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

Abstract

The present invention discloses a nitrile derivative compound represented by formula (I), its stereoisomers, deuterated compounds, co-crystals, solvates or pharmaceutically acceptable salts, and each group is 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, bronchiectasis, 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 enzymatic 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. Since DPP1 plays a central role in the activation of these proteases, it is considered an effective therapeutic target (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, relevant patents have reported 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-amino amide 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-amino amide 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 first provides a compound of formula (I), (II), or (III), its stereoisomers, deuterated compounds, cocrystals, solvates, or pharmaceutically acceptable salts:

[0006]

[0007] Wherein, Cy is a 5-12 membered fused heterocyclic ring or 5-12 membered spiro heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and the fused heterocyclic ring and spiro heterocyclic ring are optionally substituted by 1-3 R8;

[0008] Or Cy is a 7-12 membered bridged heterocyclic ring containing 1-3 heteroatoms selected from N, S, O having the structure of T1, T2, or a monocyclic heterocyclic ring having the structure of T3, T4, and the bridged heterocyclic ring and monocyclic heterocyclic ring are optionally substituted by 1-3 R8;

[0009]

[0010] m is an integer from 0 to 2;

[0011] q is an integer from 1 to 3;

[0012] r is 0 or 1;

[0013] Q is O, S, CH2 or NH;

[0014] G is CH2 or NH;

[0015] # represents the site that can be connected to W;

[0016] Or Cy is a heterocycle having the structure of T5, and the heterocycle is substituted with 1 to 3 R9;

[0017]

[0018] In some specific embodiments, Cy is a 6- to 10-membered fused heterocycle or an 8- to 10-membered spiro heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, and the fused heterocycle and the spiro heterocycle are optionally substituted with 1 to 3 R8;

[0019] Or Cy is a 7- to 10-membered bridged heterocycle containing 1 to 3 heteroatoms selected from N, S, and O having the structures of T1 and T2, or a monocyclic heterocycle having the structures of T3 and T4, and the bridged heterocycle and the monocyclic heterocycle are optionally substituted with 1 to 3 R8;

[0020]

[0021] m is 0 or 1;

[0022] q is 1 or 2;

[0023] r is 0 or 1;

[0024] Q is O, S, CH2 or NH;

[0025] G is CH2 or NH;

[0026] # represents the site that can be connected to W;

[0027] Or Cy is a heterocycle having the structure of T5, and the heterocycle is substituted with 1 to 3 R9;

[0028]

[0029] [[ID=5&]]In some specific embodiments, Cy is The Cy is optionally substituted with 1 to 3 R 8 substituted;

[0030] m1 and m2 are each independently 0, 1 or 2, and are not both 0 and not both 2;

[0031] m3 is 0, 1 or 2;

[0032] m4 is 0 or 1;

[0033] p is 1, 2 or 3;

[0034] D1 is O, NR C or C(R C )2;

[0035] D2 is NH, O or S;

[0036] r is 0 or 1;

[0037] Q is O, CH2 or NH;

[0038] G is CH2 or NH;

[0039] # represents a site that can be connected to W;

[0040] Each Rc is independently R8, and two Rcs located on adjacent ring atoms together with the ring atoms to which they are connected form a 3-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl containing one N atom;

[0041] Each R8 is independently selected from H, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, -CONH2, -S(O)NH2, -S(O)2NH2;

[0042] Or Cy is and is substituted by 1-3 R9s;

[0043] Each R9 is independently selected from halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, -C 1-4 alkyl-C 1-4 alkoxy, halo-C 1-4 alkyl, C 1-4 alkoxy, 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)NH2, -S(O)2NH2;

[0044] In some specific embodiments, Cy is optionally substituted by 1-3 R8s

[0045] Each R8 is independently selected from H, halogen, cyano, hydroxy, NH2, -COOH, C1-4 alkyl, -CONH2, -S(O)NH2, -S(O)2NH2;

[0046] In some specific embodiments, Cy is substituted with 1 - 3 R9s

[0047] Each R9 is independently selected from halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, -C 1-4 alkyl-C 1-4 alkoxy, halo-C 1-4 alkyl, C 1-4 alkoxy, 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)NH2, -S(O)2NH2;

[0048] W is C(=O), C(=S), C(=N-R W ), S(=O) or S(=O)2;

[0049] In some specific embodiments, W is C(=O);

[0050] R W is OH, CN, or C 1-4 alkyl;

[0051] M is NR M or O, R M is H, C 1-4 alkyl or C 3-6 cycloalkyl;

[0052] In some specific embodiments, M is NH;

[0053] 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, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle are optionally substituted with 1 - 3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxy, NH2 and -COOH;

[0054] Optionally, R1 and R2 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, wherein the cycloalkyl group or heterocyclic ring 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;

[0055] 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, and alkynyl are optionally substituted with 1 to 3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxy, NH2, and COOH;

[0056] Optionally, R1 and R2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group or a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group or heterocyclic ring is optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxy, NH2, COOH, C 1-4 alkyl;

[0057] A is a benzene ring or a 5- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and ring A is optionally substituted with 1 to 3 R A substituents;

[0058] * represents the end connected to the alkyl carbon;

[0059] 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;

[0060] In some specific embodiments, A is a benzene ring optionally substituted with 1 to 3 R A substituents;

[0061] Each R A is independently selected from H, 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, -COOC1-4 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; R A The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups in are optionally substituted by 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and -COOH;

[0062] In some specific embodiments, R A are each independently selected from H;

[0063] Y1 and Y2 are each independently selected from CR4, N;

[0064] Each R4 is independently selected from H, 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 groups in R4 are optionally substituted by 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and -COOH;

[0065] In some specific embodiments, R4 is H;

[0066] X1, X2, and X3 are each independently selected from NR5, O, CR6R7, S(O)R5, S(O)2R5, and SR5;

[0067] In some specific embodiments, X1, X2, and X3 are each independently selected from NR5, O, CR6R7;

[0068] Each R5 is independently selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6Cycloalkyl; the alkyl, alkenyl, alkynyl, cycloalkyl group is optionally substituted by 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2 and COOH;

[0069] In some embodiments, each R5 is independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl; the alkyl group or cycloalkyl group is optionally substituted by 1 to 3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2 and COOH;

[0070] In some embodiments, each R5 is independently selected from H, C 1-4 alkyl;

[0071] In some embodiments, R5 is selected from H or methyl;

[0072] 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;

[0073] Alternatively, R6 and R7 form =0; or

[0074] R6 and R7 form a C 3-12 A carbocyclic ring or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1-3 heteroatoms selected from =O, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 radical substitution of cycloalkyl groups;

[0075] In some 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 is optionally substituted by 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2 and COOH;

[0076] Alternatively, R6 and R7 form =0; or

[0077] R6 and R7 together with the carbon atoms to which they are attached form a C 3-6 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 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;

[0078] 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 groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and COOH;

[0079] Optionally, R6 and R7 form ═O;

[0080] Each R8 is independently selected from H, deuterium, ═O, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, halo-C 1-4 alkyl, C 1-4 alkoxy, 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;

[0081] In some specific embodiments, each R8 is independently selected from H, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, -CONH2, -S(O)NH2, -S(O)2NH2;

[0082] Each R9 is independently selected from halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, -C 1-4 alkyl-C 1-4 alkoxy, halo-C 1-4 alkyl, C 1-4 alkoxy, 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, -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;

[0083] In some specific embodiments, each R9 is independently selected from halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, -C 1-4 alkyl-C 1-4 alkoxy, halo-C 1-4 alkyl, C 1-4 alkoxy, 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)NH2, -S(O)2NH2.

[0084] 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:

[0085]

[0086] Wherein, Cy is a 5-12 membered fused heterocyclic ring or 5-12 membered spiro heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and the fused heterocyclic ring and spiro heterocyclic ring are optionally substituted by 1-3 R8;

[0087] Alternatively, Cy is a 7- to 12-membered bridged heterocyclic ring having a T1, T2 structure and containing 1 to 3 heteroatoms selected from N, S, O, or a monocyclic heterocyclic ring having a T3, T4 structure, and the bridged heterocyclic ring and the monocyclic heterocyclic ring are optionally substituted with 1 to 3 R8;

[0088]

[0089] m is an integer from 0 to 2;

[0090] q is an integer from 1 to 3;

[0091] r is 0 or 1;

[0092] Q is O, S, CH2, or NH;

[0093] G is CH2 or NH;

[0094] # represents the site that can be connected to W;

[0095] Alternatively, Cy is a heterocyclic ring having a T5 structure, and the heterocyclic ring is substituted with 1 to 3 R9;

[0096]

[0097] W is C(=O), C(=S), C(=N-R W ), S(=O), or S(=O)2;

[0098] R W is OH, CN, or C 1-4 alkyl;

[0099] M is NR M or O;

[0100] R M is H, C 1-4 alkyl, or C 3-6 cycloalkyl;

[0101] 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 heterocyclic rings containing 1 to 3 heteroatoms selected from N, S, O, and the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic rings are optionally substituted with 1 to 3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxy, NH2, and -COOH;

[0102] Optionally, R1 and R2 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, wherein the cycloalkyl group or heterocyclic ring 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;

[0103] A is a benzene ring or a 5- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and ring A is optionally substituted with 1 to 3 R A substituents;

[0104] * represents the end connected to the alkyl carbon;

[0105] Ring B is C 3-12 a carbocyclic ring or a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O;

[0106] Each R A is independently selected from H, 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 R A are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and -COOH;

[0107] Y1 and Y2 are each independently selected from CR4, N;

[0108] Each R4 is independently selected from H, 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(C1-4 (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, alkoxy, 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;

[0109] X1, X2, and X3 are each independently selected from NR5, O, CR6R7, S(O)R5, S(O)2R5, and SR5;

[0110] Each R5 is independently selected from H, C 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;

[0111] 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- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and -COOH;

[0112] Optionally, R6 and R7 form =O; or

[0113] R6 and R7 together with the carbon atom to which they are attached form a C 3-12 carbocyclic ring or a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, the carbocyclic ring or heterocycle being 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;

[0114] Each R8 is independently selected from H, deuterium, =O, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, halo C1-4 Alkyl, C 1-4 Alkoxy, halogenated 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;

[0115] Each R9 is independently selected from halogen, cyano, hydroxy, NH2, -COOH, C 1-4 Alkyl, -C 1-4 Alkyl-C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated 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, -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.

[0116] As the second technical solution of the present invention, a compound of formula (I), its stereoisomers, deuterated compounds, cocrystals, solvates or pharmaceutically acceptable salts, the compound has the structure of formula (II):

[0117]

[0118] wherein, t is an integer from 1 to 3;

[0119] The undefined groups are as described in the first technical solution.

[0120] As the third technical solution of the present invention, a compound of formula (I) or formula (II), its stereoisomers, deuterated compounds, cocrystals, solvates or pharmaceutically acceptable salts, wherein,

[0121] Cy is a 6-10 membered fused heterocyclic ring or an 8-10 membered spiro heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and the fused heterocyclic ring and the spiro heterocyclic ring are optionally substituted by 1-3 R8;

[0122] Or Cy is a 7-10 membered bridged heterocyclic ring having the structures of T1 and T2, or a monocyclic heterocyclic ring having the structures of T3 and T4, containing 1-3 heteroatoms selected from N, S, O, and the bridged heterocyclic ring and the monocyclic heterocyclic ring are optionally substituted by 1-3 R8;

[0123]

[0124] m is 0 or 1;

[0125] q is 1 or 2;

[0126] r is 0 or 1;

[0127] Q is O, S, CH2 or NH;

[0128] G is CH2 or NH;

[0129] # represents the site that can be connected to W;

[0130] Or Cy is a heterocyclic ring having the structure of T5, and the heterocyclic ring is substituted by 1-3 R9;

[0131]

[0132] 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, alkynyl are optionally substituted by 1-3 groups selected from halogen, C 1-4 alkyl, cyano, hydroxyl, NH2 and COOH;

[0133] Optionally, R1 and R2 together with the carbon atom to which they are attached form a C 3-6 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 with 1 to 3 groups selected from halogen, cyano, hydroxy, NH2, COOH, C 1-4 alkyl groups;

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

[0135] X1, X2, and X3 are each independently selected from NR5, O, and CR6R7;

[0136] Each R5 is independently selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl; and the alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and COOH;

[0137] 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; and the alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2, and COOH;

[0138] Optionally, R6 and R7 together form ═O; or

[0139] R6 and R7 together with the carbon atom to which they are attached form a C 3-6 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 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 groups;

[0140] The undefined groups are as described in the first or second technical solution as described above.

[0141] As the fourth technical solution of the present invention, a compound of formula (I) or formula (II), its stereoisomers, deuterated compounds, cocrystals, solvates, or pharmaceutically acceptable salts, wherein the compound has the structure of formula (III):

[0142]

[0143] Wherein, X1, X2 and X3 are each independently selected from NR5, O, CR6R7;

[0144] Each R5 is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl; the alkyl and cycloalkyl are optionally substituted by 1 - 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2 and COOH;

[0145] 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 by 1 - 3 groups selected from deuterium, halogen, cyano, hydroxy, NH2 and COOH;

[0146] Optionally, R6 and R7 form =O;

[0147] Undefined groups are as described in the foregoing first, second or third technology.

[0148] As the fifth technical solution of the present invention, a compound of formula (I), formula (II) or formula (III), its stereoisomers, deuterated compounds, cocrystals, solvates or pharmaceutically acceptable salts, wherein,

[0149] Cy is The Cy is optionally substituted by 1 - 3 R8;

[0150] m1 and m2 are each independently 0, 1 or 2, and are not both 0 and not both 2;

[0151] m3 is 0, 1 or 2;

[0152] m4 is 0 or 1;

[0153] p is 1, 2 or 3;

[0154] D1 is O, NR C or C(R C )2;

[0155] D2 is NH, O or S;

[0156] Q is O, S, CH2 or NH;

[0157] G is CH2 or NH;

[0158] Each Rc is R8, and two Rc located on adjacent ring atoms together with the ring atoms to which they are attached form a 3 - 6 - membered cycloalkyl or a 5 - 6 - membered heteroalkyl containing one N atom;

[0159] Each R8 is independently selected from H, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, -CONH2, -S(O)NH2, -S(O)2NH2;

[0160] Or Cy is said Cy is substituted by 1 - 3 R9s;

[0161] Each R9 is independently selected from halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, -C 1-4 alkyl - C 1-4 alkoxy, halo - C 1-4 alkyl, C 1-4 alkoxy, 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)NH2, -S(O)2NH2

[0162] The undefined group is as described in the foregoing first, second, third or fourth technical solution.

[0163] As the sixth technical solution of the present invention, the compound of formula (I), formula (II) or formula (III), its stereoisomers, deuterated compounds, co - crystals, solvates or pharmaceutically acceptable salts, wherein Cy is optionally substituted by 1 - 3 R8s and is one of the following structures:

[0164]

[0165] Each R8 is independently selected from H, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, -CONH2, -S(O)NH2, -S(O)2NH2; or

[0166] Cy is substituted by 1 - 3 R9s of

[0167] Each R9 is independently selected from halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, -C 1-4 alkyl - C 1-4 alkoxy, halo - C 1-4 alkyl, C 1-4 alkoxy, halo - C 1-4 alkoxy, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -CONH2, -CONHC1-4 alkyl, -CON(C 1-4 alkyl)2, -S(O)NH2, -S(O)2NH2.

[0168] As the seventh technical solution of the present invention, the compound of formula (I), formula (II) or formula (III), its stereoisomers, deuterated compounds, co-crystals, solvates or pharmaceutically acceptable salts, wherein, selected from one of the following structures:

[0169]

[0170] For the compound of formula (I), formula (II) or formula (III) of the present invention, except for the clearly marked connection sites of each group, the connection can be made through any carbon atom or heteroatom on the group. For example, when Cy is , Cy can be connected to W through the carbon atom or nitrogen atom on the heterocycle, or can be connected to W through the carbon atom on the spiroalkyl group.

[0171] As the eighth technical solution of the present invention, the compound of formula (I), formula (II) or formula (III), its stereoisomers, deuterated compounds, co-crystals, solvates or pharmaceutically acceptable salts, wherein, the compound is selected from one of the following structures:

[0172]

[0173]

[0174] As the ninth technical solution of the present invention, the compound of formula (I), (II) or formula (III), its stereoisomers, deuterated compounds, co-crystals, solvates or pharmaceutically acceptable salts, wherein, the compound is selected from one of the following structures:

[0175]

[0176]

[0177] The present invention also provides a tenth technical solution, providing a compound of formula (I') or (II'), its stereoisomers, deuterated compounds, co-crystals, solvates or pharmaceutically acceptable salts:

[0178]

[0179] In some embodiments, the compound has the structure of formula (Ia), or (IIa):

[0180]

[0181] In formula (I'), (Ia), (II'), or (IIa), Cy is a 5- to 12-membered fused heterocyclic ring, 5- to 12-membered spiroheterocyclic ring, or 5- to 12-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and the fused heterocyclic ring, spiroheterocyclic ring, and monocyclic heterocyclic ring are 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, C 1-4 alkoxy, halo-C 1-4 alkoxy, hydroxy-C 1-4 alkyl, C 1-6 alkoxyalkyl, 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;

[0182] In some specific embodiments, Cy is a 6- to 10-membered fused heterocyclic ring or 8- to 10-membered spiroheterocyclic ring or 6- to 8-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and the fused heterocyclic ring, spiroheterocyclic ring, and monocyclic heterocyclic ring are optionally substituted with 1 to 3 groups selected from H, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, halo-C 1-4 alkyl, C 1-4 alkoxy, -CONH2, -S(O)NH2, -S(O)2NH2;

[0183] In some specific embodiments, Cy is a 6- to 8-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and the monocyclic heterocyclic ring is optionally substituted with 1 to 3 groups selected from H, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, halo-C 1-4 alkyl, C 1-4Substituted by alkoxy, -CONH2, -S(O)NH2, -S(O)2NH2 groups;

[0184] In some specific embodiments, Cy is Cy is optionally substituted by 1-3 groups selected from H, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, halo-C 1-4 alkyl, C 1-4 alkoxy, -CONH2, -S(O)NH2, -S(O)2NH2 groups;

[0185] 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;

[0186] In some specific embodiments, W is C(=O);

[0187] M is NR M or O, R M is H, C 1-4 alkyl or C 3-6 cycloalkyl;

[0188] In some specific embodiments, M is NH;

[0189] 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, said 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 groups;

[0190] 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, said 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 3-6 cycloalkyl groups;

[0191] In some specific embodiments, R1, R2 and R3 are each independently selected from H, deuterium, halogen, C1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl and C 2-6 Alkynyl, wherein 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;

[0192] 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, C 1-4 alkyl;

[0193] In some specific embodiments, R1, R2, and R3 are each independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl and alkoxy are optionally substituted with 1 - 3 groups selected from halogen, cyano, hydroxy, NH2, and COOH;

[0194] A is a benzene ring or a 5 - 10 - membered heterocycle containing 1 - 3 heteroatoms selected from N, S, and O, and ring A is optionally substituted with 1 - 3 R A substituents;

[0195] * represents the end connected to the alkyl carbon;

[0196] Ring B is C 3-12 a carbocyclic ring or a 4 - 7 - membered heterocycle containing 1 - 3 heteroatoms selected from N, S, and O;

[0197] In some specific embodiments, A is

[0198] Each R A 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 - 7 - membered heterocycle containing 1 - 3 heteroatoms selected from N, S, and O; R AThe alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups therein are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0199] In some specific embodiments, R A is 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, -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, and -NHCOC 1-4 alkyl;

[0200] In some specific embodiments, R A is 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, and NH2;

[0201] Y1 and Y2 are each independently selected from CR4, N;

[0202] Each R4 is independently selected from H, 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, hydroxyl, NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COOH, -COC 1-4 alkyl, -COOC 1-4 alkyl, -CONHC 1-4 alkyl, -CON(C 1-4 alkyl)2, -NHCOC 1-4 alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O; the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups in R4 are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2, and -COOH;

[0203] In some embodiments, each R4 is independently selected from H, halogen, C 1-4 Alkyl, -SC 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, cyano, hydroxy, NH2; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1-3 groups selected from deuterium, halogen, cyano, hydroxy, NH2 and COOH;

[0204] In some embodiments, each R4 is independently selected from H, halogen, C 1-4 Alkyl, cyano, hydroxy, NH2; the alkyl group is optionally substituted by 1-3 groups selected from halogen, cyano, hydroxy, NH2 and COOH;

[0205] In some embodiments, R4 is H;

[0206] X1, X2, X3, X4 and X5 are each independently selected from a bond, NR5, O, CR6R7, S(O), S(O)2, and S, and X2, X3, X4 and X5 are not simultaneously a bond;

[0207] In some embodiments, X1 is a bond, NR5, O, CR6R7, S(O), S(O)2, or S;

[0208] X2 and X4 are independently a bond, O, NR5 or CR6R7;

[0209] X3 and X5 are independently a bond, O, NR5 or CR6R7;

[0210] In some specific embodiments, X1 is NR5;

[0211] X2 and X4 are independently a bond, O or CR6R7;

[0212] X3 and X5 are independently a bond, NR5 or CR6R7;

[0213] Each R5 is independently selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl and 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycle are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2 and -COOH;

[0214] In some embodiments, each R5 is independently selected from H, C 1-4Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycle are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2 and -COOH;

[0215] Each R6 and R7 are 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;

[0216] Alternatively, R6 and R7 form ═O;

[0217] In some embodiments, each of R6 and R7 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; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2 and COOH;

[0218] Alternatively, R6 and R7 form ═O;

[0219] In some embodiments, each R6 and R7 are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy; the alkyl group, alkoxy group is optionally substituted by 1-3 groups selected from halogen, cyano, hydroxyl, NH2 and COOH;

[0220] Alternatively, R6 and R7 form ═O;

[0221] S1 and S2 are each independently an integer from 0 to 3 and are not both 0;

[0222] In some embodiments, S1 and S2 are each independently 1 or 2;

[0223] In some specific embodiments, Select one of the following structures:

[0224]

[0225] R5, R6, and R7 are as defined above.

[0226] As a more specific eleventh technical solution of the present invention, a compound of formula (I') or (Ia), its stereoisomers, deuterated compounds, cocrystals, solvates, or pharmaceutically acceptable salts,

[0227]

[0228] wherein Cy is a 5- to 12-membered fused heterocyclic ring, 5- to 12-membered spiro heterocyclic ring, or 5- to 12-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and the fused heterocyclic ring, spiro heterocyclic ring, and monocyclic heterocyclic ring are 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, C 1-4 alkoxy, halo-C 1-4 alkoxy, hydroxy-C 1-4 alkyl, C 1-6 alkoxyalkyl, 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;

[0229] W is C(═O), C(═S), C(═N-R W ), S(═O), or S(═O)2;

[0230] M is NR M or O;

[0231] R W is OH, CN, or C 1-4 alkyl;

[0232] R M is H, C 1-4alkyl or C 3-6 cycloalkyl;

[0233] 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, 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;

[0234] 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, 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;

[0235] A is a benzene ring or a 5- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O, and ring A is optionally substituted with 1 to 3 R A substituents;

[0236] * represents the end connected to the alkyl carbon;

[0237] 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;

[0238] Each R A 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 4- to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, O; RA The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocyclic groups therein are optionally substituted by 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2 and -COOH;

[0239] Y1 and Y2 are each independently selected from CR4 and N;

[0240] Each R4 is independently selected from H, 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, hydroxyl, NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, -COOH, -COC 1-4 alkyl, -COOC 1-4 alkyl, -CONHC 1-4 alkyl, -CON(C 1-4 alkyl)2, -NHCOC 1-4 alkyl, and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, O; the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclic groups in R4 are optionally substituted by 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2 and -COOH;

[0241] X1, X2, X3, X4 and X5 are each independently selected from a bond, NR5, O, CR6R7, S(O), S(O)2, and S, and X2, X3, X4 and X5 are not simultaneously a bond;

[0242] Each R5 is independently selected from H, C 1-4 alkyl, 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, alkenyl, alkynyl, cycloalkyl and heterocycle are optionally substituted by 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2 and -COOH;

[0243] Each R6 and R7 is independently selected from H, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6Cycloalkyl, cyano, hydroxyl, NH2, -COOH, and a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocyclic ring are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxyl, NH2 and -COOH;

[0244] Optionally, R6 and R7 form ═O;

[0245] S1 and S2 are each independently an integer from 0 to 3 and are not both 0 at the same time.

[0246] As the twelfth technical solution of the present invention, a compound of formula (Ia) or (I'), its stereoisomers, deuterated compounds, cocrystals, solvates or pharmaceutically acceptable salts, the compound has the structure of formula (II') or (IIa):

[0247]

[0248] Wherein, Cy is a 6-10 membered fused heterocyclic ring, an 8-10 membered spiro heterocyclic ring or a 6-8 membered monocyclic heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and the fused heterocyclic ring, spiro heterocyclic ring and monocyclic heterocyclic ring are optionally substituted with 1-3 groups selected from H, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, -CONH2, -S(O)NH2, -S(O)2NH2;

[0249] 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, hydroxyl, NH2 and COOH;

[0250] 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, hydroxyl, NH2, COOH, C 1-4 alkyl;

[0251] R A is 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, -NHC1-4 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, and -NHCOC 1-4 alkyl;

[0252] Y1 and Y2 are each independently selected from CR4, N;

[0253] Each R4 is independently selected from H, 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; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxy, NH2 and COOH;

[0254] X1 is a bond, NR5, O, CR6R7, S(O), S(O)2, or S;

[0255] X2 and X4 are independently a bond, O, NR5 or CR6R7;

[0256] X3 and X5 are independently a bond, O, NR5 or CR6R7;

[0257] Each R5 is independently selected from H, C 1-4 alkyl, 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, the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycle are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxy, NH2 and -COOH;

[0258] Each R6 and R7 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; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl are optionally substituted with 1-3 groups selected from deuterium, halogen, cyano, hydroxy, NH2 and COOH;

[0259] Optionally, R6 and R7 form =O;

[0260] S1 and S2 are each independently 1 or 2;

[0261] Undefined groups are as described in the tenth aspect.

[0262] As the thirteenth aspect of the present invention, a compound of formula (IIa) or formula (II'), its stereoisomers, deuterated compounds, co-crystals, solvates or pharmaceutically acceptable salts, wherein,

[0263] Cy is a 6- 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 H, halogen, cyano, hydroxyl, NH2, -COOH, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, -CONH2, -S(O)NH2, -S(O)2NH2;

[0264] R1, R2 and R3 are each independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl and alkoxy are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2 and COOH;

[0265] R A is 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, and NH2;

[0266] Y1 and Y2 are each independently selected from CR4, N;

[0267] Each R4 is independently selected from H, halogen, C 1-4 alkyl, cyano, hydroxyl, NH2; and the alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2 and COOH;

[0268] X1 is NR5;

[0269] X2 and X4 are independently a bond, O or CR6R7;

[0270] X3 and X5 are independently a bond, NR5 or CR6R7;

[0271] Each R5 is independently selected from H, C 1-4 alkyl, C 3-6Cycloalkyl and 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl and heterocycle optionally substituted by 1-3 groups selected from deuterium, halogen, cyano, hydroxy, NH2 and -COOH;

[0272] Each R6 and R7 are each independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy; said alkyl and alkoxy optionally substituted by 1-3 groups selected from halogen, cyano, hydroxy, NH2 and COOH;

[0273] Optionally, R6 and R7 form =O;

[0274] S1 and S2 are each independently 1 or 2;

[0275] Undefined groups are as described in the eleventh or twelfth aspect.

[0276] As the fourteenth aspect of the present invention, a compound of formula (II) or formula (II'), its stereoisomers, deuterated compounds, co-crystals, solvates or pharmaceutically acceptable salts, wherein Cy is Cy is optionally substituted by 1-3 groups selected from H, halogen, cyano, hydroxy, NH2, -COOH, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, -CONH2, -S(O)NH2, -S(O)2NH2;

[0277] Undefined groups are as described in the eleventh, twelfth or thirteenth aspect.

[0278] As the fifteenth aspect of the present invention, a compound of formula (IIa) or formula (II'), its stereoisomers, deuterated compounds, co-crystals, solvates or pharmaceutically acceptable salts, wherein,

[0279] Selected from one of the following structures:

[0280]

[0281] Each R5 is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl and heterocycle optionally substituted by 1-3 groups selected from deuterium, halogen, cyano, hydroxy, NH2 and -COOH;

[0282] Each R6 and R7 are each independently selected from H, halogen, C 1-4 alkyl, C 1-4Alkoxy; the alkyl and alkoxy groups are optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH;

[0283] Optionally, R6 and R7 form =O;

[0284] Undefined groups are as described in the eleventh, twelfth, thirteenth, or fourteenth aspect.

[0285] As the sixteenth aspect of the present invention, a compound of formula (Ia) or (I'), its stereoisomers, deuterated compounds, co-crystals, solvates, or pharmaceutically acceptable salts, wherein the compound is selected from one of the following structures:

[0286]

[0287] As the seventeenth aspect of the present invention, a compound of formula (Ia) or (I'), its stereoisomers, deuterated compounds, co-crystals, solvates, or pharmaceutically acceptable salts, wherein the compound is selected from one of the following structures:

[0288]

[0289] As the eighteenth aspect of the present invention, the present invention also provides a pharmaceutical composition comprising the compound described in any one of the first to seventeenth aspects, its stereoisomers, deuterated compounds, co-crystals, solvates, or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier and / or excipient.

[0290] The present invention further provides the use of the compound described in any one of the first to seventeenth aspects, its stereoisomers, deuterated compounds, co-crystals, solvates, or pharmaceutically acceptable salts, or the composition described in the eighteenth aspect in the preparation of a drug for treating diseases mediated by dipeptidyl peptidase 1.

[0291] 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.

[0292] Synthetic route

[0293] Those skilled in the art can prepare the compounds of the present invention by combining known organic synthesis techniques, and the starting materials are commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include: Titan Technology, Energy Chemical, Shanghai Dermachem, Chengdu Kelong Chemical Industry, Shanghai Yuanye Bio-Technology, Nanjing Pharmaron, WuXi AppTec, and J&K Scientific, etc.

[0294] Reference books and monographs in this field have introduced in detail the synthesis of reactants that can be used to prepare the compounds described herein, or provided articles describing the 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.

[0295] Specific and analogous reactants can be selectively identified through indexes of known chemical substances prepared by the Chemical Abstracts Service of the American Chemical Society. 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 factories, and many standard chemical supply factories (e.g., those listed above) offer custom synthesis services. References for the preparation and selection of the pharmaceutical salts of the compounds described herein are P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0296] The term

[0297] "halogen" as used herein refers to F, Cl, Br, I, or their isotopes.

[0298] "halo" or "halogen substituted" means substituted by one or more of F, Cl, Br, I, or their isotopes, and the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted on the group being substituted. Without special limitation, the number of halogen substituents is any integer between 1 and this upper limit. When the number of halogen substituents is greater than 1, substitution can be by the same or different halogens.

[0299] "deuterated" means the situation where at least one hydrogen atom on a group such as alkyl, cycloalkyl, alkylene, aryl, heteroaryl, alkenyl, alkynyl, etc. is substituted by the isotope deuterium. The upper limit of the number of deuterations is equal to the sum of the number of hydrogens that can be substituted on the group being substituted. Without special limitation, the number of deuterations is any integer between 1 and this upper limit, preferably 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.

[0300] "alkyl" means a monovalent straight-chain or branched-chain saturated aliphatic hydrocarbon group. Unless otherwise specified, it is an alkyl group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 8 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, and further preferably an alkyl group having 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 isomers.

[0301] "alkylene" means a divalent straight-chain and branched-chain saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, etc.

[0302] "Alkenyl" refers to a monovalent unsaturated aliphatic group having at least one double bond, including straight-chain and branched-chain groups. For example, the term "alkenyl" includes straight-chain alkenyls (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched-chain alkenyls.

[0303] "Alkenylene" refers to a divalent unsaturated aliphatic group having at least one double bond, including straight-chain and branched-chain groups.

[0304] "Alkynyl" refers to a monovalent unsaturated aliphatic group having at least one triple bond, including straight-chain and branched-chain groups. For example, "alkynyl" includes straight-chain alkynyls (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched-chain alkynyls. The term "C2-C6" includes alkynyls containing two to six carbon atoms.

[0305] "Alkynylene" refers to a divalent unsaturated aliphatic group having at least one triple bond, including straight-chain and branched-chain groups.

[0306] "Cycloalkyl" refers to a monovalent saturated, substituted or unsubstituted carbocyclic hydrocarbon group, which usually has 3 to 12 carbon atoms, preferably 3 - 6 carbon atoms, and more preferably 3 - 4 carbon atoms when there is no special description. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, etc.

[0307] "Cycloalkylene" refers to a divalent saturated, substituted or unsubstituted cycloalkyl, and non-limiting examples include

[0308] "Carbocycle" 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 polycycles with three or more rings, etc. It usually has 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., and bicyclic bridged rings such as etc., bicyclic fused rings such as and etc., bicyclic spiro rings such as etc., and tricycles such as etc.

[0309] "Heterocycle" or "heterocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic heterocyclic ring, which, unless otherwise specified, contains 1 to 5 heteroatoms selected from N, O, or S, preferably 1 to 4 heteroatoms, more preferably 1 - 3 heteroatoms, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, and bicyclic spiro heterocycles, as well as heterocycles with three or more rings, etc. Preferably, it is a 3 - to 15 - membered heterocycle, more preferably a 4 - to 14 - membered heterocycle, still more preferably a 4 - to 10 - membered heterocycle or a 5 - to 12 - membered heterocycle, and further preferably a 5 - to 8 - membered heterocycle or a 5 - to 6 - membered 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]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantyl, and oxaspiro[3.3]heptanyl, etc.

[0310] "Sub - heterocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non - aromatic divalent heterocyclic group. Non - limiting examples include etc.

[0311] "Aryl" refers to a group with aromaticity, including 5 - and 6 - membered monocyclic aromatic groups that may contain 0 to 4 N, S, or O heteroatoms, and polycyclic systems with 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 aryls (tricyclic or bicyclic) such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxybenzene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine. Those aryls with heteroatoms in the ring structure can also be referred to as "aryl heterocycle", "heteroaryl", or "heteroaromatic ring".

[0312] "Spiro ring" refers to a bonding mode in which two rings share one atom, such as

[0313] "Fused ring" or "condensed ring" refers to a bonding pattern where two rings share two atoms, such as

[0314] "Bridged ring" refers to a bonding pattern where two rings share three or more atoms, such as

[0315] "Alkoxy" or "alkyloxy" refers to -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy, and cyclobutoxy, etc.

[0316] "Halogenated alkoxy" refers to -O-haloalkyl. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, etc.

[0317] "Alkylamino" or "alkamino" refers to 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.

[0318] "Optionally" or "optionally" means that the subsequent described event or circumstance can but does not have to occur, and this description includes the occasions where the event or circumstance occurs or does not occur. For example: "Optionally F-substituted alkyl" means that the alkyl can but does not have to be substituted by F, and the description includes the situation where the alkyl is substituted by F and the situation where the alkyl is not substituted by F.

[0319] "Pharmaceutically acceptable salt" means a salt of the 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.

[0320] "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 a physiologically / pharmaceutically acceptable carrier and / or excipient.

[0321] "Carrier" refers to a system that does not cause obvious 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.

[0322] "Excipient" means: a substance that is not itself a therapeutic agent and is used as a diluent, adjuvant, binder, and / or vehicle, which is added 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, emulsifiers, disintegrants, absorbents, preservatives, surfactants, coloring agents, 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.

[0323] "Stereoisomer" refers to isomers generated by different arrangements of atoms in space within a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0324] "Solvate" refers to a substance formed by the combination of a compound or its salt of the present invention with a stoichiometric or non-stoichiometric amount of a solvent through intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

[0325] "Co-crystal" refers to a crystal formed by the combination 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, including binary co-crystals formed between two neutral solids, as well as multi-component co-crystals formed between a neutral solid and a salt or a solvate. Detailed Description

[0326] The content of the present invention will be described in detail below through examples. For those not specified in the examples, the conventional experimental methods are adopted. The examples are provided to better illustrate the content of the present invention, but it should not be construed that the content of the present invention is limited to the given examples. The non-essential improvements and adjustments made by those skilled in the art to the implementation solutions based on the above-mentioned invention content still fall within the protection scope of the present invention.

[0327] Detection method

[0328] 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);

[0329] The MS measurement is performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0330] The HPLC measurement is performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5 μM);

[0331] The thin-layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used in thin-layer chromatography (TLC) are 0.15 mm - 0.20 mm, and the specifications of the silica gel plates used for thin-layer chromatography separation and purification of products are 0.4 mm - 0.5 mm;

[0332] Column chromatography generally uses Yantai Huanghai silica gel with 200 - 300 mesh as the carrier.

[0333] Abbreviation description:

[0334] TEMPO: 2,2,6,6 - tetramethylpiperidine oxide

[0335] Pd(dppf)Cl2: dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II)

[0336] TBSCl: tert-butyldimethylchlorosilane

[0337] PE: petroleum ether

[0338] EA: ethyl acetate

[0339] TBAF: tetrabutylammonium fluoride

[0340] DIPEA: N,N - diisopropylethylamine

[0341] HATU: 2-(7 - azabenzotriazol - 1 - yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0342] Burgess reagent: (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt

[0343] X - Phos: 2 - dicyclohexylphosphino - 2',4',6'-triisopropylbiphenyl

[0344] DMF: N,N - dimethylformamide

[0345] LDA: Lithium diisopropylamide

[0346] INT - 1: (S)-2 - amino - 3-(4-(3 - methyl - 2 - oxo - dihydrobenzo[d]oxazol - 5 - yl)phenyl)propanenitrile

[0347] (S)-2 - amino - 3-(4-(3 - methyl - 2 - oxo - 2,3 - dihydrobenzo[d]oxazol - 5 - yl)phenyl)

[0348] propanenitrile

[0349]

[0350] INT - 1 is prepared from 1a as the raw material with reference to the method of WO2015110826A1

[0351] INT - 2: (S)-2 - amino - 3-(2 - fluoro - 4-(3 - methyl - 2 - oxo - 2,3 - dihydrobenzo[d]oxazol - 5 - yl)phenyl)propanenitrile

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

[0353]

[0354] The first step: (S)-tert - butyl (1 - cyano - 2-(2 - fluoro - 4-(3 - methyl - 2 - oxo - 2,3 - dihydrobenzo[d]oxazol - 5 - yl)phenyl)ethyl)carbamate (2c)

[0355] (S)-tert-butyl(1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3–dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate(2c)

[0356] Dissolve 1b (0.29 g, 0.85 mmol, the synthesis method refers to WO 2016016242 A1) 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] palladium dichloride 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 2c (white solid, 0.34 g, 99.0%).

[0357] LC-MS (ESI): m / z = 412.1 [M+H] + .

[0358] Step 2: (S)-2-amino-3-(2-fluoro-4-(3-methyl-2-oxo-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile (INT-2)

[0359] (S)-2-amino-3-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile(INT-2)

[0360] Dissolve 2c (0.34 g, 0.83 mmol) in formic acid (5 mL). After addition, react at room temperature overnight. 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 obtain the crude product of the title compound INT-2 (pale yellow solid, 0.21 g, 69.5%).

[0361] LC-MS (ESI): m / z = 312.1 [M+H] + .

[0362] INT-3: (2S,6R)-2-(((benzyloxy)methyl)-6-hydroxy-1,4-oxazepane-4-carboxylic acid tert-butyl ester

[0363] tert-butyl(2S,6R)-2-((benzyloxy)methyl)-6-hydroxy-1,4-oxazepane-4-carboxylate

[0364]

[0365] Step 1: (2S,6R)-2-((benzyloxy)methyl)-6-((tert-butyldimethylsilyl)oxy)-4-tosyl-1,4-oxazepane (3b)

[0366] (2S,6R)-2-((benzyloxy)methyl)-6-((tert-butyldimethylsilyl)oxy)-4-tosyl-1,4-oxazepane(3b)

[0367] Dissolve 3a (1.3 g, 3.32 mmol, the preparation method refers to Eur. J. Org. Chem. 2007, 2107–2113 (DOI: 10.1002 / ejoc.200700011)) in dichloromethane (20 mL), add imidazole (0.9 g, 13.38 mmol) and TBSCl (1.0 g, 6.64 mmol), after reacting at room temperature for 3 h, add water (30 mL), extract with DCM (20 mL x 3), wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (PE:EA = 10:1 - 4:1) to obtain colorless oily substance 3b (1.01 g, yield 60%).

[0368] Step 2: (2S,6R)-2-((benzyloxy)methyl)-6-((tert-butyldimethylsilyl)oxy)-1,4-oxazepane (3c)

[0369] (2S,6R)-2-((benzyloxy)methyl)-6-((tert-butyldimethylsilyl)oxy)-1,4-oxazepane(3c)

[0370] Dissolve 3b (0.3 g, 0.59 mmol) in methanol (10 mL), add magnesium chips (2.36 g, 97.08 mmol), after sonicating at 50 °C for 2 h, react at room temperature for 16 h, filter, concentrate to obtain colorless oily substance 3c (0.2 g, yield 96%) for direct use in the next step.

[0371] Step 3: tert-Butyl (2S,6R)-2-((benzyloxy)methyl)-6-((tert-butyldimethylsilyl)oxy)-1,4-oxazepane-4-carboxylate (3d)

[0372] Methyl(2S,6R)-tert-butyl 2-((benzyloxy)methyl)-6-((tert-butyldimethylsilyl)oxy)-1,4-oxazepane-4-carboxylate(3d)

[0373] Dissolve 3c (0.2 g, 0.57 mmol) in DCM (10 mL), add triethylamine (0.087 g, 0.85 mmol) and TBSCl (0.37 g, 1.71 mmol) successively. Under nitrogen protection, react at room temperature for 2 hours, then concentrate to dryness and purify by column chromatography (PE:EA = 10:1 - 4:1) to obtain colorless oily substance 3d (0.13 g, yield 50%).

[0374] Step 4: tert-Butyl (2S,6R)-2-((benzyloxy)methyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (INT-3)

[0375] tert-butyl(2S,6R)-2-((benzyloxy)methyl)-6-hydroxy-1,4-oxazepane-4-carboxylate

[0376] Add compound 3d (10 g, 22.1 mmol) to the THF solution of TFBA (100 ml, 1.0 mol / L). Stir at 40 °C for 2 hours, then concentrate part of the THF. Add ethyl acetate (200 ml) to the residue, wash with water (50 ml), dilute hydrochloric acid (50 ml, 0.5 mol / L), water (50 ml), saturated brine (50 ml), dry over anhydrous sodium sulfate, and concentrate to obtain INT-3 (6.2 g, 83.2%).

[0377] LC-MS(ESI): m / z = 282.0 [M + H - 56] + .

[0378] INT-4: tert-Butyl (S)-(1-cyano-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate

[0379] tert-butyl(S)-(1-cyano-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate

[0380]

[0381] Compound 2a (2.0 g, 5.8 mmol, prepared with reference to WO2016016242) was dissolved in ethylene glycol dimethyl ether (40 ml), and bis(pinacolato)diboron (2.23 g, 8.7 mmol), potassium acetate (1.70 g, 17.4 mmol), and Pd(dppf)Cl2 (423.1 mg, 0.58 mmol) were added. After heating to 90 °C and reacting for 3 hours, the reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (eluent ratio petroleum ether:ethyl acetate (v / v) = 1:0 to 10:1) to obtain INT-4 as a white solid (2.1 g, yield 92.1%).

[0382] LCMS m / z = 335.2 [M+1-56] +

[0383] 1 H NMR (400 MHz, CDCl3) δ 7.56 (d, 1H), 7.50 (d, 1H), 7.29 (d, 1H), 4.99 (d, 1H), 4.82 (s, 1H), 3.18 - 3.16 (m, 2H), 1.42 (s, 9H), 1.34 (s, 12H).

[0384] Example 1

[0385] (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6,6-difluoro-1,4-oxazepane-2-carboxamide (Compound 1)

[0386] (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6,6-difluoro-1,4-oxazepane-2-carboxamide (compound 1)

[0387]

[0388] Step 1: (S)-2-((benzyloxy)methyl)-6,6-difluoro-4-tosyl-1,4-oxazepane (1B)

[0389] (S)-2-((benzyloxy)methyl)-6,6-difluoro-4-tosyl-1,4-oxazepane(1B)

[0390] Dissolve 1A (0.33 g, 0.85 mmol) in dichloromethane (10 mL), cool to 0 °C, add bis(2-methoxyethyl)aminosulfur trifluoride (1.50 g, 6.80 mmol). After addition, stir at room temperature overnight. Cool to room temperature, add saturated aqueous sodium bicarbonate 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 (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain the title compound 1B as a colorless liquid (0.30 g, 85.8%).

[0391] LC-MS (ESI): m / z = 412.0 [M+H] + .

[0392] Step 2: (S)-2-((benzyloxy)methyl)-6,6-difluoro-1,4-oxazepane (1C)

[0393] (S)-2-((benzyloxy)methyl)-6,6-difluoro-1,4-oxazepane(1C)

[0394] Dissolve 1B (0.30 g, 0.83 mmol) in methanol (10 mL), add magnesium (0.09 g, 3.65 mmol). After addition, sonicate at 50 °C for 2 h and then stir at room temperature overnight. Concentrate to dryness, add saturated aqueous ammonium chloride solution (50 mL), extract with ethyl acetate (25 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate to obtain the title compound 1C as a pale yellow liquid (0.19 g, 100%), which is directly used in the next step reaction.

[0395] LC-MS (ESI): m / z = 258.2 [M+H] +.

[0396] Step 3: (S)-2-((benzyloxy)methyl)-6,6-difluoro-1,4-oxazepane-4-carboxylic acid tert-butyl ester (1D)

[0397] tert-butyl (S)-2-((benzyloxy)methyl)-6,6-difluoro-1,4-oxazepane-4-carboxylate (1D)

[0398] Dissolve 1C (0.19 g, 0.77 mmol) in dichloromethane (10 mL), add triethylamine (0.24 g, 2.34 mmol) and di-tert-butyl carbonate (0.26 g, 1.17 mmol). After addition, react at room temperature overnight. Dropwise add saturated ammonium chloride aqueous solution to adjust to neutrality, add saturated sodium chloride aqueous solution (30 mL), 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 (petroleum ether:ethyl acetate (v / v)=8:1) to obtain the title compound 1D, colorless liquid (0.18 g, 64.6%).

[0399] LC-MS (ESI): m / z = 302.1 [M - 57 + H] + .

[0400] Step 4: tert-butyl (S)-6,6-difluoro-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (1E)

[0401] tert-butyl (S)-6,6-difluoro-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (1E)

[0402] Dissolve 1D (0.18 g, 0.50 mmol) in methanol (10 mL), add palladium on carbon (90 mg, 10% w / w), displace hydrogen three times, and react at room temperature overnight. Filter, concentrate to dryness to obtain the title compound 1E, colorless liquid (0.13 g, 97.3%), which is directly used in the next step of the reaction.

[0403] LC-MS (ESI): m / z = 212.1 [M - 57 + H] + .

[0404] Step 5: (S)-4-(tert-butoxycarbonyl)-6,6-difluoro-1,4-oxazepane-2-carboxylic acid (1F)

[0405] (S)-4-(tert-butoxycarbonyl)-6,6-difluoro-1,4-oxazepane-2-carboxylic acid (1F)

[0406] Dissolve 1E (0.13 g, 0.49 mmol) in dichloromethane (10 mL) and water (5 mL), cool to 0 °C, add iodobenzene diacetate (0.32 g, 0.98 mmol) and 2,2,6,6-tetramethylpiperidine 1-oxyl (8 mg, 0.05 mmol). After addition, react at room temperature overnight. Add methanol (2 mL) dropwise, stir for 10 min, separate the organic layer, and extract the aqueous layer with dichloromethane:methanol (v / v) = 5:1 (20 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound 1F, a yellow liquid (0.13 g, 94.3%).

[0407] LC-MS (ESI): m / z = 226.1 [M - 57 + H] + .

[0408] Step 6: tert-butyl (S)-2-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6,6-difluoro-1,4-oxazepane-4-carboxylate (1G)

[0409] tert-butyl (S)-2-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6,6-difluoro-1,4-oxazepane-4-carboxylate (1G)

[0410] Dissolve 1F (0.12 g, 0.44 mmol) in N,N-dimethylformamide (10 mL), add INT-1 (0.13 g, 0.44 mmol, the preparation method refers to WO2015110826A1), diisopropylethylamine (0.17 g, 1.32 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.25 g, 0.66 mmol). 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, and concentrate to obtain the title compound 1G, a pale yellow solid (0.32 g, 99.0%), which is directly used in the next step of the reaction.

[0411] LC-MS (ESI): m / z = 501.1 [M - 57 + H] + .

[0412] Step 7: (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6,6-difluoro-1,4-oxazepane-2-carboxamide (Compound 1)

[0413] tert-butyl(S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6,6-difluoro-1,4-oxazepane-2-carboxamide(compound1)

[0414] Dissolve 1G (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 to pH ~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 (petroleum ether:ethyl acetate (v / v) = 1:2) to obtain the title compound 1 (30 mg, 24.3%).

[0415] 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, 2H), 7.40–7.28 (m, 3H), 7.13 (d, 1H), 7.04 (d, 1H), 5.16 (dt, 1H), 4.17 (m, 2H), 3.99 (m, 1H), 3.57 (dd, 1H), 3.46 (s, 3H), 3.43–3.31 (m, 1H), 3.28–3.10 (m, 3H), 2.89 (dd, 1H).

[0416] LC-MS (ESI): m / z = 457.1 [M+H] + .

[0417] Example 2

[0418] 2(S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6,6-difluoro-1,4-oxazepane-2-carboxamide (Compound 2)

[0419] (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6,6-difluoro-1,4-oxazepane-2-carboxamide (compound 2)

[0420]

[0421] Step 1: 1-((benzylamino)methyl)cyclopropan-1-ol (2B)

[0422] 1-((benzylamino)methyl)cyclopropan-1-ol (2B)

[0423] Dissolve benzaldehyde (1.00 g, 9.4 mmol) in dichloromethane (10 mL), add 2A (0.98 g, 11.3 mmol), acetic acid (0.57 g, 9.4 mmol). After addition, react at room temperature overnight. Add sodium triacetoxyborohydride (7.99 g, 1.27 mmol), and react at room temperature for 4 h after addition. Add saturated aqueous sodium chloride solution (50 mL), separate the organic layer, extract with ethyl acetate (30 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound 2B, a yellow liquid (1.20 g, 71.8%), which is directly used in the next step of the reaction.

[0424] LC-MS (ESI): m / z = 178.1 [M+H] + .

[0425] Step 2: (R)-1-((benzyl(oxiran-2-ylmethyl)amino)methyl)cyclopropan-1-ol (2C)

[0426] (R)-1-((benzyl(oxiran-2-ylmethyl)amino)methyl)cyclopropan-1-ol (2C)

[0427] Dissolve 2B (1.00 g, 5.64 mmol) in 1,4-dioxane (10 mL), add (S)-(+)-glycidyl m-nitrobenzenesulfonate (2.19 g, 8.46 mmol), potassium carbonate (2.34 g, 16.92 mmol). After addition, react at 58 °C for 3 h. Cool to room temperature, filter, and concentrate. The residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to obtain the title compound 2C, a white solid (1.00 g, 76.0%).

[0428] LC-MS (ESI): m / z = 234.1 [M+H] + .

[0429] Step 3: (S)-(7-Benzyl-4-oxa-7-azaspiro[2.5]octan-5-yl)methanol (2D)

[0430] (S)-(7-benzyl-4-oxa-7-azaspiro[2.5]octan-5-yl)methanol(2D)

[0431] Dissolve 2C (1.00 g, 4.29 mmol) in methanol (5 mL) and add sodium methoxide (0.70 g, 12.87 mmol). After complete addition, react at room temperature overnight. Add saturated aqueous ammonium chloride to neutralize the mixture, then extract with ethyl acetate (25 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to afford the title compound 2D as a yellow oil (0.67 g, 66.9%).

[0432] LC-MS (ESI): m / z = 234.1 [M+H] + .

[0433] Step 4: (S)-tert-Butyl 5-(hydroxymethyl)-4-oxa-7-azaspiro[2.5]octane-7-carboxylate (2E)

[0434] tert-butyl(S)-5-(hydroxymethyl)-4-oxa-7-azaspiro[2.5]octane-7-carboxylate(2E)

[0435] Dissolve 2D (0.67 g, 2.87 mmol) in methanol (10 mL). Add triethylamine (0.87 g, 8.61 mmol), di-tert-butyl carbonate (0.75 g, 4.30 mmol), and palladium on carbon (10%, w / w) (0.67 g). After complete addition, replace the hydrogen atmosphere three times and allow to react at room temperature overnight. Filter and concentrate to obtain the title compound 2E as a yellow liquid (0.60 g, 85.9%), which was used directly in the next step.

[0436] LC-MS(ESI):m / z=188.1[M-57+H] + .

[0437] Step 5: (S)-7-(tert-Butyloxycarbonyl)-4-oxa-7-azaspiro[2.5]octane-5-carboxylic acid (2F)

[0438] (S)-7-(tert-butoxycarbonyl)-4-oxa-7-azaspiro[2.5]octane-5-carboxylic acid(2F)

[0439] Dissolve 2E (0.50 g, 2.06 mmol) in dichloromethane (10 mL) and water (5 mL), cool to 0 °C, add diacetoxyiodobenzene (1.33 g, 4.12 mmol) and 2,2,6,6-tetramethylpiperidine N-oxide (32.2 mg, 0.21 mmol). After addition, stir at room temperature overnight. Add methanol (2 mL) dropwise, stir for 10 min, separate the organic layer, extract the aqueous layer with dichloromethane:methanol (v / v) = 5:1 (20 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound 2F as a yellow liquid (0.53 g, 99.9%), which is directly used in the next step of the reaction.

[0440] LC-MS (ESI): m / z = 202.1 [M - 57 + H] + .

[0441] Step 6: tert-butyl (S)-5-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-4-oxa-7-azaspiro[2.5]octane-7-carboxylate (2G)

[0442] tert-butyl(S)-5-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-4-oxa-7-azaspiro[2.5]octane-7-carboxylate(2G)

[0443] Dissolve 2F (0.86 g, 3.33 mmol) in N,N-dimethylformamide (10 mL), add INT-1 (0.65 g, 2.22 mmol, the preparation method refers to WO2015110826A1), diisopropylethylamine (0.86 g, 6.66 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.27 g, 3.33 mmol). After adding, 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 (petroleum ether: ethyl acetate (v / v) = 2:1) to obtain the title compound 2G, a pale yellow solid (0.60 g, 50.8%).

[0444] LC-MS (ESI): m / z = 433.2 [M - 100 + H] + .

[0445] Step 7: (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-4-oxa-7-azaspiro[2.5]octane-5-carboxamide (Compound 2)

[0446] (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-4-oxa-7-azaspiro[2.5]octane-5-carboxamide (compound 2)

[0447] Dissolve 2G (0.60 g, 0.59 mmol) in formic acid (2.5 mL), react at room temperature overnight. Concentrate to dryness, add ethyl acetate (20 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×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 2 (0.32 g, 65.3%).

[0448] 11H NMR (400 MHz, CDCl3) δ 7.56 (d, 2H), 7.37 (d, 2H), 7.34–7.22 (m, 2H), 6.87 (d, 1H), 5.15 (dd, 1H), 3.52–3.40 (s, 3H), 3.32 (m, 2H), 3.16 (t, 2H), 2.66–2.53 (m, 1H), 2.37–2.07 (m, 2H), 0.90 (m, 1H), 0.80–0.66 (m, 1H), 0.64 (m, 1H), 0.60–0.41 (m, 1H).

[0449] LC-MS (ESI): m / z=433.2 [M+H] + .

[0450] Example 3

[0451] (2S,6R)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-hydroxy-1,4-oxazepane-2-carboxamide (Compound 3)

[0452] (2S,6R)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-hydroxy-1,4-oxazepane-2-carboxamide (compound 3)

[0453]

[0454] Step 1: (2S,6R)-tert-butyl 6-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (3A)

[0455] (2S,6R)-tert-butyl 6-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (3A)

[0456] Dissolve 3d (0.29 g, 0.64 mmol) in methanol (10 mL), add palladium on carbon (0.1 g, 10%), react under a hydrogen atmosphere for 24 hours, filter, and concentrate to dryness to obtain colorless oil 3A (0.2 g, yield 86%).

[0457] Step 2: (2S,6R)-4-(tert-butoxycarbonyl)-6-((tert-butyldimethylsilyl)oxy)-1,4-oxazepane-2-carboxylic acid (3B)

[0458] (2S,6R)-4-(tert-butoxycarbonyl)-6-((tert-butyldimethylsilyl)oxy)-1,4-oxazepane-2-carboxylic acid(3B)

[0459] Dissolve 3A (0.2 g, 0.48 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 3B (0.13 g, yield 62%).

[0460] Step 3: (2S,6R)-tert-butyl 6-(((tert-butyldimethylsilyl)oxy)-2-((((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (3C)

[0461] (2S,6R)-tert-butyl 6-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(3C)

[0462] Dissolve 3B (0.2 g, 0.53 mmol) in dichloromethane (10 mL), add INT-1 (0.16 g, 0.53 mmol), DIPEA (0.21 g, 1.59 mmol), HATU (0.26 g, 0.69 mmol), react at room temperature for 1 hour, concentrate to dryness, purify by column chromatography (PE:EA = 10:1 - 2:1) to obtain a white solid 3C (0.2 g, yield 57%).

[0463] LC-MS(ESI): m / z = 551.3 [M+1] +

[0464] Step 4: (2S,6R)-tert-butyl 2-((((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (3D)

[0465] (2S,6R)-tert-butyl 2-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-hydroxy-1,4-oxazepane-4-carboxylate(3D)

[0466] Dissolve 3C (0.2 g, 0.31 mmol) in tetrahydrofuran (10 mL), add TBAF (3 mL, 1 mol / L), react at room temperature for 1 h, add water (30 mL), extract with EA (20 mL x 3), wash with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate to obtain yellow solid 3D (0.13 g, yield 78%).

[0467] Step 5: (2S,6R)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-hydroxy-1,4-oxazepane-2-carboxamide (Compound 3)

[0468] (2S,6R)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-hydroxy-1,4-oxazepane-2-carboxamide (compound 3)

[0469] Dissolve 3D (0.18 g, 0.34 mmol) in formic acid (10 mL), react at 50 °C for 0.5 h, add sodium bicarbonate to adjust pH = 7 - 8, add water (30 mL), extract with DCM (20 mL x 3), wash with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (DCM:MeOH = 40:1 - 10:1) to obtain the title compound 3 (90 mg, yield 60%).

[0470] LC-MS(ESI): m / z = 437.1 [M+1]+

[0471] 1 H NMR(400 MHz, DMSO-d6) δ 9.03 - 9.01 (m, 1H), 7.68 - 7.60 (m, 3H), 7.43 - 7.38 (m, 4H), 5.68 (s, 1H), 5.05 - 4.99 (m, 1H), 4.42 - 4.39 (m, 1H), 4.07 - 3.97 (m, 2H), 3.64 - 3.60 (m, 1H), 3.41 - 3.30 (m, 5H), 3.25 - 3.09 (m, 4H), 2.87 - 2.81 (m, 1H).

[0472] Example 4

[0473] (2S,6R)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide (Compound 4)

[0474] (2S,6R)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide (compound 4)

[0475]

[0476] First step: (2S,6R)-2-(((benzyloxy)methyl)-6-methoxy-4-tosyl-1,4-oxazepane (4A)

[0477] (2S,6R)-2-((benzyloxy)methyl)-6-methoxy-4-tosyl-1,4-oxazepane (4A)

[0478] Dissolve 3a (0.5 g, 1.28 mmol) in tetrahydrofuran (20 mL). At 0 °C, add sodium hydride (0.26 g, 6.4 mmol). After stirring for 30 min, 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 colorless oily substance 4A (0.4 g, yield 77%).

[0479] Step 2: (2S,6R)-2-((benzyloxy)methyl)-6-methoxy-1,4-oxazepane(4B)

[0480] (2S,6R)-2-((benzyloxy)methyl)-6-methoxy-1,4-oxazepane(4B)

[0481] Dissolve 4A (0.3 g, 0.74 mmol) in methanol (10 mL), add magnesium chips (2.36 g, 97.08 mmol), after ultrasonic treatment at 50 °C for 2 h, react at room temperature for 16 h, filter, and concentrate to obtain a white oily substance 4B (0.18 g, yield 96%) for direct use in the next step.

[0482] LC-MS (ESI): m / z = 252.3 [M+1] +

[0483] Step 3: (2S,6R)-2-((benzyloxy)methyl)-6-methoxy-1,4-oxazepane(4C)

[0484] (2S,6R)-tert-butyl 2-((benzyloxy)methyl)-6-methoxy-1,4-oxazepane-4-carboxylate(4C) Dissolve 4B (0.18 g, 0.72 mmol) in DCM (10 mL), successively add triethylamine (0.087 g, 0.85 mmol) and TBSCl (0.37 g, 1.71 mmol), under nitrogen protection, react at room temperature for 2 h, then concentrate to dryness and purify by column chromatography (PE:EA = 10:1 - 4:1) to obtain a colorless oily substance 4C (0.12 g, yield 47%).

[0485] Step 4: (2S,6R)2-(hydroxymethyl)-6-methoxy-1,4-oxazepane-4-carboxylic acid tert-butyl ester(4D)

[0486] (2S,6R)-tert-butyl 2-(hydroxymethyl)-6-methoxy-1,4-oxazepane-4-carboxylate(4D)

[0487] Dissolve 4C (0.12 g, 0.34 mmol) in methanol (10 mL), add palladium on carbon (0.1 g, 10%), react under a hydrogen atmosphere for 24 h, then filter and concentrate to dryness to obtain a colorless oily substance 4D (0.08 g, yield 86%).

[0488] Step 5: (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazepane-2-carboxylic acid (4E)

[0489] (2S,6R)-4-(tert-butoxycarbonyl)-6-methoxy-1,4-oxazepane-2-carboxylic acid (4E)

[0490] Dissolve 4D (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 4E (0.046 g, yield 44%).

[0491] Step 6: (2S,6R)-tert-butyl 2-((((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-methoxy-1,4-oxazepane-4-carboxylate (4F)

[0492] (2S,6R)-tert-butyl 2-((((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-methoxy-1,4-oxazepane-4-carboxylate (4F)

[0493] (2S,6R)-tert-butyl 2-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-methoxy-1,4-oxazepane-4-carboxylate (4F)

[0494] Dissolve 4E (0.046 g, 0.17 mmol) in dichloromethane (10 mL), add INT-1 (0.16 g, 0.53 mmol), DIPEA (0.21 g, 1.59 mmol), HATU (0.26 g, 0.69 mmol), react at room temperature for 1 hour, concentrate to dryness, purify by column chromatography (PE:EA = 10:1 - 2:1) to obtain a white solid 4F (0.04 g, yield 42%).

[0495] LC-MS (ESI): m / z = 495.2 [M + 1] +

[0496] Step 7: (2S,6R)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide (Compound 4)

[0497] (2S,6R)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide(compound 4)

[0498] Dissolve 4F (0.03 g, 0.054 mmol) in formic acid (10 mL), react at 50 °C for 0.5 h, add sodium bicarbonate to adjust the pH to 7 - 8, add water (30 mL), extract with DCM (20 mL × 3), wash with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (DCM:MeOH = 40:1 - 10:1) to obtain white solid Compound 4 (20 mg, yield 82%).

[0499] LC-MS (ESI): m / z = 451.1 [M+1] +

[0500] 1 1H NMR (400 MHz, DMSO-d6) δ 9.05 - 9.03 (m, 1H), 7.68 - 7.60 (m, 3H), 7.44 - 7.38 (m, 4H), 5.05 - 4.99 (m, 1H), 4.34 - 4.31 (m, 1H), 4.03 - 3.99 (m, 1H), 3.82 - 3.76 (m, 2H), 3.41 (s, 3H), 3.38 - 3.35 (m, 2H), 3.33 - 3.31 (m, 4H), 3.25 - 3.09 (m, 3H), 2.87 - 2.81 (m, 1H).

[0501] Example 5

[0502] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-hydroxy-1,4-oxazepane-2-carboxamide (Compound 5)

[0503] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-hydroxy-1,4-oxazepane-2-carboxamide (compound 5)

[0504]

[0505] Using intermediate 3B and intermediate INT-2 (for the preparation method, refer to reference WO2014140075) as raw materials, compound 5 was synthesized with reference to the synthesis method of compound 3.

[0506] LC-MS (ESI): m / z = 455.1 [M+1] +

[0507] 1 1H NMR (400 MHz, DMSO-d6) δ 9.05 - 9.03 (m, 1H), 7.68 - 7.39 (m, 6H), 5.58 (s, 1H), 5.07 - 5.01 (m, 1H), 4.39 - 4.35 (m, 1H), 4.11 - 3.97 (m, 2H), 3.63 - 3.59 (m, 1H), 3.41 (s, 3H), 3.37 - 3.30 (m, 4H), 3.23 - 3.16 (m, 1H), 3.10 - 3.09 (m, 1H), 2.87 - 2.81 (m, 1H).

[0508] Example 6

[0509] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide (compound 6)

[0510] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide (compound 6)

[0511]

[0512] Using intermediate 4E and INT-2 as raw materials, compound 6 was synthesized with reference to the synthesis method of compound 4.

[0513] LC-MS (ESI): m / z = 469.1 [M+1] +

[0514] 1 H NMR (400 MHz, DMSO-d6) δ 8.85 - 8.83 (m, 1H), 7.66 - 7.20 (m, 6H), 5.07 - 5.01 (m, 1H), 4.11 - 4.08 (m, 1H), 4.03 - 3.99 (m, 1H), 3.67 - 3.62 (m, 1H), 3.58 - 3.51 (m, 1H), 3.41 (s, 3H), 3.32 - 3.26 (m, 5H), 3.23 - 3.14 (m, 2H), 3.06 - 3.01 (m, 1H), 2.88 - 2.84 (m, 1H), 2.51 - 2.49 (m, 1H).

[0515] Example 7

[0516] (S)-6-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-5-oxa-8-azaspiro[2.6]nonane-6-carboxamide (Compound 7)

[0517] (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-5-oxa-8-azaspiro[2.6]nonane-6-carboxamide (Compound 7)

[0518]

[0519] First step: (S)-2-((benzyloxy)methyl)-6-methylene-4-tosyl-1,4-oxazepane (7B)

[0520] (S)-2-((benzyloxy)methyl)-6-methylene-4-tosyl-1,4-oxazepane (7B)

[0521] Under N₂ protection, methyltriphenylphosphonium bromide (1.56 g, 4.37 mmol) was dissolved in dry tetrahydrofuran (20 mL), cooled to below -20 °C, and 2.5 mol / L n-butyllithium n-hexane solution (2.26 mL, 5.65 mmol) was slowly added dropwise. After the addition, the mixture was stirred at below 0 °C for 30 minutes, and then a tetrahydrofuran solution (5 mL) of 1A (1 g, 2.57 mmol) was added dropwise. After the addition, the reaction mixture was allowed to warm to room temperature naturally and react. After 4 hours, the reaction solution was poured into saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain a crude product, and purified by column chromatography to obtain the title compound 7B (0.60 g, 60.25%).

[0522] LC-MS(ESI): m / z=388.0[M+H] + .

[0523] Step 2: (S)-6-((benzyloxy)methyl)-8-tosyl-5-oxa-8-azaspiro[2.6]nonane (7C)

[0524] (S)-6-((benzyloxy)methyl)-8-tosyl-5-oxa-8-azaspiro[2.6]nonane(7C)

[0525] Under N₂ protection, 7B (0.60 g, 1.53 mmol) was dissolved in dry dichloromethane (10 mL), cooled to -20 °C, and diiodomethane (1.25 mL, 15.3 mmol) was added dropwise. After stirring for 30 minutes, 2 mol / L diethylzinc solution (3 mL, 6.0 mmol) was added dropwise. After the addition, the reaction mixture was allowed to warm to room temperature naturally and stirred. After 4 hours, the reaction solution was slowly added to saturated ammonium chloride aqueous solution (50 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane again. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the title compound 7C (0.2 g, 32.2%).

[0526] LC-MS(ESI): m / z=402.2[M+H] +.

[0527] Step 3: (S)-6-((benzyloxy)methyl)-5-oxa-8-azaspiro[2.6]nonane (7D)

[0528] (S)-6-((benzyloxy)methyl)-5-oxa-8-azaspiro[2.6]nonane(7D)

[0529] Dissolve 7C (0.2 g, 0.5 mmol) in methanol (10 mL), add magnesium turnings (300 mg, 12.5 mmol), and ultrasonically treat at 40 °C for 6 hours. Filter, and concentrate the filtrate to obtain 7D (120 mg, 98.6%).

[0530] LC-MS (ESI): m / z = 248.2 [M+H] + .

[0531] Step 4: tert-butyl (S)-6-((benzyloxy)methyl)-5-oxa-8-azaspiro[2.6]nonane-8-carboxylate (7E)

[0532] tert-butyl (S)-6-((benzyloxy)methyl)-5-oxa-8-azaspiro[2.6]nonane-8-carboxylate (7E)

[0533] Add the 7D (120 mg, 0.49 mmol) obtained in the previous step to dichloromethane (10 ml), dropwise add triethylamine (150 mg, 1.5 mmol), add di-tert-butyl dicarbonate (218 mg, 1.0 mmol), stir the reaction at room temperature. After 4 hours, dilute the reaction solution with dichloromethane, wash with water, wash with dilute hydrochloric acid, wash with water again, dry over anhydrous sodium sulfate, concentrate to obtain the crude product, and perform column chromatography to obtain

[0534] 7E (120 mg, 72.0%).

[0535] LC-MS (ESI): m / z = 292.2 [M-56+H] + .

[0536] Step 5: tert-butyl (S)-6-(hydroxymethyl)-5-oxa-8-azaspiro[2.6]nonane-8-carboxylate (7F)

[0537] tert-butyl (S)-6-(hydroxymethyl)-5-oxa-8-azaspiro[2.6]nonane-8-carboxylate (7F)

[0538] Add 7E (120 mg, 0.35 mmol) to methanol (5 ml), add palladium on carbon (120 mg, 10%), displace with hydrogen 3 times, then stir the reaction under hydrogen. After 18 hours, filter through a small amount of diatomaceous earth, and concentrate the filtrate to obtain 7F (65 mg, 74.3%).

[0539] LC-MS (ESI): m / z = 202.1 [M-56+H] + .

[0540] Step 6: (S)-8-(tert-butoxycarbonyl)-5-oxa-8-azaspiro[2.6]nonane-6-carboxylic acid (7H)

[0541] (S)-8-(tert-butoxycarbonyl)-5-oxa-8-azaspiro[2.6]nonane-6-carboxylic acid(7H)

[0542] Dissolve 7F (65 mg, 0.45 mmol) in acetone (7 mL), add saturated sodium bicarbonate (3 mL), sodium bromide (25 mg, 0.24 mmol), TEMPO (4 mg, 0.024 mmol), add trichloroisocyanuric acid (250 mg, 1.06 mmol) at 0 °C, stir at room temperature for 16 hours after natural warming to room temperature, 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 7H (40 mg, 59.0%).

[0543] LC-MS (ESI): m / z = 216.2 [M - 56 + H] + .

[0544] Step 7: tert-butyl (S)-6-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-5-oxa-8-azaspiro[2.6]nonane-8-carboxylate (7G)

[0545] tert-butyl (S)-6-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-5-oxa-8-azaspiro[2.6]nonane-8-carboxylate(7G)

[0546] Dissolve 7H (40 mg, 0.15 mmol) in dichloromethane (10 mL), add intermediate 2 (160 mg, 0.53 mmol), DIPEA (200 mg, 1.59 mmol), HATU (260 mg, 0.69 mmol), react at room temperature for 1 hour, concentrate to dryness, purify by column chromatography (PE:EA = 10:1 - 2:1) to obtain a white solid 7G (45 mg, 54.9%).

[0547] LC-MS (ESI): m / z = 491.2 [M - 56 + H]+ .

[0548] Step 8: (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-5-oxa-8-azaspiro[2.6]nonane-6-carboxamide (Compound 7)

[0549] (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-5-oxa-8-azaspiro[2.6]nonane-6-carboxamide (compound7)

[0550] Dissolve 7G (45 mg, 0.08 mmol) in formic acid (10 mL), react at 50 °C for 0.5 h, add sodium bicarbonate to adjust pH = 7 - 8, add water (30 mL), extract with DCM (20 mL x 3), wash with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (DCM:MeOH = 40:1 - 10:1) to obtain Compound 7 (15 mg, 42.0%).

[0551] 1 H NMR (400 MHz, CDCl3) δ 7.56 (d, 2H), 7.40–7.28 (m, 4H), 7.13 (d, 1H), 5.16 (dt, 1H), 4.6 (d, 1H), 3.82 - 3.57 (m, 3H), 3.45 (s, 3H), 3.22–3.10 (m, 5H), 0.99 - 0.65 (m, 4H).

[0552] LC-MS (ESI): m / z = 447.2 [M+H] + .

[0553] Example 8

[0554] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-deuterio-methoxy-1,4-oxazepane-2-carboxamide (Compound 8)

[0555] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(methoxy-d3)-1,4-oxazepane-2-carboxamide (compound 8)

[0556]

[0557] Step 1: (2S,6R)-2-((benzyloxy)methyl)-6-methoxy-1,4-oxazepane (8A)

[0558] tert-butyl(2S,6R)-2-((benzyloxy)methyl)-6-(methoxy-d3)-1,4-oxazepane-4-carboxylate (8A)

[0559] Dissolve INT-3 (200 mg, 0.59 mmol) in tetrahydrofuran (20 mL). At 0 °C, add sodium hydride (80 mg, 2.0 mmol), stir for 30 min, then dropwise add deuterated iodomethane (130 mg, 0.9 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 oil, 8A (170 mg, 81.4%).

[0560] LCMS m / z = 355.2 [M+1-56] +

[0561] Step 2: (2S,6R) 2-(hydroxymethyl)-6-deuterated methoxy-1,4-oxazepane-4-carboxylic acid tert-butyl ester (8B)

[0562] (2S,6R)-tert-butyl 2-(hydroxymethyl)-6-(methoxy-d3)-1,4-oxazepane-4-carboxylate (8B)

[0563] Dissolve 8A (170 mg, 0.48 mmol) in methanol (10 mL), add palladium on carbon (0.1 g, 10%). After displacing hydrogen 3 times, react under a hydrogen atmosphere for 24 h, then filter and concentrate to dryness to obtain a colorless oil, 8B (110 mg, yield 86.8%).

[0564] LCMS m / z = 265.2 [M+1] +

[0565] Step 3: (2S,6R)-4-(tert-butoxycarbonyl)-6-(methoxy-d3)-1,4-oxazepane-2-carboxylic acid (8C)

[0566] (2S,6R)-4-(tert-butoxycarbonyl)-6-(methoxy-d3)-1,4-oxazepane-2-carboxylic acid(8C)

[0567] Dissolve 8B (110 mg, 0.41 mmol) in acetone (7 mL), add saturated sodium bicarbonate (3 mL), sodium bromide (25 mg, 0.24 mmol), TEMPO (4 mg, 0.024 mmol), add trichloroisocyanuric acid (250 mg, 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, and obtain yellow oil 8C (90 mg, yield 78.9%).

[0568] LCMS m / z = 279.2 [M+1 - 56] +

[0569] Step 4: tert-butyl (2S,6R)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-(methoxy-d3)-1,4-oxazepane-4-carboxylate (8D)

[0570] tert-butyl(2S,6R)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-(methoxy-d3)-1,4-oxazepane-4-carboxylate(8D)

[0571] Dissolve 8C (90 mg, 0.32 mmol) in dichloromethane (10 mL), add INT-2 (160 mg, 0.53 mmol), DIPEA (210 mg, 1.59 mmol), HATU (260 mg, 0.69 mmol), react at room temperature for 1 hour, concentrate to dryness, and purify by column chromatography (PE:EA = 10:1 - 2:1) to obtain white solid 8D (130 mg, 71.1%).

[0572] LCMS m / z = 516.2 [M + 1 - 56] +

[0573] Step 5: (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(methoxy-d3)-1,4-oxazepane-2-carboxamide (Compound 8)

[0574] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(methoxy-d3)-1,4-oxazepane-2-carboxamide (compound 8)

[0575] Dissolve 8D (130 mg, 0.22 mmol) in formic acid (10 mL), react at 50 °C for 0.5 h, add sodium bicarbonate to adjust the pH to 7 - 8, add water (30 mL), extract with DCM (20 mL x 3), wash with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (DCM:MeOH = 40:1 - 10:1) to obtain compound 8 (55 mg, yield 53.1%).

[0576] LCMS m / z = 472.2 [M + 1] +

[0577] 1 1H NMR (400 MHz, CDCl3) δ 7.29 - 7.26 (m, 2H), 7.24 - 7.18 (m, 2H), 7.08 - 7.04 (m, 2H), 5.14 - 5.08 (m, 1H), 4.09 - 4.00 (m, 2H), 3.67 - 3.63 (m, 1H), 3.48 - 3.45 (m, 1H), 3.39 (s, 3H), 3.35 - 3.350 (m, 1H), 3.20 - 3.07 (m, 3H), 2.85 - 2.81 (m, 1H), 1.99 (s, 3H).

[0578] Example 9

[0579] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-ethoxy-1,4-oxazepane-2-carboxamide (Compound 9)

[0580] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-ethoxy-1,4-oxazepane-2-carboxamide(compound 9)

[0581]

[0582] Step 1: (2S,6R)-2-(((Benzyloxy)methyl)-6-ethoxy-4-tosyl-1,4-oxazepane (9A)

[0583] (2S,6R)-2-((benzyloxy)methyl)-6-ethoxy-4-tosyl-1,4-oxazepane(9A)

[0584] 3a (0.7 g, 1.79 mmol) was dissolved in tetrahydrofuran (20 mL). Sodium hydride (0.143 g, 3.58 mmol) was added at 0°C. After stirring for 30 min, iodoethane (0.56 g, 3.58 mmol) was added. After reacting at room temperature for 3 h, water (30 mL) was added at 0°C. The mixture was extracted with EA (20 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 9A (0.7 g, 93% yield) as a colorless oil.

[0585] Step 2: (2S,6R)-2-((Benzyloxy)methyl)-6-ethoxy-1,4-oxazepane (9B)

[0586] (2S,6R)-2-((benzyloxy)methyl)-6-ethoxy-1,4-oxazepane(9B)

[0587] 9A (0.7 g, 1.68 mmol) was dissolved in methanol (20 mL), and magnesium turnings (2.36 g, 97.08 mmol) were added. The mixture was ultrasonicated at 50°C for 2 h, and then reacted at room temperature for 16 h. The mixture was filtered and concentrated to obtain a white oily product 9B (crude product), which was directly used for the next step.

[0588] LC-MS (ESI): m / z = 266.2 [M+1] +

[0589] Step 3: (2S,6R)-2-((Benzyloxy)methyl)-6-ethoxy-1,4-oxazepane (9C)

[0590] (2S,6R)-tert-butyl 2-((benzyloxy)methyl)-6-ethoxy-1,4-oxazepane-4-carboxylate(9C)

[0591] Dissolve 9B (crude) in DCM (10 mL), successively add triethylamine (0.348 g, 3.4 mmol) and di-tert-butyl dicarbonate (0.74 g, 3.41 mmol). Under nitrogen protection, react at room temperature for 2 hours, then concentrate to dryness and purify by column chromatography (PE:EA = 10:1 - 4:1) to obtain colorless oily substance 9C (0.10 g, 0.27 mmol).

[0592] Step 4: (2S,6R)-tert-butyl 2-(hydroxymethyl)-6-ethoxy-1,4-oxazepane-4-carboxylate(4D)

[0593] (2S,6R)-tert-butyl 2-(hydroxymethyl)-6-ethoxy-1,4-oxazepane-4-carboxylate(9D)

[0594] Dissolve 9C (0.10 g, 0.27 mmol) in methanol (10 mL), add palladium on carbon (0.1 g, 10%), and react under a hydrogen atmosphere for 24 hours. Then filter and concentrate to dryness to obtain colorless oily substance 9D (0.06 g, yield 81%).

[0595] Step 5: (2S,6R)-4-(tert-butoxycarbonyl)-6-ethoxy-1,4-oxazepane-2-carboxylic acid(9E)

[0596] (2S,6R)-4-(tert-butoxycarbonyl)-6-ethoxy-1,4-oxazepane-2-carboxylic acid(9E)

[0597] Dissolve 9D (0.06 g, 0.22 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), and 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, and concentrate to dryness to obtain yellow oily substance 9E (0.08 g, crude product is directly used for the next step).

[0598] Step 6: Tert-butyl (2S,6R)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-ethoxy-1,4-oxazepane-4-carboxylate (9F)

[0599] tert-butyl(2S,6R)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-ethoxy-1,4-oxazepane-4-carboxylate(9F)

[0600] 9E (0.08 g, crude product) was dissolved in dichloromethane (10 mL), and INT-2 (0.16 g, 0.53 mmol), DIPEA (0.21 g, 1.59 mmol), and HATU (0.26 g, 0.69 mmol) were added. The mixture was reacted at room temperature for 1 hour, concentrated to dryness, and purified by column chromatography (PE:EA=10:1-2:1) to obtain 9F (0.05 g, 0.09 mmol) as a white solid.

[0601] LC-MS (ESI): m / z = 583.3 [M+1] +

[0602] Step 7: (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-ethoxy-1,4-oxazepane-2-carboxamide (Compound 9)

[0603] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-ethoxy-1,4-oxazepane-2-carboxamide(compound 9)

[0604] Dissolve 9F (0.05 g, 0.09 mmol) in acetonitrile (5 mL), add p-toluenesulfonic acid (0.05 g, 0.27 mmol), react at 30 °C for 3 hours, add sodium bicarbonate to adjust pH = 7 - 8, add water (30 mL), extract with DCM (20 mL x 3), wash with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (DCM:MeOH = 40:1 - 10:1) to obtain compound 9 (30 mg, yield 69%).

[0605] LC-MS (ESI): m / z = 483.3 [M+1] +

[0606] 1 1H NMR (400 MHz, CDCl3) δ 7.36 - 7.18 (m, 5H), 7.12 (d, 1H), 5.17 (dd, 1H), 4.17 (dd, 1H), 4.08 (dd, 1H), 3.71 (dd, 1H), 3.68–3.58 (m, 1H), 3.57 - 3.48 (m, 2H), 3.46 (s, 3H), 3.39 (dd, 1H), 3.29–3.11 (m, 3H), 2.92 (dd, 1H), 2.63 (dd, 1H), 1.20 (t, 3H).

[0607] Example 10

[0608] (2S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(methoxymethyl)-1,4-oxazepane-2-carboxamide (Compound 10)

[0609] (2S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(methoxymethyl)-1,4-oxazepane-2-carboxamide (compound 10)

[0610]

[0611] Step 1: Ethyl (S)-2-((benzyloxy)methyl)-6-oxo-1,4-oxazepane-4-carboxylate (10A)

[0612] tert-butyl(S)-2-((benzyloxy)methyl)-6-oxo-1,4-oxazepane-4-carboxylate(10A)

[0613] Dissolve INT-3 (200 mg, 0.59 mmol) in dichloromethane (5 mL). Add Dess-Martin periodinane (400 mg, 1.0 mmol) at room temperature and stir the reaction for 2 hours. Add saturated aqueous sodium carbonate solution (5 mL), stir for 30 minutes, separate the dichloromethane layer, extract the aqueous phase with dichloromethane twice more, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain colorless viscous substance 10A (180 mg, 90.2%).

[0614] LCMS m / z=336.2[M+1] +

[0615] Step 2: Ethyl tert-butyl (S,Z)-2-((benzyloxy)methyl)-6-(methoxymethylene)-1,4-oxazepane-4-carboxylate (10B)

[0616] tert-butyl(S,Z)-2-((benzyloxy)methyl)-6-(methoxymethylene)-1,4-oxazepane-4-carboxylate(10B)

[0617] Dissolve 10A (150 mg, 0.45 mmol) in methanol (20 mL). At 0 °C, add dimethyl (1-diazo-2-oxopropyl)phosphonate (172 mg, 0.9 mmol) and potassium carbonate (186 mg, 1.35 mmol). Stir at room temperature for 4 hours, then concentrate off some of the methanol. Add EA to the residue, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain colorless oily substance 10B (80 mg, 49.9%).

[0618] LCMS m / z=308.2[M+1-56] +

[0619] Step 3: Ethyl tert-butyl (2S)-2-(hydroxymethyl)-6-(methoxymethyl)-1,4-oxazepane-4-carboxylate (10C)

[0620] tert-butyl(2S)-2-(hydroxymethyl)-6-(methoxymethyl)-1,4-oxazepane-4-carboxylate(10C)

[0621] Dissolve 10B (80 mg, 0.22 mmol) in methanol (10 mL), add palladium on carbon (0.1 g, 10%), replace with hydrogen 3 times, then react under a hydrogen atmosphere for 24 hours. Filter, concentrate to dryness, and obtain a colorless oil 10C (60 mg, yield 99.2%).

[0622] LCMS m / z = 220.2 [M+1-56] +

[0623] Step 4: (2S)-4-(tert-butoxycarbonyl)-6-(methoxymethyl)-1,4-oxazepane-2-carboxylic acid (10D)

[0624] (2S)-4-(tert-butoxycarbonyl)-6-(methoxymethyl)-1,4-oxazepane-2-carboxylic acid(10D)

[0625] Dissolve 10C (60 mg, 0.21 mmol) in acetone (7 mL), add saturated sodium bicarbonate (3 mL), sodium bromide (15 mg, 0.16 mmol), TEMPO (3 mg, 0.02 mmol), add trichloroisocyanuric acid (180 mg, 0.77 mmol) at 0 °C, stir and react at room temperature 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, and obtain a yellow oil 10D (40 mg, yield 65.9%).

[0626] LCMS m / z = 234.2 [M+1-56] +

[0627] Step 5: Ethyl tert-butyl(2S)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-(methoxymethyl)-1,4-oxazepane-4-carboxylate (10E)

[0628] tert-butyl(2S)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-(methoxymethyl)-1,4-oxazepane-4-carboxylate(10E)

[0629] Dissolve 10D (40 mg, 0.13 mmol) in dichloromethane (10 mL), add INT-2 (60 mg, 0.20 mmol), DIPEA (52 mg, 0.4 mmol), HATU (95 mg, 0.25 mmol), react at room temperature for 1 hour, concentrate to dryness, and purify by column chromatography (PE:EA = 10:1 - 2:1) to obtain white solid 10E (60 mg, 78.1%).

[0630] LCMS m / z = 517.2 [M + 1 - 56] +

[0631] Step 6: (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-deuterio-methoxy-1,4-oxazepane-2-carboxamide (Compound 10)

[0632] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(methoxy-d3)-1,4-oxazepane-2-carboxamide (compound 10)

[0633] Dissolve 10E (60 mg, 0.10 mmol) in formic acid (10 mL), react at 50 °C for 0.5 hour, add sodium bicarbonate to adjust the pH to 7 - 8, add water (30 mL), extract with DCM (20 mL x 3), wash with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (DCM:MeOH = 40:1 - 10:1) to obtain compound 10 (30 mg, yield 62.2%).

[0634] LCMS m / z = 483.2 [M + 1] +

[0635] 1 H NMR (400 MHz, d6-DMSO) δ 8.72 - 8.63 (m, 1H), 7.66 - 7.33 (m, 5H), 5.08 - 5.04 (m, 1H), 3.97 - 3.89 (m, 2H), 3.79 - 3.70 (m, 1H), 3.48 - 3.45 (m, 1H), 3.41 (s, 3H), 3.35 - 3.20 (m, 1H), 3.22 (s, 3H), 3.20 - 3.07 (m, 3H), 2.70 - 2.62 (m, 2H), 2.4 - 2.25 (m, 2H).

[0636] Example 11

[0637] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide (Compound 11)

[0638] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide

[0639]

[0640] First step: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)carbamate (11B)

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

[0642] 11A (0.21 g, 0.92 mmol), INT (0.30 g, 0.77 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.11 g, 0.15 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 sodium chloride aqueous 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 11B, a brown solid (0.26 g, yield 86%).

[0643] LCMS m / z = 410.1 [M+1] + .

[0644] Second step: (S)-2-amino-3-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)propanenitrile (11C)

[0645] (S)-2-amino-3-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)propanenitrile

[0646] Dissolve 11B (0.26 g, 0.63 mmol) in formic acid (6.0 mL), and react at 50 °C for 10 minutes after addition. Concentrate to dryness, add ethyl acetate (60 mL), and adjust the pH to ~8 by dropwise addition of saturated aqueous sodium bicarbonate. Separate the organic layer, extract the aqueous phase with ethyl acetate (60 mL × 2). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound 11C (0.16 g, yield 83%).

[0647] LCMS m / z = 310.1 [M+1] + .

[0648] Step 3: tert-butyl (2S,6R)-2-(((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)carbamoyl)-6-methoxy-1,4-oxazepane-4-carboxylate (11D)

[0649] tert-butyl(2S,6R)-2-(((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)carbamoyl)-6-methoxy-1,4-oxazepane-4-carboxylate

[0650] Dissolve 11C (0.16 g, 0.52 mmol) in N,N-dimethylformamide (10 mL), add 4E (0.14 g, 0.52 mmol), diisopropylethylamine (0.19 g, 1.5 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.24 g, 0.62 mmol). React at room temperature for 1 hour after addition. Add saturated aqueous sodium chloride (30 mL), extract with ethyl acetate (60 mL × 2). Wash the organic phase with saturated aqueous sodium chloride (60 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate the residue by silica gel column chromatography (PE:EA (v / v) = 2:1 ~ 1:2) to obtain the title compound 11D, a pale yellow solid (0.19 g, yield 64%).

[0651] Step 4: (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamide (Compound 11)

[0652] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)-6-methoxy-1,4-oxazepane-2-carboxamidee

[0653] Dissolve 11D (0.19 g, 0.34 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 ~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 11 (92 mg, yield 58%).

[0654] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (dd, 1H), 7.92 (s, 1H), 7.83 - 7.77 (m, 1H), 7.73 (d, 1H), 7.65–7.55 (m, 2H), 7.48 (t, 1H), 5.10–4.95 (m, 1H), 4.51 (s, 2H), 4.08–3.94 (m, 2H), 3.66 - 3.56 (m, 1H), 3.54–3.41 (m, 1H), 3.29 (s, 3H), 3.24–3.17 (m, 2H), 3.10 (s, 3H), 3.04–2.94 (m, 1H), 2.89 - 2.79 (m, 1H), 2.73–2.64 (m, 1H), 2.61–2.54 (m, 1H).

[0655] LC-MS m / z = 467.3 [M+1] +

[0656] Example 12

[0657] (2S)-N-((1S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3,7,7a-tetrahydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-methyl-1,4-oxazepane-2-carboxamide (Compound 12)

[0658] (2S)-N-((1S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3,7,7a-tetrahydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-methyl-1,4-oxazepane-2-carboxamide (compound 12)

[0659]

[0660] Step 1: (S)-2-(((benzyloxy)methyl)-6-methylene-1,4-oxazepane (12A)

[0661] (S)-2-((benzyloxy)methyl)-6-methylene-1,4-oxazepane (12A)

[0662] Dissolve 7B (300 mg, 0.77 mmol) in methanol (10 mL), add magnesium turnings (300 mg, 12.5 mmol), sonicate at 40 °C for 6 hours, filter, and use the filtrate directly for the next step after concentration.

[0663] LC-MS (ESI): m / z = 234.2 [M+H] +.

[0664] Step 2: tert-butyl (S)-2-((benzyloxy)methyl)-6-methylene-1,4-oxazepane-4-carboxylate (12B)

[0665] tert-butyl (S)-2-((benzyloxy)methyl)-6-methylene-1,4-oxazepane-4-carboxylate (12B)

[0666] Add the crude product obtained in the previous step to dichloromethane (10 ml), dropwise add triethylamine (200 mg, 2.0 mmol), add di-tert-butyl dicarbonate (330 mg, 1.5 mmol), stir and react at room temperature. After 4 hours, dilute the reaction solution with dichloromethane, wash with water, wash with dilute hydrochloric acid, wash with water again, dry over anhydrous sodium sulfate, concentrate to obtain the crude product, and perform column chromatography to obtain the title compound 12B (220 mg, 85.7%).

[0667] LC-MS (ESI): m / z = 278.2 [M+H-56] + .

[0668] Step 3: tert-butyl (2S)-2-(hydroxymethyl)-6-methyl-1,4-oxazepane-4-carboxylate (12C)

[0669] tert-butyl(2S)-2-(hydroxymethyl)-6-methyl-1,4-oxazepane-4-carboxylate(12C)

[0670] 12B (220 mg, 0.66 mmol) was added to methanol (5 ml), palladium on carbon (200 mg, 10%) was added, and after replacing with hydrogen three times, the reaction was stirred under hydrogen. After 18 hours, it was filtered through a small amount of diatomaceous earth, and the filtrate was concentrated to obtain 12C (110 mg, 68%).

[0671] LC-MS(ESI): m / z=246.2[M+H] + .

[0672] Step 4: (2S)-4-(tert-butoxycarbonyl)-6-methyl-1,4-oxazepane-2-carboxylic acid(12D)

[0673] (2S)-4-(tert-butoxycarbonyl)-6-methyl-1,4-oxazepane-2-carboxylic acid(12D)

[0674] 12C (110 mg, 0.45 mmol) was dissolved in acetone (7 mL), saturated sodium bicarbonate (3 mL), sodium bromide (25 mg, 0.24 mmol), TEMPO (4 mg, 0.024 mmol) were added, and trichloroisocyanuric acid (250 mg, 1.06 mmol) was added at 0 °C. After stirring at room temperature for 16 hours, the pH was adjusted to 5 - 6 with dilute hydrochloric acid, water (30 mL) was added, and it was extracted with dichloromethane (20 mL × 3), washed with water (30 mL), washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a yellow oil 12D (80 mg, 68.3%).

[0675] LC-MS(ESI): m / z=204.1[M-56+H] + .

[0676] Step 5: tert-butyl(2S)-2-((((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl]]]ethyl)carbamoyl)-6-methyl-1,4-oxazepane-4-carboxylate(12E)

[0677] tert-butyl(2S)-2-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-methyl-1,4-oxazepane-4-carboxylate(12E)

[0678] Dissolve 12D (80 mg, 0.31 mmol) in dichloromethane (10 mL), add intermediate 2 (160 mg, 0.53 mmol), DIPEA (200 mg, 1.59 mmol), and HATU (260 mg, 0.69 mmol). React at room temperature for 1 hour, concentrate to dryness, and purify by column chromatography (PE:EA = 10:1 - 2:1) to obtain white solid 12E (80 mg, 48.5%).

[0679] LC-MS (ESI): m / z = 480.2 [M - 56 + H] + .

[0680] Step 6: (2S)-N-((1S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3,7,7a-tetrahydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-methyl-1,4-oxazepane-2-carboxamide (Compound 12)

[0681] tert-butyl(2S)-N-((1S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3,7,7a-tetrahydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-methyl-1,4-oxazepane-2-carboxamide (compound 12)

[0682] Dissolve 12E (80 mg, 0.18 mmol) in formic acid (10 mL), react at 50 °C for 0.5 hour, add sodium bicarbonate to adjust the pH to 7 - 8, add water (30 mL), extract with DCM (20 mL x 3), wash with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (DCM:MeOH = 40:1 - 10:1) to obtain compound 12 (15 mg, yield 19.1%).

[0683] 11H NMR (400 MHz, CDCl3) δ 7.50 - 7.47 (m, 2H), 7.34–7.29 (m, 2H), 7.25 - 7.23 (m, 1H), 7.19–7.11 (m, 1H), 7.07–7.05 (m, 1H), 5.14 - 5.06 (m, 1H), 4.16 - 4.06 (m, 1H), 3.88 - 3.78 (m, 1H), 3.52 - 3.45 (m, 1H), 3.30–3.25 (m, 1H), 3.10–3.05 (m, 3H), 2.82–2.74 (m, 1H), 2.58 - 2.55 (m, 1H), 2.45 - 2.38 (m, 1H), 1.99 (s, 3H), 0.88 (d, 3H).

[0684] LC-MS (ESI): m / z=435.2 [M+H] + .

[0685] Example 13

[0686] Compound 13-1 and Compound 13-2 (7S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-oxa-2-azabicyclo[3.2.1]octane-7-carboxamide and (7R)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-oxa-2-azabicyclo[3.2.1]octane-7-carboxamide

[0687] (7S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-oxa-2-azabicyclo[3.2.1]octane-7-carboxamide and (7R)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-oxa-2-azabicyclo[3.2.1]octane-7-carboxamide

[0688]

[0689] The first step: 13B-1 and 13B-2

[0690] tert-butyl(7S)-7-(hydroxymethyl)-6-oxa-2-azabicyclo[3.2.1]octane-2-carboxylate and tert-butyl(7R)-7-(hydroxymethyl)-6-oxa-2-azabicyclo[3.2.1]octane-2-carboxylate

[0691] tert-butyl(7S)-7-(hydroxymethyl)-6-oxa-2-azabicyclo[3.2.1]octane-2-carboxylate and tert-butyl(7R)-7-(hydroxymethyl)-6-oxa-2-azabicyclo[3.2.1]octane-2-carboxylate

[0692] Dissolve compound 13A (3.72 g, 10.1 mmol) (prepared according to J. Org. Chem. 2017, 82, 15, 8048–8057, a mixture of two isomers) in methanol (40 mL), add Boc anhydride (4.36 g, 20 mmol) and Pd / C (0.74 g), and react under a hydrogen atmosphere for 48 h. After the reaction, filter through diatomaceous earth, concentrate the filtrate under reduced pressure, and separate by silica gel column chromatography (PE:EA = 1:1) to obtain two isomers 13B-1 and 13B-2 of the compound.

[0693] 13B-1 (1.42 g, transparent oil):

[0694] 1 H NMR (400 MHz, CDCl3) δ 4.66 - 4.57 (m, 1H), 4.57–4.45 (m, 1H), 4.05–3.92 (m, 1H), 3.78 - 3.60 m, 1H), 3.44–3.24 (m, 3H), 2.83 (s, 1H), 2.14 - 2.01 m, 1H), 1.97–1.67 (m, 3H), 1.48 (s, 9H).

[0695] LC-MS m / z = 188.1 [M - t Bu+1] +

[0696] 13B-2 (0.32 g, transparent oil):

[0697] 11H NMR (400 MHz, CDCl3) δ 4.60–4.52 (m, 2H), 4.16 - 4.08 (m, 1H), 3.92 - 3.84 (m, 1H), 3.62 - 3.54 (m, 1H), 3.52 - 3.46 (m, 1H), 3.28 - 3.18 (m, 1H), 2.33 (s, 1H), 1.96 - 1.83 (m, 1H), 1.80 - 1.70 (m, 1H), 1.70–1.52 (m, 2H), 1.46 (s, 9H).

[0698] LC-MS m / z = 188.1 [M - t Bu + 1] +

[0699] Step 2: Preparation of 13C-1

[0700] Under ice bath, in a 50 mL single-necked flask, successively add the reactant 13B-1 (0.48 g, 1.97 mmol) dissolved in acetone (15 mL) and saturated sodium bicarbonate (5 mL). Then successively add sodium bromide (61 mg, 0.59 mmol), TEMPO (9.2 mg), and then add trichloroisocyanuric acid (0.46 g, 1.97 mmol) portionwise under ice bath. After addition, the temperature can be raised to room temperature and stirred for the reaction overnight. Then add isopropanol (6 mL) to the reaction solution, stir for 30 min, filter through diatomaceous earth, wash with ethyl acetate (20 mL), concentrate the filtrate under reduced pressure to a yellow oily crude product. The crude product is dissolved in 1 M sodium carbonate solution (50 mL), washed with ethyl acetate (40 mL), adjust the pH of the aqueous phase to 4 - 5 with 2 N hydrochloric acid, and extract with dichloromethane (50 mL × 3). The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound 13C-1, a white solid (0.35 g, yield 69%).

[0701] LC-MS m / z = 202.1 [M - t Bu + 1] +

[0702] Step 3: Preparation of 13D-1

[0703] Dissolve 13C-1 (0.17 g, 0.68 mmol) in N,N-dimethylformamide (10 mL), add INT-1 (0.2 g, 0.68 mmol), triethylamine (0.2 g, 2 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.27 g, 0.72 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)=2:1~1:4) to obtain the title compound 13D-1, a pale yellow solid (0.16 g, yield 44%).

[0704] LC-MS m / z=477.2[M- t Bu+1] +

[0705] Step 4: (7S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-oxa-2-azabicyclo[3.2.1]octane-7-carboxamide and (7R)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-oxa-2-azabicyclo[3.2.1]octane-7-carboxamide

[0706] Compound 13-1 and Compound 13-2

[0707] (7S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-oxa-2-azabicyclo[3.2.1]octane-7-carboxamide and(7R)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-oxa-2-azabicyclo[3.2.1]octane-7-carboxamide

[0708] 13D-1 (0.6 g, 0.3 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 ~8 by dropwise addition of saturated aqueous sodium bicarbonate. The organic layer was separated, 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) = 10:1) to obtain compound 13-1 (52 mg, yield 40%).

[0709] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (d, 1H), 7.67–7.60 (m, 2H), 7.54 (s, 1H), 7.45–7.33 (m, 4H), 5.15 (q, 1H), 4.49 (t, 1H), 4.33 (d, 1H), 3.54 (s, 1H), 3.40 (s, 3H), 3.26 (d, 2H), 2.37 - 2.27 m, 1H), 2.25 - 2.15 (m, 1H), 1.87 - 1.81 (m, 1H), 1.65 (d, 1H), 1.53–1.35 (m, 2H).

[0710] LC-MS m / z = 433.3 [M+1] +

[0711] Using 13B-2 as the starting material, compound 13-2 was synthesized by referring to the synthetic method of compound 13-1: [[ID=1ģ]]

[0712] 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (d, 1H), 7.67–7.61 (m, 2H), 7.56 (t, 1H), 7.44–7.34 (m, 4H), 5.05 (q, 1H), 4.51 (t, 1H), 4.38 (s, 1H), 3.40 (s, 3H), 3.27–3.14 (m, 3H), 2.96 - 2.84 (m, 1H), 2.78 - 2.68 (m, 1H), 1.56–1.38 (m, 2H), ı.38 - 1.30 (d, 1H), 1.16–1.09 (m, 1H).

[0713] LC-MS m / z = 433.2 [M+1] + .

[0714] Example 14

[0715] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(trifluoromethoxy)-1,4-oxazepane-2-carboxamide (compound 14)

[0716] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(trifluoromethoxy)-1,4-oxazepane-2-carboxamide(compound 14)

[0717]

[0718] Step 1: (2S,6R)-2-((benzyloxy)methyl)-6-(trifluoromethoxy)-1,4-oxazepane (14A)

[0719] tert-butyl(2S,6R)-2-((benzyloxy)methyl)-6-(trifluoromethoxy)-1,4-oxazepane-4-carboxylate(14A)

[0720] Dissolve INT-3 (300 mg, 0.89 mmol) in ethyl acetate (6 mL). Sequentially add potassium fluoride (207 mg, 3.56 mmol), silver trifluoromethanesulfonate (686 mg, 2.67 mmol), selectfluor (472 mg, 1.33 mmol), 2-fluoropyridine (259 mg, 2.67 mmol), (trifluoromethyl)trimethylsilane (379 mg, 2.67 mmol). After addition, stir the reaction mixture at room temperature for 16 hours. Dilute the reaction solution with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to obtain a crude product, and purify by column chromatography to obtain a colorless oil 14A (130 mg, 36.2%).

[0721] LCMS m / z = 350.1 [M+1 - 56] +

[0722] Step 2: (2S,6R)-2-(hydroxymethyl)-6-(trifluoromethoxy)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (14B)

[0723] (2S,6R)-tert-butyl 2-(hydroxymethyl)-6-(trifluoromethoxy)-1,4-oxazepane-4-carboxylate(14B)

[0724] Dissolve 14A (130 mg, 0.34 mmol) in methanol (10 mL), add palladium on carbon (0.1 g, 10%), after displacing hydrogen three times, react under a hydrogen atmosphere for 24 hours, then filter and concentrate to dryness to obtain a colorless oil, 14B (80 mg, yield 79.1%).

[0725] LCMS m / z = 260.2 [M+1-56] +

[0726] Step 3: (2S,6R)-4-(tert-butoxycarbonyl)-6-(trifluoromethoxy)-1,4-oxazepane-2-carboxylic acid(14C)

[0727] (2S,6R)-4-(tert-butoxycarbonyl)-6-(trifluoromethoxy)-1,4-oxazepane-2-carboxylic acid(14C)

[0728] Dissolve 14B (80 mg, 0.25 mmol) in acetone (3.5 mL), add saturated sodium bicarbonate (1.5 mL), sodium bromide (2.57 mg, 0.025 mmol), Tempo (3.91 mg, 0.025 mmol), add trichloroisocyanuric acid (116 mg, 0.5 mmol) at 0 °C, react at room temperature for 16 hours, adjust the pH to 5 - 6 with dilute hydrochloric acid, add water (10 mL), extract with dichloromethane (10 mL * 3), wash with water (10 mL), wash with saturated sodium chloride (10 mL), dry over anhydrous sodium sulfate, and concentrate to dryness to obtain a yellow oil, 14C (55 mg, yield 66.8%).

[0729] LCMS m / z = 330.2 [M+1] +

[0730] Step 4: (2S,6R)-tert-butyl 2-((((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-,6-(trifluoromethoxy)-1,4-oxazepane-4-carboxylate(14D)

[0731] tert-butyl(2S,6R)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-(trifluoromethoxy)-1,4-oxazepane-4-carboxylate(14D)

[0732] Dissolve 14C (55 mg, 0.18 mmol) in dichloromethane (5 mL), add intermediate 2 (61 mg, 0.20 mmol), DIPEA (47 mg, 0.36 mmol), HATU (100 mg, 0.27 mmol), react at room temperature for 1 hour, concentrate to dryness, and purify by column chromatography (PE:EA = 10:1 - 2:1) to obtain white solid 14D (85 mg, 78.3%).

[0733] LCMS m / z = 567.2 [M+1 - 56] +

[0734] Step 5: (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(trifluoromethoxy)-1,4-oxazepane-2-carboxamide (Compound 14)

[0735] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(trifluoromethoxy)-1,4-oxazepane-2-carboxamide (compound 14)

[0736] Dissolve 14D (85 mg, 0.14 mmol) in formic acid (2 mL), react at 50 °C for 0.5 hour, add sodium bicarbonate to adjust pH = 7 - 8, add water (30 mL), extract with DCM (20 mL x 3), wash with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (DCM:MeOH = 40:1 - 10:1) to obtain the title compound 14 (30 mg, yield 41.02%).

[0737] LCMS m / z = 523.1 [M+1] +

[0738] 11H NMR (400 MHz, CDCl3) δ 7.39 - 7.31 (m, 2H), 7.29 - 7.25 (m, 2H), 7.14 - 7.11 (m, 2H), 5.20 - 5.14 (m, 1H), 4.56 - 4.53 (m, 1H), 4.30 - 4.19 (m, 2H), 3.86 - 3.81 (m, 1H), 3.53 - 3.49 (m, 1H), 3.46 (s, 3H), 3.27 - 3.17 (m, 4H), 2.88 - 2.82 (m, 1H).

[0739] Example 15

[0740] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(trifluoromethoxy)-1,4-oxazepane-2-carboxamide (Compound 15)

[0741] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(trifluoromethoxy)-1,4-oxazepane-2-carboxamide (compound 15)

[0742]

[0743] Step 1: tert-butyl (2S,6R)-2-((benzyloxy)methyl)-6-(difluoromethoxy)-1,4-oxazepane-4-carboxylate (15A)

[0744] tert-butyl (2S,6R)-2-((benzyloxy)methyl)-6-(difluoromethoxy)-1,4-oxazepane-4-carboxylate (15A)

[0745] Dissolve INT-3 (300 mg, 0.89 mmol) in acetonitrile (5 mL), add copper(I) iodide (339 mg, 1.78 mmol), heat to 50 °C under nitrogen protection, slowly dropwise add 2-fluorosulfonyldifluoroacetic acid (317 mg, 1.78 mmol). After addition, stir the reaction mixture at 50 °C for 2 hours. Let it cool to room temperature naturally, then pour the reaction solution into ammonia water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to obtain the crude product, and purify by column chromatography to obtain a colorless oil 15A (80 mg, 23.2%).

[0746] LCMS m / z = 332.1 [M+1 - 56] +

[0747] Step 2: (2S,6R)-tert-butyl 2-(hydroxymethyl)-6-(difluoromethoxy)-1,4-oxazepane-4-carboxylate (15B)

[0748] (2S,6R)-tert-butyl 2-(hydroxymethyl)-6-(difluoromethoxy)-1,4-oxazepane-4-carboxylate(15B)

[0749] Dissolve 15A (80 mg, 0.21 mmol) in methanol (10 mL), add palladium on carbon (0.1 g, 10%), after displacing hydrogen 3 times, react under a hydrogen atmosphere for 24 hours, then filter and concentrate to dryness to obtain a colorless oil 15B (50 mg, yield 80.1%).

[0750] LCMS m / z = 242.2 [M+1] +

[0751] Step 3: (2S,6R)-4-(tert-butoxycarbonyl)-6-(difluoromethoxy)-1,4-oxazepane-2-carboxylic acid (15C)

[0752] (2S,6R)-4-(tert-butoxycarbonyl)-6-(difluoromethoxy)-1,4-oxazepane-2-carboxylic acid(15C)

[0753] Dissolve 15B (50 mg, 0.17 mmol) in acetone (2.1 mL), add saturated sodium bicarbonate (1 mL), sodium bromide (1.75 mg, 0.017 mmol), Tempo (2.66 mg, 0.017 mmol), add trichloroisocyanuric acid (79 mg, 0.34 mmol) at 0 °C, react at room temperature for 16 hours, adjust the pH to 5 - 6 with dilute hydrochloric acid, add water (10 mL), extract with dichloromethane (10 mL * 3), wash with water (10 mL), wash with saturated sodium chloride (10 mL), dry over anhydrous sodium sulfate, and concentrate to dryness to obtain a yellow oil 15C (50 mg, yield 94.5%).

[0754] LCMS m / z = 312.2 [M+1]<* +

[0755] Step 4: (2S,6R)-tert-butyl 2-((((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-(difluoromethoxy)-1,4-oxazepane-4-carboxylate (15D)

[0756] tert-butyl(2S,6R)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-6-(difluoromethoxy)-1,4-oxazepane-4-carboxylate(15D)

[0757] Dissolve 15C (50 mg, 0.16 mmol) in dichloromethane (5 mL), add intermediate 2 (50 mg, 0.16 mmol), DIPEA (42 mg, 0.32 mmol), HATU (90 mg, 0.24 mmol), react at room temperature for 1 hour, concentrate to dryness, and purify by column chromatography (PE:EA = 10:1 - 2:1) to obtain white solid 15D (60 mg, 62.03%).

[0758] LCMS m / z = 549.2 [M+1-56] +

[0759] Step 5: (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(difluoromethoxy)-1,4-oxazepane-2-carboxamide (Compound 15)

[0760] (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(difluoromethoxy)-1,4-oxazepane-2-carboxamide (compound 15)

[0761] 15D (55 mg, 0.091 mmol) was dissolved in formic acid (2 mL), and the reaction was carried out at 50 °C for 0.5 h. Sodium bicarbonate was added to adjust the pH to 7 - 8, water (30 mL) was added, and it was extracted with DCM (20 mL × 3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH = 40:1 - 10:1) to obtain the title compound 15 (35 mg, yield 76.2%).

[0762] LCMS m / z = 505.1 [M + 1] +

[0763] 1 H NMR (400 MHz, CDCl3) δ 7.33 - 7.24 (m, 2H), 7.23 - 7.18 (m, 2H), 7.05 - 7.03 (m, 2H), 6.40 - 6.03 (m, 1H), 5.14 - 5.08 (m, 1H), 4.51 - 4.49 (m, 1H), 4.17 - 4.09 (m, 2H), 3.71 - 3.67 (m, 1H), 3.32 (s, 3H), 3.33 - 3.29 (m, 1H), 3.22 - 3.02 (m, 4H), 2.74 - 2.68 (m, 1H).

[0764] Example 16

[0765] N - ((S)-1 - cyano - 2 - (4 - (3 - methyl - 2 - oxo - 2,3 - dihydrobenzo[d]oxazol - 5 - yl)phenyl)ethyl)-1,4 - oxazepane - 7 - carboxamide (Compound 16)

[0766] N - ((S)-1 - cyano - 2 - (4 - (3 - methyl - 2 - oxo - 2,3 - dihydrobenzo[d]oxazol - 5 - yl)phenyl)ethyl)-1,4 - oxazepane - 7 - carboxamide

[0767]

[0768] The first step: 6 - (hydroxymethyl)tetrahydro - 2H - pyran - 3,4 - diol (16B)

[0769] 6 - (hydroxymethyl)tetrahydro - 2H - pyran - 3,4 - diol

[0770] In a 500 mL autoclave, kojic acid 16A (6.0 g, 42.22 mmol), 10% palladium on carbon (1.0 g), and methanol (200 mL) were added in sequence. The mixture was purged with hydrogen three times, pressurized to 3.0 MPa, heated to 130 °C, and stirred for reaction for 24 h. After cooling to room temperature, the palladium on carbon was filtered through diatomaceous earth, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (eluent: DCM / MeOH = 30 / 1) to obtain the title compound 16B, a colorless oil (5.0 g, yield 80%).

[0771] Step 2: 4-hydroxy-3-(2-oxoethoxy)butanal (16C)

[0772] 4-hydroxy-3-(2-oxoethoxy)butanal

[0773] In a 100 mL single-necked flask, compound 16B (6 g, 40.5 mmol) was dissolved in water (20 mL). A solution of sodium periodate (11.26 g, 52.65 mmol) in water (20 mL) was added dropwise to the reaction solution under an ice bath. After the addition was complete, the temperature was raised to room temperature and stirred for 17 h. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to obtain a colorless oily crude product 16C (5.9 g, yield 99.7%), which was directly used in the next step without purification.

[0774] Step 3: (4-benzyl-1,4-oxazepan-7-yl)methanol (16D)

[0775] (4-benzyl-1,4-oxazepan-7-yl)methanol

[0776] In a 100 mL single-necked flask, compound 16C (7.0 g, 47.9 mmol), benzylamine (3.85 g, 35.9 mmol), and methanol (200 mL) were added in sequence. Sodium cyanoborohydride (7.53 g, 120 mmol) was added in batches, and the mixture was stirred at room temperature for 17 h. The reaction solution was concentrated under reduced pressure to obtain a yellow crude product. The crude product was dissolved in dichloromethane (50 mL), washed twice with water (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was subjected to flash column chromatography to obtain the title compound, a colorless oil 16D (8.0 g, yield 75.47%).

[0777] 11H NMR (400 MHz, CDCl3) δ 7.35 - 7.22 (m, 5H), 3.93 - 3.84 (m, 2H), 3.69 - 3.61 (m, 1H), 3.65 (s, 2H), 3.54 - 3.45 (m, 2H), 2.77 - 2.64 (m, 4H), 1.89 - 1.81 (m, 1H), 1.70 - 1.61 (m, 1H).

[0778] LCMS m / z = 222.2 [M+1] + .

[0779] Step 4: tert-butyl 7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (16E)

[0780] tert-butyl 7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate

[0781] In a 250 mL autoclave, successively add compound 16D (0.65 g, 2.94 mmol), 10% palladium on carbon (0.65 g), methanol (80 mL), di-tert-butyl dicarbonate (0.78 g, 3.6 mmol), triethylamine (0.45 g, 4.5 mmol). Replace with hydrogen three times, pressurize to 3.0 MPa, and stir the reaction at room temperature for 24 h. Filter the reaction solution through diatomaceous earth, concentrate under reduced pressure to obtain a yellow crude product. The crude product is purified by flash column chromatography (DCM / MeOH = 90 / 10) to obtain the title compound as a colorless oil 16E (0.4 g, yield 58.8%).

[0782] LCMS m / z = 132.2 [M - 100] + .

[0783] Step 5: 4-(tert-butoxycarbonyl)-1,4-oxazepane-7-carboxylic acid (16F)

[0784] 4-(tert-butoxycarbonyl)-1,4-oxazepane-7-carboxylic acid

[0785] At 0 °C, sodium bromide (62 mg, 0.6 mmol), TEMPO (100 mg, 0.06 mmol) and 16E (0.46 g, 2.0 mmol) were successively added to a mixed solution of acetone (7.5 mL) and saturated sodium bicarbonate (2.5 mL). 1,3,5-Trichloro-1,3,5-triazine-2,4,6-trione (1.02 g, 4.4 mmol) was added in batches, and the temperature was raised to room temperature and stirred for 18 h. Isopropanol (10 mL) was added to quench the reaction, and the mixture was stirred for 30 min. The insoluble matter was filtered through diatomaceous earth, and the solid was washed with ethyl acetate, concentrated under reduced pressure, redissolved in 1 M sodium carbonate solution (20 mL), and extracted with ethyl acetate (80 mL). The aqueous phase was acidified with 2 M HCl (20 mL) and extracted with dichloromethane (80 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 16F as a colorless oil (0.49 g, yield 77.5%)

[0786] LCMS m / z = 146.1 [M-99] + .

[0787] Step 6: tert-butyl 7-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (16H)

[0788] tert-butyl 7-(((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

[0789] To a 50 mL single-necked flask were successively added 16F (220 mg, 0.88 mmol), DMF (6 mL), DIPEA (180 mg, 1.36 mmol), HATU (280 mg, 0.75 mmol), and INT-1 (200 mg, 0.68 mmol), and the mixture was stirred at room temperature for 3 h. Saturated aqueous sodium bicarbonate (30 mL) was added to the reaction to quench the reaction, and the mixture was extracted and allowed to stand for phase separation. The aqueous phase was washed with dichloromethane (100 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was obtained as a crude product, and the crude product was separated by column chromatography (eluent: EA / PE = 1 / 2) to obtain the title compound 16H (210 mg).

[0790] LC-MS (ESI): m / z = 421.1 [M-99] + .

[0791] Step 7: N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-7-carboxamide (Compound 16)

[0792] N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-7-carboxamide

[0793] Compound 16H (110 mg, 0.61 mmol) and formic acid (6 mL) were stirred at room temperature for 2 h. After monitoring the completion of the reaction by LCMS, formic acid was concentrated under reduced pressure to obtain a crude yellow oil. The crude product was dissolved in 10% aqueous sodium bicarbonate solution and extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by flash column chromatography (eluent: DCM / MeOH = 20 / 1) to obtain the title compound 16 (60 mg, yield 74.3%).

[0794] 1 H NMR (400 MHz, DMSO-d6) δ 8.65 - 8.63 (m, 1H), 7.65 - 7.63 (m, 2H), 7.57 - 7.56 (m, 1H), 7.42 - 7.36 (m, 4H), 5.06 - 5.00 (m, 1H), 4.16 - 4.11 (m, 1H), 3.82 - 3.77 (m, 1H), 3.58 - 3.52 (m, 1H), 3.46 - 3.41 (m, 1H), 3.40 (s, 3H), 3.19 - 3.16 (m, 2H), 2.82 - 2.67 (m, 3H), 2.66 - 2.53 (m, 1H), 2.02 - 1.95 (m, 1H), 1.63 - 1.54 (m, 1H).

[0795] LCMS m / z = 421.2 [M+1] + .

[0796] Examples 17 and 18

[0797] (2S,6S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(methylamino)-1,4-oxazepane-2-carboxamide and (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(methylamino)-1,4-oxazepane-2-carboxamide (Compound 17 and Compound 18)

[0798] (2S,6S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(methylamino)-1,4-oxazepane-2-carboxamide and(2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(methylamino)-1,4-oxazepane-2-carboxamide(Compound 17and Compound 18)

[0799]

[0800] Step 1: (2S,6R)-4-(tert-butyl)-2-methyl-6-((tert-butyldimethylsilyl)oxy)-1,4-oxazepane-2,4-dicarboxylate (17A)

[0801] Dissolve 3B (3.75 g, 10 mmol) in acetonitrile (30 mL), add potassium carbonate (4.14 g, 30 mmol) and methyl iodide (4.23 g, 30 mmol), react at 80 °C for 4 h, filter after cooling, add water (30 mL) to the filtrate, extract with EA (60 mL x 3), wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to obtain Compound 17A (2.65 g).

[0802] Step 2: (2S,6R)-4-tert-butyl 2-methyl 6-hydroxy-1,4-oxazepane-2,4-dicarboxylate (17B)

[0803] (2S,6R)-4-tert-butyl 2-methyl 6-hydroxy-1,4-oxazepane-2,4-dicarboxylate

[0804] Dissolve 17A (1.0 g, 2.57 mmol) in tetrahydrofuran (20 mL), add a tetrahydrofuran solution of TBAF (5 mL, 1.0 mol / L), react at room temperature for 3 h, add water (30 mL), extract with EA (20 mL×3), wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to obtain compound 17B (0.65 g, yield 92.8%).

[0805] Step 3: (S)-4-tert-butyl 2-methyl 6-oxo-1,4-oxazepane-2,4-dicarboxylate (17C)

[0806] (S)-4-tert-butyl 2-methyl 6-oxo-1,4-oxazepane-2,4-dicarboxylate

[0807] Dissolve 17B (0.5 g, 1.82 mmol) in dichloromethane (15 mL), add Dess-Martin reagent (1.5 g, 3.64 mmol), react at room temperature for 1 h, filter, concentrate to dryness, and purify by column chromatography (PE:EA = 5:1 - 2:1) to obtain compound 17C (0.62 g, yield 96.9%).

[0808] Step 4: (2S)-4-tert-butyl 2-methyl 6-(methylamino)-1,4-oxazepane-2,4-dicarboxylate (17D)

[0809] (2S)-4-tert-butyl 2-methyl 6-(methylamino)-1,4-oxazepane-2,4-dicarboxylate

[0810] Dissolve 17C (0.5 g, 1.70 mmol) in DCM (10 mL), successively add methylamine (0.26 g, 8.50 mmol) and acetic acid (0.05 g, 0.85 mmol). Under nitrogen protection, after reacting at room temperature for 16 hours, add sodium triacetoxyborohydride (1.10 g, 5.1 mmol). After reacting at room temperature for 1 h, 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, and purify by column chromatography (DCM:MeOH = 20:1 - 8:1) to obtain compound 17D (0.31 g, yield 59.6%).

[0811] LCMS m / z = 289.2 [M+1] +

[0812] Step 5: (2S)-4-tert-butyl 2-methyl 6-((tert-butoxycarbonyl)(methyl)amino)-1,4-oxazepane-2,4-dicarboxylate (17E)

[0813] (2S)-4-tert-butyl 2-methyl 6-((tert-butoxycarbonyl)(methyl)amino)-1,4-oxazepane-2,4-dicarboxylate

[0814] Dissolve 17D (0.12 g, 0.42 mmol) in dichloromethane (10 mL), add triethylamine (0.13 g, 1.26 mmol) and di-tert-butyl dicarbonate (0.18 g, 0.84 mmol). After reacting at room temperature for 3 h, concentrate to dryness and purify by column chromatography (PE:EA = 10:1 - 2:1) to obtain compound 17E (0.10 g, yield 61.3%).

[0815] Step 6: (2S)-4-(tert-butoxycarbonyl)-6-((tert-butoxycarbonyl)(methyl)amino)-1,4-oxazepane-2-carboxylic acid (17F)

[0816] (2S)-4-(tert-butoxycarbonyl)-6-((tert-butoxycarbonyl)(methyl)amino)-1,4-oxazepane-2-carboxylic acid

[0817] Dissolve 17E (0.2 g, 0.52 mmol) in methanol (10 mL), add lithium hydroxide (0.06 g, 2.60 mmol) and water (2 mL), react at room temperature for 3 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, and obtain compound 17F (0.13 g, yield 67.8%).

[0818] Step 7: (2S)-tert-butyl 6-((tert-butoxycarbonyl)(methyl)amino)-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 (17G)

[0819] (2S)-tert-butyl 6-((tert-butoxycarbonyl)(methyl)amino)-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

[0820] Dissolve 17F (0.2 g, 0.73 mmol) in dichloromethane (10 mL), add INT-2 (0.23 g, 0.73 mmol), DIPEA (0.28 g, 2.19 mmol), HATU (0.36 g, 0.95 mmol), react at room temperature for 1 hour, concentrate to dryness, and purify by column chromatography (PE:EA = 10:1 - 2:1) to obtain compound 17G (0.21 g, yield 50.6%).

[0821] LCMS m / z = 512.2 [M + 1] +

[0822] Step 8: (2S,6S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(methylamino)-1,4-oxazepane-2-carboxamide and (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(methylamino)-1,4-oxazepane-2-carboxamide (Compound 17 and Compound 18)

[0823] (2S,6S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(methylamino)-1,4-oxazepane-2-carboxamide and (2S,6R)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-6-(methylamino)-1,4-oxazepane-2-carboxamide

[0824] Dissolve 17G (0.31 g, 0.46 mmol) in acetonitrile (10 mL), add p-toluenesulfonic acid (0.35 g, 2.04 mmol), react at 50 °C for 2 h, concentrate to dryness, and purify by column chromatography (DCM:MeOH:Et3N = 40:1:0.1 - 10:1:0.1) to obtain compound 17 (0.03 g, yield 13.8%) and compound 18 (0.02 g, yield 9.2%).

[0825] Compound 17: LCMS m / z = 468.2 [M+1] + , 1 H NMR (400 MHz, DMSO-d6) δ 8.97 - 8.95 (m, 1H), 7.66 - 7.39 (m, 6H), 5.09 - 5.03 (m, 1H), 4.23 - 4.19 (m, 1H), 4.01 - 3.92 (m, 2H), 3.41 (s, 3H), 3.32 - 3.17 (m, 6H), 3.06 - 3.01 (m, 1H), 2.67 - 2.63 (m, 1H), 2.58 - 2.52 (m, 2H).

[0826] Compound 18: LCMS m / z = 468.2 [M+1] + , 1H NMR (400 MHz, DMSO-d6) δ 9.06 - 9.04 (m, 1H), 7.68 - 7.32 (m, 6H), 5.07 - 5.01 (m, 1H), 4.26 - 4.22 (m, 1H), 4.13 - 4.10 (m, 1H), 4.00 - 3.96 (m, 1H), 3.41 (s, 3H), 3.34 - 3.25 (m, 6H), 2.83 - 2.68 (m, 2H), 2.55 - 2.53 (m, 2H).

[0827] Example 19

[0828] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1'-methyl-2-oxospiro[indoline-3,4'-piperidin]-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 19)

[0829] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1'-methyl-2-oxospiro[indoline-3,4'-piperidin]-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 19)

[0830]

[0831] First step: tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(1'-methyl-2-oxospiro[indoline-3,4'-piperidin]-5-yl)phenyl)ethyl)carbamate (19B)

[0832] tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(1'-methyl-2-oxospiro[indoline-3,4'-piperidin]-5-yl)phenyl)ethyl)carbamate (19B)

[0833] Dissolve INT-4 (1.5 g, 3.84 mmol) in 1,4-dioxane (15 mL) and water (1 mL), add 1A (1.25 g, 4.22 mmol, the preparation method refers to WO2008077811), potassium carbonate (1.59 g, 11.52 mmol), palladium acetate (0.17 g, 0.77 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (0.73 g, 1.54 mmol). After adding, react at 100 °C for 3 h. Cool to room temperature, add saturated brine (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (methylene chloride:methanol (v / v) = 8:1) to obtain the title compound 19B (0.45 g, 24%).

[0834] LC-MS (ESI): m / z = 479.2 [M+H] + .

[0835] Step 2: (S)-2-amino-3-(2-fluoro-4-(1'-methyl-2-oxospiro[indoline-3,4'-piperidin]-5-yl)phenyl)propane nitrile (19C)

[0836] (S)-2-amino-3-(2-fluoro-4-(1'-methyl-2-oxospiro[indoline-3,4'-piperidin]-5-yl)phenyl)propane nitrile(19C)

[0837] 19B (0.45 g, 0.94 mmol) was added to formic acid (5 ml), and the reaction was carried out at room temperature for 16 h. The reaction solution was dropped into an aqueous sodium bicarbonate solution, adjusted to pH = 7 - 8, extracted with dichloromethane:methanol = 10:1 (20 ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 19C (0.35 g, 93%).

[0838] LC-MS (ESI): m / z = 379.2 [M + H] + .

[0839] Step 3: tert-butyl (S)-2-((((S)-1-cyano-2-(2-fluoro-4-(1'-methyl-2-oxospiro[indoline-3,4'-piperidin]-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (19D)

[0840] 19C (350 mg, 0.92 mmol) was dissolved in N,N-dimethylformamide (5 ml), and (S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (0.23 g, 0.92 mmol, the preparation method refers to WO2015110826), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.42 g, 1.1 mmol), and N,N-diisopropylethylamine (0.36 g, 2.76 mmol) were added, and the reaction was carried out at room temperature for 3 h. Saturated brine (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v)=8:1) to obtain the title compound 19D (0.24 g, 43%).

[0841] LC-MS (ESI): m / z = 606.3 [M+H] + .

[0842] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1'-methyl-2-oxospiro[indoline-3,4'-piperidin]-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound 19)

[0843] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(1'-methyl-2-oxospiro[indoline-3,4'-piperidin]-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (compound 19)

[0844] 19D (240 mg, 0.4 mmol) was added to formic acid (5 ml), and the reaction was carried out at room temperature for 16 h. The reaction solution was dropped into an aqueous sodium bicarbonate solution, adjusted to pH = 7 - 8, extracted with dichloromethane:methanol = 10:1 (20 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative HPLC to obtain compound 19 (100 mg, 50%). Preparative HPLC separation method: 1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm×250 mm) 2. The sample was dissolved in DMF, filtered through a 0.45 μm filter head to prepare a sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% ammonia water); b. Gradient elution, the content of mobile phase A ranged from 5% - 50%; c. Flow rate 12 mL / min; d. Elution time 20 min. Retention time: 8.5 min.

[0845] 1 H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 8.67 (d, 1H), 7.69 (d, 1H), 7.53–7.37 (m, 4H), 6.92 (d, 1H), 5.04 (q, 1H), 4.00 (dd, 1H), 3.90–3.82 (m, 1H), 3.75 - 3.70 (m, 1H), 3.29–3.25 (m, 2H), 3.20–3.15 (m, 1H), 3.05 (dd, 1H), 2.82–2.72 (m, 3H), 2.65–2.52 (m, 4H), 2.30 (s, 3H), 1.86–1.66 (m, 6H).

[0846] LC-MS (ESI): m / z = 506.3 [M + H] + .

[0847] Biological test

[0848] In vitro DPP1 enzyme activity detection experiment

[0849] Recombinant human DPP1 enzyme (R&D Systems, Cat. No 1071-CY) at a final concentration of 100 μg / mL was mixed with recombinant human cathepsin L (R&D System, Cat. No 952-CY) at a final concentration of 20 μg / mL and incubated at room temperature for 1 hour to activate the DPP1 enzyme. The activated DPP1 enzyme was diluted 100-fold. 5 μL of compounds at different concentrations and 5 μL of the diluted DPP1 enzyme were added to a 384-well plate and incubated at room temperature for 30 minutes. After adding 10 μL of the substrate Gly-Arg-AMC (bachem, Cat. No I-1215) at a concentration of 20 μM, incubation was continued at room temperature for 60 minutes, and the fluorescence intensity was detected with a microplate reader, where the excitation light was 380 nm and the emission light was 460 nm. The IC 50 value was calculated using the DosResp function of Origin2019 software.

[0850] Test results: The compounds of the present invention showed inhibitory activity against the DPP1 receptor. The IC50 values of the example compounds for the DPP1 receptor were within the range of less than 100 nM. Among them, the test results of some examples are shown in Table 1.

[0851] Table 1 DPP1 inhibitory activity

[0852] Compound Number <![CDATA[IC 50 / nM]]> INS1007 5.0 Compound 3 0.4 Compound 4 0.5 Compound 5 0.09 Compound 6 0.05 Compound 9 0.2 Compound 11 0.5 Compound 15 4.5 Compound 19 0.6

[0853] Conclusion: The compounds of the present invention showed high inhibitory activity against the DPP1 receptor.

Claims

1. A compound as shown below, or a pharmaceutically acceptable salt:

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from one of the following structures:

3. A pharmaceutical composition, wherein, Containing the compound or pharmaceutically acceptable salt according to any one of claims 1-2, and a pharmaceutically acceptable carrier and / or excipient.

4. Use of the compound or pharmaceutically acceptable salt according to any one of claims 1-2, or the composition according to claim 3, in the preparation of a medicament for treating a disease mediated by dipeptidyl peptidase 1.

5. The use according to claim 4, wherein, The disease is selected from chronic obstructive pulmonary disease, cystic fibrosis.

6. The use according to claim 4, wherein, The disease is selected from bronchiectasis, asthma, emphysema.

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