A nitrile derivative as a dipeptidyl peptidase 1 inhibitor and its use

Abstract

Provided is a nitrile derivative compound represented by formula (I), its stereoisomers, deuterated compounds, cocrystals, solvates or pharmaceutically acceptable salts, with each group as defined in the specification. The compound has dipeptidyl peptidase 1 inhibitory activity and can be used for preparing drugs for treating diseases including airway obstructive diseases, bronchodilation, cystic fibrosis, asthma, emphysema and chronic obstructive pulmonary disease, etc.

Description

Technical Field

[0001] The present invention relates to a nitrile derivative as a dipeptidyl peptidase 1 inhibitor, its stereoisomers, deuterated compounds, cocrystals, solvates or pharmaceutically acceptable salts, and their use in the preparation of a medicament for treating dipeptidyl peptidase 1-mediated diseases. Background Art

[0002] Dipeptidyl peptidase 1 (DPP1), also known as cathepsin C, is a lysosomal cysteine protease that can remove dipeptides from the amino terminus of protein substrates. DPP1 was first discovered by Gutman and Fruton in 1948 (J Biol Chem, 174, 851-858); however, the cDNA of the human enzyme was first described in 1995 (FEBS Lett, 369, 326-330). DPP1 is the only member of the papain family that functions as a tetramer and consists 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 of the lung, kidney, liver, and spleen (Biol.Chem.Hoppe Seyler 373:367-373, 1992). Consistent with its role in the activation of serine proteases by hematopoietic stem cells, DPP1 is also relatively highly expressed in neutrophils, cytotoxic lymphocytes, natural killer cells, alveolar macrophages, and mast cells. Recent data indicate that, in addition to being an important enzyme in lysosomal protein degradation, DPP1 also plays a key enzyme role in the activation of granule serine 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 (chymase and plasmin; J Biol.Chem. 276:18551-18556, 2001), and neutrophils (cathepsin G, elastase, and proteinase 3; J Clin.Invest. 109:363.371, 2002). Once activated, these proteases can degrade a variety of extracellular matrix components, leading to tissue damage and chronic inflammation. DPP1 is considered an effective therapeutic target because of its central role in activating these proteases (J Clin Invest, 2002, 109, 363-271; J Immunol, 2004, 173, 7277-7281).

[0004] Accordingly, cathepsin C inhibitors can potentially be used to treat the following diseases: neutrophil-dominated 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 activating some pro-inflammatory serine proteases, the preparation of compounds that inhibit its activity and thereby inhibit the activity of downstream serine proteases has good clinical application prospects. Currently, there are related patents reporting the synthesis of DPP1 inhibitors. WO2004 / 110988 relates to certain nitrile derivatives and their use as DPP1 inhibitors. WO2009 / 074829 relates to peptidyl nitriles and their use as DPP1 inhibitors. WO2010 / 128324 relates to α-aminoamide nitriles and their use as DPP1 inhibitors. WO2012 / 119941 relates to peptidyl nitrile compounds and their use as DPP1 inhibitors. WO2013 / 041497 relates to N-[1-cyano-2-(phenyl)ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide and its use as a DPP1 inhibitor. WO2001 / 096285 and WO2003 / 048123 relate to β-aminoamide nitriles having inhibitory activity against cysteine proteases. However, so far, there is still no marketed DPP1 inhibitor. Therefore, DPP1 inhibitors with high inhibitory activity and low toxicity are still an unmet clinical need. Summary of the Invention

[0005] The present invention firstly provides a compound of formula (I), (II), (III) or (IV), its stereoisomers, deuterated compounds, cocrystals, solvates or pharmaceutically acceptable salts, which have high activity, high bioavailability, good pharmacokinetics and low toxicity and side effects:

[0006]

[0007] Wherein, ring G is a 5- to 12-membered carbocyclic ring, a 5- to 12-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, O or a fused ring of formula (I-1) L1 replaces any hydrogen atom on the ring atoms of ring G (for example, the carbon atoms on the 5- to 12-membered carbocyclic ring, the ring carbon atoms or ring heteroatoms on the 5- to 12-membered monocyclic heterocyclic ring, the ring carbon atoms or ring heteroatoms on the fused ring of formula (I-1)) for connection, and the carbocyclic ring or monocyclic heterocyclic ring is optionally substituted by 1 to 3 R G substituted;

[0008] Optionally, formula (I-1) has the structure

[0009] Optionally, formula (I-1) has the structure

[0010] In some embodiments, ring G is a 5- to 9-membered monocyclic carbocyclic ring, a 5- to 7-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, O, or a fused ring of formula (I-1). Optionally, formula (I-1) has structure (I-11). Optionally, formula (I-1) has structure (I-12);

[0011] In some embodiments, ring G is a cyclopentane, cyclohexane, cycloheptane, benzene ring optionally substituted with 1 to 3 R G substituents, or ring G is

[0012] Optionally, formula (I-2) has the structure

[0013] Optionally, formula (I-2) has the structure

[0014] In some embodiments, is selected from one of the following structures:

[0015]

[0016] In some embodiments, ring G is a benzene ring optionally substituted with 1 to 2 R G substituents or

[0017] Each R G is independently selected from deuterium, SF5, ═O, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COC 1-4 alkyl, -COOC 1-4 alkyl, -CONH2, -CONHC 1-4 alkyl, -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)C1-4 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 alkyl)2, -S(O)2NH2, and 4- to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, O, wherein said R G is optionally further substituted by 1 to 3 groups selected from deuterium, C 1-4 alkyl, halo C 1-4 alkyl, hydroxy C 1-4 alkyl, -CONH2, NH2, C 1-6 alkoxy, hydroxy, -COOH, halogen, and 5- to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, O, and further, said 5- to 7-membered heterocycle is optionally substituted by 1 to 2 ═O, halogen, cyano, C 1-4 alkyl, halo C 1-4 alkyl;

[0018] In some embodiments, each R G is independently selected from deuterium, SF5, ═O, halogen, cyano, hydroxy, NH2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COC 1-4 alkyl, -CONH2, -CONHC 1-4 alkyl, -CON(C 1-4 alkyl)2, -NHCOC 1-4 alkyl, -P(O)(C 1-4 alkyl)2, and 4- to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, O, wherein said R G is optionally further substituted by 1 to 3 groups selected from deuterium, C 1-4 alkyl, halo C 1-4 alkyl, hydroxy C 1-4 alkyl, -CONH2, NH2, C 1-6 alkoxy, hydroxy, halogen, and 5- to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, O, and further, said 5- to 7-membered heterocycle is optionally substituted by 1 to 2 ═O, halogen, cyano, C 1-4 alkyl, halo C 1-4 alkyl;

[0019] In some embodiments, each R GIndependently selected from F, Cl, Br, I, methyl, ethyl, propyl, SF5 and CN; the methyl, ethyl, propyl are optionally further substituted by 1-3 groups selected from deuterium, F, Cl, Br and I;

[0020] Cy is a 5-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and the heterocyclic ring is optionally substituted by 1-3 groups selected from deuterium, =O, halogen, cyano, hydroxy, 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 alkynyl, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COC 1-4 alkyl, -COOC 1-4 alkyl, -CONH2, -CONHC 1-4 alkyl, -CON(C 1-4 alkyl)2, -NHCOC 1-4 alkyl, -S(O)C 1-4 alkyl, -S(O)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, -S(O)2N(C 1-4 alkyl)2;

[0021] In some specific embodiments, Cy is a 5-12 membered monocyclic heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and the monocyclic heterocyclic ring is optionally substituted by 1-3 groups selected from deuterium, =O, halogen, cyano, hydroxy, 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 alkynyl, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COC 1-4 alkyl, -COOC1-4 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, -S(O)2N(C 1-4 alkyl)2;

[0022] In some specific embodiments, Cy is a group selected from the following groups containing 1-3 heteroatoms of N, S, and O: 5- to 8-membered monocyclic heterocycles, 7- to 10-membered spiro heterocycles, 6- to 9-membered bridged heterocycles, or 6- to 10-membered fused heterocycles. Cy is optionally substituted with 1-3 groups selected from =O, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkoxy, C 1-6 alkoxyalkyl, haloC 1-4 alkoxy, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COC 1-4 alkyl, -CONH2, -CONHC 1-4 alkyl, -CON(C 1-4 alkyl)2, -NHCOC 1-4 alkyl, -S(O)C 1-4 alkyl, -S(O)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, -S(O)2N(C 1-4 alkyl)2;

[0023] In some specific embodiments, Cy is a 5- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the monocyclic heterocycle is optionally substituted with 1-3 groups selected from =O, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, C1-4 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, -S(O)2N(C 1-4 alkyl)2 groups substituted;

[0024] In some specific embodiments, Cy is a 5- to 8-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, S, O, and the monocyclic heterocycle is optionally substituted with 1 to 3 groups selected from =O, halogen, cyano, hydroxy, 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 1-4 alkyl)2, -S(O)2NH2, -S(O)2NHC 1-4 alkyl, -S(O)2N(C 1-4 alkyl)2 groups substituted;

[0025] In some specific embodiments, Cy is

[0026] wherein Rc is H, =O, halogen, cyano, hydroxy, 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 alkoxy;

[0027] In some specific embodiments, Rc is H, halogen, C 1-2 alkyl or C 1-2 alkoxy;

[0028] W is C(=O), C(=S), C(=N-R W ), S(=O) or S(=O)2, R W is OH, CN, or C 1-4 alkyl;

[0029] In some specific embodiments, W is C(=O);

[0030] M is NR M or O, R M is H, C 1-4 alkyl or C 3-6 cycloalkyl;

[0031] In some specific embodiments, M is NH;

[0032] R1, R2 and R3 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and 4- to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle are optionally substituted with 1 to 3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxy, NH2 and -COOH; optionally, R1 and R2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O, wherein the cycloalkyl or heterocycle is optionally substituted with 1 to 3 groups selected from =O, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl;

[0033] In some specific embodiments, R1, R2 and R3 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl and C 2-6 alkynyl, wherein the alkyl, alkoxy, alkenyl, alkynyl are optionally substituted with 1 to 3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxy, NH2 and COOH;

[0034] Optionally, R1 and R2 together with the carbon atom to which they are attached form a C3-6 A cycloalkyl group or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl group or heterocyclic ring being optionally substituted with 1-3 groups selected from halogen, cyano, hydroxy, NH2, COOH, C 1-4 alkyl groups;

[0035] In some specific embodiments, R1, R2 and R3 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, said alkyl and alkoxy groups being optionally substituted with 1-3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxy, NH2 and COOH;

[0036] Optionally, R1 and R2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group, said cycloalkyl group being optionally substituted with 1-3 groups selected from halogen, cyano, hydroxy, NH2, COOH, C 1-4 alkyl groups;

[0037] In some specific embodiments, R1, R2 and R3 are each independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy or ethoxy being optionally substituted with 1-3 groups selected from F, Cl, Br, cyano, hydroxy and NH2;

[0038] L1 is a bond, C 1-3 alkylene, -NH-, -N(C 1-4 alkyl)-, -O-, -S-, C 2-6 alkenylene, C 2-6 alkynylene, -CO-, or -CONH-, wherein said alkylene, alkenylene or alkynylene is optionally substituted with 1-3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxy, NH2 and -COOH;

[0039] In some specific embodiments, L1 is a bond, C 1-3 alkylene, -NH-, -O-, -S-, C 2-6 alkenylene, C 2-6 alkynylene, or -CO-, said alkylene, alkenylene or alkynylene being optionally substituted with 1-3 groups selected from halogen, cyano, hydroxy, and NH2;

[0040] In some specific embodiments, L1 is a bond,

[0041] Y1 and Y2 are each independently selected from CR4 or N;

[0042] In some specific embodiments, Y1 and Y2 are CH;

[0043] Each R4 is independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, cyano, hydroxy, NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COOH, -COC 1-4 alkyl, -COOC 1-4 alkyl, -CONHC 1-4 alkyl, -CON(C 1-4 alkyl)2, -NHCOC 1-4 alkyl, and a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O; the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups in R4 are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and -COOH;

[0044] In some specific embodiments, each R4 is independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, cyano, hydroxy, NH2; the alkyl, alkenyl, alkynyl, and cycloalkyl in R4 are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and COOH;

[0045] In some specific embodiments, R4 is H;

[0046] X1, X2, X3, and X4 are each independently selected from a bond, NR5, O, CR6R7, S, S(O), and S(O)2, and at most one of X1, X2, X3, and X4 is a bond;

[0047] Each R5 is independently selected from H, C 1-4 alkyl, -COC 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl; the alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and COOH;

[0048] In some specific embodiments, each R5 is independently selected from H, C 1-4 alkyl, -COC 1-4 alkyl, C 3-6Cycloalkyl; the alkyl and cycloalkyl are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH;

[0049] In some specific embodiments, R5 is methyl;

[0050] R6 and R7 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, cyano, hydroxyl, NH2, -COOH, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0051] Optionally, R6 and R7 form =O;

[0052] Optionally, two R5 on adjacent ring atoms, two R6 on adjacent ring atoms, or R5 and R6 on adjacent ring atoms together with the atoms to which they are attached form a double bond;

[0053] Optionally, R6 and R7 on the same carbon atom together with the carbon atom to which they are attached form a C 3-12 carbocycle or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, the carbocycle or heterocycle is optionally substituted with 1-3 groups selected from =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl groups;

[0054] In some specific embodiments, R6 and R7 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and COOH;

[0055] Optionally, R6 and R7 form =O;

[0056] Optionally, two R5 on adjacent ring atoms, two R6 on adjacent ring atoms, or R5 and R6 on adjacent ring atoms together with the atoms to which they are attached form a double bond;

[0057] Optionally, R6 and R7 on the same carbon atom form a C with the carbon atom to which they are attached 3-6 cycloalkyl or a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O, and the cycloalkyl or heterocycle is optionally substituted with 1 to 3 groups selected from ═O, halogen, cyano, hydroxy, NH2, COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;

[0058] In some specific embodiments, R6 and R7 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy; the alkyl and alkoxy are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and COOH;

[0059] Optionally, R6 and R7 form ═O;

[0060] Optionally, two R5s on adjacent ring atoms among X1, X2, X3, and X4, two R6s on adjacent ring atoms, or R5 and R6 on adjacent ring atoms together with the atoms to which they are attached form a double bond;

[0061] Z is CH or N;

[0062] The compounds of formulas (I)-(III) satisfy one of the conditions (1)-(4),

[0063] (1) A is a six-membered heteroaryl or a 5- to 10-membered non-aromatic heterocycle, the heteroaryl and non-aromatic heterocycle contain 1 to 3 heteroatoms selected from N, S, O, and the hetero A is optionally substituted with 1 to 3 R8s;

[0064] * represents the end connected to the alkyl carbon;

[0065] Ring B is C 3-12 a carbocyclic ring or a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O;

[0066] Each R8 is independently selected from H, ═O, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, -SC 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, cyano, hydroxy, NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COOH, -COC1-4 alkyl, -COOC 1-4 alkyl, -CONHC 1-4 alkyl, -CON(C 1-4 alkyl)2, -NHCOC 1-4 alkyl, and a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups in R8 are optionally substituted by 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and -COOH;

[0067] and Cy is not substituted or unsubstituted

[0068] In some specific embodiments, A is a six-membered heteroaryl or a 5- to 7-membered non-aromatic monocyclic heterocycle, the heteroaryl and non-aromatic monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, and the A is optionally substituted by 1 to 3 R8;

[0069] * represents the end connected to the alkyl carbon;

[0070] Ring B is C 4-6 a carbocyclic ring or a 5- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O;

[0071] Each R8 is independently selected from 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, hydroxy, -COOH, NH2, and C 3-6 cycloalkyl; the alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted by 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and -COOH;

[0072] In some other specific embodiments, A is Ring A is optionally substituted by 1 to 3 R8;

[0073] Each R8 is independently selected from halogen, =O, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;

[0074] * represents the end connected to the alkyl carbon;

[0075] r is an integer from 1 to 3;

[0076] E is selected from NH, S, O;

[0077] In some other specific embodiments, A is Ring A is optionally substituted with 1 - 3 R8; the substituents are located at any substitutable positions on ring A, including on the benzene ring carbon atoms and on the carbon atoms or heteroatoms of the rings fused thereto;

[0078] Each R8 is independently selected from halogen, =O, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, C 1-4 alkoxy, -SC 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;

[0079] * indicates the end connected to the alkyl carbon;

[0080] Or,

[0081] (2) A is a five - membered heteroaryl containing 1 - 3 heteroatoms selected from N, S, O, and said A is optionally substituted with 1 - 3 R8;

[0082] Each R8 is independently selected from H, =O, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, -SC 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, cyano, hydroxy, NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COOH, -COC 1-4 alkyl, -COOC 1-4 alkyl, -CONHC 1-4 alkyl, -CON(C 1-4 alkyl)2, -NHCOC 1-4 alkyl, and a 4 - 7 - membered heterocycle containing 1 - 3 heteroatoms selected from N, S, O; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups in R8 are optionally substituted with 1 - 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and -COOH;

[0083] And Cy is not substituted or unsubstituted

[0084] In some specific embodiments, A is a five - membered heteroaryl containing 1 - 3 heteroatoms selected from N, S, O, and said A is optionally substituted with 1 - 3 R8;

[0085] Each R8 is independently selected from 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 cycloalkyl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl are optionally substituted by 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2 and -COOH;

[0086] and Cy is unsubstituted or substituted

[0087] In some specific embodiments, A is A is optionally substituted by 1-3 R8;

[0088] Each R8 is independently selected from halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl;

[0089] Z1 and Z2 are each independently CH or N;

[0090] Z3 is S, O or NH;

[0091] * represents the end connected to the alkyl carbon;

[0092] In some specific embodiments, A is A is optionally substituted by 1-3 groups selected from halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl;

[0093] and Cy is

[0094] * represents the end connected to the alkyl carbon;

[0095] Or,

[0096] (3) A is * represents the end connected to the alkyl carbon;

[0097] R A1 、R A2 、R A3 、R A4 are each independently R8, and R A1 、RA2 , R A3 , R A4 are not simultaneously H;

[0098] Each R8 is independently selected from H, ═O, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, -SC 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, cyano, hydroxy, NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COOH, -COC 1-4 alkyl, -COOC 1-4 alkyl, -CONHC 1-4 alkyl, -CON(C 1-4 alkyl)2, -NHCOC 1-4 alkyl, and a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups in R8 are optionally substituted by 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and -COOH;

[0099] Cy is a 5- to 12-membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N, S, O, and the monocyclic heterocycle is optionally substituted by 1 to 3 groups selected from deuterium, ═O, halogen, cyano, hydroxy, 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 alkynyl, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COC 1-4 alkyl, -COOC 1-4 alkyl, -CONH2, -CONHC 1-4 alkyl, -CON(C 1-4 alkyl)2, -NHCOC 1-4 alkyl, -S(O)C 1-4 alkyl, -S(O)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)2NHC1-4 alkyl, -S(O)2N(C 1-4 alkyl)2 group substitution;

[0100] and Cy is not substituted or unsubstituted

[0101] In some specific embodiments, A is * indicates the end connected to the alkyl carbon;

[0102] R A1 、R A2 、R A3 、R A4 are each independently R8, and R A1 、R A2 、R A3 、R A4 are not simultaneously H;

[0103] Each R8 is independently selected from 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, hydroxy, -COOH, NH2, and C 3-6 cycloalkyl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and -COOH;

[0104] Cy is a 5-8 membered monocyclic heterocycle containing 1-3 heteroatoms selected from N, S, O, and the monocyclic heterocycle is optionally substituted with 1-3 groups selected from =O, halogen, cyano, hydroxy, 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(C1-4 (alkyl)2, -S(O)2NH2, -S(O)2NHC 1-4 alkyl, -S(O)2N(C 1-4 alkyl)2 group substitution;

[0105] In some specific embodiments, A is * represents the end connected to the alkyl carbon;

[0106] R A1 , R A2 , R A3 , R A4 are each independently R8, and R A1 , R A2 , R A3 , R A4 are not simultaneously H;

[0107] Each R8 is independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxy, NH2, COOH; the alkyl and alkoxy are optionally substituted by 1 - 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2 and COOH;

[0108] And Cy is

[0109] Or,

[0110] (4) A is * represents the connection to the alkyl carbon;

[0111] R1, R2 and R3 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and 4 - 7 membered heterocycles containing 1 - 3 heteroatoms selected from N, S, O, and the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle are optionally substituted by 1 - 3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxy, NH2 and -COOH, and R1, R2 and R3 are not simultaneously H;

[0112] Optionally, R1 and R2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or a 4 - 7 membered heterocycle containing 1 - 3 heteroatoms selected from N, S, O, and the cycloalkyl or heterocycle is optionally substituted by 1 - 3 groups selected from =O, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6Substitution with a cycloalkyl group;

[0113] In some specific embodiments, A is * indicates connection to an alkyl carbon;

[0114] R1, R2, and R3 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, and the alkyl, alkoxy, alkenyl, and alkynyl are optionally substituted with 1 - 3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxy, NH2, and COOH, and R1, R2, and R3 are not simultaneously H;

[0115] Optionally, R1 and R2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, and the cycloalkyl is optionally substituted with 1 - 3 groups selected from =O, halogen, cyano, hydroxy, NH2, COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl;

[0116] In some specific embodiments, A is * indicates connection to an alkyl carbon;

[0117] R1, R2, and R3 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, and the alkyl, alkoxy, alkenyl, and alkynyl are optionally substituted with 1 - 3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxy, NH2, and COOH, and R1, R2, and R3 are not simultaneously H;

[0118] Optionally, R1 and R2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, and the cycloalkyl is optionally substituted with 1 - 3 groups selected from halogen, cyano, hydroxy, NH2, COOH;

[0119] In the present invention, represents the connection site.

[0120] As a more specific first technical solution of the present invention, the present invention provides a compound of formula (I), its stereoisomers, deuterated compounds, cocrystals, solvates, or pharmaceutically acceptable salts:

[0121]

[0122] Among them, ring G is a 5- to 12-membered carbocyclic ring, a 5- to 12-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, or a fused ring of formula (I-1) L1 is connected by replacing any hydrogen atom on the ring atoms of ring G (for example, the carbon atoms on the 5- to 12-membered carbocyclic ring, the ring carbon atoms or ring heteroatoms on the 5- to 12-membered monocyclic heterocyclic ring, or the ring carbon atoms or ring heteroatoms on the fused ring of formula (I-1)), and the carbocyclic ring or monocyclic heterocyclic ring is optionally substituted by 1 to 3 R G substituents;

[0123] Optionally, formula (I-1) has the structure

[0124] Optionally, formula (I-1) has the structure

[0125] Each R G is independently selected from 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, C 2-6 alkenyl, C 2-6 alkynyl, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COC 1-4 alkyl, -COOC 1-4 alkyl, -CONH2, -CONHC 1-4 alkyl, -CONHC 3-6 cycloalkyl, -CON(C 1-4 alkyl)2, -NHCOC 1-4 alkyl, -NHCOC 3-6 cycloalkyl, -P(O)(C 1-4 alkyl)2, -S(O)C 1-4 alkyl, -S(O)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 alkyl)2, -S(O)2NH2, and a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and the R G is optionally further substituted by 1 to 3 substituents selected from deuterium, C 1-4 alkyl, halo C 1-4 alkyl, hydroxy C 1-4 alkyl, -CONH2, NH2, C 1-6substituted by alkoxy, hydroxy, -COOH, halogen, and a group of a 5- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, and further, the 5- to 7-membered heterocycle is optionally substituted by 1 to 2 groups selected from =O, halogen, cyano, C 1-4 alkyl, halo-C 1-4 alkyl;

[0126] Cy is a 5- to 12-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, and the heterocycle is optionally substituted by 1 to 3 groups selected from deuterium, =O, halogen, cyano, hydroxy, 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 alkynyl, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COC 1-4 alkyl, -COOC 1-4 alkyl, -CONH2, -CONHC 1-4 alkyl, -CON(C 1-4 alkyl)2, -NHCOC 1-4 alkyl, -S(O)C 1-4 alkyl, -S(O)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 alkyl)2;

[0127] W is C(=O), C(=S), C(=N-R W ), S(=O) or S(=O)2;

[0128] M is NR M or O;

[0129] R W is OH, CN, or C 1-4 alkyl;

[0130] R M is H, C 1-4 alkyl or C 3-6 cycloalkyl;

[0131] R1, R2, and R3 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and 4- 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 halogen, C 1-4 alkyl, cyano, hydroxy, NH2, and -COOH;

[0132] Optionally, R1 and R2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl or heterocycle is optionally substituted with 1 to 3 groups selected from =O, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;

[0133] L1 is a bond, C 1-3 alkylene, -NH-, -N(C 1-4 alkyl)-, -O-, -S-, C 2-6 alkenylene, C 2-6 alkynylene, -CO-, or -CONH-, wherein the alkylene, alkenylene, or alkynylene is optionally substituted with 1 to 3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxy, NH2, and -COOH;

[0134] Y1 and Y2 are each independently selected from CR4, N;

[0135] Each R4 is independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, cyano, hydroxy, NH2, -NH C 1-4 alkyl, -N(C 1-4 alkyl)2, -COOH, -CO C 1-4 alkyl, -COO C 1-4 alkyl, -CONH C 1-4 alkyl, -CON(C 1-4 alkyl)2, -NHCO C 1-4alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O; the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups in R4 are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and -COOH;

[0136] X1, X2, X3, and X4 are each independently selected from a bond, NR5, O, CR6R7, S, S(O), and S(O)2, and at most one of X1, X2, X3, and X4 is a bond;

[0137] Each R5 is independently selected from H, C 1-4 alkyl, -COC 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and COOH;

[0138] R6 and R7 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, cyano, hydroxy, NH2, -COOH, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and -COOH;

[0139] Optionally, R6 and R7 form =O;

[0140] Optionally, two R5 on adjacent ring atoms, two R6 on adjacent ring atoms, or R5 and R6 on adjacent ring atoms together with the atoms to which they are attached form a double bond;

[0141] Optionally, R6 and R7 on the same carbon atom together with the carbon atom to which they are attached form a C 3-12 carbocycle or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, the carbocycle or heterocycle being optionally substituted with 1-3 groups selected from =O, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl groups;

[0142] Provided that,

[0143] (1) A is A six-membered heteroaryl or a 5- to 10-membered non-aromatic heterocycle, wherein A is optionally substituted with 1 to 3 R8s;

[0144] * indicates the end connected to the alkyl carbon;

[0145] Ring B is a C 3-12 carbocyclic ring or a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and the carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 3 groups selected from =O, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, C 1-4 alkoxy, -SC 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl groups;

[0146] Each R8 is independently selected from H, =O, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, -SC 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, cyano, hydroxy, NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COOH, -COC 1-4 alkyl, -COOC 1-4 alkyl, -CONHC 1-4 alkyl, -CON(C 1-4 alkyl)2, -NHCOC 1-4 alkyl, and a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic ring groups in R8 are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and -COOH;

[0147] and Cy is not substituted or unsubstituted

[0148] Or,

[0149] (2) A is a five-membered heteroaryl containing 1 to 3 heteroatoms selected from N, S, and O, and A is optionally substituted with 1 to 3 R8s;

[0150] Each R8 is independently selected from H, =O, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, -SC 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6Cycloalkyl, cyano, hydroxy, NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COOH, -COC 1-4 alkyl, -COOC 1-4 alkyl, -CONHC 1-4 alkyl, -CON(C 1-4 alkyl)2, -NHCOC 1-4 alkyl, and a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups in R8 are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and -COOH;

[0151] and Cy is not substituted or unsubstituted

[0152] Or,

[0153] (3) A is * represents the end connected to the alkyl carbon;

[0154] R A1 、R A2 、R A3 、R A4 are each independently R8, and R A1 、R A2 、R A3 、R A4 are not simultaneously H;

[0155] Each R8 is independently selected from H, =O, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, -SC 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, cyano, hydroxy, NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COOH, -COC 1-4 alkyl, -COOC 1-4 alkyl, -CONHC 1-4 alkyl, -CON(C 1-4 alkyl)2, -NHCOC 1-4 alkyl, and a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups in R8 are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and -COOH;

[0156] 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 optionally substituted with 1 to 3 groups selected from deuterium, ═O, halogen, cyano, hydroxy, 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 alkynyl, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COC 1-4 alkyl, -COOC 1-4 alkyl, -CONH2, -CONHC 1-4 alkyl, -CON(C 1-4 alkyl)2, -NHCOC 1-4 alkyl, -S(O)C 1-4 alkyl, -S(O)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, -S(O)2N(C 1-4 alkyl)2;

[0157] and Cy is not a substituted or unsubstituted

[0158] Or,

[0159] (4) A is * indicates connection to an alkyl carbon;

[0160] R1, R2, and R3 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, and the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are optionally substituted with 1 to 3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxy, NH2, and -COOH, and R1, R2, and R3 are not simultaneously H;

[0161] Optionally, R1 and R2 together with the carbon atom to which they are attached form a C3-6 A cycloalkyl group or a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and the cycloalkyl group or heterocyclic ring is optionally substituted by 1 to 3 groups selected from ═O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl groups.

[0162] As the second technical solution of the present invention, the compound of formula (I), its stereoisomers, deuterated compounds, cocrystals, solvates or pharmaceutically acceptable salts, and the compound has the structure of formula (II):

[0163]

[0164] Each group is as described in the first technical solution.

[0165] As the third technical solution of the present invention, the compound of formula (II), its stereoisomers, deuterated compounds, cocrystals, solvates or pharmaceutically acceptable salts, wherein,

[0166] Ring G is a 5- to 9-membered monocyclic carbocyclic ring, a 5- to 7-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, or a fused ring of formula (I-1) L1 is connected by replacing any hydrogen atom on the ring atoms of ring G, and the monocyclic carbocyclic ring or monocyclic heterocyclic ring is optionally substituted by 1 to 3 R G substituents;

[0167] Optionally, formula (I-1) has the structure

[0168] Optionally, formula (I-1) has the structure

[0169] Each R G independently selected from 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, C 2-6 alkenyl, C 2-6 alkynyl, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COC 1-4 alkyl, -COOC 1-4 alkyl, -CONH2, -CONHC 1-4 alkyl, -CONHC 3-6 cycloalkyl, -CON(C1-4 (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 (alkyl)2, -S(O)2NH2, and a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, wherein the R G is optionally further substituted by 1 to 3 groups selected from deuterium, C 1-4 alkyl, halo C 1-4 alkyl, hydroxy C 1-4 alkyl, -CONH2, NH2, C 1-6 alkoxy, hydroxy, -COOH, halogen, and a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and further, the 5- to 7-membered heterocyclic ring is optionally substituted by 1 to 2 ═O, halogen, cyano, C 1-4 alkyl, halo C 1-4 alkyl;

[0170] Cy is a group containing 1 to 3 heteroatoms selected from N, S, and O: a 5- to 8-membered monocyclic heterocyclic ring, a 7- to 10-membered spiro heterocyclic ring, a 6- to 9-membered bridged heterocyclic ring, or a 6- to 10-membered fused heterocyclic ring, and Cy is optionally substituted by 1 to 3 groups selected from ═O, halogen, cyano, hydroxy, 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 1-4alkyl, -S(O)2N(C 1-4 alkyl)2 groups substituted;

[0171] R1, R2, and R3 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, and C 2-6 alkynyl, and the alkyl, alkoxy, alkenyl, and alkynyl are optionally substituted with 1-3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxy, NH2, and COOH;

[0172] Optionally, R1 and R2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the cycloalkyl or heterocycle is optionally substituted with 1-3 groups selected from halogen, cyano, hydroxy, NH2, COOH, C 1-4 alkyl;

[0173] Each R4 is independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, cyano, hydroxy, NH2; the alkyl, alkenyl, alkynyl, and cycloalkyl in R4 are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and COOH;

[0174] R6 and R7 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl; the alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and COOH;

[0175] Optionally, R6 and R7 form =O;

[0176] Optionally, two R5 on adjacent ring atoms among X1, X2, X3, and X4, two R6 on adjacent ring atoms, or R5 and R6 on adjacent ring atoms together with the atoms to which they are attached form a double bond;

[0177] Optionally, R6 and R7 on the same carbon atom together with the carbon atom to which they are attached form a C 3-6A cycloalkyl group or a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, said cycloalkyl group or heterocyclic ring being optionally substituted by 1 to 3 groups selected from ═O, halogen, cyano, hydroxy, NH2, COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;

[0178] Provided that,

[0179] (1) A is a six-membered heteroaryl group or a 5- to 7-membered non-aromatic monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, said A being optionally substituted by 1 to 3 R8;

[0180] * represents the end connected to the alkyl carbon;

[0181] Ring B is C 4-6 a carbocyclic ring or a 5- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, said carbocyclic ring or heterocyclic ring being optionally substituted by 1 to 3 groups selected from ═O, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, C 1-4 alkoxy, -SC 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;

[0182] Each R8 is independently selected from 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, hydroxy, -COOH, NH2, and C 3-6 cycloalkyl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl being optionally substituted by 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and -COOH;

[0183] and Cy is not substituted or unsubstituted

[0184] Or,

[0185] (2) A is a five-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, and O, said A being optionally substituted by 1 to 3 R8;

[0186] Each R8 is independently selected from H, ═O, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, -SC1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, hydroxyl, -COOH, NH2, and C 3-6 cycloalkyl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl are optionally substituted by 1 - 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0187] and Cy is not substituted or unsubstituted

[0188] Or,

[0189] (3) A is * represents the end connected to the alkyl carbon;

[0190] R A1 , R A2 , R A3 , R A4 are each independently R8, and R A1 , R A2 , R A3 , R A4 are not simultaneously H;

[0191] Each R8 is independently selected from 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 cycloalkyl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl are optionally substituted by 1 - 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0192] Cy is a 5 - 8 - membered monocyclic heterocycle containing 1 - 3 heteroatoms selected from N, S, O, and the monocyclic heterocycle is optionally substituted by 1 - 3 groups selected from =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, -S(O)2N(C 1-4 (alkyl)2;

[0193] and Cy is unsubstituted or substituted

[0194] Or,

[0195] (4) A is * indicates connection to alkyl carbon;

[0196] R1, R2 and R3 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, and the alkyl, alkoxy, alkenyl, alkynyl are optionally substituted by 1 - 3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxyl, NH2 and COOH, and R1, R2 and R3 are not simultaneously H;

[0197] Optionally, R1 and R2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, and the cycloalkyl is optionally substituted by 1 - 3 groups selected from =O, halogen, cyano, hydroxyl, NH2, COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl;

[0198] The undefined groups are as described in the second technical solution.

[0199] As the fourth technical solution of the present invention, the compound of formula (I) or formula (II), its stereoisomers, deuterated compounds, cocrystals, solvates or pharmaceutically acceptable salts, wherein the compound further has the structure of formula (III):

[0200]

[0201] wherein, 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, C1-6 alkyloxyalkyl, or halo-C 1-4 alkoxy;

[0202] R1, R2, and R3 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, wherein the alkyl and alkoxy are optionally substituted with 1 - 3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxy, NH2, and COOH;

[0203] Optionally, R1 and R2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 - 3 groups selected from halogen, cyano, hydroxy, NH2, COOH, C 1-4 alkyl;

[0204] L1 is a bond, 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 - 3 groups selected from halogen, cyano, hydroxy, and NH2;

[0205] Each R5 is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl; wherein the alkyl and cycloalkyl are optionally substituted with 1 - 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and COOH;

[0206] R6 and R7 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy; wherein the alkyl and alkoxy are optionally substituted with 1 - 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and COOH;

[0207] Optionally, R6 and R7 form =O;

[0208] Optionally, two R5 on adjacent ring atoms among X1, X2, X3, and X4, two R6 on adjacent ring atoms, or R5 and R6 on adjacent ring atoms together with the atoms to which they are attached form a double bond;

[0209] Provided that,

[0210] (1) A is Ring A is optionally substituted with 1 - 3 R8; the substituents are located at any substitutable positions on ring A, including the benzene ring carbon atoms and the carbon atoms or heteroatoms of the fused rings;

[0211] Each R8 is independently selected from halogen, =O, cyano, hydroxyl, NH2, -COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;

[0212] * represents the end connected to the alkyl carbon;

[0213] r is an integer from 1 to 3;

[0214] E is selected from NH, S, O;

[0215] Or,

[0216] (2) A is A is optionally substituted by 1 to 3 R8s;

[0217] Each R8 is independently selected from halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;

[0218] Z1 and Z2 are each independently CH or N;

[0219] Z3 is S, O, or NH;

[0220] * represents the end connected to the alkyl carbon;

[0221] Or,

[0222] (3) A is * represents the end connected to the alkyl carbon;

[0223] R A1 、R A2 、R A3 、R A4 are each independently R8, and R A1 、R A2 、R A3 、R A4 are not simultaneously H;

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

[0225] Or,

[0226] (4) A is * represents connection to the alkyl carbon;

[0227] R1, R2, and R3 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, and the alkyl, alkoxy, alkenyl, and alkynyl are optionally substituted with 1 - 3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxy, NH2, and COOH, and R1, R2, and R3 are not simultaneously H;

[0228] Optionally, R1 and R2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, and the cycloalkyl is optionally substituted with 1 - 3 groups selected from halogen, cyano, hydroxy, NH2, and COOH;

[0229] The undefined group is as described in the third technical solution.

[0230] As the fifth technical solution of the present invention, a compound of formula (III), its stereoisomers, deuterated compounds, cocrystals, solvates, or pharmaceutically acceptable salts, wherein,

[0231] Ring G is a cyclopentane, cyclohexane, cycloheptane, benzene ring optionally substituted with 1 - 3 R G substituents, or Ring G is

[0232] Optionally, formula (I - 2) has a structure

[0233] Optionally, formula (I - 2) has a structure

[0234] L1 is connected by replacing any hydrogen atom on the ring atoms of Ring G,

[0235] Each R G is independently selected from deuterium, SF5, =O, halogen, cyano, hydroxy, NH2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COC 1-4 alkyl, -CONH2, -CONHC 1-4 alkyl, -CON(C 1-4 alkyl)2, -NHCOC 1-4 alkyl, -P(O)(C 1-4(alkyl)2, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said R G is optionally further substituted by 1-3 groups selected from deuterium, C 1-4 alkyl, halo C 1-4 alkyl, hydroxy C 1-4 alkyl, -CONH2, NH2, C 1-6 alkoxy, hydroxy, halogen, and a 5-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O; further, said 5-7 membered heterocycle is optionally substituted by 1-2 =O, halogen, cyano, C 1-4 alkyl, halo C 1-4 alkyl;

[0236] Provided that,

[0237] (1) A is Ring A is optionally substituted by 1-3 R8; the substituents are located at any substitutable positions on ring A, including the benzene ring carbon atoms and the carbon atoms or heteroatoms of the ring fused thereto;

[0238] Each R8 is independently selected from =O, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl;

[0239] * represents the end connected to the alkyl carbon; or

[0240] (2) A is A is optionally substituted by 1-3 groups selected from halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl;

[0241] * represents the end connected to the alkyl carbon;

[0242] Or,

[0243] (3) A is * represents the end connected to the alkyl carbon;

[0244] R A1 、R A2 、R A3 、R A4 are each independently R8, and R A1 、R A2 、R A3 、R A4 are not simultaneously H;

[0245] Each R8 is independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxy, NH2, COOH; the alkyl and alkoxy are optionally substituted by 1-3 groups selected from deuterium, halogen, cyano, hydroxy, NH2 and COOH;

[0246] Or,

[0247] (4) A is * indicates connection to the alkyl carbon;

[0248] R1, R2 and R3 are each independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, and the alkyl, alkoxy, alkenyl and alkynyl are optionally substituted by 1-3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxy, NH2 and COOH, and R1, R2 and R3 are not simultaneously H;

[0249] Optionally, R1 and R2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, and the cycloalkyl is optionally substituted by 1-3 groups selected from halogen, cyano, hydroxy, NH2, COOH,

[0250] The undefined group is as described in the fourth technical solution.

[0251] As the sixth technical solution of the present invention, the compound of formula (III), its stereoisomer, deuterated compound, cocrystal, solvate or pharmaceutically acceptable salt, wherein, Selected from one of the following structures:

[0252]

[0253]

[0254] The undefined group is as described in the fifth technical solution.

[0255] As the seventh technical solution of the present invention, the compound of formula (I), its stereoisomer, deuterated compound, cocrystal, solvate or pharmaceutically acceptable salt, and the compound has the structure of formula (IV):

[0256]

[0257] Wherein, Rc is H, halogen, C 1-2 alkyl or C 1-2 alkoxy;

[0258] R1, R2, and R3 are each independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, methoxy, or ethoxy, wherein the methyl, ethyl, methoxy, or ethoxy is optionally substituted with 1 - 3 groups selected from F, Cl, Br, cyano, hydroxy, and NH2;

[0259] Z is CH or N;

[0260] Ring G is a benzene ring optionally substituted with 1 - 2 Rs G or

[0261] each R G is independently selected from F, Cl, Br, I, methyl, ethyl, propyl, SF5, and CN, wherein the methyl, ethyl, or propyl is optionally further substituted with 1 - 3 groups selected from deuterium, F, Cl, Br, and I.

[0262] As the eighth technical solution of the present invention, a compound of formula (I), its stereoisomers, deuterated compounds, cocrystals, solvates, or pharmaceutically acceptable salts, wherein the compound is selected from one of the following structures:

[0263]

[0264]

[0265] As the ninth technical solution of the present invention, a compound of formula (I), its stereoisomers, deuterated compounds, cocrystals, solvates, or pharmaceutically acceptable salts, wherein the compound is selected from one of the following structures:

[0266]

[0267]

[0268] As the tenth technical solution of the present invention, the present invention further provides a pharmaceutical composition comprising the compound described in any one of the first to ninth technical solutions, its stereoisomers, deuterated compounds, cocrystals, solvates, or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier and / or excipient.

[0269] The present invention further provides the use of the compound described in any one of the first to ninth technical solutions, its stereoisomers, deuterated compounds, cocrystals, solvates, or pharmaceutically acceptable salts, or the composition described in the tenth technical solution in the preparation of a drug for treating diseases mediated by dipeptidyl peptidase 1.

[0270] Furthermore, the diseases mediated by dipeptidyl peptidase 1 are selected from airway obstructive diseases, bronchiectasis, cystic fibrosis, asthma, emphysema, and chronic obstructive pulmonary disease, etc.

[0271] Synthetic route

[0272] Those skilled in the art can prepare the compounds of the present invention by combining known organic synthesis techniques, and the starting materials thereof are commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and the suppliers include companies such as Titan Technology, Energy Chemical, Shanghai Dermachem, Chengdu Kelong Chemical Industry, Shaoyuan Chemical Technology, Nanjing Pharmatech, WuXi AppTec, and J&K Scientific, etc.

[0273] Reference books and monographs in this field have detailed descriptions of the synthesis of reactants that can be used to prepare the compounds described herein, or provide articles describing such preparation methods for reference. These reference books and monographs include: “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S.R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H.O. House, “Modern Synthetic Reactions”, 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. 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, R.V. “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 and Intermediates: An Ullmann’s Encyclopedia” (1999), John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942 - 2000), John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups”, John Wiley & Sons, in 73 volumes.

[0274] The indexes of known chemical substances prepared by the Chemical Abstracts Service of the American Chemical Society can be used to selectively identify specific and similar reactants. These indexes are available in most public and university libraries, as well as online. Chemicals that are known but not commercially available in catalogs can optionally be prepared by custom chemical synthesis plants, and many standard chemical supply plants (e.g., those listed above) offer custom synthesis services. A reference for the preparation and selection of the pharmaceutical salts of the compounds described herein is P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0275] The term

[0276] Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:

[0277] In the groups and compounds described in the present invention, carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen all include their isotopes, and carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds described in the present invention are optionally further replaced by one or more of their corresponding isotopes. Isotopes of carbon include 12 C, 13 C, and 14 C. Isotopes of hydrogen include protium (H), deuterium (deuterium, also known as heavy hydrogen), tritium (T, also known as superheavy hydrogen). Isotopes of oxygen include 16 O, 17 O, and 18 O. Isotopes of sulfur include 32 S, 33 S, 34 S, and 36 S. Isotopes of nitrogen include 14 N, and 15 N. Isotopes of fluorine 19 F. Isotopes of chlorine include 35 Cl, and 37 Cl. Isotopes of bromine include 79 Br, and 81 Br.

[0278] "Halogen" as used herein refers to F, Cl, Br, I, or their isotopes.

[0279] "Halogenated" or "halogen substitution" means substitution by more than one selected from F, Cl, Br, I, or their isotopes. The upper limit of the number of halogen substituents is equal to the sum of the hydrogen atoms that can be substituted in the group being substituted. Without special limitation, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, the substitution can be by the same or different halogens. It generally includes cases of 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, and 1 halogen substitution.

[0280] "Deuterium" refers to the isotope deuterium of hydrogen (H).

[0281] "Deuterated" means the situation where at least one hydrogen atom on groups such as alkyl, cycloalkyl, alkylene, aryl, heteroaryl, alkenyl, alkynyl, etc. is substituted by the isotope deuterium. The upper limit of the number of deuterium substitutions is equal to the sum of the hydrogen atoms that can be substituted in the group being substituted. Without special limitation, the number of deuterium substitutions is any integer between 1 and the upper limit. Preferably, it is substituted by 1-20 deuterium atoms, more preferably by 1-10 deuterium atoms, more preferably by 1-6 deuterium atoms, and further preferably by 1-3 deuterium atoms.

[0282] "C x-y " group means a group containing x to y carbon atoms. For example, "C 1-6 alkyl" refers to an alkyl group containing 1-6 carbon atoms.

[0283] "Alkyl" means a monovalent straight-chain or branched-chain saturated aliphatic hydrocarbon group. Without special indication, it is an alkyl group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms, more preferably an alkyl group with 1 to 6 carbon atoms, and further preferably an alkyl group with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched-chain isomers.

[0284] "Alkylene" means a divalent straight-chain and branched-chain saturated alkyl group. Examples of alkylene include but are not limited to methylene, ethylene, etc.

[0285] "Halogenated alkyl" means the situation where one or more hydrogens in an alkyl group are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, iodine, or their isotopes). The upper limit of the number of halogen substituents is equal to the sum of the hydrogen atoms that can be substituted in 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 by 1-5 halogens, or 1-3 halogens, or 1-2 halogens, or 1 halogen; when the number of halogen substituents is greater than 1, the substitution can be by the same or different halogens; specific examples include but are not limited to -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0286] "Alkoxy" or "alkyloxy" means -O-alkyl. For example, -O-C 1-8 alkyl, -O-C 1-6 alkyl, -O-C 1-4 alkyl or -O-C 1-2 alkyl. Specific non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy, cyclobutoxy, etc.; the alkoxy may be optionally substituted with substituents.

[0287] "Halogenated alkoxy" means -O-haloalkyl. For example, -O-haloC 1-8 alkyl, -O-haloC 1-6 alkyl, -O-haloC 1-4 alkyl or -O-haloC 1-2 alkyl; the upper limit of the number of halogen substituents is equal to the sum of the hydrogen atoms that the substituted group can be substituted with. Without special limitation, the number of halogen substituents is any integer between 1 and this upper limit, preferably 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, 1 halogen substitution; when the number of halogen substituents is greater than 1, it can be substituted with the same or different halogens; non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, etc.

[0288] "Alkylamino" or "alkamino" means an amino group substituted by one or two alkyl groups, also written as -N-(alkyl)2 or -NH-alkyl, and the latter is also written as monoalkylamino. Non-limiting examples include dimethylamino, monomethylamino, diethylamino, monoethylamino, etc.

[0289] "Alkenyl" means a straight-chain or branched-chain hydrocarbon group containing at least one carbon-carbon double bond (C═C), usually containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and still further such as 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc.; the alkenyl may be optionally further substituted with substituents.

[0290] "Alkenylene" refers to a divalent unsaturated hydrocarbon group that is straight-chain or branched-chain and contains at least one carbon-carbon double bond (C═C). Unless otherwise specified, the alkenylene contains 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. Non-limiting examples include ethynylene. The alkenylene may optionally be substituted with substituents.

[0291] "Alkynyl" refers to a straight-chain or branched-chain hydrocarbon group that contains at least one carbon-carbon triple bond (C≡C), usually containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, and still further containing 2 to 4 carbon atoms. Examples thereof include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, etc.; the alkynyl may optionally be substituted with substituents.

[0292] "Alkynylene" refers to a divalent unsaturated hydrocarbon group that is straight-chain or branched-chain and contains a carbon-carbon triple bond (C≡C), usually containing 2 to 6 carbon atoms, further containing 2 to 4 carbon atoms. Non-limiting examples include ethynylene, propynylene, butynylene. The alkynylene may optionally be substituted with substituents. "Cycloalkyl" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group that does not contain ring heteroatoms. The cycloalkyl may be monocyclic, bicyclic or polycyclic. The bicyclic or polycyclic may be a fused ring, a spiro ring, a bridged ring or a combination thereof. The bicyclic or polycyclic may include one or more aromatic rings, but the entire ring system is not aromatic. The connecting site may be on the aromatic ring or the non-aromatic ring. Usually, the cycloalkyl contains 3 to 20 carbon atoms, further contains 3 - 8 carbon atoms, and still further contains 3 - 6 carbon atoms; when it is a monocyclic cycloalkyl, it contains 3 - 15 carbon atoms, or 3 - 10 carbon atoms, or 3 - 8 carbon atoms, or 3 - 6 carbon atoms; when it is a bicyclic or polycyclic cycloalkyl, it contains 5 - 12 carbon atoms, or contains 5 - 11 carbon atoms, or contains 6 - 10 carbon atoms; non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl, etc., and the cycloalkyl may optionally be substituted with substituents. "Cycloalkylene" refers to a divalent saturated, substituted or unsubstituted cycloalkyl. Non-limiting examples include

[0293] "Carbocyclic" or "carbocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic carbocyclic group, including monocyclic carbocycles and bicyclic bridged rings, bicyclic fused rings, bicyclic spiro rings, and polycyclic rings with three or more rings, etc. There are usually 3 to 14 carbon atoms, preferably 3 - 12 carbon atoms, more preferably 6 - 8 carbon atoms or 3 - 6 carbon atoms. In non-limiting examples, monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, etc. Bicyclic bridged rings such as etc., bicyclic fused rings such as etc., bicyclic spiro rings such as etc., tricyclic rings such as etc.

[0294] "Heterocyclic" or "heterocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, and when not specifically limited, contains 1 to 5 heteroatoms selected from N, O, or S, preferably contains 1 to 4 heteroatoms, more preferably contains 1 - 3 heteroatoms, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, and bicyclic spiro heterocycles, as well as heterocyclic rings with three or more rings, etc. Preferably, it is a 3 - 15 membered heterocycle, more preferably a 4 - 14 membered heterocycle, more preferably a 4 - 10 membered heterocycle, 5 - 12 membered heterocycle, and further preferably a 5 - 8 membered heterocycle, 5 - 6 membered heterocycle. The heterocycle is preferably a saturated heterocycle, such as a 5 - 12 membered saturated heterocycle, and further preferably a 5 - 8 membered saturated heterocycle, 7 - membered saturated heterocycle, or 5 - 6 membered saturated heterocycle. The ring atoms N and S of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom. Non-limiting examples include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, 1,3 - dioxolanyl, 1,4 - dioxolanyl, 1,3 - dioxanyl, piperazinyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N - alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3 - dithiolyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azadamantyl, and oxaspiro[3.3]heptyl, etc.

[0295] "Heterocyclene group" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic divalent heterocyclic group. Non-limiting examples include etc.

[0296] "Aryl" refers to a group having aromaticity, including 5- and 6-membered monocyclic aromatic groups that may contain 0 to 4 N, S, O heteroatoms, and polycyclic systems having at least one aromatic ring. Its concept includes aromatic carbocycles and heteroaromatic rings, such as phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine, etc. Polycyclic aryl (tricyclic or bicyclic) such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxybenzene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycle", "heteroaryl", or "heteroaromatic ring".

[0297] "Spiro ring" refers to a polycyclic group in which the rings share a single carbon atom (called the spiro atom), which may contain 0 or more than 1 double bond or triple bond, and may contain 0 to 5 heteroatoms selected from N, O, S, P, Si and their oxidation states. Usually, the spiro ring is a 6- to 14-membered ring, or a 6- to 12-membered ring, or a 6- to 10-membered ring. Usually, the spiro ring is trispirotricyclo (indicating a tricyclic ring spiro trispiro), trispiro tetra, trispiro penta, trispiro hexa, tetraspiro tetra, tetraspiro penta, tetraspiro hexa, pentaspiro penta or pentaspiro hexa. Non-limiting examples of the spiro ring include

[0298] The described spiro ring may be optionally substituted by substituents.

[0299] "Fused ring" refers to a polycyclic group in which the rings share two adjacent ring atoms and a chemical bond, which may contain one or more double bonds or triple bonds, and the fused ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. Usually, the fused 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. Usually, the fused ring is tricyclic-fused-tetracyclic (indicating a fused ring formed by a tricyclic ring and a tetracyclic ring, according to the IUPC naming rules, it may be a fused ring with the tricyclic ring as the basic ring or the tetracyclic ring as the basic ring, and the same applies hereinafter), tricyclic-fused-pentacyclic, tricyclic-fused-hexacyclic, tetracyclic-fused-tetracyclic, tetracyclic-fused-pentacyclic, tetracyclic-fused-hexacyclic, pentacyclic-fused-pentacyclic, pentacyclic-fused-hexacyclic, hexacyclic-fused-hexacyclic. Non-limiting examples of the fused ring include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene,

[0300] The described fused ring may be optionally substituted by substituents.

[0301] "Bridged ring" means that two rings share two non-adjacent ring atoms and may contain one or more double bonds or triple bonds. The bridged ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidized states. Generally, the ring atoms of the bridged ring are 5 to 20, or 5 to 14, or 5 to 12, or 5 to 10. Non-limiting examples of bridged rings include adamantane,

[0302]

[0303] "Substituted" or "substituent", unless otherwise specified, means any substitution at a position allowed by chemical theory, and the number of substituents conforms to the chemical bond rules. Exemplary substituents include, but are not limited to: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 heteroalkyl, C 5-12 aryl, 5-12 membered heteroaryl, hydroxy, C 1-6 alkoxy, C 5-12 aryloxy, mercapto, 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 alkyl, etc.

[0304] "Optional" or "optionally" means that the subsequently described event or circumstance may but does not have to occur, and this description includes the instances where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted by F" means that the alkyl may but does not have to be substituted by F, and the description includes the case where the alkyl is substituted by F and the case where the alkyl is not substituted by F.

[0305] When a substituent is optionally further substituted, groups that cannot be formed according to chemical common sense are not included.

[0306] When a group is selected from atoms or groups such as H or deuterium, if the group is optionally further substituted, further substitution of H or deuterium atoms is not included.

[0307] "Pharmaceutically acceptable salt" means a salt of a compound of the present invention that retains the biological activity and characteristics of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0308] "Pharmaceutical composition" means a mixture of one or more compounds described herein or their stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals, and other components, where the other components include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0309] "Carrier" refers to a system that does not cause significant irritation to the organism, does not eliminate the biological activity and characteristics of the administered compound, can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug, and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0310] "Excipient" means: a substance which is not itself a therapeutic agent and which is used as a diluent, adjuvant, binder and / or vehicle for addition to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate the formation of a unit dosage form for administration of a compound or pharmaceutical composition. As is known to those skilled in the art, pharmaceutical excipients can provide various functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifying agents, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents and sweetening agents. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose and cross-linked carboxymethyl cellulose (e.g., sodium cross-linked carboxymethyl cellulose); (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) diols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic and compatible substances used in pharmaceutical formulations.

[0311] "Stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0312] "Solvate" refers to a substance formed by the compound or its salt of the present invention in combination with a stoichiometric or non-stoichiometric amount of a solvent through intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

[0313] "Co-crystal" refers to a crystal formed by the binding of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) through hydrogen bonding or other non-covalent bonds, where both the pure states of the API and the CCF are solids at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate. Detailed Description

[0314] The content of the present invention will be described in detail below by way of examples. For those conditions not specified in the examples, the experimental methods under conventional conditions are adopted. The examples are given to better illustrate the content of the present invention, but it should not be understood that the content of the present invention is limited to the given examples. Non-essential improvements and adjustments made by those of ordinary skill in the art to the implementation solutions based on the above invention content still fall within the protection scope of the present invention.

[0315] Detection method

[0316] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10-6 (ppm). The NMR measurement is performed using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometers, and the solvents for measurement are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS);

[0317] The MS measurement is performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0318] The HPLC measurement is performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);

[0319] The thin-layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specification of the silica gel plates used for thin-layer chromatography (TLC) is 0.15mm - 0.20mm, and the specification of the silica gel plates used for thin-layer chromatography separation and purification of products is 0.4mm - 0.5mm;

[0320] Column chromatography generally uses Yantai Huanghai silica gel with 200 - 300 mesh as the carrier.

[0321] Abbreviation description:

[0322] Burgess reagent: (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt

[0323] Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II)

[0324] X-Phos: 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

[0325] DMF: N,N-dimethylformamide

[0326] HATU: 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0327] DIPEA: N,N-Diisopropylethylamine

[0328] LDA: Lithium diisopropylamide

[0329] PE: Petroleum ether

[0330] EA: Ethyl acetate

[0331] THF: Tetrahydrofuran

[0332] MeOH: Methanol

[0333] DCM: Dichloromethane

[0334] TMSOTf: Trimethylsilyl trifluoromethanesulfonate

[0335] Intermediate

[0336] INT-1: tert-Butyl (S)-(1-cyano-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate

[0337] 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, the preparation method refers to WO2013041497) was dissolved in 1,4-dioxane (45 ml), then pinacol borane (3.12 g, 24.2 mmol), triethylamine (3.67 g, 36.3 mmol), and Pd(dppf)Cl2 (877 mg, 1.2 mmol) were added. After the addition, the reaction was carried out under microwave irradiation at 100 °C for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (the eluent ratio was PE:EA (v / v) = 1:0 to 10:1) to obtain INT-1, a white solid (2.1 g, yield 46.7%). LCMS m / z = 373.2 [M+1] + 。

[0340] 1H NMR (400MHz, CDCl3) δ7.81(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: (S)-tert-butyl (1-cyano-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate

[0342] tert-butyl(S)-(1-cyano-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate

[0343]

[0344] Compound 2a (2.0 g, 5.8 mmol, preparation method refer to WO2016016242) was dissolved in ethylene glycol dimethyl ether (40 ml), and diboric acid pinacol ester (2.23 g, 8.7 mmol), potassium acetate (1.70 g, 17.4 mmol), Pd (dppf) Cl2 (423.1 mg, 0.58 mmol) were added and heated to 90 ° C for 3 hours. After the reaction was completed, the filtrate was filtered and concentrated. The residue was separated and purified by silica gel column chromatography (eluent ratio PE: EA (v / v) = 1: 0 ~ 10: 1) to obtain INT-2, a white solid (2.1 g, yield 92.1%). LCMS m / z = 335.2 [M + 1-56] + .

[0345] 1 H NMR (400MHz, CDCl3) δ7.56(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).

[0346] Example 1: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxaazepine-2-carboxamide (Compound 1)

[0347] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 1)

[0348]

[0349] Step 1: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate (1B)

[0350] (S)-tert-butyl(1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate(1B)

[0351] Dissolve 1A (0.29 g, 0.85 mmol, the synthesis method refers to WO 2016016242A1) in 1,4-dioxane (10 mL) and water (0.4 mL), add intermediate 2a (0.35 g, 1.27 mmol), potassium carbonate (0.24 g, 1.70 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (70 mg, 0.09 mmol). After addition, react at 90 °C for 3 h. Cool to room temperature, add saturated sodium chloride aqueous solution (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue 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] + 。

[0352] Step 2: (S)-2-amino-3-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile (1C)

[0353] (S)-2-amino-3-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile(1C)

[0354] 1B (0.34 g, 0.83 mmol) was dissolved in formic acid (5 mL). After addition, the reaction was carried out at room temperature overnight. It was concentrated to dryness, ethyl acetate (25 mL) was added, and saturated aqueous sodium bicarbonate was added dropwise to adjust the pH to about 8. The organic layer was separated, extracted with ethyl acetate (25 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, the title compound 1C (pale yellow solid, 0.21 g, 69.5%). LC-MS (ESI): m / z = 312.1 [M+H] + 。

[0355] Step 3: (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (1D)

[0356] (S)-tert-butyl 2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3–dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(1D)

[0357] 1C (0.21 g, 0.60 mmol) was dissolved in DMF (10 mL), DIPEA (0.23 g, 1.80 mmol), HATU (0.34 g, 0.90 mmol), and INT-3 (0.22 g, 0.90 mmol, the preparation method refers to WO2015110826) were added. After addition, the reaction was carried out at room temperature overnight. The reaction was quenched by adding saturated aqueous ammonium chloride dropwise, saturated aqueous sodium chloride (30 mL) was added, extracted with ethyl acetate (25 mL), the organic phase was washed with saturated aqueous sodium chloride (25 mL × 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 directly used in the next step. LC-MS (ESI): m / z = 483.1 [M - 57+H] + 。

[0358] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 1)

[0359] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 1)

[0360] Dissolve 1D (0.32 g, 0.59 mmol) in formic acid (2.5 mL). After addition, react at 50 °C for 10 min. Concentrate to dryness, add ethyl acetate (20 mL), adjust to pH about 8 by dropwise addition of saturated aqueous sodium bicarbonate solution, separate the organic layer, extract with ethyl acetate (25 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (methylene chloride:methanol (v / v) = 20:1) to obtain the title compound 1 (0.15 g, 58.0%). LC-MS (ESI): m / z = 439.1 [M+H] + 。

[0361] 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).

[0362] Example 2: N-((S)-1-cyano-2-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 2)

[0363] N-((S)-1-cyano-2-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 2)

[0364]

[0365] The first step: 4-bromo-1-(bromomethyl)-2-methoxybenzene (2B)

[0366] 4-bromo-1-(bromomethyl)-2-methoxybenzene(2B)

[0367] (2A) (4 g, 18.43 mmol) was dissolved in DCM (60 mL), CBr4 (9.09 g, 27.64 mmol) was added, and PPh3 (7.24 g, 27.64 mmol) was slowly added. The reaction was carried out at room temperature for 1 h. PE / EA (v / v = 5:1, 12 mL) was added to the reaction solution, stirred, filtered by suction, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (PE:EA (v / v) = 30:1 - 20:1) to obtain the title compound (2B), a white solid (3.9 g, yield 76%).

[0368] Step 2: (2S,5R)-2-(4-bromo-2-methoxybenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine(2C)

[0369] (2S,5R)-2-(4-bromo-2-methoxybenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine(2C)

[0370] (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1 g, 5.43 mmol) was dissolved in THF (20 mL), purged with nitrogen, cooled to -78 °C, n-butyllithium (6.5 mmol, 2.5 M in toluene, 2.6 mL) was added, and the reaction was carried out for 1 h. Subsequently, a THF (8 mL) solution of 2B (1.67 g, 5.97 mmol) was added, and the reaction was continued at -78 °C for 2 h. The reaction was quenched with saturated NH4Cl solution, the system was extracted with EA (10 mL × 3), the organic phases were combined, the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (EA / PE (v / v) = 0% - 6%) to obtain the title compound (2C), a colorless oil (1.82 g, yield 87%). LCMS m / z = 383.3 [M+1] +

[0371] Step 3: methyl (S)-2-amino-3-(4-bromo-2-methoxyphenyl)propanoate(2D)

[0372] methyl (S)-2-amino-3-(4-bromo-2-methoxyphenyl)propanoate(2D)

[0373] Dissolve 2C (1.82 g, 4.75 mmol) in acetonitrile (15 mL), add 1 M HCl (5 mL), and react at room temperature overnight. Rotate the system to dryness, add saturated sodium bicarbonate aqueous solution to neutralize the system to weak alkalinity, add EA (15 mL × 3) for extraction and liquid separation. Combine the organic phases, wash the organic phase with saturated brine (10 mL), dry with anhydrous sodium sulfate, concentrate, and purify the residue by silica gel column chromatography (DCM: MeOH (v / v) = 20:1 - 10:1) to obtain 2D (1.34 g, yield 97%). LCMS m / z = 288.1 [M+1] +

[0374] Step 4: Methyl (S)-3-(4-bromo-2-methoxyphenyl)-2-((tert-butoxycarbonyl)amino)propanoate (2E)

[0375] methyl(S)-3-(4-bromo-2-methoxyphenyl)-2-((tert-butoxycarbonyl)amino)propanoate(2E)

[0376] Dissolve 2D (1.34 g, 4.69 mmol) in DCM (20 mL), add triethylamine (1.3 mL) and di-tert-butyl dicarbonate (1.23 g, 5.63 mmol), and react at room temperature for 3 h. Add water to the system, perform extraction and liquid separation. Combine the organic phases, wash the organic phase with saturated brine (10 mL), dry with anhydrous sodium sulfate, concentrate, and purify the residue by silica gel column chromatography (DCM: MeOH (v / v) = 20:1 - 10:1) to obtain 2E, colorless oil (0.7 g, yield 31%). LCMS m / z = 288.1 [M-boc+1] +

[0377] Step 5: (S)-3-(4-bromo-2-methoxyphenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (2F)

[0378] (S)-3-(4-bromo-2-methoxyphenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid(2F)

[0379] Dissolve 2E (0.7 g, 1.87 mmol) in methanol (10 mL) and water (6 mL), add NaOH (1.50 g, 3.74 mmol), and react at room temperature for 2 h. Rotate off the methanol, add dilute hydrochloric acid to adjust the pH to weak acidity, add EA (10 mL × 3) for extraction and liquid separation, and rotate the organic phase to dryness to obtain the crude product (2F) (0.65 g). LCMS m / z = 274.2 [M-boc+1] +

[0380] Step 6: (S)-tert-butyl (1-amino-3-(4-bromo-2-methoxyphenyl)-1-oxopropan-2-yl)carbamate (2G)

[0381] tert-butyl(S)-(1-amino-3-(4-bromo-2-methoxyphenyl)-1-oxopropan-2-yl)carbamate(2G)

[0382] Dissolve 2F (0.65 g, 1.73 mmol), NH4Cl (0.74 g), HATU (0.66 g, 1.73 mmol) in DMF (15 mL), add DIPEA (1.15 mL), react at room temperature overnight, add water and EA, separate and extract, dry and concentrate the organic phase over anhydrous Na2SO4 to obtain a crude product (2G) (0.62 g). LCMS m / z = 273.1 [M-boc+1] +

[0383] Step 7: (S)-tert-butyl (2-(4-bromo-2-methoxyphenyl)-1-cyanoethyl)carbamate (2H)

[0384] tert-butyl(S)-(2-(4-bromo-2-methoxyphenyl)-1-cyanoethyl)carbamate(2H)

[0385] 2G (0.62 g, 1.66 mmol) was dissolved in DCM (10 mL), and Burgess reagent (0.79 g, 3.32 mmol) was added, and the reaction was allowed to react at room temperature overnight. The system was concentrated and dried, and the crude product was separated and purified by silica gel column chromatography (EA / PE (v / v) = 0% -25%) to obtain 2H (0.5 g, yield 85%). LCMS m / z = 355.1 [M+1] +

[0386] Step 8: (S)-tert-butyl (1-cyano-2-(2-methoxy-4-(3-methyl-2-oxy-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate (2I)

[0387] tert-butyl(S)-(1-cyano-2-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate(2I)

[0388] Dissolve 2H (0.5 g, 1.41 mmol), 1B (0.11 g, 1.41 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (115 mg, 0.14 mmol), and potassium carbonate (390 mg, 2.82 mmol) in 1,4-dioxane (20 mL). Protect the system by purging with nitrogen, and react at 90 °C for 3 hours. Concentrate and rotary evaporate to dryness, dissolve in DCM, filter through diatomaceous earth, rotary evaporate the filtrate, and separate the crude product by silica gel column chromatography (EA / PE (v / v) = 0% - 40%) to obtain 2I, a pale yellow solid (550 mg, yield 92%). LCMS m / z = 424.2 [M+1] +

[0389] Step 9: (S)-2-amino-3-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile (2J)

[0390] (S)-2-amino-3-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile(2J)

[0391] Dissolve 2I (135 mg, 0.32 mmol) in formic acid (8 mL), and stir at room temperature overnight. Dilute the system with DCM, adjust to weak alkalinity by adding saturated sodium bicarbonate solution, separate the DCM and water layers, dry and concentrate the organic phase, and rotary evaporate to dryness to obtain the crude product (2J) (90 mg), which is directly used in the next step. LCMS m / z = 324.1 [M+1] +

[0392] Step 10: tert-butyl (S)-2-(((S)-1-cyano-2-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (2K)

[0393] tert-butyl(S)-2-(((S)-1-cyano-2-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(2K)

[0394] Dissolve 2J (90 mg, 0.28 mmol) and INT-3 (82 mg, 0.34 mmol) in DMF (5 mL), add HATU (0.12 g, 0.31 mmol) and DIPEA (0.2 mL), and react at room temperature overnight. Add water and EA to the reaction system, perform liquid-liquid extraction, dry and concentrate the organic phase to obtain a pale yellow oily crude product, and obtain 2K (90 mg) through MeOH / DCM (v / v) = 0 - 10%. LCMS m / z = 549.1 [M+1] +

[0395] Step 11: (S)-N-((S)-1-cyano-2-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 2)

[0396] (S)-N-((S)-1-cyano-2-(2-methoxy-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 2)

[0397] Dissolve 2K (90 mg, 0.16 mmol) in formic acid (5 mL), and react at room temperature for 4 hours. Dilute the system with DCM, adjust to weak alkalinity by adding saturated sodium bicarbonate solution, separate the DCM and water by liquid-liquid extraction, dry and concentrate the organic phase, and rotary evaporate to obtain a residue. The residue is purified by silica gel column chromatography (DCM:MeOH (v / v) = 50:1 - 5:1) to obtain the title compound 2 (13 mg, yield 18%). LC-MS m / z = 451.2 [M+1] +

[0398] 1 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).

[0399] Example 3: N-((S)-1-cyano-2-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 3)

[0400] (S)-N-((S)-1-cyano-2-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 3)

[0401]

[0402] Compound 3 was prepared from Compound 3A according to the preparation method of Reference Compound 2. LC-MS m / z = 439.2 [M+1] +

[0403] 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).

[0404] 19 F NMR (376 MHz, CDCl3) δ -117.13.

[0405] Example 4: (S)-N-((S)-1-cyano-2-(5-(1-methyl-2-oxoindolin-6-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 4)

[0406] (S)-N-((S)-1-cyano-2-(5-(1-methyl-2-oxoindolin-6-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 4)

[0407]

[0408] Step 1: 6-bromo-1-methylindolin-2-one(4B)

[0409] 6-bromo-1-methylindolin-2-one(4B)

[0410] Dissolve 4A (5 g, 23.5 mmol) in 200 mL of acetonitrile, add potassium carbonate (23 g, 94.32 mmol) and methyl iodide (2.96 mL, 47.16 mmol), and heat to 70 °C and stir overnight. Concentrate the reaction solution, extract with DCM and water, dry and concentrate the organic phase, and separate 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] + 。

[0411] Step 2: 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(4C)

[0412] methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(4C)

[0413] Mix compound 4B (1 g, 4.42 mmol), palladium acetate (200 mg, 0.88 mmol), potassium acetate (0.87 g, 8.84 mmol), 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (1.2 g, 2.65 mmol), and bis(pinacolato)diboron (1.35 g, 5.3 mmol) and dissolve in 50 mL of 1,4-dioxane. Heat to 95 °C under N2 protection and react for 3 hours. Monitor the reaction by LCMS until completion. Concentrate the reaction solution and separate by column chromatography (PE:EA (v / v) = 1:1) to obtain pale yellow solid 4C (880 mg, 73%). LC-MS (ESI): m / z = 274.2 [M+H] + 。

[0414] Step 3: tert-butyl-(S)-(1-cyano-2-(5-(1-methyl-2-oxoindolin-6-yl)thiophen-2-yl)ethyl)carbamate(4D)

[0415] tert-butyl-(S)-(1-cyano-2-(5-(1-methyl-2-oxoindolin-6-yl)thiophen-2-yl)ethyl)carbamate(4D)

[0416] tert-Butyl N-[(1S)-2-(5-bromothiophen-2-yl)-1-cyanoethyl]carbamate (480 mg, 1.45 mmol), 4C (475 mg, 1.74 mmol), potassium carbonate (400 mg, 2.9 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (21 mg, 0.29 mmol) were mixed in 5 mL of 1,4-dioxane and 0.1 mL of water, and the mixture was heated to 120 °C by microwave irradiation for 1 h. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated, and the residue was purified by column chromatography (PE:EA (v / v) = 1:1) to give a pale yellow solid 4D (175 mg, 33%). LC-MS (ESI): m / z = 398.2 [M+H] + 。

[0417] Step 4: (S)-2-Amino-3-(5-(1-methyl-2-oxoindolin-6-yl)thiophen-2-yl)propanenitrile (4E)

[0418] (S)-2-amino-3-(5-(1-methyl-2-oxoindolin-6-yl)thiophen-2-yl)propanenitrile(4E)

[0419] Formic acid (3 mL) was added to compound 4D (175 mg, 0.44 mmol), and the mixture was stirred at room temperature for 3 h. After the reaction was monitored by LCMS until completion, the reaction mixture was adjusted to pH 10 with saturated sodium carbonate solution, extracted with DCM, and the organic layer was dried and concentrated to give the product 4E (119 mg, 91%). LC-MS (ESI): m / z = 298.1 [M+H] + 。

[0420] Step 5: tert-Butyl (S)-2-(((S)-1-cyano-2-(5-(1-methyl-2-oxoindolin-6-yl)thiophen-2-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (4F)

[0421] tert-butyl-(S)-2-(((S)-1-cyano-2-(5-(1-methyl-2-oxoindolin-6-yl)thiophen-2-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(4F)

[0422] Compound 4E (119 mg, 0.4 mmol), INT-3 (98 mg, 0.4 mmol), HATU (180 mg, 0.48 mmol), and DIEA (0.13 mL, 0.8 mmol) were mixed and dissolved in DMF, and stirred at room temperature overnight. The reaction was monitored by LCMS until completion. Water was added, and the mixture was extracted with EA. The organic phase was dried and concentrated, and separated by column chromatography (PE:EA (v / v) = 1:1) to obtain yellow solid 4F (165 mg, 78%). LC-MS (ESI): m / z = 525.2 [M+H] + 。

[0423] Step 6: (S)-N-((S)-1-cyano-2-(5-(1-methyl-2-oxoindolin-6-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 4)

[0424] (S)-N-((S)-1-cyano-2-(5-(1-methyl-2-oxoindolin-6-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 4)

[0425] Compound 4F (145 mg, 0.28 mmol) was dissolved in 3 mL of formic acid solution and reacted at room temperature for 3 hours. The reaction was monitored by LCMS until completion. The reaction solution was poured into saturated sodium carbonate solution, adjusted to pH 10, extracted with EA. The organic phase was dried and concentrated, and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 1:100 - 1:10) to obtain compound 4 (45 mg, 38%). LC-MS (ESI): m / z = 425.2 [M+H] + 。

[0426] 1 1H 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).

[0427] Example 5: ((S)-N-((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 5)

[0428] (S)-N-((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 5)

[0429]

[0430] First step: (S)-3-(5-bromothiophen-2-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (5B)

[0431] (S)-3-(5-bromothiophen-2-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (5B)

[0432] Dissolve 5A (10 g, 40.3 mmol) in methanol (200 mL), add triethylamine (12.2 g, 120.9 mmol), add di-tert-butyl dicarbonate (10.5 g, 48.36 mmol), react at room temperature for 2 hours, concentrate, adjust the pH to 6 - 7 with dilute hydrochloric acid (1 N), extract with dichloromethane, and then concentrate and purify by silica gel column chromatography (methanol:dichloromethane (v / v) = 1:100 - 1:10) to obtain the title compound (5B), a yellow solid (14 g, yield 99%). LCMS m / z = 350.23 [M+1] +

[0433] Second step: tert-butyl (S)-(1-amino-3-(5-bromothiophen-2-yl)-1-oxopropan-2-yl)carbamate (5C)

[0434] tert-butyl (S)-(1-amino-3-(5-bromothiophen-2-yl)-1-oxopropan-2-yl)carbamate (5C)

[0435] 5B (4 g, 11.5 mmol) was dissolved in DMF (50 mL), ammonium chloride (620 mg, 11.5 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (4.4 mg, 13.8 mmol), and DIPEA (2.9 g, 23.0 mmol) were added. The reaction was carried out overnight at room temperature. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3), washed with water three times (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 1:100 - 1:10) to obtain the title compound (5C), a pale yellow solid (1.8 g, yield 45%). LC-MS m / z = 349.01 [M+1] +

[0436] Step 3: tert-butyl (S)-(2-(5-bromothiophen-2-yl)-1-cyanoethyl)carbamate (5D)

[0437] tert-butyl(S)-(2-(5-bromothiophen-2-yl)-1-cyanoethyl)carbamate(5D)

[0438] 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 reaction was carried out at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA (v / v) = 1:10 - 1:5) to obtain the title compound (5D), a pale yellow solid (1.4 g, yield 81%). LCMS m / z = 331.23 [M+1] +

[0439] Step 4: tert-butyl (S)-(1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)carbamate (5E)

[0440] tert-butyl(S)-(1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)carbamate(5E)

[0441] 5D (700 mg, 2.1 mmol) was dissolved in dioxane (10 mL), and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H) (825 mg, 3.0 mmol), potassium carbonate (869 mg, 6.3 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (70 mg) were added. Then water (2 mL) was added, and the reaction was carried out at 100 °C for 12 hours under nitrogen protection. After concentration, it was purified by silica gel column chromatography (PE:EA (v / v) = 1:5 - 1:1) to obtain the title compound (5E), a yellow solid (290 mg, yield 34%). LCMS m / z = 400.13 [M+1] +

[0442] Step 5: ((S)-2-Amino-3-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl]thiophen-2-yl)propanenitrile (5F)

[0443] (S)-2-amino-3-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)propanenitrile(5F)

[0444] 5E (290 mg, 0.73 mmol) was dissolved in formic acid (5 mL), and the reaction was carried out at room temperature for 3 hours. The pH was adjusted to 7 - 8 with saturated aqueous sodium carbonate solution, and it was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 1:100 - 1:10) to obtain the title compound (5F), a yellow solid (150 mg, yield 69%). LCMS m / z = 300.07 [M+1] +

[0445] Step 6: (S)-2-(((S)-1-Cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (5G)

[0446] tert-butyl(S)-2-(((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(5G)

[0447] Dissolve 5F (90 mg, 0.30 mmol) in DMF (10 mL). Sequentially add HATU (152 mg, 0.4 mmol), DIEA (116 mg, 0.9 mmol), and (S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (73 mg, 0.30 mmol). React at room temperature for 12 hours. Add water (30 mL), extract with ethyl acetate (30 mL × 3). Combine the organic phases, wash the organic phases with water (30 mL × 2), then wash with saturated brine (30 mL × 1), dry over anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography (methanol:dichloromethane (v / v) = 1:100 - 1:10) to obtain the title compound (5G), a yellow solid (100 mg, yield 64%). LCMS m / z = 527.19 [M+1] +

[0448] Step 7: (S)-N-((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 5)

[0449] (S)-N-((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide(compound 5)

[0450] Dissolve 5G (100 mg, 0.19 mmol) in formic acid (2 mL). React at room temperature for 3 hours. Adjust the pH to 7 - 8 with saturated aqueous sodium carbonate, extract with dichloromethane (30 mL × 3). Combine the organic phases, wash the organic phases with saturated aqueous sodium chloride (50 mL), dry over anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography (methanol:dichloromethane (v / v) = 1:100 - 1:10) to obtain the title compound 5 (25 mg, yield 31%). LCMS M / Z (ESI): m / z = 427.14 [M+1] +

[0451] 1 1H 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).

[0452] Example 6: (S)-N-((S)-2-(4-(7-Acetamido-2,3-dihydro-1H-inden-4-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (Compound 6)

[0453] (S)-N-((S)-2-(4-(7-acetamido-2,3-dihydro-1H-inden-4-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (compound 6)

[0454]

[0455] First step: tert-butyl (S)-(2-(4-(7-acetamido-2,3-dihydro-1H-inden-4-yl)-2-fluorophenyl)-1-cyanoethyl)carbamate (6B)

[0456] tert-butyl (S)-(2-(4-(7-acetamido-2,3-dihydro-1H-inden-4-yl)-2-fluorophenyl)-1-cyanoethyl)carbamate (6B)

[0457] 6A (254.0 mg, 1.00 mmol, preparation method reference: Journal of Medicinal Chemistry, 2015, 58, 878–887), INT-2 (470.0 mg, 1.20 mmol), Pd(dppf)Cl2 (160.0 mg, 0.20 mmol) and potassium carbonate (280.0 mg, 2.00 mmol) were added to a single-necked flask, and then 1,4-dioxane (10 mL) and water (0.4 mL) were added. After purging with nitrogen three times, the reaction was carried out at 95 °C for 4 hours. After cooling to room temperature, the mixture was concentrated and purified by silica gel column chromatography (PE: EA (v / v) = 2:1) to obtain the title compound 6B, a white solid (360.0 mg, 82.3%). LC-MS (ESI): m / z = 381.1 [M - 57 + H] + 。

[0458] Step 2: (S)-N-(7-(4-(2-Amino-2-cyanoethyl)-3-fluorophenyl)-2,3-dihydro-1H-inden-4-yl)acetamide (6C)

[0459] (S)-N-(7-(4-(2-amino-2-cyanoethyl)-3-fluorophenyl)-2,3-dihydro-1H-inden-4-yl)acetamide (6C)

[0460] 6B (360.0 mg, 0.82 mmol) was dissolved in formic acid (5 mL), and the reaction was carried out at 35 °C for 4 h. The reaction system was adjusted to alkaline with saturated potassium carbonate solution, extracted with ethyl acetate (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 6C, a pale yellow oil (270.0 mg, 97.6%), which was directly used in the next step. LC-MS (ESI): m / z = 338.2 [M + H] + 。

[0461] Step 3: tert-butyl (S)-2-(((S)-2-(4-(7-Acetamido-2,3-dihydro-1H-inden-4-yl)-2-fluorophenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (6D)

[0462] tert-butyl (S)-2-(((S)-2-(4-(7-acetamido-2,3-dihydro-1H-inden-4-yl)-2-fluorophenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (6D)

[0463] Dissolve 6C (270 mg, 0.80 mmol) in DMF (5 mL), add INT-3 (235.2 mg, 0.96 mmol), HATU (364.8 mg, 0.96 mmol) and DIPEA (309.6 mg, 2.40 mmol). After addition, react overnight at room temperature. Add water (20 mL) to the system, extract with ethyl acetate (30 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (PE:EA (v / v) = 2:1) to obtain the title compound 6D, a white solid (370.0 mg, 82.0%). LC-MS (ESI): m / z = 563.3 [M-H] -.

[0464] Step 4: (S)-N-((S)-2-(4-(7-acetamido-2,3-dihydro-1H-inden-4-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (Compound 6)

[0465] (S)-N-((S)-2-(4-(7-acetamido-2,3-dihydro-1H-inden-4-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (compound 6)

[0466] Dissolve 6D (370 mg, 0.66 mmol) in formic acid (5 mL), and react at 35 °C for 4 h. Adjust the reaction system to alkaline with saturated potassium carbonate solution, extract with ethyl acetate (30 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (methylene chloride:methanol (v / v) = 30:1) to obtain the title compound 6 (90.0 mg, 30.0%).

[0467] 1 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]+ 。

[0468] Example 7: (S)-N-((S)-1-cyano-2-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 7)

[0469] (S)-N-((S)-1-cyano-2-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 7)

[0470]

[0471] First step: Tert-butyl (S)-(1-cyano-2-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-2-fluorophenyl)ethyl)carbamate (7B)

[0472] Tert-butyl (S)-(1-cyano-2-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-2-fluorophenyl)ethyl)carbamate (7B)

[0473] Dissolve 7A (0.200 g, 0.81 mmol, preparation method refers to EP3342765), INT-2 (0.316 g, 0.81 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (0.066 g, 0.081 mmol) and potassium carbonate (0.33 g, 2.43 mmol) in 1,4-dioxane (10 mL), add water (2 mL) and then displace with nitrogen 3 times, and react at 90 °C for 4 hours under a nitrogen atmosphere. Concentrate the reaction solution to dryness, dissolve it in dichloromethane, filter, concentrate, and purify the residue by silica gel column chromatography (PE:EA (v / v) = 5:1) to obtain the title compound 7B, a white solid (0.25 g, 71.8%). LC-MS (ESI): m / z = 431.1 [M+H] + 。

[0474] Second step: (S)-2-Amino-3-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-2-fluorophenyl)propanenitrile 4-methylbenzenesulfonate (7C)

[0475] (S)-2-amino-3-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-2-fluorophenyl)propanenitrile 4-methylbenzenesulfonate(7C)

[0476] Dissolve 7B (0.25 g, 0.58 mmol) in acetonitrile (5 mL), add p-toluenesulfonic acid (0.331 g, 1.74 mmol). After addition, react at room temperature for 16 h, filter, wash the filter cake once with acetonitrile (2 mL), and rotary evaporate the filter cake to obtain the title compound 7C, a white solid (0.240 g, 82.2%), which is directly used in the next step of the reaction.

[0477] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-2-fluorophenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(7D)

[0478] tert-butyl(S)-2-(((S)-1-cyano-2-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-2-fluorophenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(7D)

[0479] Dissolve INT-3 (0.161 g, 0.66 mmol) in dichloromethane (10 mL), add triethylamine (0.17 g, 1.32 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.25 g, 0.66 mmol). After addition, stir at room temperature for 1 h, then add 7C (0.24 g, 0.477 mmol), and react overnight at room temperature. After completion of the reaction, concentrate, and the crude product 7D is directly used in the next step of the reaction. LC-MS (ESI): m / z = 556.3 [M-H] - .

[0480] Step 4: (S)-N-((S)-1-cyano-2-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 7)

[0481] (S)-N-((S)-1-cyano-2-(4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 7)

[0482] The crude product 7D was dissolved in acetonitrile (10 mL), and p-toluenesulfonic acid (0.331 g, 1.74 mmol) was added. After the addition, the reaction was carried out at room temperature for 16 h. The mixture was concentrated to dryness, ethyl acetate (25 mL) was added, and the pH was adjusted to about 8 by dropwise addition of saturated aqueous sodium bicarbonate. The organic layer was separated, extracted with ethyl acetate (25 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (methylene chloride:methanol (v / v) = 20:1) to obtain the title compound 7 (110 mg, overall yield in two steps 50.5%).

[0483] 1 H 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] + 。

[0484] Example 8: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 8)

[0485] (S)-N-((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide

[0486]

[0487] Step 1: tert-butyl (S)-(1-cyano-2-(3-fluoro-4'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate (8A)

[0488] tert-butyl(S)-(1-cyano-2-(3-fluoro-4'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate

[0489] Dissolve INT-2 (0.69 g, 1.77 mmol) in dioxane (30 mL), add (4-bromophenyl)pentafluorosulfide (0.5 g, 1.77 mmol), potassium carbonate (0.24 g, 1.77 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (260 mg, 0.35 mmol), then add water (6 mL). React under nitrogen protection at 100 °C for 4 hours. After concentration, purify by silica gel column chromatography (PE:EA (v / v) = 1:10 - 1:5) to obtain the title compound 8A (600 mg, yield 80%). LCMS m / z = 467.11 [M+1] +

[0490] Step 2: (S)-2-amino-3-(3-fluoro-4'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)propanenitrile (8B)

[0491] (S)-2-amino-3-(3-fluoro-4'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)propanenitrile

[0492] Dissolve 8A (0.6 g, 1.29 mmol) in acetonitrile (20 mL), add p-toluenesulfonic acid (0.67 g, 3.87 mmol), react at 30 °C for 2 hours, add water (30 mL), adjust the pH = 7 - 8 with saturated aqueous sodium carbonate solution, extract with dichloromethane (50 mL × 3), wash with saturated brine (50 mL × 1), dry over anhydrous sodium sulfate and concentrate to obtain the title compound 8B (0.4 g, yield 84%). LCMS m / z = 367.32 [M+1] +

[0493] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (8C)

[0494] tert-butyl(S)-2-(((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0495] Dissolve 8B (200 mg, 0.55 mmol) in DMF (10 mL), and successively add HATU (250 mg, 0.66 mmol), DIPEA (260 mg, 2.02 mmol), and INT-3 (130 mg, 0.55 mmol). React at room temperature for 12 hours, add water (30 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash the organic phase with water (30 mL × 2), then wash with saturated brine (30 mL × 1), dry over anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography (ethyl acetate:dichloromethane (v / v) = 1:10 - 1:5) to obtain the title compound 8C (250 mg, yield 76%). LCMS m / z = 594.18 [M+1] +

[0496] Step 4: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 8)

[0497] (S)-N-((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide

[0498] 8C (250 mg, 0.42 mmol) was dissolved in acetonitrile (20 mL), p-toluenesulfonic acid (220 mg, 1.26 mmol) was added, and the reaction was carried out at 30 °C for 3 hours. The pH was adjusted to 7 - 8 with saturated aqueous sodium carbonate solution, and the mixture was extracted with dichloromethane (40 mL × 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 0.01:1 - 0.1:1) to obtain the title compound 8 (80 mg, 38%).

[0499] 1 H 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] +

[0500] Example 9: (S)-N-((S)-1-cyano-2-(3-fluoro-3'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 9)

[0501] (S)-N-((S)-1-cyano-2-(3-fluoro-3'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide

[0502]

[0503] First step: tert-butyl (S)-(1-cyano-2-(3-fluoro-3'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate (9A)

[0504] tert-butyl (S)-(1-cyano-2-(3-fluoro-3'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate

[0505] Dissolve INT-2 (0.69 g, 1.77 mmol) in dioxane (30 mL), add (3-bromophenyl)pentafluorosulfide (0.5 g, 1.77 mmol), potassium carbonate (0.24 g, 1.77 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (260 mg, 0.35 mmol), then add water (6 mL). React under nitrogen protection at 100 °C for 4 hours. After concentration, purify by silica gel column chromatography (PE:EA (v / v) = 1:10 - 1:5) to obtain the title compound 9A (600 mg, yield 80%). LCMS m / z = 467.11 [M+1] +

[0506] Step 2: (S)-2-amino-3-(3-fluoro-4'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)propanenitrile (9B)

[0507] (S)-2-amino-3-(3-fluoro-4'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)propanenitrile

[0508] Dissolve 9A (0.6 g, 1.29 mmol) in acetonitrile (20 mL), add p-toluenesulfonic acid (0.67 g, 3.87 mmol), react at 30 °C for 2 hours, add water (30 mL), adjust the pH to 7 - 8 with saturated aqueous sodium carbonate solution, extract with dichloromethane (50 mL × 3), wash with saturated brine (50 mL × 1), dry over anhydrous sodium sulfate and concentrate to obtain the title compound 9B (0.4 g, yield 84%). LCMS m / z = 367.32 [M+1] +

[0509] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(3-fluoro-3'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (9C)

[0510] tert-butyl(S)-2-(((S)-1-cyano-2-(3-fluoro-3'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0511] 9B (200 mg, 0.55 mmol) was dissolved in DMF (10 mL). HATU (250 mg, 0.66 mmol), DIEA (260 mg, 2.02 mmol), and INT-3 (130 mg, 0.55 mmol) were added successively. The reaction was carried out at room temperature for 12 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with water (30 mL × 2), then with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (ethyl acetate:dichloromethane (v / v) = 1:10 - 1:5) to obtain the title compound 9C (250 mg, yield 76%). LCMS m / z = 594.18 [M+1] +

[0512] Step 4: (S)-N-((S)-1-cyano-2-(3-fluoro-3'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 9)

[0513] (S)-N-((S)-1-cyano-2-(3-fluoro-3'-(pentafluoro-l6-sulfaneyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide

[0514] 9C (250 mg, 0.42 mmol) was dissolved in acetonitrile (20 mL). p-Toluenesulfonic acid (220 mg, 1.26 mmol) was added, and the reaction was carried out at 30 °C for 3 hours. The pH was adjusted to 7 - 8 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (40 mL × 3). The organic phases were combined, washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 0.01:1 - 0.1:1) to obtain the title compound 9 (78 mg, 37%).

[0515] 11H 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] +

[0516] Example 10: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 10)

[0517] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0518]

[0519] Step 1: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)carbamate (10A)

[0520] tert-butyl(S)-(1-cyano-2-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)carbamate

[0521] 4A (0.27 g, 1.2 mmol), INT-2 (0.36 g, 0.92 mmol), dichlorobis[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (71 mg, 0.1 mmol), and potassium carbonate (0.28 g, 2.0 mmol) were successively added to 1,4-dioxane (15 mL) and water (3 mL). The system was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction, it was cooled to room temperature, water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE:EA = 3:1 - 1:1) to obtain 10A, a brown solid (0.32 g, yield 84%). LCMS m / z = 410.2 [M+1] + 。

[0522] Step 2: (S)-2-amino-3-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)propanenitrile (10B)

[0523] (S)-2-amino-3-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)propanenitrile

[0524] 10A (0.32 g, 0.78 mmol) was dissolved in formic acid (5.0 mL), and after addition, the reaction was carried out at 50 °C for 10 min. It was concentrated to dryness, ethyl acetate (60 mL) was added, and the pH was adjusted to about 8 by dropwise addition of saturated aqueous sodium bicarbonate solution. The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (60 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 10B (0.24 g, yield 100%). LCMS m / z = 310.2 [M+1] + 。

[0525] Step 3: tert-butyl(S)-2-(((S)-1-cyano-2-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (10C)

[0526] tert-butyl(S)-2-(((S)-1-cyano-2-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0527] Dissolve 10B (0.24 g, 0.78 mmol) in DMF (10 mL), add INT-3 (0.25 g, 1.0 mmol), diisopropylethylamine (0.19 g, 1.5 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.38 g, 1 mmol). After addition, react at room temperature for 1 hour. Add saturated sodium chloride aqueous solution (30 mL), extract with ethyl acetate (60 mL × 2). Wash the organic phase with saturated sodium chloride aqueous solution (60 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate the residue by silica gel column chromatography (PE:EA = 2:1 - 1:2) to obtain the title compound 10C, a pale yellow solid (0.25 g, yield 60%).

[0528] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 10)

[0529] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0530] Dissolve 10C (0.25 g, 0.47 mmol) in formic acid (5.0 mL), react at 50 °C for 10 minutes. Concentrate under reduced pressure, add ethyl acetate (60 mL), adjust the pH to about 8 by dropwise addition of saturated sodium bicarbonate aqueous solution, separate the organic layer, extract with ethyl acetate (60 mL × 5). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (methylene chloride:methanol (v / v) = 4:1) to obtain Compound 10 (0.12 g, yield 59%).

[0531] 11H NMR (400 MHz, DMSO-d6) δ 8.78 (d, 1H), 7.96–7.87 (m, 2H), 7.70–7.64 (m, 2H), 7.63–7.53 (m, 2H), 7.47 (t, 1H), 5.11–5.01 (m, 1H), 4.13 - 4.06 (m, 1H), 3.92 - 3.82 (m, 1H), 3.78 - 3.70 (m, 1H), 3.43–3.31 (m, 2H), 3.26–3.10 (m, 2H), 2.97 (t, 2H), 2.94–2.84 (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] +

[0532] Example 11: (S)-N-((S)-1-cyano-2-(4-(cyclopentylethynyl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 11)

[0533] (S)-N-((S)-1-cyano-2-(4-(cyclopentylethynyl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 11)

[0534]

[0535] First step: tert-butyl (S)-(1-cyano-2-(4-(cyclopentylethynyl)-2-fluorophenyl)ethyl)carbamate (11B)

[0536] tert-butyl (S)-(1-cyano-2-(4-(cyclopentylethynyl)-2-fluorophenyl)ethyl)carbamate (11B)

[0537] 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-necked flask, followed by the addition of 1,4-dioxane (10 mL) and water (0.4 mL). After purging with nitrogen three times, the reaction was carried out at 95 °C for 4 hours. After cooling to room temperature, the mixture was concentrated and purified by silica gel column chromatography (PE:EA (v / v) = 3:1) to obtain the title compound 11B, a white solid (172.0 mg, 83.5%). LC-MS (ESI): m / z = 300.1 [M - 57 + H] + 。

[0538] Step 2: (S)-2-amino-3-(4-(cyclopentylethynyl)-2-fluorophenyl)propanenitrile (11C)

[0539] (S)-2-amino-3-(4-(cyclopentylethynyl)-2-fluorophenyl)propanenitrile(11C)

[0540] 11B (172 mg, 0.48 mmol) was dissolved in formic acid (5 mL), and the reaction was carried out at 35 °C for 4 h. The reaction system was adjusted to alkaline with saturated potassium carbonate solution, extracted with ethyl acetate (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 11C, a pale yellow oil (130 mg, 100.0%), which was directly used in the next step. LC-MS (ESI): m / z = 257.1 [M + H] + 。

[0541] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(4-(cyclopentylethynyl)-2-fluorophenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (11D)

[0542] tert-butyl(S)-2-(((S)-1-cyano-2-(4-(cyclopentylethynyl)-2-fluorophenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(11D)

[0543] Dissolve 11C (130 mg, 0.51 mmol) in DMF (5 mL), add INT-3 (150 mg, 0.61 mmol), HATU (230 mg, 0.61 mmol) and DIPEA (200 mg, 1.53 mmol). After addition, react overnight at room temperature. Add water (20 mL) to the system, extract with ethyl acetate (30 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (PE:EA (v / v) = 2:1) to obtain the title compound 11D, white solid (190.0 mg, 77.0%). LC-MS (ESI): m / z = 428.3 [M - 57 + H] + 。

[0544] Step 4: (S)-N-((S)-1-cyano-2-(4-(cyclopentylethynyl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 11)

[0545] (S)-N-((S)-1-cyano-2-(4-(cyclopentylethynyl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 11)

[0546] Dissolve 11D (190 mg, 0.39 mmol) in formic acid (5 mL), and react at 35 °C for 4 h. Adjust the reaction system to alkaline with saturated potassium carbonate solution, extract with ethyl acetate (30 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (dichloromethane:methanol (v / v) = 30:1) to obtain Compound 11 (50.0 mg, 33.0%).

[0547] 1 1H 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] + 。

[0548] Example 12: (S)-N-((S)-1-cyano-2-(4-(5-cyano-4-methylthiazol-2-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 12)

[0549] (S)-N-((S)-1-cyano-2-(4-(5-cyano-4-methylthiazol-2-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 12)

[0550]

[0551] First step: 2-bromo-4-methylthiazole-5-carboxamide (12B)

[0552] 2-bromo-4-methylthiazole-5-carboxamide (12B)

[0553] Dissolve 12A (1.20 g, 4.8 mmol) in 30% ammonia water (30 mL), and react at 35 °C for 24 h. Cool to room temperature, extract with ethyl acetate (30 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate to obtain the title compound 12B, a yellow solid (0.80 g, 75.4%). LC-MS (ESI): m / z = 221.0 [M+H] + 。

[0554] Second step: 2-bromo-4-methylthiazole-5-carbonitrile (12C)

[0555] 2-bromo-4-methylthiazole-5-carbonitrile (12C)

[0556] Dissolve 12B (0.55 g, 2.49 mmol) in dichloromethane (25 mL), add Burgess reagent (1.19 g, 4.98 mmol), and react at room temperature overnight after addition. Concentrate and purify by silica gel column chromatography (PE:EA (v / v) = 5:1) to obtain the title compound 12C, a white solid (0.40 g, 80.1%). LC-MS (ESI): m / z = 203.0 [M+H] + 。

[0557] Third step: tert-butyl (S)-(1-cyano-2-(4-(5-cyano-4-methylthiazol-2-yl)-2-fluorophenyl)ethyl)carbamate (12D)

[0558] (S)-(1-cyano-2-(4-(5-cyano-4-methylthiazol-2-yl)-2-fluorophenyl)ethyl)tert-butyl carbamate(12D)

[0559] 12C (199 mg, 0.98 mmol), INT-2 (458.9 mg, 1.18 mmol), Pd(dppf)Cl2 (160.5 mg, 0.20 mmol) and potassium carbonate (270.9 mg, 1.96 mmol) were added to a single-necked flask, followed by 1,4-dioxane (10 mL) and water (0.4 mL). After purging with nitrogen three times, the reaction was carried out at 95 °C for 4 hours. After cooling to room temperature, the mixture was concentrated 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] + 。

[0560] Step 4: (S)-2-(4-(2-amino-2-cyanoethyl)-3-fluorophenyl)-4-methylthiazole-5-carbonitrile (12E)

[0561] (S)-2-(4-(2-amino-2-cyanoethyl)-3-fluorophenyl)-4-methylthiazole-5-carbonitrile(12E)

[0562] 12D (172 mg, 0.45 mmol) was dissolved in formic acid (5 mL), and the reaction was carried out at 35 °C for 4 h. The reaction system was adjusted to alkaline with saturated potassium carbonate solution, extracted with ethyl acetate (30 mL × 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 directly used in the next step. LC-MS (ESI): m / z = 287.1 [M + H] + 。

[0563] Step 5: (S)-2-(((S)-1-cyano-2-(4-(5-cyano-4-methylthiazol-2-yl)-2-fluorophenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (12F)

[0564] (S)-tert-butyl 2-(((S)-1-cyano-2-(4-(5-cyano-4-methylthiazol-2-yl)-2-fluorophenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (12F)

[0565] 12E (120 mg, 0.42 mmol) was dissolved in DMF (5 mL), and INT-3 (120 mg, 0.50 mmol), HATU (190 mg, 0.50 mmol) and DIPEA (160 mg, 1.26 mmol) were added. After the addition, the reaction was carried out overnight at room temperature. Water (20 mL) was added to the system, and the mixture was extracted with ethyl acetate (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, 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] + .

[0566] Step 6: (S)-N-((S)-1-cyano-2-(4-(5-cyano-4-methylthiazol-2-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 12)

[0567] (S)-N-((S)-1-cyano-2-(4-(5-cyano-4-methylthiazol-2-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 12)

[0568] 12F (160 mg, 0.31 mmol) was dissolved in formic acid (5 mL), and the reaction was carried out at 35 °C for 4 h. The reaction system was adjusted to alkaline with saturated potassium carbonate solution, extracted with ethyl acetate (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 30:1) to obtain the title compound 12 (50.0 mg, 39.0%).

[0569] 11H 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] + 。

[0570] Example 13: (S)-N-((S)-2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (Compound 13)

[0571] (S)-N-((S)-2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide

[0572]

[0573] First step: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate (13B)

[0574] tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate

[0575] Dissolve INT-2 (5.00 g, 14.57 mmol) in 1,4-dioxane (100 mL), add bis(pinacolato)diboron (4.81 g, 18.94 mmol), potassium acetate (4.29 g, 43.71 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (2.39 g, 2.91 mmol). After addition, protect with nitrogen and heat to 100 °C for reaction for 2 h. Cool to room temperature, filter, concentrate, and purify the residue by silica gel column chromatography (PE:EA (v / v) = 6:1) to obtain the title compound 13B, colorless liquid (5.00 g, 87.93%). LC-MS (ESI): m / z = 391.2 [M+H]+ .

[0576] Step 2: tert-butyl (S)-(2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)carbamate (13C)

[0577] tert-butyl(S)-(2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)carbamate

[0578] Dissolve 13B (0.40 g, 1.02 mmol) in 1,4-dioxane (10 mL) and water (0.4 mL), add 2-bromobenzothiazole (0.26 g, 1.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.17 g, 0.20 mmol), and potassium carbonate (0.28 g, 2.04 mmol). After addition, protect with nitrogen and heat to 90 °C for reaction for 2 h. React overnight at room temperature. Concentrate to dryness, add saturated ammonium chloride aqueous solution (50 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (PE:EA (v / v) = 4:1) to obtain the title compound 13C, a pale yellow liquid (0.24 g, 59.20%). LC-MS (ESI): m / z = 398.1 [M+H] + .

[0579] Step 3: (S)-2-amino-3-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)propanenitrile (13D)

[0580] (S)-2-amino-3-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)propanenitrile

[0581] Dissolve 13C (0.32 g, 0.81 mmol) in formic acid (5 mL), and after addition, react at 30 °C for 3 h. Dropwise add saturated sodium bicarbonate aqueous solution to adjust the pH to about 8, extract with ethyl acetate (25 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, to obtain the title compound 13D, a colorless liquid (0.24 g, 99.65%), which is directly used for the next step reaction. LC-MS (ESI): m / z = 298.1 [M+H] + .

[0582] Step 4: tert-butyl (S)-2-(((S)-2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (13E)

[0583] tert-butyl(S)-2-(((S)-2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0584] Dissolve 13D (0.24 g, 0.81 mmol) in dichloromethane (10 mL), add INT-1 (0.26 g, 1.05 mmol), diisopropylethylamine (0.31 g, 2.43 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.46 g, 1.22 mmol). After addition, react at room temperature overnight. Add saturated sodium chloride aqueous solution (30 mL), extract with ethyl acetate (25 mL). Wash the organic phase with saturated sodium chloride aqueous solution (25 mL × 3), dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (PE: EA (v / v) = 4:1) to obtain the title compound 13E, a pale yellow solid (0.25 g, 58.83%). LC-MS (ESI): m / z = 469.2 [M - 57 + H] + 。

[0585] Step 5: (S)-N-((S)-2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (Compound 13)

[0586] (S)-N-((S)-2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide

[0587] Dissolve 13E (0.32 g, 0.59 mmol) in formic acid (2.0 mL). After addition, react at 35 °C for 4 h. Concentrate to dryness, add ethyl acetate (25 mL), adjust the pH to about 8 by dropwise addition of saturated sodium bicarbonate aqueous solution, separate the organic layer, extract with ethyl acetate (25 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (dichloromethane: methanol (v / v) = 20:1) to obtain the title compound 13 (30 mg, 14.72%).

[0588] 1 1H 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] + 。

[0589] Example 14: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 14)

[0590] (S)-N-((S)-1-cyano-2-(3-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 14)

[0591]

[0592] Step 1: tert-butyl (S)-(1-cyano-2-(3-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate (14B)

[0593] tert-butyl-(S)-(1-cyano-2-(3-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate (14B)

[0594] 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]dichloropalladium (0.98 g, 1.34 mmol) were dissolved in 1,4-dioxane (100 ml) and water (10 ml). After purging with nitrogen three times, the mixture was heated to 95 °C and refluxed for 3 h. The mixture was filtered, and the filter cake was washed with ethyl acetate (100 ml). The filtrate was dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 0% - 15%) to obtain the title compound 14B, a dark brown solid (3.00 g, 99.0%). LC-MS (ESI): m / z = 453.3 [M+H] + .

[0595] Step 2: (S)-2-amino-3-(3-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)propanenitrile (14C)

[0596] (S)-2-amino-3-(3-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)propanenitrile(14C)

[0597] 14B (3.26 g, 7.2 mmol) was dissolved in formic acid (40 ml). The mixture was stirred at room temperature overnight, water (40 ml) and dichloromethane (80 ml) were added, and the pH was adjusted to basic with sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (80 ml x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 0% - 10%) to obtain the title compound 14C, a dark brown oil (2.32 g, 91.3%). LC-MS (ESI): m / z = 353.3 [M+H] + .

[0598] Step 3: (S)-2-(((S)-1-cyano-2-(3-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (14D)

[0599] tert-butyl-(S)-2-(((S)-1-cyano-2-(3-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(14D)

[0600] Dissolve 14C (500 mg, 1.42 mmol), INT-3 (348 mg, 1.42 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (648 mg, 1.70 mmol) and DIPEA (366 mg, 2.84 mmol) in dichloromethane (15 ml), stir at room temperature for 4 h, wash the reaction solution with saturated sodium bicarbonate solution (10 ml x 3), separate the organic phase, dry over anhydrous sodium sulfate, concentrate, and purify the obtained residue by silica gel column chromatography (methanol:dichloromethane (v / v) = 0% - 10%) to obtain the title compound 14D, a yellow solid (400 mg, 48.6%). LC-MS (ESI): m / z = 580.3 [M+H] + 。

[0601] Step 4: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 14)

[0602] (S)-N-((S)-1-cyano-2-(3-fluoro-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 14)

[0603] 14D (400 mg, 0.69 mmol) and 2,6-lutidine (74 mg, 0.69 mmol) were dissolved in dichloromethane (20 mL), stirred in an ice-water bath, and tert-butyldimethylsilyl trifluoromethanesulfonate (550 mg, 2.07 mmol) was added dropwise to the reaction flask. After the addition was complete, the ice-water bath was removed, and the reaction was stirred at room temperature for 2 h. The reaction solution was washed with saturated sodium bicarbonate solution (20 mL×2), the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography (methanol:dichloromethane (v / v)=0% - 15%) to obtain the title compound 14 (57 mg, 17.2%). LC-MS (ESI): m / z = 480.3 [M+H] + 。

[0604] 1 1H 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).

[0605] Example 15: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(4-methylthiazol-2-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 15)

[0606] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(4-methylthiazol-2-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 15)

[0607]

[0608] The first step: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(4-methylthiazol-2-yl)phenyl)ethyl)carbamate (15B)

[0609] tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(4-methylthiazol-2-yl)phenyl)ethyl)carbamate (15B)

[0610] Dissolve 15A (0.23 g, 1.28 mmol), INT-2 (0.50 g, 1.28 mmol), [1,1'-(diphenylphosphino)ferrocene]dichloropalladium (94 mg, 0.13 mmol), and potassium carbonate (0.53 g, 3.84 mmol) in a mixed solvent of dioxane (27 mL) and water (3 mL). Under nitrogen protection, react at 90 °C for 5 h. Cool to room temperature, add 50 mL of water, extract with ethyl acetate (20 mL × 3), combine the organic layers, wash successively with saturated sodium bicarbonate (20 mL) and saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate, and purify the residue 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] + 。

[0611] Step 2: (S)-2-amino-3-(2-fluoro-4-(4-methylthiazol-2-yl)phenyl)propanenitrile (15C)

[0612] (S)-2-amino-3-(2-fluoro-4-(4-methylthiazol-2-yl)phenyl)propanenitrile (15C)

[0613] Dissolve 15B (0.25 g, 0.68 mmol) in anhydrous formic acid (4 mL) and react at 50 °C for 20 min. Cool to room temperature, concentrate to remove most of the solvent, add saturated sodium bicarbonate solution (20 mL) to the residue, extract with ethyl acetate (10 mL × 3), combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and purify the residue by silica gel column chromatography (methylene chloride:methanol (v / v) = 97:3) to obtain the title compound 15C (0.17 g, 96%). LC-MS (ESI): m / z = 262.2 [M + H] + 。

[0614] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(4-methylthiazol-2-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (15D)

[0615] tert-butyl(S)-2-(((S)-1-cyano-2-(2-fluoro-4-(4-methylthiazol-2-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(15D)

[0616] Dissolve INT-3 (0.18 g, 0.73 mmol) in DMF (5 mL). Under nitrogen protection, add HATU (0.42 g, 1.09 mmol) and DIPEA (0.28 g, 2.19 mmol). After stirring at room temperature for 20 min, add 15C (0.19 g, 0.73 mmol) and react at room temperature for 1 h. Add 30 mL of water to the reaction, extract with ethyl acetate (15 mL x 5), combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and purify the residue by silica gel column chromatography (methylene chloride:methanol (v / v) = 97:3) to obtain the title compound 15D (0.26 g, 73%). LC-MS (ESI): m / z = 489.1 [M+H] + 。

[0617] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(4-methylthiazol-2-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 15)

[0618] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(4-methylthiazol-2-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 15)

[0619] Dissolve 15D (0.26 g, 0.53 mmol) in formic acid (4.0 mL) and react at 50 °C for 30 min after addition. Concentrate to dryness, add ethyl acetate (25 mL), adjust the pH to about 8 by dropwise addition of saturated aqueous sodium bicarbonate solution, separate the organic layer, extract with ethyl acetate (25 mL x 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (PE:EA (v / v) = 1:2) to obtain the title compound 15 (80 mg, 39%).

[0620] 11H NMR (400 MHz, DMSO-d6) 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] + 。

[0621] Example 16: (S)-N-((S)-2-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (Compound 16)

[0622] (S)-N-((S)-2-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (compound 16)

[0623]

[0624] First step: tert-butyl (S)-(2-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-1-cyanoethyl)carbamate (16B)

[0625] tert-butyl (S)-(2-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-1-cyanoethyl)carbamate (16B)

[0626] 16A (0.200 g, 0.83 mmol), INT-2 (0.323 g, 0.83 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.067 g, 0.083 mmol) and potassium carbonate (0.343 g, 2.49 mmol) were dissolved in 1,4-dioxane (10 mL), water (2 mL) was added, and the mixture was purged with nitrogen three times. The reaction was carried out at 90 °C for 4 h under a nitrogen atmosphere. The reaction solution was concentrated to dryness, dissolved in dichloromethane, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE:EA (v / v) = 5:1) to obtain the title compound 16B, a white solid (0.100 g, 28.4%). LC-MS (ESI): m / z = 424.1 [M+H] + 。

[0627] Step 2: (S)-3-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-2-aminopropanenitrile 4-methylbenzenesulfonate (16C)

[0628] (S)-3-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-2-aminopropanenitrile 4-methylbenzenesulfonate(16C)

[0629] 16B (0.100 g, 0.24 mmol) was dissolved in acetonitrile (2 mL), p-toluenesulfonic acid monohydrate (0.134 g, 0.71 mmol) was added, and the mixture was reacted at room temperature for 16 h after addition. It was filtered, and the filter cake was rinsed once with acetonitrile (1 mL). The filter cake was dried by rotary evaporation to obtain the title compound 16C, a white solid (0.100 g, 85.5%), which was directly used in the next step of the reaction.

[0630] Step 3: tert-butyl tert-butyl (S)-2-(((S)-2-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (16D)

[0631] tert-butyl tert-butyl(S)-2-(((S)-2-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(16D)

[0632] INT-3 (0.074 g, 0.303 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (0.061 g, 0.606 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.115 g, 0.303 mmol) were added. After addition, the reaction mixture was stirred at room temperature for 1 hour, then 16C (0.100 g, 0.202 mmol) was added, and the reaction was carried out overnight at room temperature. After the reaction was completed, the mixture was concentrated, and the crude product 16D was directly used for the next step reaction. LC-MS (ESI): m / z = 549.2 [M-H] - .

[0633] Step 4: (S)-N-((S)-2-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (Compound 16)

[0634] (S)-N-((S)-2-(4-(1-acetylindolin-5-yl)-2-fluorophenyl)-1-cyanoethyl)-1,4-oxazepane-2-carboxamide (compound 16)

[0635] The crude product 16D was dissolved in acetonitrile (10 mL), and p-toluenesulfonic acid monohydrate (0.134 g, 0.71 mmol) was added. After addition, the reaction was carried out at room temperature for 16 h, concentrated to dryness, ethyl acetate (25 mL) was added, and the pH was adjusted to about 8 by dropwise addition of saturated aqueous sodium bicarbonate solution. The organic layer was separated, extracted with ethyl acetate (25 mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain the title compound 16 (27 mg, overall yield of two steps 29.7%).

[0636] 1 1H 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] + 。

[0637] Example 17: (S)-N-((S)-1-cyano-2-(4'-cyano-3'-cyclopropyl-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 17)

[0638] (S)-N-((S)-1-cyano-2-(4'-cyano-3'-cyclopropyl-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 17)

[0639]

[0640] First step: tert-butyl (S)-(1-cyano-2-(4'-cyano-3'-cyclopropyl-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamate (17B)

[0641] tert-butyl (S)-(1-cyano-2-(4'-cyano-3'-cyclopropyl-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamate (17B)

[0642] Dissolve 17A (0.300 g, 1.67 mmol), INT-2 (0.646 g, 1.67 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.134 g, 0.167 mmol) and potassium carbonate (0.686 g, 4.98 mmol) in 1,4-dioxane (15 mL), add water (3 mL), then displace with nitrogen 3 times, and react at 100 °C for 16 h under a nitrogen atmosphere. Concentrate the reaction solution to dryness, dissolve with dichloromethane, filter, concentrate, and purify the residue by silica gel column chromatography (PE: EA (v / v) = 5:1) to obtain the title compound 17B, a white solid (0.380 g, 55.4%). LC-MS (ESI): m / z = 406.1 [M+H] + .

[0643] Second step: (S)-4'-(2-amino-2-cyanoethyl)-3-cyclopropyl-3'-fluoro-[1,1'-biphenyl]-4-carbonitrile 4-methylbenzenesulfonate

[0644] (S)-4'-(2-Amino-2-cyanoethyl)-3-cyclopropyl-3'-fluoro-[1,1'-biphenyl]-4-carbonitrile 4-methylbenzenesulfonate (17C)

[0645] Dissolve 17B (0.380 g, 0.94 mmol) in acetonitrile (5 mL), add p-toluenesulfonic acid monohydrate (534 g, 2.81 mmol). After addition, react at room temperature for 16 h, filter, wash the filter cake once with acetonitrile (2 mL), and spin-dry the filter cake to obtain the title compound 17C, a white solid (0.360 g, 80.5%), which is directly used in the next step of the reaction.

[0646] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(4'-cyano-3'-cyclopropyl-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (17D)

[0647] tert-butyl (S)-2-(((S)-1-cyano-2-(4'-cyano-3'-cyclopropyl-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (17D)

[0648] Dissolve INT-3 (0.123 g, 0.503 mmol) in dichloromethane (5 mL), add triethylamine (0.101 g, 1.00 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.193 g, 0.503 mmol). After addition, stir at room temperature for 1 h, then add 17C (0.160 g, 0.335 mmol), and stir overnight at room temperature. After the reaction is complete, concentrate, and the crude product 17D is directly used in the next step of the reaction. LC-MS (ESI): m / z = 531.2 [M-H] - .

[0649] Step 4: (S)-N-((S)-1-cyano-2-(4'-cyano-3'-cyclopropyl-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 17)

[0650] (S)-N-((S)-1-cyano-2-(4'-cyano-3'-cyclopropyl-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 17)

[0651] The crude product 17D was dissolved in acetonitrile (10 mL). p-Toluenesulfonic acid monohydrate (0.190 g, 1.00 mmol) was added. After addition, the reaction was carried out at room temperature for 16 h. It was concentrated to dryness, ethyl acetate (25 mL) was added, and saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to about 8. The organic layer was separated, extracted with ethyl acetate (25 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (methylene chloride:methanol (v / v) = 20:1) to obtain the title compound 17 (60 mg, overall yield in two steps 41.4%).

[0652] 1 H 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] + 。

[0653] Example 18: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 18)

[0654] (S)-N-((S)-1-cyano-2-(3-fluoro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 18)

[0655]

[0656] Step 1: tert-butyl (S)-(1-cyano-2-(3-fluoro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate (18B)

[0657] tert-butyl(S)-(1-cyano-2-(3-fluoro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate(18B)

[0658] Dissolve 18A (0.50 g, 1.46 mmol), 2a (0.26 g, 1.46 mmol), [1,1'-(diphenylphosphino)ferrocene]dichloropalladium (0.11 mg, 0.15 mmol), and potassium carbonate (0.61 g, 4.38 mmol) in a mixed solvent of dioxane (27 mL) and water (3 mL). Under nitrogen protection, react at 90 °C for 5 h. Cool to room temperature, add 50 mL of water, extract with ethyl acetate (20 mL × 3), combine the organic layers, wash successively with saturated sodium bicarbonate (20 mL) and saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate, and purify the residue 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] + 。

[0659] Step 2: (S)-4'-(2-amino-2-cyanoethyl)-3'-fluoro-N-methyl-[1,1'-biphenyl]-4-carboxamide (18C)

[0660] (S)-4'-(2-amino-2-cyanoethyl)-3'-fluoro-N-methyl-[1,1'-biphenyl]-4-carboxamide(18C)

[0661] Dissolve 18B (0.34 g, 0.86 mmol) in anhydrous formic acid (4 mL), and react at 50 °C for 20 min. Cool to room temperature, concentrate to remove most of the solvent, add saturated sodium bicarbonate solution (20 mL) to the residue, extract with ethyl acetate (10 mL × 3), combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and purify the residue by silica gel column chromatography (methylene chloride:methanol (v / v) = 97:3) to obtain the title compound 18C (0.22 g, 87%). LC-MS (ESI): m / z = 298.1 [M+H] + 。

[0662] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(3-fluoro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (18D)

[0663] tert-butyl(S)-2-(((S)-1-cyano-2-(3-fluoro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(18D)

[0664] Dissolve INT-3 (0.23 g, 0.76 mmol) in DMF (5 mL). Under nitrogen protection, add HATU (0.43 g, 1.14 mmol) and DIPEA (0.29 g, 2.28 mmol). After stirring at room temperature for 20 min, add 18C (0.23 g, 0.76 mmol) and react at room temperature for 1 h. Add 30 mL of water to the reaction. Extract with ethyl acetate (15 mL × 5). Combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and purify the residue by silica gel column chromatography (methylene chloride: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] + 。

[0665] Step 4: (S)-N-((S)-1-cyano-2-(3-fluoro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 18)

[0666] (S)-N-((S)-1-cyano-2-(3-fluoro-4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide(compound 18)

[0667] Dissolve 18D (0.31 g, 0.59 mmol) in formic acid (4.0 mL). After addition, react at 50 °C for 30 min. Concentrate to dryness, add ethyl acetate (25 mL), adjust to pH about 8 by dropwise addition of saturated aqueous sodium bicarbonate solution, separate the organic layer, extract with ethyl acetate (25 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (PE:EA (v / v) = 1:2) to obtain the title compound 18 (50 mg, 20%).

[0668] 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] + 。

[0669] Example 19: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-methyl-1H-indol-2-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 19)

[0670] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-methyl-1H-indol-2-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0671]

[0672] First step: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(1-methyl-1H-indol-2-yl)phenyl)ethyl)carbamate (19B)

[0673] tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(1-methyl-1H-indol-2-yl)phenyl)ethyl)carbamate

[0674] 2a (0.40 g, 1.17 mmol) was dissolved in 1,4 - dioxane (10 mL) and water (0.4 mL). 1 - methyl - 2 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)-1H - indole (0.39 g, 1.52 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.19 g, 0.23 mmol), and potassium carbonate (0.32 g, 2.34 mmol) were added. After addition, the reaction mixture was protected by nitrogen and heated to 90 °C for 2 h. The reaction was continued overnight at room temperature. The reaction mixture was concentrated to dryness, saturated aqueous ammonium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE:EA(v / v)=10:1, 4:1) to give the title compound 19B as a white solid (0.25 g, 54.31%). LC - MS(ESI): m / z = 394.2 [M + H] + 。

[0675] Step 2: (S)-2 - amino - 3-(2 - fluoro - 4-(1 - methyl - 1H - indol - 2 - yl)phenyl)propanenitrile (19C)

[0676] (S)-2 - amino - 3-(2 - fluoro - 4-(1 - methyl - 1H - indol - 2 - yl)phenyl)propanenitrile

[0677] 19B (0.37 g, 0.94 mmol) was dissolved in acetonitrile (30 mL). p - Toluenesulfonic acid monohydrate (0.54 g, 2.82 mmol) was added. After addition, the reaction was carried out at room temperature for 4 h. The reaction mixture was concentrated to dryness, ethyl acetate (25 mL) was added, and the pH was adjusted to about 8 by dropwise addition of saturated aqueous sodium bicarbonate solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (25 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE:EA(v / v)=1:1) to give the title 19C as a pale yellow solid (0.25 g, 90.67%). LC - MS(ESI): m / z = 294.3 [M + H] + 。

[0678] Step 3: tert - butyl (S)-2 - (((S)-1 - cyano - 2-(2 - fluoro - 4-(1 - methyl - 1H - indol - 2 - yl)phenyl)ethyl)carbamoyl)-1,4 - oxazepane - 4 - carboxylate (19D)

[0679] tert-butyl(S)-2-(((S)-1-cyano-2-(2-fluoro-4-(1-methyl-1H-indol-2-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0680] Dissolve 19C (0.25 g, 0.85 mmol) in dichloromethane (10 mL), add INT-3 (0.21 g, 0.85 mmol), diisopropylethylamine (0.55 g, 4.25 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.32 g, 0.85 mmol). After addition, react at room temperature overnight. Add saturated sodium chloride aqueous solution (30 mL), extract with ethyl acetate (25 mL). Wash the organic phase with saturated sodium chloride aqueous solution (25 mL×3), dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (PE:EA(v / v)=2:1) to obtain the title compound 19D, a white solid (0.40 g, 90.39%). LC-MS(ESI): m / z = 485.1[M - 57 + H] + 。

[0681] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-methyl-1H-indol-2-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 19)

[0682] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-methyl-1H-indol-2-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0683] Dissolve 19D (0.40 g, 0.77 mmol) in acetonitrile (30 mL), add p-toluenesulfonic acid monohydrate (0.44 g, 2.31 mmol). After addition, react at room temperature for 4 h. Concentrate to dryness, add ethyl acetate (25 mL), adjust the pH to about 8 by dropwise addition of saturated sodium bicarbonate aqueous solution, separate the organic layer, extract with ethyl acetate (25 mL×3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (dichloromethane:methanol(v / v)=20:1) to obtain the title compound 19, a pale yellow solid (0.15 g, 46.33%).

[0684] 11H 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] + 。

[0685] Example 20: (S)-N-((S)-1-cyano-2-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 20)

[0686] (S)-N-((S)-1-cyano-2-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 20)

[0687]

[0688] Step 1: tert-butyl (S)-(1-cyano-2-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamate (20B)

[0689] tert-butyl (S)-(1-cyano-2-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamate (20B)

[0690] 20A (0.200 g, 1.29 mmol), INT-2 (0.502 g, 1.29 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.105 g, 0.129 mmol) and potassium carbonate (0.534 g, 3.87 mmol) were dissolved in 1,4-dioxane (15 mL), water (3 mL) was added, and the mixture was purged with nitrogen three times. The reaction was carried out at 90 °C for 4 h under a nitrogen atmosphere. The reaction solution was concentrated to dryness, dissolved in dichloromethane, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE:EA (v / v) = 5:1) to obtain the title compound 20B, a white solid (0.420 g, 78.5%). LC-MS (ESI): m / z = 417.2 [M+H] + 。

[0691] Step 2: (S)-2-amino-3-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)propanenitrile 4-methylbenzenesulfonate (20C)

[0692] (S)-2-amino-3-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)propanenitrile 4-methylbenzenesulfonate(20C)

[0693] 20B (0.420 g, 1.01 mmol) was dissolved in acetonitrile (8 mL), p-toluenesulfonic acid monohydrate (0.575 g, 3.03 mmol) was added, and the mixture was reacted at room temperature for 16 h after addition. The mixture was filtered, and the filter cake was rinsed once with acetonitrile (2 mL). The filter cake was dried by rotary evaporation to obtain the title compound 20C, a white solid (0.500 g, 99.9%), which was directly used in the next step of the reaction.

[0694] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (20D)

[0695] tert-butyl(S)-2-(((S)-1-cyano-2-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(20D)

[0696] Dissolve INT-3 (0.148 g, 0.605 mmol) in dichloromethane (10 mL), add triethylamine (0.124 g, 1.23 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.230 g, 0.605 mmol). After addition, stir at room temperature for 1 hour, then add 20C (0.200 g, 0.41 mmol), and stir overnight at room temperature. After completion of the reaction, concentrate. The crude product 20D is directly used for the next reaction. LC-MS (ESI): m / z = 542.2 [M-H] - .

[0697] Step 4: (S)-N-((S)-1-cyano-2-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 20)

[0698] (S)-N-((S)-1-cyano-2-(4'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 20)

[0699] Dissolve the crude product 20D in acetonitrile (10 mL), add p-toluenesulfonic acid monohydrate (0.234 g, 1.23 mmol). After addition, react at room temperature for 16 h, concentrate to dryness, add ethyl acetate (25 mL), adjust the pH to about 8 by dropwise addition of saturated aqueous sodium bicarbonate solution, separate the organic layer, extract with ethyl acetate (25 mL × 2), dry the combined organic phases over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain the title compound 20 (60 mg, two-step yield 33.1%).

[0700] 1 H 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]+ 。

[0701] Example 21: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 21)

[0702] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 21)

[0703]

[0704] First step: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)carbamate (21B)

[0705] tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)carbamate (21B)

[0706] Dissolve the reactants 21A (0.47 g, 2.0 mmol) and INT-2 (0.69 g, 2.0 mmol) in 1,4-dioxane (50 ml), then add potassium carbonate (0.83 g, 6.0 mmol) and Pd(dppf)Cl2 (0.15 g, 0.2 mmol) thereto, protect with nitrogen replacement, and react at 100 °C. TLC and LC-MS show that there is a small amount of remaining raw material. Concentrate and rotary evaporate to dryness, dissolve in DCM, filter through diatomaceous earth, rotary evaporate the filtrate and column chromatograph (EA / PE = 0%-40%) to obtain the title compound 21B, a pale yellow solid (0.50 g, 67.3%). LC-MS (ESI): m / z = 372.3 [M+H] + 。

[0707] Second step: (S)-2-amino-3-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)propanenitrile (21C)

[0708] (S)-2-amino-3-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)propanenitrile(21C)

[0709] Dissolve 21B (0.5 g, 1.35 mmol) in anhydrous formic acid (10 ml). After reacting at 50 °C for 0.5 h, TLC detection found that the substrate reaction was complete. Spin off the formic acid at low temperature, add saturated sodium bicarbonate solution to adjust the pH to 8 - 10, extract with DCM (20 ml x 2), dry over anhydrous sodium sulfate, spin dry and column chromatograph (DCM:CH3OH = 10:1) to obtain the title compound 21C, a pale yellow liquid (0.35 g, 95.6%). LC-MS (ESI): m / z = 272.3 [M+H] + 。

[0710] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(21D)

[0711] tert-butyl(S)-2-(((S)-1-cyano-2-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(21D)

[0712] At room temperature, dissolve INT-3 (0.32 g, 1.29 mmol), HATU (0.59 g, 1.55 mmol), and DIPEA (0.5 ml) in dichloromethane (30 ml). After stirring at room temperature for 10 min, add 21C (0.35 g, 1.29 mmol) to it and stir at room temperature for 1 h. Monitor the reaction by TLC until it is complete. Quench the reaction by adding water (10 ml), extract with dichloromethane (15 ml × 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure and purify 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] + 。

[0713] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 21)

[0714] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 21)

[0715] Dissolve 21D (0.4 g, 0.8 mmol) in anhydrous formic acid (10 ml). After stirring at 50 °C for 0.5 h, TLC detection showed that the substrate reaction was complete. Spin off the formic acid at low temperature, add saturated sodium bicarbonate solution to adjust the pH to 8 - 10, extract with dichloromethane (20 ml × 2), dry over anhydrous sodium sulfate, spin dry and column chromatograph (DCM:CH3OH = 10:1) to obtain compound 21 (0.2 g, 62.7%). LC-MS (ESI): m / z = 399.1 [M+H] + 。

[0716] 1 H 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),.

[0717] Example 22: (S)-N-((S)-1-cyano-2-(4-(1-ethyl-1H-pyrazol-4-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 22)

[0718] (S)-N-((S)-1-cyano-2-(4-(1-ethyl-1H-pyrazol-4-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 22)

[0719]

[0720] Step 1: (S)-tert-butyl(1-cyano-2-(4-(1-ethyl-1H-pyrazol-4-yl)-2-fluorophenyl)ethyl)carbamate (22B)

[0721] (S)-tert-butyl(1-cyano-2-(4-(1-ethyl-1H-pyrazol-4-yl)-2-fluorophenyl)ethyl)carbamate(22B)

[0722] Dissolve 2a (0.32 g, 1.46 mmol) in DMF (10 mL), add intermediate 1 (0.5 g, 1.46 mmol), potassium carbonate (0.61 g, 4.38 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (0.11 g, 0.15 mmol). After addition, react at 100 °C for 3 hours. Cool to room temperature, add aqueous solution (20 mL), extract with dichloromethane (20 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (PE:EA (v / v) = 2:1) to obtain the title compound 22B, a colorless liquid (0.44 g, 84.1%). LC-MS (ESI): m / z = 359.1 [M+H] + 。

[0723] Step 2: (S)-2-amino-3-(4-(1-ethyl-1H-pyrazol-4-yl)-2-fluorophenyl)propanenitrile (22C)

[0724] (S)-2-amino-3-(4-(1-ethyl-1H-pyrazol-4-yl)-2-fluorophenyl)propanenitrile(22C)

[0725] Dissolve 22B (0.40 g, 1.12 mmol) in formic acid (10 mL). After addition, react at 50 °C for 2 h. Concentrate to dryness, add ethyl acetate (25 mL), adjust the pH to about 8 by dropwise addition of saturated sodium bicarbonate aqueous solution, separate the organic layer, extract with ethyl acetate (25 mL × 2). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, to obtain the title compound 22C, a colorless liquid (0.29 g, 100%), which is directly used in the next step of the reaction.

[0726] Step 3: (S)-2-(((S)-1-cyano-2-(4-(1-ethyl-1H-pyrazol-4-yl)-2-fluorophenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (22D)

[0727] (S)-tert-butyl 2-(((S)-1-cyano-2-(4-(1-ethyl-1H-pyrazol-4-yl)-2-fluorophenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(22D)

[0728] Dissolve 22C (0.30 g, 1.16 mmol) in DMF (10 mL), add INT-3 (0.28 g, 1.16 mmol), diisopropylethylamine (0.45 g, 3.48 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.66 g, 1.74 mmol). After addition, react at room temperature overnight. Add saturated sodium chloride aqueous solution (30 mL), extract with ethyl acetate (25 mL). Wash the organic phase with saturated sodium chloride aqueous solution (25 mL×3), dry over anhydrous sodium sulfate, filter, concentrate to obtain the title compound 22D, a pale yellow solid (0.30 g, 53.3%). Directly use it for the next reaction. LC-MS (ESI): m / z = 430.1 [M - 57 + H] + 。

[0729] Step 4: (S)-N-((S)-1-cyano-2-(4-(1-ethyl-1H-pyrazol-4-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 22)

[0730] (S)-N-((S)-1-cyano-2-(4-(1-ethyl-1H-pyrazol-4-yl)-2-fluorophenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 22)

[0731] Dissolve 22D (0.15 g, 0.31 mmol) in formic acid (2.0 mL). After addition, react at 35 °C for 4 h. Concentrate to dryness, add ethyl acetate (25 mL), adjust the pH to about 8 by dropwise adding saturated sodium bicarbonate aqueous solution. Separate the organic layer, extract with ethyl acetate (25 mL×2). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate. Purify the residue by silica gel column chromatography (PE:EA (v / v) = 1:2) to obtain the title compound 22 (80 mg, 66.9%).

[0732] 11H 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] + 。

[0733] Example 23: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 23)

[0734] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 23)

[0735]

[0736] First step: 5-chloro-3-(methyl-d3)benzo[d]oxazol-2(3H)-one (23B)

[0737] 5-chloro-3-(methyl-d3)benzo[d]oxazol-2(3H)-one (23B)

[0738] Dissolve 23A (5 g, 29.49 mmol) in DMF (25 mL), add cesium carbonate (10.57 g, 32.44 mmol), methyl-d3 iodide (4.28 g, 29.52 mmol), react at 25 °C for 4 hours. After the reaction is completed, pour the reaction solution into water (60 mL), filter, collect the filter cake, dissolve the filter cake in dichloromethane, wash with saturated brine, collect the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 23B, a brown solid (5.4 g, yield 98.1%). LCMS m / z = 187.0 [M+1] +

[0739] Step 2: 3-(Methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (23C)

[0740] 3-(methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one(23C)

[0741] Compound 23B (5.4 g, 28.94 mmol) was dissolved in 1,4-dioxane (54 ml), and pinacol borane (12.49 g, 49.20 mmol), potassium acetate (8.52 g, 86.82 mmol), palladium acetate (652 mg, 2.89 mmol), and X-Phos (2.73 g, 5.79 mmol) were added. The temperature was raised to 100°C and the reaction was continued for 3 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (eluent ratio PE: EA (v / v) = 1:0-10:1) to obtain 23C as a white solid (7.2 g, yield 89.8%). LC-MS m / z = 279.2 [M+1] +

[0742] Step 3: (S)-tert-butyl (1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate (23D)

[0743] tert-butyl(S)-(1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate(23D)

[0744] Compound 23C (2.0 g, 7.19 mmol) was dissolved in a mixed solvent of 1,4-dioxane (20 ml) and water (4 ml). 2a (2.47 mg, 7.19 mmol) was added, followed by potassium carbonate (2.98 g, 21.57 mmol), palladium acetate (161 mg, 0.72 mmol) and X-Phos (686 mg, 1.44 mmol). After purging with nitrogen three times, the temperature was raised to 100 °C and the reaction was carried out for 5 hours. After the reaction was completed, it was directly concentrated. The obtained residue was separated and purified by silica gel column chromatography (eluent ratio PE:EA (v / v) = 1:0 - 5:1) to obtain compound 23D, a white solid (2.57 g, 86.2%). LCMS m / z = 415.3 [M+1] +

[0745] Step 4: (S)-2-Amino-3-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile (23E)

[0746] (S)-2-amino-3-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile(23E)

[0747] Compound 23D (1 g, 2.41 mmol) was dissolved in anhydrous formic acid (10 ml). It was stirred at 25 °C for 5 hours. After the reaction was completed, the reaction solution was slowly poured into saturated sodium bicarbonate solution (100 ml), with pH = 7 - 8. Then it was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 23E, a pale yellow solid (710 mg, 93.5%). LCMS m / z = 315.2 [M+1] +

[0748] Step 5: (S)-2-(((S)-1-Cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (23F)

[0749] tert-butyl(S)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(23F)

[0750] Under nitrogen protection, compound 23E (656 mg, 2.07 mmol) was dissolved in DMF (7 ml), and INT-3 (510 mg, 2.07 mmol), diisopropylethylamine (1.34 g, 10.35 mmol), and 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.18 g, 3.10 mmol) were added. After the addition, the temperature was raised to 25 °C and the reaction was carried out for 3 hours. After the reaction was completed, the reaction solution was poured into water (20 ml), and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (40 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (the eluent ratio PE:EA (v / v)=1:0 to 1:1) to obtain compound 23F, a yellow solid (837 mg, 74.7%). LCMS m / z = 486.3 [M-tBu+1] +

[0751] Step 6: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 23)

[0752] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound23)

[0753] Compound 23F (837 mg, 1.55 mmol) was dissolved in anhydrous formic acid (3 ml) and stirred at 25 °C for 3 hours. After the reaction was completed, the reaction solution was slowly poured into saturated sodium bicarbonate solution (30 ml) with pH = 7 - 8. Then it was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated and purified by preparative liquid chromatography. Preparative liquid chromatography conditions: C18 reversed-phase preparative column, mobile phase: deionized water containing 0.1% trifluoroacetic acid (A), acetonitrile containing 0.1% trifluoroacetic acid (B), gradient elution, the content of mobile phase B = 5% - 50%, elution time 15 min, flow rate 12 mL / min, column temperature: 30 °C; retention time, 3.7 min, to obtain compound 23 (300 mg, yield 43.8%)

[0754] 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] +

[0755] Example 24: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 24)

[0756] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0757]

[0758] The first step: 6-bromo-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (24B)

[0759] 6-bromo-2-methyl-3,4-dihydroisoquinolin-1(2H)-one

[0760] Dissolve 24A (0.57 g, 2.5 mmol) in dry N,N-dimethylformamide (20 mL), cool to 0 °C under nitrogen protection, and add sodium hydride (0.12 g, 3.0 mmol, 60% wt) portionwise. After addition, stir the reaction mixture for 20 minutes, then add methyl iodide (0.51 g, 3.6 mmol) dropwise to the system. After addition, stir the reaction at room temperature for 30 minutes. Quench the reaction by adding water (100 mL), extract with ethyl acetate (100 mL × 2), combine the organic phases, wash with saturated brine (100 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated by silica gel column chromatography (PE:EA = 6:1) to obtain the target compound 6-bromo-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (24B), a yellow solid (0.48 g, yield 79%).

[0761] Step 2: (S)-(1-Cyano-2-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)carbamate (24C)

[0762] tert-butyl(S)-(1-cyano-2-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)carbamate

[0763] Add 24B (0.29 g, 1.2 mmol), INT-2 (0.39 g, 1.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (71 mg, 0.1 mmol), and potassium carbonate (0.28 g, 2.0 mmol) successively to 1,4-dioxane (15 mL) and water (3 mL). Purge the system with nitrogen three times and react at 100 °C for 2 hours. After the reaction is completed, cool to room temperature, add water (50 mL), extract the aqueous phase with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated sodium chloride aqueous solution (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated by silica gel column chromatography (PE:EA = 3:1 - 2:1) to obtain 24C, a brown solid (0.35 g, yield 83%). LCMS m / z = 424.2 [M+1] + 。

[0764] Step 3: (S)-2-amino-3-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)propanenitrile (24D)

[0765] (S)-2-amino-3-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)propanenitrile

[0766] Dissolve 24C (0.35 g, 0.83 mmol) in formic acid (6.0 mL). After addition, react at 50 °C for 10 minutes. Concentrate to dryness, add ethyl acetate (60 mL), adjust to pH about 8 by dropwise addition of saturated aqueous sodium bicarbonate solution, separate the organic layer, extract the aqueous phase with ethyl acetate (60 mL × 2), dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound 24D (0.24 g, yield 89%).

[0767] Step 4: tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (24E)

[0768] tert-butyl(S)-2-(((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0769] Dissolve 24D (0.24 g, 0.74 mmol) in DMF (10 mL), add INT-3 (0.25 g, 1.0 mmol), diisopropylethylamine (0.19 g, 1.5 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.38 g, 1 mmol). After addition, react at room temperature for 1 hour. Add water (30 mL), extract with ethyl acetate (60 mL × 2), wash the organic phase with saturated aqueous sodium chloride solution (60 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate the residue by silica gel column chromatography (PE:EA = 2:1 to 1:2) to obtain the title compound 24E, a pale yellow solid (0.28 g, yield 69%).

[0770] Step 5: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 24)

[0771] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0772] Dissolve 24E (0.28 g, 0.51 mmol) in formic acid (6.0 mL), and react at 50 °C for 10 minutes. Concentrate under reduced pressure, add ethyl acetate (60 mL), adjust the pH to about 8 by dropwise addition of saturated aqueous sodium bicarbonate solution, separate the organic layer, extract with ethyl acetate (60 mL × 5), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (methylene chloride:methanol (v / v) = 10:1) to obtain Compound 24 (0.18 g, yield 78%).

[0773] 1 H NMR (400 MHz, DMSO-d6) δ 8.82 (d, 1H), 7.93 (d, 1H), 7.71–7.63 (m, 2H), 7.63–7.53 (m, 2H), 7.47 (t, 1H), 5.11–5.01 (m, 1H), 4.15 (dd, 1H), 3.94 - 3.84 (m, 1H), 3.80 - 3.70 (m, 1H), 3.58 (t, 2H), 3.37–3.16 (m, 4H), 3.08–3.01 (m, 4H), 3.00 - 2.90 (m, 1H), 2.89–2.65 (m, 2H), 1.88 - 1.74 (m, 2H). LC-MS (ESI): m / z = 451.3 [M + H] + 。

[0774] Example 25: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 25)

[0775] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0776]

[0777] Step 1: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)carbamate (25B)

[0778] tert-butyl(S)-(1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)carbamate

[0779] 25A (0.27 g, 1.2 mmol), INT-2 (0.36 g, 0.92 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (71 mg, 0.1 mmol), and potassium carbonate (0.28 g, 2.0 mmol) were successively added to 1,4-dioxane (15 mL) and water (3 mL). The system was purged with nitrogen three times and reacted at 100 °C for 2 hours. After the reaction, it was cooled to room temperature, water (50 mL) was added, the aqueous phase was extracted with ethyl acetate (50 mL × 2), the combined organic phases were washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE:EA = 3:1 - 2:1) to obtain 25B, a brown solid (0.36 g, yield 95%). LCMS m / z = 410.1 [M+1] + 。

[0780] Step 2: (S)-2-amino-3-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)propanenitrile (25C)

[0781] (S)-2-amino-3-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)propanenitrile

[0782] 25B (0.36 g, 0.88 mmol) was dissolved in formic acid (6.0 mL), and after addition, the reaction was carried out at 50 °C for 10 minutes. It was concentrated to dryness, ethyl acetate (60 mL) was added, and the pH was adjusted to about 8 by dropwise addition of saturated aqueous sodium bicarbonate solution. The organic layer was separated, the aqueous phase was extracted with ethyl acetate (60 mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 25C (0.28 g, yield 100%). LCMS m / z = 310.1 [M+1] + 。

[0783] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (25D)

[0784] tert-butyl(S)-2-(((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0785] Dissolve 25C (0.28 g, 0.88 mmol) in DMF (10 mL), add INT-3 (0.25 g, 1.0 mmol), diisopropylethylamine (0.19 g, 1.5 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.38 g, 1 mmol). After addition, react at room temperature for 1 hour. Add saturated sodium chloride aqueous solution (30 mL), extract with ethyl acetate (60 mL × 2). Wash the organic phase with saturated sodium chloride aqueous solution (60 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate the residue by silica gel column chromatography (PE:EA = 2:1 - 1:2) to obtain the title compound 25D, a pale yellow solid (0.29 g, yield 60%).

[0786] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 25)

[0787] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0788] Dissolve 25D (0.29 g, 0.55 mmol) in formic acid (6.0 mL), react at 50 °C for 10 minutes. Concentrate under reduced pressure, add ethyl acetate (60 mL), adjust the pH to about 8 by dropwise addition of saturated sodium bicarbonate aqueous solution, separate the organic layer, extract with ethyl acetate (60 mL × 5). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (methylene chloride:methanol (v / v) = 10:1) to obtain Compound 25 (0.15 g, yield 64%).

[0789] 1 1H NMR (400 MHz, DMSO-d6) δ 8.84 (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] +

[0790] Example 26: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 26)

[0791] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamid (compound26)

[0792]

[0793] First step: 6-fluorobenzo[d]oxazol-2(3H)-one (26B)

[0794] 6-fluorobenzo[d]oxazol-2(3H)-one (26B)

[0795] Dissolve 26A (10 g, 78.67 mmol) in anhydrous DMF (130 mL), and dropwise add a solution of N,N'-carbonyldiimidazole (15.31 g, 94.40 mmol) in DMF (100 mL) under an ice bath. After addition, react at 60 °C for 4 h. Cool to room temperature, add 600 mL of water, extract with EA (100 mL × 4), combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify the residue 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] + 。

[0796] Step 2: 6-Fluoro-5-iodobenzo[d]oxazol-2(3H)-one (26C)

[0797] 6-fluoro-5-iodobenzo[d]oxazol-2(3H)-one(26C)

[0798] 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 batches. The mixture was reacted at 40°C overnight. After cooling to room temperature, the reaction solution was poured into 500 mL of water and extracted with EA (50 mL x 5). The organic layers were combined and backwashed with saturated aqueous sodium bicarbonate solution (200 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was 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] + .

[0799] Step 3: 6-Fluoro-5-iodo-3-methylbenzo[d]oxazol-2(3H)-one (26D)

[0800] 6-fluoro-5-iodo-3-methylbenzo[d]oxazol-2(3H)-one(26D)

[0801] 26C (1 g, 3.58 mmol) was dissolved in acetonitrile (40 mL), potassium carbonate (0.59 g, 4.30 mmol) was added, and the mixture was stirred at 40 °C for 30 min, transferred to room temperature, iodomethane (1.02 g, 7.16 mmol) was added dropwise, and the mixture was reacted at room temperature overnight. The insoluble matter was removed by filtration, and the mixture was extracted with EA (50 mL x 3). The organic layers were combined and backwashed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. 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] + .

[0802] Step 4: 6-Fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (26E)

[0803] 6-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one(26E)

[0804] 26D (0.92 g, 3.14 mmol), bis(pinacolato)diboron (0.96 g, 3.77 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.23 g, 0.31 mmol), and potassium acetate (0.92 g, 9.42 mmol) were dissolved in dioxane (40 mL). Under nitrogen protection, the reaction was carried out at 100 °C for 5 h. After cooling to room temperature, 120 mL of water was added, and the mixture was extracted with EA (30 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (PE:EA (v / v) = 5:1) to obtain the title compound 26E (0.52 g, 56%).

[0805] 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] + 。

[0806] Step 5: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate (26F)

[0807] tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate (26F)

[0808] 2a (0.62 g, 1.81 mmol), 26E (0.53 g, 1.81 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (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). Under nitrogen protection, the reaction was carried out at 90 °C for 5 h. After cooling to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed successively with saturated sodium bicarbonate (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was 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] + 。

[0809] Step 6: (S)-2-amino-3-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile (26G)

[0810] (S)-2-amino-3-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile(26G)

[0811] Dissolve 26F (0.6 g, 1.40 mmol) in anhydrous formic acid (3 mL), and react at 50 °C for 20 min. Cool to room temperature, concentrate to remove most of the solvent, add saturated sodium bicarbonate solution (20 mL) to the residue, extract with EA (10 mL × 3), combine the organic layers, dry over anhydrous sodium sulfate, and purify the residue by silica gel column chromatography (methylene chloride:methanol (v / v) = 97:3) to obtain the title compound 26G (0.36 g, 78%). LC-MS (ESI): m / z = 330.0 [M+H] + 。

[0812] Step 7: tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (Compound 26H)

[0813] tert-butyl(S)-2-(((S)-1-cyano-2-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(compound 26H)

[0814] INT-3 (0.26 g, 1.06 mmol) was dissolved in DMF (5 mL). Under nitrogen protection, HATU (0.6 g, 1.59 mmol) and DIPEA (0.41 g, 3.18 mmol) were added. After stirring at room temperature for 20 min, 26G (0.35 g, 1.06 mmol) was added and the reaction was carried out at room temperature for 1 h. 30 mL of water was added to the reaction, and it was extracted with EA (15 mL × 5). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (methylene chloride:methanol (v / v) = 97:3) to obtain the title compound 26H (0.33 g, 56%). LC-MS (ESI): m / z = 501.1 [M+H] + 。

[0815] Step 8: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 26)

[0816] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(6-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamid (compound26)

[0817] 26H (0.33 g, 0.59 mmol) was dissolved in anhydrous formic acid (3 mL) and reacted at 50 °C for 1 h. It was cooled to room temperature, concentrated to remove most of the solvent, saturated sodium bicarbonate solution (25 mL) was added to the residue, and it was extracted with EA multiple times until there was no product in the aqueous layer. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (methylene chloride:methanol (v / v) = 10:1) to obtain Compound 26 (120 mg, 44%).

[0818] 11H 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] + 。

[0819] Example 27: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0820] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0821]

[0822] Step 1: 1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yltrifluoromethanesulfonate (27B)

[0823] 1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yltrifluoromethanesulfonate

[0824] Under nitrogen protection at -78 °C, LDA (2.6 mL, 5.2 mmol) was slowly added dropwise to a solution of 27A (400 mg, 2.6 mmol, the preparation method refers to WO2016 / 172496A1) in THF (4.0 mL). After stirring at this temperature for 30 minutes, a solution of N,N-bis(trifluoromethanesulfonyl)aniline (1.40 g, 3.9 mmol) in THF (2.0 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by adding 5 mL of water, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with water (5 mL × 1), saturated sodium chloride solution (5 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 50:1 - 20:1) to obtain a pale yellow liquid 27B (240 mg, 32.4%). LC-MS (ESI): m / z = 288.1 [M+H] + 。

[0825] Step 2: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)carbamate (27C)

[0826] tert-butyl-(S)-(1-cyano-2-(2-fluoro-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)carbamate

[0827] At room temperature, 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). The reaction mixture was purged with nitrogen three times and heated to 60 °C for 2 hours. After cooling to room temperature, the reaction solution was concentrated by rotary evaporation and directly purified by column chromatography (DCM:MeOH = 50:1 - 20:1) to obtain the title compound 27C, a yellow solid (180 mg, 64%). LC-MS (ESI): m / z = 402.2 [M+H] + 。

[0828] Step 3: (S)-2-amino-3-(2-fluoro-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)propanenitrile (27D)

[0829] (S)-2-amino-3-(2-fluoro-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)propanenitrile

[0830] At room temperature, 27C (180 mg, 0.4 mmol) was added to anhydrous formic acid (3.0 mL). The temperature was raised to 50 °C and the reaction was carried out for 20 minutes. Most of the formic acid was removed under reduced pressure. Saturated sodium bicarbonate was added to neutralize to alkalinity. Extraction was carried out with dichloromethane (10 mL × 4), washed with saturated sodium chloride (5 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of compound 27D, a yellow viscous substance (200 mg). LC-MS (ESI): m / z = 302.2 [M+H] + 。

[0831] Step 4: tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (27E)

[0832] tert-butyl-(S)-2-(((S)-1-cyano-2-(2-fluoro-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0833] At room temperature, the crude product of 27D (200 mg), INT-3 (170 mg, 0.7 mmol) and DIPEA (180 mg, 1.4 mmol) were added to dichloromethane, and then HATU (270 mg, 0.7 mmol) was added. Stirring was continued at room temperature for 1 hour. After evaporation of the reaction solution, it was directly purified by column chromatography (DCM:MeOH = 50:1 - 20:1) to obtain yellow solid 27E (200 mg, two-step yield 94%). LC-MS (ESI): m / z = 529.3 [M+H] + 。

[0834] Step 5: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 27)

[0835] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0836] At room temperature, 27E (150 mg, 0.3 mmol) was added to anhydrous formic acid (3.0 mL). The temperature was raised to 50 °C and the reaction was carried out for 30 minutes. Most of the formic acid was removed under reduced pressure. Saturated sodium bicarbonate was added to neutralize to alkalinity. Extraction was carried out with dichloromethane (10 mL × 4), washed with saturated sodium chloride (5 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 27 (40 mg, 33%). LC-MS (ESI): m / z = 429.3 [M+H] + 。

[0837] 1 H 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).

[0838] Example 28: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(7-methoxy-1-methyl-1H-indol-4-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 28)

[0839] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(7-methoxy-1-methyl-1H-indol-4-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0840]

[0841] The first step: 4-bromo-7-methoxy-1-methyl-1H-indole (28B)

[0842] 4-bromo-7-methoxy-1-methyl-1H-indole

[0843] Dissolve 28A (0.50 g, 2.21 mmol) in acetonitrile (5 mL), add cesium carbonate (1.44 g, 4.22 mmol) and methyl iodide (0.47 g, 3.31 mmol). After addition, react at room temperature overnight. Add water (25 mL), extract with ethyl acetate (30 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (PE:EA(v / v) = 4:1) to obtain the title compound 28B, a white solid (0.50 g, 94.23%). LC-MS(ESI): m / z = 240.1 [M+H] + 。

[0844] Step 2: tert-butyl (S)-(2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)carbamate (28C)

[0845] tert-butyl (S)-(2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)carbamate

[0846] Dissolve 28B (0.40 g, 1.02 mmol) in 1,4-dioxane (10 mL) and water (0.4 mL), add INT-2 (0.26 g, 1.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.17 g, 0.20 mmol), and potassium carbonate (0.28 g, 2.04 mmol). After addition, protect with nitrogen and heat to 90 °C for 2 h. React at room temperature overnight. Concentrate to dryness, add saturated ammonium chloride aqueous solution (50 mL), extract with ethyl acetate (20 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (PE:EA(v / v) = 4:1) to obtain the title compound 28C, a pale yellow liquid (0.24 g, 59.20%). LC-MS(ESI): m / z = 398.1 [M+H] + 。

[0847] Step 3: (S)-2-amino-3-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)propanenitrile (28D)

[0848] (S)-2-amino-3-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)propanenitrile

[0849] Dissolve 28C (0.32 g, 0.81 mmol) in formic acid (5 mL), and react at 30 °C for 3 h after addition. Dropwise add saturated aqueous sodium bicarbonate solution to adjust the pH to about 8, extract with ethyl acetate (25 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound 28D, a colorless liquid (0.24 g, 99.65%), which is directly used for the next reaction. LC-MS (ESI): m / z = 298.1 [M+H] + 。

[0850] Step 4: tert-butyl (S)-2-(((S)-2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (28E)

[0851] tert-butyl(S)-2-(((S)-2-(4-(benzo[d]thiazol-2-yl)-2-fluorophenyl)-1-cyanoethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0852] Dissolve 28D (0.24 g, 0.81 mmol) in dichloromethane (10 mL), add INT-3 (0.26 g, 1.05 mmol), diisopropylethylamine (0.31 g, 2.43 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.46 g, 1.22 mmol), and react at room temperature overnight after addition. Add saturated aqueous sodium chloride solution (30 mL), extract with ethyl acetate (25 mL), wash the organic phase with saturated aqueous sodium chloride solution (25 mL × 3), dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (PE:EA (v / v) = 4:1) to obtain the title compound 28E, a pale yellow solid (0.25 g, 58.83%). LC-MS (ESI): m / z = 469.2 [M - 57 + H] + 。

[0853] Step 5: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(7-methoxy-1-methyl-1H-indol-4-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 28)

[0854] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(7-methoxy-1-methyl-1H-indol-4-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0855] Dissolve 28E (0.32 g, 0.59 mmol) in formic acid (2.0 mL), and react at 35 °C for 4 h after addition. Concentrate to dryness, add ethyl acetate (25 mL), adjust the pH to about 8 by dropwise addition of saturated aqueous sodium bicarbonate solution, separate the organic layer, extract with ethyl acetate (25 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (methylene chloride:methanol (v / v) = 20:1) to obtain the title compound 28 (30 mg, 14.72%).

[0856] 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] + 。

[0857] Example 29: (S)-N-((S)-1-cyano-2-(4'-cyano-3-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 29)

[0858] (S)-N-((S)-1-cyano-2-(4'-cyano-3-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 29)

[0859]

[0860] First step: tert-Butyl (S)-(1-cyano-2-(4'-cyano-3-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate (29B)

[0861] tert-butyl (S)-(1-cyano-2-(4'-cyano-3-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamate (29B)

[0862] 29A (300.0 mg, 1.00 mmol), INT-2 (470.0 mg, 1.20 mmol), Pd(dppf)Cl2 (160.0 mg, 0.20 mmol) and potassium carbonate (280.0 mg, 2.00 mmol) were added to a single-necked flask, followed by the addition of 1,4-dioxane (10 mL) and water (0.4 mL). After purging with nitrogen three times, the reaction was carried out at 95 °C for 4 hours. After cooling to room temperature, the mixture was concentrated and purified by silica gel column chromatography (PE:EA(v / v)=2:1) to obtain the title compound 29B, a white solid (230.0 mg, 53.1%). LC-MS(ESI): m / z = 377.1 [M - 57 + H] + 。

[0863] Step 2: (S)-4'-(2-amino-2-cyanoethyl)-3'-fluoro-3-(trifluoromethyl)-[1,1'-biphenyl]-4-carbonitrile (29C)

[0864] (S)-4'-(2-amino-2-cyanoethyl)-3'-fluoro-3-(trifluoromethyl)-[1,1'-biphenyl]-4-carbonitrile (29C)

[0865] 29B (230.0 mg, 0.53 mmol) was dissolved in formic acid (5 mL), and the reaction was carried out at 35 °C for 4 h. The reaction system was adjusted to alkaline with saturated potassium carbonate solution, extracted with ethyl acetate (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 29C, a pale yellow oil (180.0 mg, 100%), which was directly used in the next step. LC-MS(ESI): m / z = 334.1 [M + H] + 。

[0866] Step 3: tert-butyl (S)-2-(((S)-1-cyano-2-(4'-cyano-3-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (29D)

[0867] tert-butyl(S)-2-(((S)-1-cyano-2-(4'-cyano-3-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(29D)

[0868] Dissolve 29C (180 mg, 0.54 mmol) in DMF (5 mL), add INT-3 (160 mg, 0.65 mmol), HATU (250 mg, 0.65 mmol) and DIPEA (210 mg, 1.62 mmol). After addition, react at room temperature overnight. Add water (20 mL) to the system, extract with ethyl acetate (30 mL×2), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (PE:EA (v / v)=2:1) to obtain the title compound 29D, a white solid (280 mg, 92.5%). LC-MS (ESI): m / z = 505.2 [M - 57 + H] + 。

[0869] Step 4: (S)-N-((S)-1-cyano-2-(4'-cyano-3-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 29)

[0870] (S)-N-((S)-1-cyano-2-(4'-cyano-3-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 29)

[0871] Dissolve 29D (280 mg, 0.50 mmol) in formic acid (5 mL), and react at 35 °C for 4 h. Adjust the reaction system to alkaline with saturated potassium carbonate solution, extract with ethyl acetate (30 mL×2), dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (methylene chloride:methanol (v / v)=30:1) to obtain the title compound 29 (100.0 mg, 43.4%).

[0872] 11H 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] + 。

[0873] Example 30: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 30)

[0874] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0875]

[0876] First step: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)ethyl)carbamate (30B)

[0877] tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)ethyl)carbamate

[0878] 30A (0.20 g, 0.95 mmol), INT-2 (0.31 g, 0.79 mmol), dichlorobis[(1,1'-bis(diphenylphosphino)ferrocene)palladium(II)] (0.12 g, 0.16 mmol), and potassium carbonate (0.22 g, 1.58 mmol) were successively added to 1,4-dioxane (20 mL) and water (4 mL). The system was purged with nitrogen three times and then reacted at 100 °C for 2.5 h. After the reaction, it was cooled to room temperature, water (40 mL) was added, and the aqueous phase was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE:EA (v / v) = 3:1 - 2:1) to obtain 30B (0.26 g, yield 83%). LCMS m / z = 396.1 [M+H] + 。

[0879] Step 2: (S)-2-amino-3-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)propanenitrile (30C)

[0880] (S)-2-amino-3-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)propanenitrile

[0881] 30B (0.26 g, 0.66 mmol) was dissolved in formic acid (5.0 mL), and the mixture was reacted at 50 °C for 10 min after addition. It was concentrated to dryness, ethyl acetate (60 mL) was added, and the pH was adjusted to about 8 by dropwise addition of saturated aqueous sodium bicarbonate solution. The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (60 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 30C (0.15 g, yield 77%). LCMS m / z = 296.1 [M+H] + 。

[0882] Step 3: tert-butyl(S)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (30D)

[0883] tert-butyl(S)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0884] 30C (0.15 g, 0.51 mmol) was dissolved in N,N-dimethylformamide (10 mL), and INT-3 (0.13 g, 0.51 mmol), triethylamine (0.1 g, 1 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.23 g, 0.61 mmol) were added. After the addition, the reaction was carried out at room temperature for 1 hour. Saturated sodium chloride aqueous solution (30 mL) was added, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phase was washed with saturated sodium chloride aqueous solution (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography (PE:EA (v / v) = 2:1 - 1:5) to obtain the title compound 30D (0.14 g, yield 53%).

[0885] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 30)

[0886] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0887] 30D (0.14 g, 0.27 mmol) was dissolved in formic acid (6.0 mL), and the reaction was carried out at 50 °C for 10 minutes. It was concentrated under reduced pressure, ethyl acetate (60 mL) was added, and the pH was adjusted to about 8 by dropwise addition of saturated sodium bicarbonate aqueous solution. The organic layer was separated, and the mixture was extracted with dichloromethane (60 mL × 5). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 4:1) to obtain Compound 30 (48 mg, yield 42%).

[0888] 1 H 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] + 。

[0889] Example 31: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 31)

[0890] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0891]

[0892] First step: 6-bromo-2-methylisoindolin-1-one (31A)

[0893] 6-bromo-2-methylisoindolin-1-one

[0894] Dissolve 30A (0.49 g, 2.3 mmol) in dry N,N-dimethylformamide (20 mL), cool to 0 °C under nitrogen protection, add sodium hydride (0.14 g, 3.45 mmol, 60% wt) portionwise. After addition, stir the reaction mixture for 20 minutes at this temperature, then add methyl iodide (0.49 g, 3.45 mmol) dropwise to the system. After addition, stir the reaction mixture at room temperature for 30 minutes. Quench the reaction by adding water (100 mL), extract with ethyl acetate (100 mL × 2), combine the organic phases, wash with saturated brine (100 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated by silica gel column chromatography (PE:EA = 6:1) to obtain the target compound 31A (0.37 g, yield 71%).

[0895] 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).

[0896] Second step: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)carbamate (31B)

[0897] tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)carbamate

[0898] 31A (0.18 g, 0.8 mmol), INT-2 (0.29 g, 0.74 mmol), dichlorobis[(1,1'-bis(diphenylphosphino)ferrocene)palladium(II)] (0.11 g, 0.15 mmol), and potassium carbonate (0.2 g, 1.48 mmol) were successively added to 1,4-dioxane (20 mL) and water (4 mL). The system was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction, it was cooled to room temperature, water (40 mL) was added, and the aqueous phase was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE:EA (v / v) = 3:1 - 1:1) to obtain 31B (0.27 g, yield 89%). LCMS m / z = 432.1 [M+Na] + 。

[0899] Step 3: (S)-2-amino-3-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)propanenitrile (31C)

[0900] (S)-2-amino-3-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)propanenitrile

[0901] 31B (0.27 g, 0.66 mmol) was dissolved in formic acid (6.0 mL), and after addition, the reaction was carried out at 50 °C for 10 min. It was concentrated to dryness, ethyl acetate (60 mL) was added, and the pH was adjusted to about 8 by dropwise addition of saturated aqueous sodium bicarbonate solution. The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (60 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 31C (0.16 g, yield 78%). LCMS m / z = 310.2 [M+H] + 。

[0902] Step 4: tert-butyl tert-butyl(S)-2-(((S)-1-cyano-2-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (31D)

[0903] tert-butyl tert-butyl(S)-2-(((S)-1-cyano-2-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0904] Dissolve 31C (0.16 g, 0.52 mmol) in N,N-dimethylformamide (10 mL), add INT-3 (0.13 g, 0.52 mmol), triethylamine (0.1 g, 1 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.24 g, 0.62 mmol), and react at room temperature for 1 hour after addition. Add saturated sodium chloride aqueous solution (30 mL), extract with ethyl acetate (60 mL×3), wash the organic phase with saturated sodium chloride aqueous solution (60 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate the residue by silica gel column chromatography (PE:EA (v / v) = 2:1~1:3) to obtain the title compound 31D (0.21 g, yield 75%). LCMS m / z = 559.2 [M+Na] + 。

[0905] Step 5: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 31)

[0906] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

[0907] Dissolve 31D (0.21 g, 0.39 mmol) in formic acid (6.0 mL), and react at 50 °C for 10 minutes. Concentrate under reduced pressure, add ethyl acetate (60 mL), adjust the pH to about 8 by dropwise addition of saturated sodium bicarbonate aqueous solution, separate the organic layer, extract with dichloromethane (60 mL×5), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain Compound 31 (100 mg, yield 59%).

[0908] 11H NMR (400 MHz, DMSO-d6) δ 8.85 (d, 1H), 7.94 - 7.90 (m, 2H), 7.68 (d, 1H), 7.65–7.56 (m, 2H), 7.46 (t, 1H), 5.11–5.01 (m, 1H), 4.51 (s, 2H), 4.18 (dd, 1H), 3.94 - 3.84 (m, 1H), 3.79 - 3.70 (m, 1H), 3.26–3.14 (m, 3H), 3.10 (s, 3H), 3.02 - 2.92 (m, 1H), 2.87–2.69 (m, 2H), 1.90 - 1.77 m, 2H). LC-MS m / z=437.2 [M+H] + 。

[0909] Example 32: (2S)-N-(1-cyano-2-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 32)

[0910] (2S)-N-(1-cyano-2-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 32)

[0911]

[0912] First step: Methyl 5-bromo-3-fluorothiophene-2-carboxylate (32B)

[0913] methyl 5-bromo-3-fluorothiophene-2-carboxylate (32B)

[0914] At room temperature, dissolve 32A (15 g, 93.7 mmol) in chloroform (200 mL), add bromine (120 g, 750 mmol), heat the reaction mixture to 80 °C and react for 3 hours. Pour the reaction solution into saturated sodium thiosulfate solution (500 mL), concentrate the organic phase to dryness, and purify by separation to obtain the title compound 32B (10 g, yield 45%).

[0915] Second step: (5-Bromo-3-fluorothiophen-2-yl)methanol (32C)

[0916] (5-bromo-3-fluorothiophen-2-yl)methanol (32C)

[0917] At room temperature, 32B (5 g, 20.9 mmol) was dissolved in dichloromethane (120 mL), and diisobutylaluminum hydride (42 mL, 62.8 mmol) was added dropwise thereto. The reaction was carried out at room temperature for 3 hours. Water (100 mL) was added thereto, and the mixture was filtered. The organic phase was concentrated to dryness to obtain the title compound 32C (4 g, yield 90%).

[0918] Step 3: 5-bromo-2-(bromomethyl)-3-fluorothiophene (32D)

[0919] 5-bromo-2-(bromomethyl)-3-fluorothiophene(32D)

[0920] At room temperature, 32C (4 g, 19.0 mmol) was dissolved in dichloromethane (60 mL), carbon tetrabromide (7.5 g, 22.7 mmol) and triphenylphosphine (7.5 g, 28.4 mmol) were added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated to dryness and directly purified by column chromatography (PE:EA (v:v) = 20:1 - 10:1) to obtain the title compound 32D (4 g, yield 77%).

[0921] Step 4: 3-(5-bromo-3-fluorothiophen-2-yl)-2-((diphenylmethylene)amino)propanenitrile (32E)

[0922] 3-(5-bromo-3-fluorothiophen-2-yl)-2-((diphenylmethylene)amino)propanenitrile(32E)

[0923] At room temperature, 32D (2 g, 7.3 mmol) was dissolved in dichloromethane (40 mL) and water (4 mL), sodium hydroxide (0.5 g, 13.1 mmol) and benzyltrimethylammonium chloride (140 mg, 0.73 mmol) were added, and the reaction was carried out at room temperature for 16 hours. The reaction solution was washed with water (50 mL×1), the organic phase was concentrated, and directly purified by column chromatography (PE:EA (v:v) = 20:1 - 10:1) to obtain the title compound 32E (1.2 g, yield 40%). LC-MS (ESI): m / z = 413.1 [M+H] + 。

[0924] Step 5: 2-((diphenylmethylene)amino)-3-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)propanenitrile (32F)

[0925] 2-((Diphenylmethylene)amino)-3-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)propanenitrile (32F)

[0926] At room temperature, dissolve 32E (1.2 g, 2.9 mmol) in dioxane (30 mL) and water (3 mL). Sequentially add 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(II) acetate (0.065 g, 0.29 mmol). React at 100 °C for three hours. Purify the reaction mixture directly by flash column chromatography (PE:EA (v:v) = 5:1 - 1:1) to obtain the title compound 32F (1.4 g, yield 70%). LC-MS (ESI): m / z = 482.1 [M+H] + 。

[0927] Step 6: 2-Amino-3-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)propanenitrile (32G)

[0928] 2-amino-3-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)propane-nitrile (32G)

[0929] At room temperature, dissolve 32F (1.4 g, 2.9 mmol) in tetrahydrofuran (20 mL). Add 1N hydrochloric acid (40 mL) and react at room temperature for 1 hour. Extract the impurities from the reaction mixture with ethyl acetate (50 mL×1). Adjust the pH of the aqueous phase to 8 - 9 with potassium carbonate and extract the product with ethyl acetate (50 mL×2). Concentrate the organic phase to obtain the title compound 32G (0.45 g, yield 49%). LC-MS (ESI): m / z = 318.1 [M+H] + 。

[0930] Step 7: (2S)-2-((1-Cyano-2-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (32H)

[0931] (2S)-tert-butyl-2-((1-cyano-2-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(32H)

[0932] 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-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.6 g, 1.6 mmol), INT-3 (0.4 g, 1.7 mmol), and diisopropylethylamine (0.5 g, 3.6 mmol) were added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was poured into water (200 mL), and extracted with ethyl acetate (100 mL×2). The organic phase was concentrated to dryness to obtain the title compound 32H (0.4 g, yield 52%). LC-MS (ESI): m / z = 545.2 [M+H] +

[0933] Step 8: (2S)-N-(1-cyano-2-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 32)

[0934] (2S)-N-(1-cyano-2-(3-fluoro-5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 32)

[0935] At room temperature, compound 32G (0.4 g, 0.73 mmol) was dissolved in acetonitrile (20 mL). p-Toluenesulfonic acid (0.5 g, 3.0 mmol) was added, and the reaction was carried out at 50 °C for 1 hour. The reaction solution was poured into saturated aqueous sodium bicarbonate (100 mL), and extracted with ethyl acetate (100 mL×2). The organic phase was concentrated and purified by column chromatography (DCM:MeOH (v:v) = 50:1 - 20:1) to obtain compound 32 (0.24 g, 70%).

[0936] 11H NMR (400 MHz, CDCl3) δ 7.33 - 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] + 。

[0937] Example 33 and Example 34: (S)-N-((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-2-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 33 and Compound 34)

[0938] (S)-N-((S)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-2-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 33 and compound 34)

[0939]

[0940] The first step: 5-bromo-2-(bromomethyl)pyridine (33B)

[0941] 5-bromo-2-(bromomethyl)pyridine (33B)

[0942] 2-Methyl-5-bromopyridine 33A (5 g, 29.07 mmol) was dissolved in carbon tetrachloride (50 mL). After adding N-bromosuccinimide (5.43 g, 30.52 mmol) and azobisisobutyronitrile (1.19 g, 7.27 mmol), the reaction was carried out at 90 °C for 2.5 h. After cooling to room temperature, the reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 10:1) to obtain the title compound 33B (4.42 g, 61%). LC-MS (ESI): m / z = 251.9 [M+H] + 。

[0943] Step 2: 3-(5-Bromopyridin-2-yl)-2-((diphenylmethylene)amino)propanenitrile (33C)

[0944] 3-(5-bromopyridin-2-yl)-2-((diphenylmethylene)amino)propanenitrile(33C)

[0945] 33B (4.42 g, 17.54 mmol) and N-(diphenylmethylene)aminoacetonitrile (3.86 g, 17.54 mmol) were dissolved in dichloromethane (50 mL). After adding benzyltrimethylammonium chloride (0.33 g, 1.75 mmol), an aqueous solution (5 mL) of sodium hydroxide (1.40 g, 35.08 mmol) was added under strong stirring, and the reaction was carried out overnight at room temperature. 100 mL of water was added, and the mixture was extracted with dichloromethane (30 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (PE:EA (v / v) = 10:1) to obtain the title compound 33C (5.20 g, 76%). LC-MS (ESI): m / z = 390.0 [M+H] + 。

[0946] Step 3: 2-((Diphenylmethylene)amino)-3-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)propanenitrile (33D)

[0947] 2-((diphenylmethylene)amino)-3-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)propanenitrile(33D)

[0948] 33C (1.73 g, 4.43 mmol), 1A (1.34 g, 4.87 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(0) (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). Under nitrogen protection, the reaction was carried out at 90 °C for 5 h. After cooling to room temperature, 200 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed successively with saturated sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (PE:EA (v / v) = 3:1) to obtain the title compound 33D (2.03 g, 68.92%). LC-MS (ESI): m / z = 459.1 [M+H] + 。

[0949] Step 4: 2-amino-3-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-2-yl)propanenitrile (33E)

[0950] 2-amino-3-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-2-yl)propanenitrile(33E)

[0951] 33D (1.02 g, 2.19 mmol) was dissolved in tetrahydrofuran (50 mL) and water (5 mL), and 2.5 mL of 1 M aqueous HCl solution was added dropwise. After completion of the addition, the reaction was carried out at room temperature for 5 h. The reaction solution was extracted with diethyl ether (15 mL × 3) and discarded. The aqueous layer was adjusted to about pH 12 with 2 M aqueous NaOH solution, and extracted with DCM (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated to obtain 580 mg of the crude title compound 33E, which was used directly in the next step without further purification. LC-MS (ESI): m / z = 295.0 [M+H] + 。

[0952] Step 5: tert-butyl (2S)-2-((1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-2-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (33F)

[0953] tert-butyl(2S)-2-((1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-2-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0954] 33E (0.4 g, 1.36 mmol) was dissolved in dichloromethane (10 mL), and DIPEA (0.34 g, 2.64 mmol), HATU (0.55 g, 1.45 mmol), and intermediate INT-3 (0.36 g, 1.5 mmol) were added in sequence, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed by TLC, water (20 mL) was poured into the reaction solution, and the layers were separated. The organic phase was washed with water (20 mL) and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily crude product. The crude product was purified by flash column chromatography (DCM: MeOH (v / v) = 96:4) to obtain a white solid 33F (0.4 g, yield 56.4%). LC-MS (ESI): m / z = 522.2 [M+H] + .

[0955] Step 6: (2S)-N-(-1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-2-yl)ethyl)-1,4-oxazepane-2-carboxamide (33G)

[0956] (2S)-N-(1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-2-yl)ethyl)-1,4-oxazepane-2-carboxamide

[0957] Compound 33F (0.3 g, 0.58 mmol) was dissolved in dichloromethane (10 mL), TMSOTf (0.19 g, 0.87 mmol) was added, 2,6-lutidine (0.12 g, 1.16 mmol) was added dropwise under ice bath, and the mixture was heated to room temperature for 1 h. The reaction solution was poured into 30 mL of saturated ammonium chloride solution, extracted with dichloromethane (20 mL×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 compound 33G (0.14 g).

[0958] Compound 33G was separated by chiral preparative SFC to obtain peak 1 (40 mg, ee% = 100%, yield 16.5%, retention time: 2.728 min, designated as compound 33) and peak 2 (50 mg, ee% = 98.5%, yield: 20.6%, retention time: 3.987 min, designated as compound 34).

[0959] The purification conditions were as follows: (Instrument name: MG Ⅱ preparative SFC (SFC-14); Column: ChiralPak AD, 250×30 mm I.D., 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 °C; Absorbance wavelength: 220 nm; Cycle time: approximately 7 min.).

[0960] Peak 1: LC-MS (ESI): m / z = 422.2 [M+H] + ;

[0961] 1 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), 5.37 - 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).

[0962] Peak 2: LC-MS (ESI): m / z = 422.2 [M+H] + ;

[0963] 11H 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).

[0964] Example 35 and Example 36: (S)-N-((S)-1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 35 and Compound 36)

[0965] (S)-N-((S)-1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 35 and compound 36)

[0966]

[0967] First step: 2-bromo-4-fluoro-5-methylpyridine (35B)

[0968] 2-bromo-4-fluoro-5-methylpyridine

[0969] Dissolve compound 2-bromo-4-amino-5-methylpyridine 35A (1.87 g, 10 mmol) in pyridine hydrofluoride (20 mL). Add sodium nitrite (0.83 g, 12 mmol) portionwise at -10 °C. After addition, allow the mixture to warm to room temperature and react overnight. After the reaction is complete, add water (100 mL), adjust the pH to 8 with saturated sodium bicarbonate, extract with ethyl acetate (100 mL x 2), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by silica gel column chromatography (PE:EA = 10:1, v / v) to obtain the target compound 35B (1.21 g, yield 63.4%).

[0970] 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] +

[0971] Step 2: 2-bromo-5-(bromomethyl)-4-fluoropyridine (35C)

[0972] 2-bromo-5-(bromomethyl)-4-fluoropyridine

[0973] Dissolve 35B (2.84 g, 15.0 mmol) in carbon tetrachloride (50 mL). Add N-bromosuccinimide (2.93 g, 16.5 mmol) and azobisisobutyronitrile (0.49 g, 3.0 mmol), then react at 90 °C for 4 h. Cool to room temperature, concentrate the reaction solution, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain the title compound 35C (2.45 g, 61%).

[0974] 1 H NMR (400 MHz, CDCl3) δ 8.40 (d, 1H), 7.28 (d, 1H), 4.43 (s, 2H).

[0975] Step 3: 3-(6-bromo-4-fluoropyridin-3-yl)-2-((diphenylmethylene)amino)propanenitrile (35D)

[0976] 3-(6-bromo-4-fluoropyridin-3-yl)-2-((diphenylmethylene)amino)propanenitrile

[0977] 35C (2.4 g, 8.9 mmol) and N-(diphenylmethylene)aminoacetonitrile (1.96 g, 8.9 mmol) were dissolved in dichloromethane (40 mL). After adding benzyltrimethylammonium chloride (0.17 g, 0.89 mmol), an aqueous solution (4 mL) of sodium hydroxide (1.07 g, 26.8 mmol) was added under strong stirring, and the reaction was carried out overnight at room temperature. 100 mL of water was added, and the mixture was extracted with dichloromethane (60 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (PE:EA (v / v) = 10:1) to obtain the title compound 35D (2.23 g, 61%). LC-MS (ESI): m / z = 408.1 [M+H] + 。

[0978] Step 4: 2-((Diphenylmethylene)amino)-3-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)propanenitrile (35E)

[0979] 2-((diphenylmethylene)amino)-3-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)propanenitrile(35E)

[0980] 35D (1.3 g, 3.18 mmol), 1A (0.87 g, 3.18 mmol), [1,1'-(diphenylphosphino)ferrocene]dichloropalladium (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). Under nitrogen protection, the reaction was carried out at 90 °C for 5 h. After cooling to room temperature, 80 mL of water was added, and the mixture was extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed successively with saturated sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (PE:EA (v / v) = 3:1) to obtain the title compound 35E (1.02 g, 67%). LC-MS (ESI): m / z = 477.2 [M+H] + 。

[0981] Step 5: 2-Amino-3-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)propanenitrile (35F)

[0982] 2-amino-3-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)propanenitrile(35F)

[0983] Dissolve 35E (1.02 g, 2.14 mmol) in tetrahydrofuran (25 mL) and water (5 mL), add dropwise 5 mL of 1 M aqueous HCl solution. After addition, react at room temperature for 5 h. Extract the reaction solution with diethyl ether (40 mL) and discard it. Adjust the pH of the aqueous layer to about 12 with 2 M aqueous NaOH solution, extract with DCM (50 mL × 3), combine the organic layers, dry over anhydrous sodium sulfate, and concentrate to obtain 0.64 g of the crude title compound 35F, which is directly used in the next reaction without further purification. LC-MS (ESI): m / z = 313.1 [M+H] + 。

[0984] Step 6: (2S)-N-(1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (35G)

[0985] (2S)-N-(1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide

[0986] Dissolve 35F (0.64 g, 2.05 mmol) in dichloromethane (10 mL), and successively add intermediate INT-3 (0.5 g, 2.05 mmol), DIPEA (0.53 g, 4.1 mmol), and HATU (0.94 g, 2.46 mmol), and react at room temperature for 1 h. After detecting the completion of the reaction by TLC, pour water (20 mL) into the reaction solution, separate the layers, wash the organic phase successively with water (20 mL) and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude yellow oil. The crude product is purified by flash column chromatography (DCM:MeOH (v / v) = 20:1) to obtain 35G (0.98 g, yield 88.6%). LC-MS (ESI): m / z = 540.2 [M+H] + 。

[0987] Step 7: (S)-N-((S)-1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 35 and Compound 36)

[0988] (S)-N-((S)-1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide and(S)-N-((R)-1-cyano-2-(4-fluoro-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide

[0989] Dissolve Compound 35G (0.98 g, 1.82 mmol) in formic acid (10 mL), and react at 50 °C for 10 min at room temperature. Concentrate under reduced pressure, add dichloromethane (40 mL) and saturated sodium bicarbonate (40 mL), separate the layers, extract the aqueous phase with dichloromethane (50 mL × 4), combine the organic phases, wash the organic phase with saturated sodium chloride (40 mL), dry over anhydrous sodium sulfate, and concentrate to obtain the target compound (0.76 g, yield 95%). Two isomers were prepared by SFC, peak 1 (retention time: 2.47 min, designated as Compound 35) and peak 2 (retention time: 3.69 min, designated as Compound 36).

[0990] Preparation conditions: Instrument: MG Ⅱ preparative SFC (SFC-14). Column: ChiralPak AD, 250 × 30 mm I.D., 10 μm. Mobile phase: A: CO2, 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: approximately 10 min. Sample preparation: The sample is dissolved in 15 ml of methanol / dichloromethane. Injection: 3.5 ml per injection.

[0991] Peak 1: LC-MS m / z = 440.1 [M+1] + 。

[0992] 1 1H 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).

[0993] Peak 2: LC-MS m / z = 440.1 [M+1] + 。

[0994] 1 1H 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).

[0995] (S)-N-((S)-1-Cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 37 and Compound 38)

[0996] (S)-N-((S)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 37 and compound 38)

[0997]

[0998] Step 1: 2-bromo-5-(bromomethyl)pyridine (37B)

[0999] 2-bromo-5-(bromomethyl)pyridine(37B)

[1000] Dissolve 37A (5 g, 29.07 mmol) in carbon tetrachloride (50 mL). After adding N-bromosuccinimide (5.43 g, 30.52 mmol) and azobisisobutyronitrile (1.19 g, 7.27 mmol), react at 90 °C for 2.5 h. Cool to room temperature, concentrate the reaction solution, and purify the residue by silica gel column chromatography (PE: EA (v / v) = 10:1) to obtain the title compound 37B (4.42 g, 61%). LC-MS (ESI): m / z = 251.9 [M+H] + 。

[1001] Step 2: 3-(6-bromopyridin-3-yl)-2-((diphenylmethylene)amino)propanenitrile (37D)

[1002] 3-(6-bromopyridin-3-yl)-2-((diphenylmethylene)amino)propanenitrile(37D)

[1003] 37B (4.42 g, 17.54 mmol) and 37C (3.86 g, 17.54 mmol) were dissolved in dichloromethane (50 mL). After adding benzyltrimethylammonium chloride (0.33 g, 1.75 mmol), an aqueous solution (5 mL) of sodium hydroxide (1.40 g, 35.08 mmol) was added under strong stirring, and the reaction was carried out overnight at room temperature. 100 mL of water was added, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (PE:EA(v / v) = 10:1) to obtain the title compound 37D (5.20 g, 76%).

[1004] 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] + 。

[1005] Step 3: 2-((Diphenylmethylene)amino)-3-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)propanenitrile (37E)

[1006] 2-((diphenylmethylene)amino)-3-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)propanenitrile (37E)

[1007] 37D (1.5 g, 3.84 mmol), 1A (1.06 g, 3.84 mmol), [1,1'-(diphenylphosphino)ferrocene]dichloropalladium (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). Under nitrogen protection, the reaction was carried out at 90 °C for 5 h. After cooling to room temperature, 200 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed successively with saturated sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (PE:EA(v / v) = 3:1) to obtain the title compound 37E (1.02 g, 57%). LC-MS (ESI): m / z = 459.1 [M+H] + 。

[1008] 1 H NMR (400MHz, CDCl3) δ8.48(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=7.7Hz,2H),4.50–4.42(m,1H),3.47(s,3H),3.29–3.24(m,2H).

[1009] Step 4: 2-amino-3-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)propionitrile (Compound 37F)

[1010] 2-amino-3-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)propanenitrile(compound 37F)

[1011] 37E (1.02 g, 2.19 mmol) was dissolved in tetrahydrofuran (50 mL) and water (5 mL), and 2.5 mL of 1 M HCl aqueous solution was added dropwise. After the addition was completed, the reaction mixture was reacted at room temperature for 5 h. The reaction solution was extracted with ether (15 mL x 3) and discarded. The aqueous layer was adjusted to pH 12 with 2 M NaOH aqueous solution and extracted with DCM (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 580 mg of the crude product of the title compound 37F, which was used directly in the next step without further purification. LC-MS (ESI): m / z = 295.1 [M+H] + .

[1012] Step 5: (2S)-tert-butyl 2-((1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (Compound 37G)

[1013] tert-butyl(2S)-2-((1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(compound 37G)

[1014] Dissolve INT-3 (0.36 g, 1.22 mmol) in DMF (5 mL). Under nitrogen protection, add HATU (0.6 g, 1.59 mmol) and N,N-diisopropylethylamine (0.47 g, 3.66 mmol). After stirring at room temperature for 20 min, add 37F (0.3 g, 1.22 mmol) and react at room temperature for 3 h. Add 30 mL of water to the reaction, extract with EA (15 mL × 5), combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and purify the residue by silica gel column chromatography (DCM:MeOH (v / v) = 97:3) to obtain the title compound 37G (0.32 g, 51%). LC-MS (ESI): m / z = 522.2 [M+H] + 。

[1015] Step 6: (S)-N-(1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 37H)

[1016] (S)-N-(1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 37H)

[1017] Dissolve 37G (0.32 g, 0.61 mmol) in anhydrous formic acid (3 mL) and react at 50 °C for 1 h. Cool to room temperature, concentrate to remove most of the solvent, add saturated sodium bicarbonate solution (25 mL) to the residue, extract with EA multiple times until there is no product in the aqueous layer, combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and purify the residue by silica gel column chromatography (DCM:MeOH (v / v) = 10:1) to obtain compound 37H (140 mg, 55%).

[1018] Compound 37H was separated by SFC chiral preparation to obtain peak 1 (63 mg, ee% = 98.22%, yield 24.8%, retention time: 2.120 min, designated as compound 37) and peak 2 (73 mg, ee% = 100%, yield: 28.7%, retention time: 2.689 min, designated as compound 38).

[1019] The purification conditions are as follows: (Instrument name: MG Ⅱ preparative SFC (SFC-14); Chromatographic column: ChiralPak AD, 250×30 mm I.D., 10 μm; Mobile phase: Phase A: CO2; Phase B: Methanol (0.1% NH3H2O); Flow rate: 80 mL / min; Column pressure: 100 bar; Column temperature: 35 °C; Absorption wavelength: 220 nm; Cycle time: approximately 16.9 min.)

[1020] Peak 1: LC-MS (ESI): m / z = 422.3 [M+H] + 。

[1021] 1 1H 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] + 。

[1022] 1 1H 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).

[1023] Example 39 and Example 40: (S)-N-((S)-1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 39 and Compound 40)

[1024] (S)-N-((S)-1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)ethyl)-1,4-oxazepane-2-carboxamide and(S)-N-((R)-1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)ethyl)-1,4-oxazepane-2-carboxamide(compound 39 and compound 40)

[1025]

[1026] First step: (2-chloropyrimidin-5-yl)methanol (39B)

[1027] (2-chloropyrimidin-5-yl)methanol

[1028] Dissolve 39A (2 g, 10.72 mmol) in anhydrous THF (20 ml), then cool the temperature to 0 °C under nitrogen protection. Take diisobutylaluminum hydride (21.5 ml) and slowly add it dropwise to the reaction solution. Stir for 0.5 h in an ice bath. Monitor the reaction by TLC until the raw materials are completely reacted. Add saturated ammonium chloride (10 ml) to quench the reaction, extract with ethyl acetate (3 x 20 ml), combine the organic phases and dry over anhydrous sodium sulfate. Column chromatography gives the product 39B (1.2 g, 77.4%). LC-MS (ESI): m / z = 145.1 [M+H] + 。

[1029] Second step: 5-(bromomethyl)-2-chloropyrimidine (39C)

[1030] 5-(bromomethyl)-2-chloropyrimidine

[1031] Dissolve 39B (1 g, 6.92 mmol) in DCM (20 ml) at room temperature. Under nitrogen protection, cool the reaction solution to 0 °C, and add triphenylphosphine (1.82 g, 6.92 mmol) and carbon tetrabromide (2.29 g, 6.92 mmol) while maintaining this temperature. After stirring at 0 °C for 0.5 h, warm the reaction solution to room temperature and continue stirring for 1.5 h. TLC monitoring shows a little substrate remaining. Rotate the reaction solution to dryness and column chromatograph (PE:EA = 5:1) to obtain 39C (1 g, 70%). LC-MS (ESI): m / z = 207.1 [M+H] + 。

[1032] Step 3: 3-(2-chloropyrimidin-5-yl)-2-((diphenylmethylene)amino)propanenitrile (39D)

[1033] 3-(2-chloropyrimidin-5-yl)-2-((diphenylmethylene)amino)propanenitrile

[1034] Dissolve 39C (1 g, 4.82 mmol), diphenylmethyleneaminoacetonitrile (1.06 g, 4.82 mmol), and benzyltrimethylammonium chloride (0.18 g, 0.96 mmol) in DCM (30 ml) at room temperature. Slowly add NaOH (0.8 ml, 19 mol / L) to the reaction solution and stir the reaction solution overnight at room temperature. Add 20 ml of water to quench the reaction, extract with DCM (20 ml × 3), combine the organic phases, dry over anhydrous sodium sulfate, rotate to dryness and column chromatograph (PE:EA = 3:1) to obtain the product 39D (1.1 g, 65.8%). LC-MS (ESI): m / z = 347.1 [M+H] + 。

[1035] Step 4: 2-((diphenylmethylene)amino)-3-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)propanenitrile (39E)

[1036] 2-((diphenylmethylene)amino)-3-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)propanenitrile

[1037] Reactants 39D (1.1 g, 3.17 mmol) and 1A (0.96 g, 3.49 mmol) were dissolved in 1,4-dioxane (100 ml). Then potassium carbonate (1.31 g, 9.51 mmol) and Pd(dppf)Cl2 (0.23, 0.32 mmol) were added thereto. After purging with nitrogen for protection, the reaction was carried out at 100 °C. TLC and LC-MS showed that a small amount of the raw materials remained. The mixture was concentrated by rotary evaporation and dried, dissolved in DCM, filtered through diatomaceous earth, and the filtrate was concentrated by rotary evaporation and purified by column chromatography with EA / PE = 0%-40%. The column chromatography gave a pale yellow solid 39E (1.1 g, 75.5%). LC-MS (ESI): m / z = 460.2 [M+H] + 。

[1038] Step 5: 2-amino-3-(2-(3-(2-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)propanenitrile (39F)

[1039] 2-amino-3-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)propanenitrile

[1040] Substrate 39E (1.1 g, 2.39 mmol) was dissolved in DCM (30 ml), and 1M HCl (7.2 ml) was added. The mixture was stirred at room temperature for 3 h. TLC showed that the raw materials had completely reacted. The pH of the solution was adjusted to 8-10, and the mixture was extracted with EA (20 ml x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to obtain product 39F (0.6 g, 85%). LC-MS (ESI): m / z = 296.1 [M+H] + 。

[1041] Step 6: (2S)-tert-butyl 2-(1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)ethylcarbamoyl)-1,4-oxazepane-4-carboxylate (39G)

[1042] (2S)-tert-butyl 2-(1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)ethylcarbamoyl)-1,4-oxazepane-4-carboxylate

[1043] Under room temperature conditions, 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). After stirring at room temperature for 10 min, 39F (0.6 g, 2.03 mmol) was added thereto, and the mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC and found to be complete. Water (10 ml) was added to quench the reaction, and the mixture was extracted with dichloromethane (15 ml × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 1:1) to obtain the product 39G (0.6 g, 56%). LC-MS (ESI): m / z = 523.2 [M+H] + .

[1044] Step 7: (2S)-N-(1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)ethyl)-1,4-oxazepane-2-carboxamide (39H)

[1045] (2S)-N-(1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-5-yl)ethyl)-1,4-oxazepane-2-carboxamide

[1046] 39G (0.6 g, 1.15 mmol) was dissolved in anhydrous formic acid (20 ml). After stirring at room temperature for 2 h, TLC detection found that the substrate reaction was complete. The formic acid was removed by rotary evaporation at low temperature, and saturated sodium bicarbonate solution was added to adjust the pH to 8 - 10. The mixture was extracted with DCM (20 ml × 2), dried over anhydrous sodium sulfate, and rotary evaporated and passed through a column (DCM:CH3OH = 10:1) to obtain the product 39H (0.15 g, 31%). Compound 39H was separated by SFC chiral preparation to obtain peak 1 (retention time: 1.528 min, designated as compound 39) and peak 2 (retention time: 2.387 min, designated as compound 40).

[1047] The resolution method is as follows: (Instrument name: MG Ⅱ preparative SFC (SFC-14); chromatographic column: ChiralPak AD, 250 × 30 mm I.D., 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 °C; absorption wavelength: 220 nm; cycle time: 3 min.)

[1048] Peak 1: 11H 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).

[1049] Peak 2: 1 1H 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).

[1050] Examples 41 and 42: (S)-N-((S)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 41 and Compound 42)

[1051] (S)-N-((S)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound 41 and compound 42)

[1052]

[1053] Step 1: 3-(bromomethyl)-6-chloropyridazine (41B)

[1054] 3-(bromomethyl)-6-chloropyridazine

[1055] Dissolve 3-(methyl)-6-chloropyridazine (12.8 g, 100 mmol) in carbon tetrachloride (300 mL), add N-bromosuccinimide (17.8 g, 100 mmol), add azobisisobutyronitrile (3.4 g, 20 mmol), react at 70 °C overnight, filter and concentrate the filtrate, then purify by silica gel column chromatography (PE:EA (v / v) = 1:10 - 1:5) to obtain the title compound (41B) (4 g, yield 20%). LCMS m / z = 207.46 [M+1] +

[1056] Step 2: ethyl 3-(6-chloropyridazin-3-yl)-2-((diphenylmethylene)amino)propanoate (41C)

[1057] ethyl 3-(6-chloropyridazin-3-yl)-2-((diphenylmethylene)amino)propanoate

[1058] Dissolve 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) in a mixed solvent of toluene (100 mL) and water (20 mL), add 41B (4.0 g, 19.28 mmol) under ice bath, allow to warm to room temperature and react for 2 hours, add water (50 mL), extract with ethyl acetate (50 mL×3), wash three times with water (50 mL×3), dry over anhydrous sodium sulfate and concentrate, then purify by silica gel column chromatography (PE:EA (v / v) = 1:10 - 1:5) to obtain the title compound (41C) (3.4 g, yield 45%). LCMS m / z = 394.12 [M+1] +

[1059] Step 3: 3-(6-chloropyridazin-3-yl)-2-((diphenylmethylene)amino)propanamide (41D)

[1060] 3-(6-chloropyridazin-3-yl)-2-((diphenylmethylene)amino)propanamide

[1061] 41C (3.4 g, 8.7 mmol) was dissolved in ammonia methanol solution (7N, 50 mL), and reacted overnight at 80 °C in a sealed tube (120 mL). After concentration, it was purified by silica gel column chromatography (MeOH:DCM (v / v) = 1:10) to obtain the title compound 41D (1.8 g, yield 56%). LCMS m / z = 365.11 [M+1] +

[1062] Step 4: 3-(6-chloropyridazin-3-yl)-2-((diphenylmethylene)amino)propanenitrile (41E)

[1063] 3-(6-chloropyridazin-3-yl)-2-((diphenylmethylene)amino)propanenitrile

[1064] 41D (1.8 g, 4.93 mmol) was dissolved in dichloromethane (30 mL), and Burgess reagent (2.35 g, 9.86 mmol) was added and reacted at room temperature for 2 hours. After concentration, it was purified by silica gel column chromatography (PE:EA (v / v) = 1:5 - 5:5) to obtain the title compound 41E (1.4 g, yield 82%). LCMS m / z = 347.13 [M+1] +

[1065] Step 5: 2-((diphenylmethylene)amino)-3-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)propanenitrile (41F)

[1066] 2-((diphenylmethylene)amino)-3-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)propanenitrile

[1067] 41E (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) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (590 mg, 0.81 mmol) were added. Then water (6 mL) was added, and the reaction was carried out in a microwave reactor under nitrogen protection at 120 °C for 2 hours. After concentration, it was purified by silica gel column chromatography (PE:EA (v / v) = 1:5 - 1:1) to obtain the title compound 41F (800 mg, yield 43%). LCMS m / z = 460.17 [M+1] +

[1068] Step 6: 2-amino-3-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)propionitrile (41G)

[1069] 2-amino-3-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)propanenitrile

[1070] Dissolve 41F (800 mg, 1.74 mmol) in dioxane (20 mL), add hydrochloric acid solution (0.5 N, 8 mL), react at room temperature for 0.5 hours, adjust pH to 7-8 with saturated sodium carbonate aqueous solution, extract with dichloromethane (30 mL × 3), combine the organic phases, wash with saturated brine (30 mL × 1), dry over anhydrous sodium sulfate, concentrate, separate and purify with silica gel column chromatography (MeOH: DCM (v / v) = 1:100-1:10) to obtain the title compound 41G (300 mg, yield 58%). LCMS m / z = 296.11 [M+1] +

[1071] Step 7: (2S)-2-((1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl]pyridazin-3-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (41H)

[1072] tert-butyl(2S)-2-((1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[1073] 41G (300 mg, 1.02 mmol) was dissolved in DMF (20 mL). HATU (390 mg, 1.02 mmol), DIPEA (260 mg, 2.02 mmol), and INT-3 (250 mg, 1.02 mmol) were added successively. The reaction was carried out at room temperature for 12 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with water (30 mL × 2), then washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (MeOH:DCM (v / v) = 1:100 - 1:10) to obtain the title compound 41H (300 mg, yield 56%). LCMS m / z = 523.22 [M+1] +

[1074] Step 8: (S)-N-((S)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 41 and Compound 42)

[1075] (S)-N-((S)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide and (S)-N-((R)-1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridazin-3-yl)ethyl)-1,4-oxazepane-2-carboxamide

[1076] 41H (300 mg, 0.57 mmol) was dissolved in acetonitrile (20 mL). p-Toluenesulfonic acid (332 mg, 1.71 mmol) was added, and the reaction was carried out at 30 °C for 3 hours. The pH was adjusted to 7 - 8 with saturated aqueous sodium carbonate solution, and the mixture was extracted with dichloromethane (40 mL × 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (DCM:MeOH (v / v) = 0.01:1 - 0.1:1).

[1077] 150 mg of the crude compound was separated by chiral preparative separation, and two optical isomer peaks were obtained after separation: peak 1 (retention time: 2.088 min, 30 mg, ee = 99%, designated as compound 41), and peak 2 (retention time: 2.955 min, 30 mg, ee = 99%, designated as compound 42). Resolution conditions: Instrument: MG Ⅱ preparative SFC (SFC-14); Column: ChiralPak AD, 250×30 mm I.D.; Mobile phase: A: CO2, 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 prepare 15 mg / ml; Injection: 1.0 ml / needle.

[1078] Peak 1: MS M / Z (ESI): m / z = 423.17 [M+1] + .

[1079] 1 H NMR (400 MHz, DMSO-d6) δ8.73 (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).

[1080] Peak 2: MS M / Z (ESI): m / z = 423.17 [M+1] + .

[1081] 1 H NMR (400 MHz, DMSO-d6) δ8.75 (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).

[1082] Example 43: N-((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide (Compound 43)

[1083] N-((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-l6-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide(compound 43)

[1084]

[1085] First step: (2S,6R)-2-(((benzyloxy)methyl)-6-methoxy-4-tosyl-1,4-oxazepane (43B)

[1086] (2S,6R)-2-((benzyloxy)methyl)-6-methoxy-4-tosyl-1,4-oxazepane(43B)

[1087] Dissolve 43A (0.5 g, 1.28 mmol, the preparation method refers to Eur. J. Org. Chem. 2007, 2107–2113 (DOI: 10.1002 / ejoc.200700011)) in tetrahydrofuran (20 mL). At 0 °C, add sodium hydride (0.26 g, 6.4 mmol), stir for 30 min, then add methyl iodide (0.91 g, 6.4 mmol). After reacting at room temperature for 3 h, add water (30 mL) at 0 °C, extract with EA (20 mL x 3), wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain a colorless oily substance 43B (0.4 g, yield 77%).

[1088] Second step: (2S,6R)-2-((benzyloxy)methyl)-6-methoxy-1,4-oxazepane (43C)

[1089] (2S,6R)-2-((benzyloxy)methyl)-6-methoxy-1,4-oxazepane(43C)

[1090] 43B (0.3 g, 0.74 mmol) was dissolved in methanol (10 mL), magnesium chips (2.36 g, 97.08 mmol) were added, and after ultrasonic treatment at 50 °C for 2 h, the reaction was carried out at room temperature for 16 h. After filtration and concentration, a white oily substance 43C (0.18 g, yield 96%) was obtained and directly used in the next step. LC-MS (ESI): m / z = 252.3 [M+1] +

[1091] Step 3: (2S,6R)-2-((Benzyloxy)methyl)-6-methoxy-1,4-oxazepane-4-carboxylic acid tert-butyl ester (43D)

[1092] (2S,6R)-tert-butyl 2-((benzyloxy)methyl)-6-methoxy-1,4-oxazepane-4-carboxylate(43D)

[1093] 43C (0.18 g, 0.72 mmol) was dissolved in DCM (10 mL), triethylamine (0.087 g, 0.85 mmol) and TBSCl (0.37 g, 1.71 mmol) were added successively. Under nitrogen protection, the reaction was carried out at room temperature for 2 h, then concentrated to dryness and purified by column chromatography (PE:EA = 10:1 - 4:1) to obtain a colorless oily substance 43D (0.12 g, yield 47%).

[1094] Step 4: (2S,6R)-2-(Hydroxymethyl)-6-methoxy-1,4-oxazepane-4-carboxylic acid tert-butyl ester (43E)

[1095] (2S,6R)-tert-butyl 2-(hydroxymethyl)-6-methoxy-1,4-oxazepane-4-carboxylate(43E) 43D (0.12 g, 0.34 mmol) was dissolved in methanol (10 mL), palladium carbon (0.1 g, 10%) was added, and the reaction was carried out in a hydrogen atmosphere for 24 h. After filtration and concentration to dryness, a colorless oily substance 43E (0.08 g, yield 86%) was obtained.

[1096] Step 5: (2S,6R)-4-(tert-Butoxycarbonyl)-6-methoxy-1,4-oxazepane-2-carboxylic acid (43F)

[1097] (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazepane-2-carboxylic acid (43F) Dissolve 43E (0.095 g, 0.3 mmol) in acetone (7 mL), add saturated sodium bicarbonate (3 mL), sodium bromide (0.025 g, 0.24 mmol), TEMPO (0.004 g, 0.024 mmol), add trichloroisocyanuric acid (0.25 g, 1.06 mmol) at 0 °C, react for 16 hours, adjust the pH to 5 - 6 with dilute hydrochloric acid, add water (30 mL), extract with dichloromethane (20 mL × 3), wash with water (30 mL), wash with saturated sodium chloride (30 mL), dry over anhydrous sodium sulfate, concentrate to dryness to obtain a yellow oil 43F (0.046 g, yield 44%).

[1098] Step 6: tert-butyl 2-(((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-6-methoxy-1,4-oxazepane-4-carboxylate (43G)

[1099] tert-butyl-2-(((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-l6-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-6-methoxy-1,4-oxazepane-4-carboxylate

[1100] Mix 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) and dissolve in DMF, stir at room temperature overnight. Monitor the reaction by LCMS until completion, add water and extract with EA, dry and concentrate the organic phase, and separate 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] + .

[1101] Step 7: N-((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-16-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide (Compound 43)

[1102] N-((S)-1-cyano-2-(3-fluoro-4'-(pentafluoro-l6-sulfanyl)-[1,1'-biphenyl]-4-yl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide

[1103] Compound 43 (512 mg, 0.82 mmol) was dissolved in 40 mL of acetonitrile, p-toluenesulfonic acid (706 mg, 2.46 mmol) was added, and the mixture was heated to 40 °C and reacted for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated, EA and saturated aqueous sodium bicarbonate were added, extraction was carried out, and the layers were separated. The organic phase was dried and concentrated, and 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] + 。

[1104] 1 1H NMR (400 MHz, DMSO-d6): δ 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).

[1105] Biological testing

[1106] 1. In vitro DPP1 enzyme activity detection experiment

[1107] Recombinant human DPP1 enzyme (R&D Systems, Cat. No 1071-CY) with a final concentration of 100 μg / mL and recombinant human cathepsin L (R&D System, Cat. No 952-CY) with a final concentration of 20 μg / mL were mixed and incubated at room temperature for 1 hour to activate the DPP1 enzyme. The activated DPP1 enzyme was diluted 100-fold. In a 384-well plate, 5 μL of compounds with different concentrations and 5 μL of the diluted DPP1 enzyme were added and incubated at room temperature for 30 minutes. After adding 10 μL of the substrate Gly-Arg-AMC (bachem, Cat. No I-1215) with a concentration of 20 μM, incubation was continued at room temperature for 60 minutes, and the fluorescence intensity was detected by a microplate reader, where the excitation light was 380 nm and the emission light was 460 nm. The Origin2019 software DosResp function was used to calculate the IC 50 value.

[1108] Test results: The compounds of the present invention show inhibitory activity against the DPP1 receptor. The IC50 values of the example compounds for the DPP1 receptor are within the range of less than 100 nM. Among them, the test results of some examples are shown in Table 1.

[1109] Table 1 DPP1 inhibitory activity

[1110] Compound Number <![CDATA[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

[1111] Conclusion: The compounds of the present invention show high inhibitory activity against the DPP1 receptor.

[1112] 2. Rat pharmacokinetics test

[1113] 1.1 Test animals: Male SD rats, about 220 g, 6 - 8 weeks old, 6 rats / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[1114] 1.2 Test design: On the test day, 6 SD rats were randomly grouped according to body weight. They were fasted for 12 - 14 h without water deprivation 1 day before dosing, and fed 4 h after dosing.

[1115] Table 2 Dosing information

[1116]

[1117] Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline; Gavage administration vehicle: 0.5% MC; Control compound INS1007, i.e., compound 2 in Patent WO2015110826A1, was prepared according to the patent method.

[1118] Blood (0.1 ml) was collected from the orbital sinus under isoflurane anesthesia before and after dosing, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm at 4°C for 10 min, and plasma was collected. Blood sampling time points for the intravenous group: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h; Blood sampling time points for the gavage group: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. All samples were stored at -80°C before analysis and detection.

[1119] Table 3 Pharmacokinetic parameters of the test compounds in rat plasma

[1120]

[1121] Conclusion: The compounds of the present invention have good bioavailability and pharmacokinetic characteristics.

[1122] 3. 14-day oral repeated-dose toxicity test in rats

[1123] SD rats were randomly grouped by body weight into a vehicle control group (0.5% MC), INS1007 groups (30, 100, 300 mg / kg), and compound groups (30, 100, 300 mg / kg). There were 16 rats in each dosing group and 10 rats in the vehicle control group, with an equal number of males and females. The corresponding concentration of the drug or vehicle was administered orally every day for 14 consecutive days, followed by a 7-day recovery period. During the dosing period, general symptoms were observed in each group, and body weight and food intake were measured. At the end of the dosing period and the recovery period, hematology, serum biochemistry, and gross anatomy were examined in each group.

[1124] Conclusion: At the same dose, the toxicity of the compound of the present invention is less than that of INS1007, and it has higher safety.

Claims

1. A compound of formula (IV), or a pharmaceutically acceptable salt thereof: Wherein, Rc is H; R1, R2 and R3 are each independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy is optionally substituted with 1 - 3 groups selected from F, Cl, Br, cyano, hydroxy and NH2; Z is CH or N; Ring G is an optionally 1- or 2-substituted benzene ring or G or Each R G is independently selected from F, Cl, Br, I, methyl, ethyl, propyl, SF5, and CN, wherein the methyl, ethyl, or propyl is optionally further substituted with 1-3 groups selected from deuterium, F, Cl, Br, and I.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is CH.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring G is optionally substituted with 1-2 R G substituted 4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein each R G is independently selected from methyl, ethyl, propyl, wherein the methyl, ethyl or propyl is optionally further substituted with 1-3 groups selected from deuterium, F, Cl, Br and I.

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein each R G is independently selected from methyl, ethyl, and propyl.

6. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein, Optionally substituted by 1 or 2 Rs G substituted selected from one of the following structures:

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from one of the following structures:

8. A compound, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from one of the following structures:

9. A compound, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is a compound selected from the following structures:

10. A compound, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is a compound selected from the following structures:

11. A pharmaceutical composition comprising the compound according to any one of claims 1 - 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

12. Use of the compound according to any one of claims 1 - 10, or a pharmaceutically acceptable salt thereof, or the composition according to claim 11 in the manufacture of a medicament for the treatment of a disease mediated by dipeptidyl peptidase 1, said disease being selected from airway obstructive diseases.

13. Use of the compound according to any one of claims 1 - 10, or a pharmaceutically acceptable salt thereof, or the composition according to claim 11 in the manufacture of a medicament for the treatment of a disease mediated by dipeptidyl peptidase 1, said disease being selected from bronchiectasis, cystic fibrosis, asthma, emphysema and chronic obstructive pulmonary disease.

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