32B (10 g, yield: 45%).

[0736] Step 2: (5-bromo-3-fluorothiophene-2-yl)methanol(32C)

[0737] 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, the organic phase was concentrated and dried, and then the title compound 32C was obtained (4 g, yield: 90%).

[0738] Step 3: 5-bromo-2-(bromomethyl)-3-fluorothiophene(32D)

[0739] 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 and dried, and the residue was directly purified by column chromatography (PE : EA (v : v) = 20 : 1 to 10 : 1) to obtain the title compound 32D (4 g, yield: 77%).

[0740] Step 4: 3-(5-bromo-3-fluorothiophene-2-yl)-2-((diphenylmethylene)amino)propanenitrile(32E)

[0741] At room temperature, 32D (2 g, 7.3 mmol) was dissolved in dichloromethane (40 mL), 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 hours. 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 obtain the title compound 32E (1.2 g, yield: 40%). LC-MS (ESI): m / z = 413.1 [M+H] + .

[0742] Step 5: 2-((diphenylmethylene)amino)-3-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)thiophene-2-yl)propanenitrile(32F)

[0743] 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 sequentially. The mixture was 100 The reaction was carried out for 3 hours, and the reaction solution was directly stirred with silica gel to obtain the title compound 32F (1.4 g, yield: 70%) for purification by column chromatography (PE : EA (v : v) = 5 : 1 to 1 : 1). LC-MS (ESI): m / z = 482.1 [M+H] + .

[0744] Step 6: 2-amino-3-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)thiophene-2-yl)propanenitrile(32G)

[0745] At room temperature, 32F (1.4 g, 2.9 mmol) was dissolved in tetrahydrofuran (20 mL), 1 N hydrochloric acid (40 mL) was added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate (50 mL x 1) to remove impurities; the pH of the aqueous phase was adjusted to 8 to 9 using potassium carbonate, and the product was extracted with ethyl acetate (50 mL x 2). The organic phase was concentrated to obtain the title compound 32G (0.45 g, yield: 49%). LC-MS (ESI): m / z = 318.1 [M+H] + .

[0746] Step 7: (2S)-tert-butyl-2-((1-cyano-2-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)thiophene-2-yl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(32H)

[0747] At room temperature, 32G (0.45 g, 1.4 mmol) was dissolved in N,N-dimethylformamide (10 mL), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uroronium 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 extracted with ethyl acetate (100 mL x 2). The organic phase was concentrated and dried to obtain the title compound 32H (0.4 g, yield: 52%). LC-MS (ESI): m / z = 545.2 [M+H] +

[0748] Step 8: (2S)-N-(1-cyano-2-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)thiophene-2-yl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 32)

[0749] 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 50 The reaction was carried out for 1 hour, and the reaction solution was poured into a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL x 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%).

[0750] 1H NMR (400 MHz, 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] + .

[0751] Examples 33 and 34: (S)-N-((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-2-yl)ethyl)-1,4-oxazepan-2-carboxamide and (S)-N-((R)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-2-yl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 33 and Compound 34)

[0752]

[0753] Step 1: 5-Bromo-2-(Bromomethyl)pyridine ( 33B )

[0754] 2-methyl-5-bromopyridine 33A (5 g, 29.07 mmol) was dissolved in carbon tetrachloride (50 mL), N-bromosuccinate (5.43 g, 30.52 mmol) and azodiisobutyronitrile (1.19 g, 7.27 mmol) were added, and the mixture was 90 The reaction was carried out 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% was obtained. LC-MS (ESI): m / z = 251.9 [M+H] + .

[0755] Step 2: 3-(5-bromopyridine-2-yl)-2-((diphenylmethylene)amino)propanenitrile( 33C )

[0756] 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. An aqueous solution (5 mL) of sodium hydroxide (1.40 g, 35.08 mmol) was added with vigorous stirring, and the mixture was reacted overnight at room temperature. 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 then concentrated. The residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 10 : 1) to obtain the title compound 33C 5.20 g, 76% was obtained. LC-MS (ESI): m / z = 390.0 [M+H] + .

[0757] Step 3: 2-((diphenylmethylene)amino)-3-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-3-yl)propanitrile( 33D )

[0758] 33C (1.73 g, 4.43 mmol), 1A [1,1'-(diphenylphosphino)ferrocene]palladium dichloride (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 heated under nitrogen protection at 90°C The reaction was carried out 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, washed sequentially 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 obtain the title compound. 33D was obtained (2.03 g, 68.92%). LC-MS (ESI): m / z = 459.1 [M+H] + .

[0759] Step 4: 2-amino-3-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-2-yl)propanitrile( 33E )

[0760] 33D (1.02 g, 2.19 mmol) was dissolved in tetrahydrofuran (50 mL) and water (5 mL), 2.5 mL of 1 M aqueous HCl solution was added dropwise, and the mixture was reacted at room temperature for 5 hours after addition. The reaction solution was extracted with ether (15 ml x 3), and the resulting organic layer was discarded. The pH of the aqueous layer was adjusted to approximately 12 using 2 M aqueous NaOH solution, and then extracted with DCM (20 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated to obtain the title compound 33E was obtained (crude product, 580 mg) and used directly in the following reaction without further purification. LC-MS (ESI): m / z = 295.0 [M+H] + .

[0761] Step 5: tert-butyl (2S)-2-((1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-2-yl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate( 33F )

[0762] 33E (0.4 g, 1.36 mmol) was dissolved in dichloromethane (10 mL), and DIPEA (0.34 mg, 2.64 mmol), HATU (0.55 mg, 1.45 mmol), and an intermediate INT-3 (0.36 g, 1.5 mmol) was added sequentially, and the mixture was reacted at room temperature for 1 hour. After TLC detection indicated a complete reaction, water (20 mL) was added to the reaction solution to induce layering. The organic phase was washed sequentially with water (20 mL) and saturated brine, dried over anhydrous sodium sulfate, and then 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] + .

[0763] Step 6: (2S)-N-(1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-2-yl)ethyl)-1,4-oxazepan-2-carboxamide( 33G )

[0764] 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 an ice bath, 2,6-rutidine (0.12 g, 1.16 mmol) was added dropwise, and after addition, the mixture was heated to room temperature and reacted for 1 hour. The reaction solution was poured into 30 mL of a 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 obtain a pale yellow oily crude product, which was purified and separated by flash column chromatography (DCM : MeOH = 95 : 5, v / v) to obtain the compound33G 0.14 g was obtained.

[0765] compound 33G Peak 1 (40 mg, ee% = 100%, yield: 16.5%, retention time: 2.728 min, set as compound 33) and Peak 2 (50 mg, ee% = 98.5%, yield: 20.6%, retention time: 3.987 min, set as compound 34) were obtained by applying SFC chiral preparative separation.

[0766] The purification conditions were as follows: (Instrument name: MG ±SFC(SFC-14); Chromatography column: ChiralPak AD, 250 Х 30 mm ID, 10 µm; Mobile phase: Phase A: CO2; Phase B: Isopropanol (0.1% NH3·H2O); Flow rate: 70 mL / min; Column pressure: 100 bar; Column temperature: 35℃, Absorption wavelength: 220 nm; and Cycle time: approx. 7 min).

[0767] Peak 1: LC-MS (ESI): m / z = 422.2 [M+H] + . ;

[0768] 1 H NMR (400 MHz, 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), 4.12-4.08 (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).

[0769] Peak 2: LC-MS (ESI): m / z = 422.2 [M+H] + ;

[0770] 1H NMR (400 MHz, 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), 4.15-4.09 (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).

[0771] Examples 35 and 36: (S)-N-((S)-1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-3-yl)ethyl)-1,4-oxazepan-2-carboxamide and (S)-N-((R)-1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-3-yl)ethyl)-1,4-oxazepan-2-carboxamide (compounds 35 and compound 36 )

[0772]

[0773] Step 1: 2-Bromo-4-fluoro-5-methylpyridine ( 35B)

[0774] compound 35A , that is, 2-bromo-4-amino-5-methylpyridine (1.87 g, 10 mmol) is dissolved in pyridine hydrofluoride (20 mL), and sodium nitrite (0.83 g, 12 mmol) is added -10 The ingredients were added in portions. After addition, the mixture was naturally heated to room temperature and reacted overnight. After the reaction was complete, 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 obtain the target compound. 35B was obtained (1.21 g, yield: 63.4%).

[0775] 1 H NMR (400 MHz, CDCl3) δ 8.20 (d, 1H), 7.19 (d, 1H), 2.23 (s, 3H). LC-MS m / z =190.0 / 192.0 [M +1] +

[0776] Step 2: 2-bromo-5-(bromomethyl)-4-fluoropyridine ( 35C)

[0777] 35B (2.84 g, 15.0 mmol) was dissolved in carbon tetrachloride (50 mL), N-bromosuccinate (2.93 g, 16.5 mmol) and azodiisobutyronitrile (0.49 g, 3.0 mmol) were added, and the mixture was 90 The reaction was carried out 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% was obtained.

[0778] 1 H NMR (400 MHz, CDCl3) δ 8.40 (d, 1H), 7.28 (d, 1H), 4.43 (s, 2H).

[0779] Step 3: 3-(6-bromo-4-fluoropyridine-3-yl)-2-((diphenylmethylene)amino)propanenitrile(35D)

[0780] 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. An aqueous solution (4 mL) of sodium hydroxide (1.07 g, 26.8 mmol) was added under vigorous stirring, and the mixture was reacted overnight at room temperature. 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 then concentrated. The residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 10 : 1) to obtain the title compound 35D was obtained (2.23 g, 61%). LC-MS (ESI): m / z = 408.1 [M+H] + .

[0781] Step 4: 2-((diphenylmethylene)amino)-3-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-3-yl)propanenitrile( 35E )

[0782] 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 heated for 5 hours at 90°C under nitrogen protection. The reaction was carried out in [location]. 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, washed sequentially 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 obtain the title compound. 35E was obtained (1.02 g, 67%). LC-MS (ESI): m / z = 477.2 [M+H] + .

[0783] Step 5: 2-amino-3-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-3-yl)propanitrile( 35F )

[0784] 35E (1.02 g, 2.14 mmol) was dissolved in tetrahydrofuran (25 mL) and water (5 mL), 5 mL of 1 M aqueous HCl solution was added dropwise, and the mixture was reacted at room temperature for 5 hours after addition. 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 approximately 12 with 2 M aqueous NaOH solution and extracted with DCM (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated to obtain the title compound 35F (Crude product, 0.64 g) was obtained and used directly in the following reaction without further purification. LC-MS (ESI): m / z = 313.1 [M+H] + .

[0785] Step 6: (2S)-N-(1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-3-yl)ethyl)-1,4-oxazepan-2-carboxamide( 35G )

[0786] 35FDissolve (0.64 g, 2.05 mmol) in dichloromethane (10 mL), and the 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 sequentially, and the mixture was reacted at room temperature for 1 hour. After TLC detection indicated a complete reaction, water (20 mL) was added to the reaction solution to induce stratification. The organic phase was washed sequentially with water (20 mL) and saturated brine, dried over anhydrous sodium sulfate, and then 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) 35G was obtained (0.98 g, yield: 88.6%). LC-MS (ESI): m / z = 540.2 [M+H] + .

[0787] Step 7: (S)-N-((S)-1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-3-yl)ethyl)-1,4-oxazepan-2-carboxamide and (S)-N-((R)-1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-3-yl)ethyl)-1,4-oxazepan-2-carboxamide (compound 35 and compound 36 )

[0788] compound 35G Dissolve (0.98 g, 1.82 mmol) in formic acid (10 mL), and 50 The reaction was carried out 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 separated into liquid and liquid phases. The aqueous phase was extracted with dichloromethane (50 mL x 4), the organic phases were combined, washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, and then concentrated to obtain the target compound (0.76 g, yield: 95%). Preparative SFC was applied to the target compound to obtain two isomers: peak 1 (retention time: 2.47 min, designated as compound 35) and peak 2 (retention time: 3.69 min, designated as compound 36).

[0789] Preparation Conditions: Instrument: MG II Preparative SFC (SFC-14). Column: ChiralPak AD, 250 x 30 mm 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: Approx. 10 min. Sample Preparation: Sample was dissolved in 15 ml methanol / dichloromethane. Injection: 3.5 ml / injection.

[0790] Peak 1: LC-MS m / z = 440.1 [M+1] + .

[0791] 1 H NMR (400 MHz, 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).

[0792] Peak 2: LC-MS m / z = 440.1 [M+1] +.

[0793] 1 H NMR (400 MHz, 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).

[0794] Examples 37 and 38: (S)-N-((S)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-3-yl)ethyl)-1,4-oxazepan-2-carboxamide and (S)-N-((R)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-3-yl)ethyl)-1,4-oxazepan-2-carboxamide (Compounds 37 and 38)

[0795]

[0796] Step 1: 2-Bromo-5-(Bromomethyl)pyridine( 37B )

[0797] 37A (5 g, 29.07 mmol) was dissolved in carbon tetrachloride (50 mL), N-bromosuccinate (5.43 g, 30.52 mmol) and azodiisobutyronitrile (1.19 g, 7.27 mmol) were added, and the mixture was 90 The reaction was carried out for 2.5 hours. The reaction solution was cooled to room temperature, 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% was obtained. LC-MS (ESI): m / z = 251.9 [M+H]+ .

[0798] Step 2: 3-(6-bromopyridine-3-yl)-2-((diphenylmethylene)amino)propanenitrile( 37D)

[0799] 37B (4.42 g, 17.54 mmol) and 37C (3.86 g, 17.54 mmol) was dissolved in dichloromethane (50 mL), and benzyltrimethylammonium chloride (0.33 g, 1.75 mmol) was added. An aqueous solution (5 mL) of sodium hydroxide (1.40 g, 35.08 mmol) was added under vigorous stirring, and the mixture was reacted overnight at room temperature. 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 then concentrated. The residue was separated and purified by silica gel column chromatography (PE : EA (v / v) = 10 : 1) to obtain the title compound 37D 5.20 g, 76% was obtained.

[0800] 1 H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.64 - 7.57 (m, 2H), 7.50 - 7.32 (m, 8H), 6.96 (q, J = 2.4 Hz, 2H), 4.40 (t, J = 6.5 Hz, 1H), 3.17 (d, J = 6.5 Hz, 2H).LC-MS (ESI): m / z =390.0 [M+H] + .

[0801] Step 3: 2-((diphenylmethylene)amino)-3-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-3-yl)propanitrile( 37E )

[0802] 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 heated for 5 hours at 90°C under nitrogen protection. The reaction was carried out in [location]. 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, washed sequentially 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 obtain the title compound. 37E was obtained (1.02 g, 57%). LC-MS (ESI): m / z = 459.1 [M+H] + .

[0803] 1 H NMR (400 MHz, 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 = 7.5 Hz, 2H), 7.28 - 7.24 (m, 1H), 6.98 (d, J = 7.7 Hz, 2H), 4.50 - 4.42 (m, 1H), 3.47 (s, 3H), 3.29 - 3.24 (m, 2H).

[0804] Step 4: 2-amino-3-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-3-yl)propanitrile(compound 37F )

[0805] 37E(1.02 g, 2.19 mmol) was dissolved in tetrahydrofuran (50 mL) and water (5 mL), 2.5 mL of 1 M aqueous HCl solution was added dropwise, and after addition, the mixture was reacted at room temperature for 5 hours. 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 approximately 12 using 2 M aqueous NaOH solution, and then extracted with DCM (20 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated to obtain the title compound 37F was obtained (crude product, 580 mg) and used directly in the following reaction without further purification. LC-MS (ESI): m / z = 295.1 [M+H] + .

[0806] Step 5: tert-butyl (2S)-2-((1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-3-yl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(compound 37G )

[0807] 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. After stirring the mixture at room temperature for 20 minutes, 37F (0.3 g, 1.22 mmol) was added. The resulting mixture was reacted at room temperature for 3 hours. 30 mL of water was added to this reaction solution. The resulting mixture was extracted with EA (15 mL x 5). The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated. The residue was separated and purified by silica gel column chromatography (DCM : MeOH (v / v) = 97 : 3) to obtain the title compound 37G 0.32 g, 51% was obtained. LC-MS (ESI): m / z = 522.2 [M+H]+ .

[0808] Step 6: (S)-N-(1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridine-3-yl)ethyl)-1,4-oxazepan-2-carboxamide(compound 37H )

[0809] 37G Dissolve (0.32 g, 0.61 mmol) in anhydrous formic acid (3 mL), and 50 The reaction was carried out for 1 hour. The reaction solution was cooled to room temperature and concentrated to remove most of the solvent. A saturated sodium bicarbonate solution (25 mL) was added to the residue, and the resulting mixture was extracted several times with EA 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 obtain the title compound. 37H was obtained (140 mg, 55%).

[0810] compound 37H Peak 1 (63 mg, ee% = 98.22%, yield: 24.8%, retention time: 2.120 min, set as compound 37) and Peak 2 (73 mg, ee% = 100%, yield: 28.7%, retention time: 2.689 min, set as compound 38) were obtained by applying SFC chiral preparative separation.

[0811] The purification conditions were as follows: (Instrument name: MG ±SFC(SFC-14); Chromatography column: ChiralPak AD, 250×30 mm ID, 10 µm; Mobile phase: Phase A: CO2; Phase B: Methanol (0.1% NH3·H2O); Flow rate: 80 mL / min; Column pressure: 100 bar; Column temperature: 35℃, Absorption wavelength: 220 nm; and Cycle time: approx. 16.9 min).

[0812] 피크 1: LC-MS (ESI): m / z = 422.3 [M+H] + .

[0813] 1 H NMR (400 MHz, 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, 6.8 Hz, 1H), 4.11 (dd, J = 8.6, 3.6 Hz, 1H), 4.03 - 3.95 (m, 1H), 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, 8.6 Hz, 1H), 1.96 - 1.78 (m, 2H). Peak 2: LC-MS (ESI): m / z = 422.3 [M+H] + .

[0814] 1 H NMR (400 MHz, 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, 6.8 Hz, 1H), 4.11 (dd, J = 8.6, 3.6 Hz, 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).

[0815] Examples 39 and 40: (S)-N-((S)-1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyrimidine-5-yl)ethyl)-1,4-oxazepan-2-carboxamide and (S)-N-((R)-1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyrimidine-5-yl)ethyl)-1,4-oxazepan-2-carboxamide (compounds 39 and compound 40 )

[0816]

[0817] Step 1: (2-chloropyrimidine-5-yl)methanol ( 39B )

[0818] Dissolve 39A (2 g, 10.72 mmol) in anhydrous THF (20 ml), and then immerse the mixture under nitrogen protection at 0 Cooled to [amount]. Diisobutylaluminum hydride (21.5 ml) was slowly added dropwise to the reaction solution. The resulting mixture was stirred in an ice bath for 0.5 hours. TLC detection indicated a complete reaction of the starting materials. The reaction was quenched by adding saturated ammonium chloride (10 mL), and the reaction solution was extracted with ethyl acetate (3 x 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 obtain product 39B (1.2 g, 77.4%). LC-MS (ESI): m / z = 145.1 [M+H] + .

[0819] Step 2: 5-(bromomethyl)-2-chloropyrimidine ( 39C )

[0820] Dissolve 39B (1 g, 6.92 mmol) in DCM (20 ml) at room temperature, and the reaction solution under nitrogen protection at 0 The solution was cooled to [temperature], and triphenylphosphine (1.82 g, 6.92 mmol) and carbon tetrabromide (2.29 g, 6.92 mmol) were added at this temperature. The mixture was stirred for 0 hours to 0°C, after which the reaction solution was heated to room temperature and stirring was continued for 1.5 hours. TLC detection indicated that a small amount of substrate was still present. The reaction solution was rotary evaporated and passed through a column (PE : EA = 5 : 1). 39C was obtained (1 g, 70%). LC-MS (ESI): m / z = 207.1 [M+H] + .

[0821] Step 3: 3-(2-chloropyrimidine-5-yl)-2-((diphenylmethylene)amino)propanenitrile( 39D )

[0822] 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 overnight at room temperature. The reaction was quenched by adding water (20 mL). The resulting mixture was extracted with DCM (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, rotary evaporated, 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] + .

[0823] Step 4: 2-((diphenylmethylene)amino)-3-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyrimidine-5-yl)propanitrile( 39E )

[0824] Reactants 39D (1.1 g, 3.17 mmol) and 1A (0.96 g, 3.49 mmol) were dissolved in 1,4-dioxane (100 ml), and 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-substituted protection, and 100 The reaction was carried out in [location]. TLC and LC-MS indicated that small amounts of starting material were still present. The reaction solution was concentrated and rotary evaporated, dissolved in DCM, filtered by suction through Celite, the filtrate was rotary evaporated, and passed through a column (EA / PE = 0% to 40%) to obtain a pale yellow solid 39E (1.1 g, 75.5%). LC-MS (ESI): m / z = 460.2 [M+H] + .

[0825] Step 5: 2-amino-3-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyrimidine-5-yl)propanitrile( 39F )

[0826] 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 hours. TLC detection indicated a complete reaction of the starting materials. The solution was adjusted to pH 8 to 10, extracted with EA (20 ml x 2), the organic phase was dried over anhydrous sodium sulfate, and then rotary evaporated to obtain product 39F (0.6 g, 85%). LC-MS (ESI): m / z = 296.1 [M+H] + .

[0827] Step 6: (2S)-tert-butyl 2-(1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyrimidine-5-yl)ethylcarbamoyl)-1,4-oxazepan-4-carboxylate( 39G )

[0828] 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 stirring the mixture at room temperature for 10 minutes, 39F (0.6 g, 2.03 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. TLC detection indicated that the reaction was complete. The reaction was quenched by adding water (10 mL), 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 obtain product 39G (0.6 g, 56%). LC-MS (ESI): m / z = 523.2 [M+H] + .

[0829] Step 7: (2S)-N-(1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyrimidine-5-yl)ethyl)-1,4-oxazepan-2-carboxamide( 39H )

[0830] 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 hours; TLC detection indicated a complete reaction of the substrate. The formic acid was removed by rotary evaporation at low temperature, and a saturated sodium bicarbonate solution was added to adjust the pH to 8 to 10. The resulting mixture was extracted with DCM (20 ml x 2), dried over anhydrous sodium sulfate, rotary evaporated, and passed through a column (DCM : CH3OH = 10 : 1) to extract the compound 39H was obtained (0.15 g, 31%). Compound 39H Peak 1 (retention time: 1.528 min, set as compound 39) and Peak 2 (retention time: 2.387 min, set as compound 40) were obtained by applying SFC chiral preparative separation.

[0831] The separation method was as follows: (Instrument name: MG ±SFC(SFC-14); Chromatography column: ChiralPak AD, 250×30 mm ID, 10 µm; Mobile phase: Phase A: CO2; Phase B: Isopropanol (0.1% NH3·H2O); Flow rate: 80 mL / min; Column pressure: 100 bar; Column temperature: 35℃, Absorption wavelength: 220 nm; and Cycle time: 3 min).

[0832] Peak 1: 1 H NMR (400 MHz, 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).

[0833] Peak 2: 1 H NMR (400 MHz, 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).

[0834] Examples 41 and 42: (S)-N-((S)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridazine-3-yl)ethyl)-1,4-oxazepan-2-carboxamide and (S)-N-((R)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridazine-3-yl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 41 and Compound 42)

[0835]

[0836] Step 1: 3-(bromomethyl)-6-chloropyridazine (41B )

[0837] 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 70 The reaction was carried out 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 was obtained (4 g, yield: 20%). LCMS m / z = 207.46 [M+1] +

[0838] Step 2: Ethyl 3-(6-chloropyridazine-3-yl)-2-((diphenylmethylene)amino)propanoate( 41C )

[0839] 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). 41 B(4.0 g, 19.28 mmol) was added under an ice bath, the mixture was naturally heated to room temperature, and reacted for 2 hours. 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, 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 41 C 3.4 g was obtained (yield: 45%). LCMS m / z = 394.12 [M+1] +

[0840] Step 3: 3-(6-chloropyridazine-3-yl)-2-((diphenylmethylene)amino)propanamide(41 D )

[0841] 41 C( 3.4 g (8.7 mmol) was dissolved in an ammonia methanol solution (7 N, 50 mL), and the mixture was placed in a sealed tube (120 mL) at 80 The reaction was carried out in [location]. After concentration, the reaction mixture was separated and purified by silica gel column chromatography (MeOH : DCM (v / v) = 1 : 10) to obtain the title compound 41 D was obtained (1.8 g, yield: 56%). LCMS m / z = 365.11 [M+1] +

[0842] Step 4: 3-(6-chloropyridazine-3-yl)-2-((diphenylmethylene)amino)propanitrile(41 E )

[0843] 41 D(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 41 E was obtained (1.4 g, yield: 82%). LCMS m / z = 347.13 [M+1] +

[0844] Step 5: 2-((diphenylmethylene)amino)-3-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridazine-3-yl)propanitrile( 41F )

[0845] 41 E (1.4 g, 4.04 mmol) was dissolved in dioxane (30 mL), and 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 heated for 2 hours under nitrogen protection for 12 hours. The reaction was carried out in a microwave reactor. After concentration, the reaction mixture was separated and purified by silica gel column chromatography (PE : EA (v / v) = 1 : 5 to 1 : 1) to obtain the title compound 41 F was obtained (800 mg, yield: 43%). LCMS m / z = 460.17 [M+1] +

[0846] Step 6: 2-amino-3-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridazine-3-yl)propanitrile(41 G )

[0847] 41 F(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 hours. The pH was adjusted to 7 to 8 using a saturated aqueous solution of sodium carbonate. 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 to 1 : 10) to obtain the title compound 41 G was obtained (300 mg, yield: 58%). LCMS m / z = 296.11 [M+1] +

[0848] Step 7: tert-butyl (2S)-2-((1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridazine-3-yl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(41 H )

[0849] 41 G (300 mg, 1.02 mmol) was dissolved in DMF (20 mL), and then HATU (390 mg, 1.02 mmol), DIPEA (260 mg, 2.02 mmol), and INT-3 (250 mg, 1.02 mmol) were added in succession. The mixture was reacted at room temperature for 12 hours. 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 obtain the title compound 41 H was obtained (300 mg, yield: 56%). LCMS m / z = 523.22 [M+1]+

[0850] Step 8: (S)-N-((S)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridazine-3-yl)ethyl)-1,4-oxazepan-2-carboxamide and (S)-N-((R)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)pyridazine-3-yl)ethyl)-1,4-oxazepan-2-carboxamide (Compound 41 and Compound 42)

[0851] 41 H (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 30 The mixture was reacted for 3 hours, then the pH was adjusted to 7 to 8 using a saturated aqueous solution of sodium carbonate, and extracted with dichloromethane (40 mL x 3). The organic phases were combined, washed with a saturated aqueous solution of sodium chloride (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 to 0.1 : 1) to obtain the compound.

[0852] 150 mg of the compound was taken, and chiral preparative separation was applied to obtain two optimal isomers: Peak 1 (Retention time: 2.088 min, 30 mg, ee = 99%, set as Compound 41) and Peak 2 (Retention time: 2.955 min, 30 mg, ee = 99%, set as Compound 42). Separation conditions: Instrument: MG II preparative SFC (SFC-14). Column: ChiralPak AD, 250 x 30 mm 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 achieve a concentration of 15 mg / ml; Injection: 1.0 ml / injection.

[0853] Peak 1: MS M / Z (ESI): m / z = 423.17 [M+1] + .

[0854] 1 H NMR (400 MHz, 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).

[0855] Peak 2: MS M / Z (ESI): m / z =423.17 [M+1] + .

[0856] 1H NMR (400 MHz, 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).

[0857] Example 43: N-((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-l6-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-6-methoxy-1,4-oxazepan-2-carboxamide (Compound 43)

[0858]

[0859] Step 1: (2S,6R)-2-((benzyloxy)methyl)-6-methoxy-4-tosyl-1,4-oxazepan(43B)

[0860] 43A (0.5 g, 1.28 mmol, prepared by referring to [Eur. J. Org. Chem. 2007, 2107-2113 (DOI: 10.1002 / ejoc.200700011)]) was dissolved in tetrahydrofuran (20 mL), and sodium hydride (0.26 g, 6.4 mmol) was added 0 Added to and stirred the mixture for 30 minutes, then iodomethane (0.91 g, 6.4 mmol) was added. The resulting mixture was reacted at room temperature for 3 hours, and water (30 mL) was added 0 It was added to the mixture. Then, the mixture was extracted with EA (20 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain colorless oil 43B (0.4 g, yield: 77%).

[0861] Step 2: (2S,6R)-2-((benzyloxy)methyl)-6-methoxy-1,4-oxazepan(43C)

[0862] Dissolve 43B (0.3 g, 0.74 mmol) in methanol (10 mL), add magnesium turnings (2.36 g, 97.08 mmol), and mix 50 The mixture was sonicated for 2 hours, reacted at room temperature for 16 hours, filtered and concentrated to obtain white oil 43C (0.18 g, yield: 96%), which was used directly in the following reaction. LC-MS (ESI): m / z = 252.3 [M+1] +

[0863] Step 3: (2S,6R)-tert-butyl 2-((benzyloxy)methyl)-6-methoxy-1,4-oxazepan-4-carboxylate(43D)

[0864] 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 sequentially, the mixture was reacted at room temperature for 2 hours under nitrogen protection, the reaction mixture was concentrated and dried, and the residue was purified by column chromatography (PE : EA = 10 : 1 to 4 : 1) to obtain colorless oil 43D (0.12 g, yield: 47%).

[0865] Step 4: (2S,6R)-tert-butyl 2-(hydroxymethyl)-6-methoxy-1,4-oxazepan-4-carboxylate (43E) 43D (0.12 g, 0.34 mmol) was dissolved in methanol (10 mL), carbonate palladium (0.1 g, 10%) was added, and the mixture was reacted under a hydrogen atmosphere for 24 hours, after which the reaction mixture was filtered and concentrated and dried to obtain colorless oil 43E (0.08 g, yield: 86%).

[0866] Step 5: (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazepan-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. Subsequently, trichloroisocyanuric acid (0.25 g, 1.06 mmol) was added. Added to the mixture. The mixture was reacted for 16 hours. Diluted hydrochloric acid was added to adjust the pH to 5 to 6, and water (30 mL) was added. The resulting mixture was extracted with dichloromethane (20 ml x 3), the organic phase was washed with water (30 mL) and saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, and then concentrated and dried to obtain yellow oil 43F (0.046 g, yield: 44%).

[0867] Step 6: tert-butyl-2-(((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-l6-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-6-methoxy-1,4-oxazepan-4-carboxylate(43G)

[0868] 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 overnight at room temperature. After the completion of the reaction was 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 obtain the title compound 43G (512 mg, 75%). LC-MS (ESI): m / z = 624.2 [M+H] + .

[0869] Step 7: N-((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-l6-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-6-methoxy-1,4-oxazepan-2-carboxamide (Compound 43)

[0870] 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 40 The mixture was heated to [value] and reacted for 2 hours. After the completion of the reaction was detected by LCMS, the reaction solution was concentrated, EA and a saturated aqueous solution of sodium bicarbonate 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] + .

[0871] 1 HNMR (400 MHz, DMSO- d 6 ): 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).

[0872] biological test

[0873] 1. In vitro analysis of DPP1 enzyme activity

[0874] Recombinant DPP1 enzyme (R&D Systems, catalog number 1071-CY) at a final concentration of 100 µg / mL was mixed with recombinant human cathepsin L (R&D Systems, catalog number 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 different concentrations and 5 µl of the diluted DPP1 enzyme were added to a 384-well plate and incubated at room temperature for 30 minutes. 10 µl of substrate Gly-Arg-AMC (bachem, catalog number I-1215) at a concentration of 20 µM was added, and incubation was continued at room temperature for 60 minutes, after which fluorescence intensity was detected using a microplate reader (excitation = 380 nm and emission = 460 nm). IC using the DosResp function of Origin2019 software 50 The value was calculated.

[0875] Test Results: The compound of the present invention exhibited inhibitory activity against the DPP1 receptor. IC5 of the compound of the example 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.

[0876] DPP1 inhibitory activity Compound number IC 50 / nM Compound 1 1.6 Compound 10 6.7 Compound 11 239 Compound 12 21 Compound 13 71 Compound 14 12.9 Compound 15 33 Compound 17 7.4 Compound 23 0.5 Compound 29 4.9 Compound 35 4.0 Compound 43 0.3

[0877] Conclusion: The compound of the present invention exhibited relatively high inhibitory activity against the DPP1 receptor.

[0878] 2. Pharmacokinetic studies in rats

[0879] 1.1 Test animals: Male SD rats, approx. 220 g, 6 to 8 weeks of age, 6 rats / compound. The rats were purchased from CHENGDU DOSSY EXPERIMENTAL ANIMALS CO., LTD.

[0880] 1.2 Experimental Design: On the day of the experiment, six SD rats were randomly grouped according to body weight. The rats were fasted for 12 to 14 hours prior to administration but were provided with water, and were fed 4 hours after administration.

[0881] Administration Information group Number of rats Administration Information cock test compound Dosage (mg / kg) Administered concentration (mg / mL) Administered volume (mL / kg) Collected samples Administration method G1 3 INS1007 1 0.2 5 plasma intravenously G2 3 Compound 1 1 0.2 5 plasma G3 3 INS1007 3 0.3 10 plasma stomach G4 3 Compound 1 3 0.3 10 plasma

[0882] Vehicle for intravenous administration: 5% DMA + 5% Solutol + 90% saline; vehicle for gastric administration: 0.5% MC; and control compound INS1007, i.e., Compound 2 from Patent WO 2015110826 A1, were prepared by reference to the method of said patent. Before and after administration, 0.1 ml of blood was taken from the eyelid of rats under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm for 10 minutes at 4°C to collect plasma. Blood sampling times for the intravenous administration group: 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours; Blood sampling times for the intragastric administration group: 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours. Before analysis and detection, all samples were stored at -80℃.

[0883] Pharmacokinetic parameters of test compounds in rat plasma test compound Administration method CL(mL / min / kg) Vd ss (L / kg) AUC 0-t (hr*ng / mL) F(%) INS1007 Intravenous (1 mg / kg) 2.08 0.738 8396 - Compound 1 1.66 0.753 9503 - INS1007 Intragastric (3 mg / kg) - - 22201 88.1 Compound 1 - - 31159 > 100

[0884] Conclusion: The compound of the present invention has relatively good bioavailability and pharmacokinetic properties.

[0885] 3. Toxicity test after 14 days of repeated oral administration in rats

[0886] SD rats were randomly divided into the following groups based on body weight: vehicle control (0.5% MC), INS1007 (30, 100, and 300 mg / kg) groups, and compound (30, 100, and 300 mg / kg) groups. For the administration groups, 16 rats were included in each group, and for the vehicle control group, 10 rats were included; the number of male and female rats in each group was equal. Rats were orally administered the corresponding concentrations of the drug or vehicle via gastrogastric feeding daily for 14 consecutive days, followed by a 7-day recovery period. During the administration period, general symptoms were observed, and body weight and food intake were measured in each group. At the end of the administration period and the recovery period, blood tests, serum biochemical tests, and whole body anatomy tests were performed individually on rats in each group.

[0887] Conclusion: The compound of the present invention is less toxic than INS1007 and is therefore safer at the same dose.

Claims

Claim 1 Compounds having the structure of Formula IV, or stereoisomers thereof, deuteration products, solvates, or pharmaceutically acceptable salts: [Formula IV] Here, Rc is H, halogen, C 1-2 alkyl or C 1-2 It is an alkoxy; R1, R2, and R3 are each independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, methoxy, or ethoxy, and methyl, ethyl, methoxy, or ethoxy are optionally substituted with 1 to 3 groups selected from F, Cl, Br, cyano, hydroxyl, and NH2; Z is CH or N; and ring G is or a benzene ring, where each has 1 to 2 R G It is optionally substituted with the gi; each R G is independently selected from F, Cl, Br, I, methyl, ethyl, propyl, SF5, and CN, wherein methyl, ethyl, or propyl is additionally optionally substituted with 1 to 3 groups selected from deuterium, F, Cl, Br, and I. Claim 2 A compound characterized in that Z is CH, or a stereoisomer, deuteration product, solvate, or pharmaceutically acceptable salt thereof, in accordance with claim 1. Claim 3 In claim 1, the ring G comprises 1 to 2 R G Selectively substituted with gi A compound characterized by being, or its stereoisomer, deuteriumation product, solvate, or pharmaceutically acceptable salt. Claim 4 In paragraph 1, each R G A compound characterized by being independently selected from methyl, ethyl, or propyl, or a stereoisomer thereof, deuteration product, solvate, or pharmaceutically acceptable salt. Claim 5 A compound selected from one of the following structural formulas, or its stereoisomer, deuteriumation product, solvate, or pharmaceutically acceptable salt: Claim 6 In claim 1, the compound is a compound selected from one of the following structural formulas, or a stereoisomer thereof, deuteration product, solvate, or pharmaceutically acceptable salt: Claim 7 A pharmaceutical composition for treating a disease mediated by dipeptidyl peptidase I, comprising a compound according to any one of claims 1 to 6, or a stereoisomer thereof, a deuteration product, a solvate or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient, wherein the disease is selected from obstructive airway disease, bronchiectasis, cystic fibrosis, asthma, emphysema, and chronic obstructive pulmonary disease. Claim 8 A compound, or a stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt thereof, characterized in that, in any one of claims 1 to 6, it is used to treat a disease mediated by dipeptidyl peptidase 1, wherein the disease is selected from obstructive airway disease, bronchiectasis, cystic fibrosis, asthma, emphysema, and chronic obstructive pulmonary disease. Claim 9 delete Claim 10 delete Claim 11 delete Claim 12 delete

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