Indoline spiro-heterocyclic compounds, processes for their preparation and uses thereof

Abstract

This invention belongs to the field of pharmaceutical technology and discloses a class of spiroheterocyclic compounds of general formula (I), their pharmaceutically acceptable salts, or their stereoisomers. The invention also discloses a preparation method, a pharmaceutical composition containing a compound of general formula (I), the preparation method thereof, and the use of said compounds and pharmaceutical compositions in growth hormone deficiency-related diseases. Formula (I)

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and more specifically, to a class of spiroheterocyclic compounds used for growth hormone deficiency-related diseases. Background Technology

[0002] The main function of growth hormone (GH) is to promote body growth, maintain muscle matrix and length, and counteract insulin and anabolism. Growth hormone is secreted by the pituitary gland. If the pituitary gland fails to secrete enough growth hormone due to various factors, it can lead to various growth hormone deficiency disorders, such as dwarfism, osteoporotic fractures, developmental delay (short stature) in children, or incomplete development of sexual organs. Currently, the main treatment for growth hormone deficiency is the injection of exogenous growth hormone or analogues; however, these drugs are expensive and treatment adherence is poor (requiring daily injections or 1-2 injections per week).

[0003] Besides exogenous growth hormone therapy, growth hormone deficiency can also be treated with growth hormone-releasing drugs. For example, the compound disclosed in patent CN1034733C (clinical trial compound code LUM-201) has a certain effect in promoting growth hormone release, but its bioavailability is low. The in vitro half-life of compound 1 disclosed in CN 114716504 A is still less than 40 minutes. Currently, there is an urgent clinical need for better small-molecule drugs that promote growth hormone release.

[0004]

[0005] This invention provides a novel spiroheterocyclic compound that, compared with existing technologies, exhibits stronger growth hormone release-promoting activity, especially higher bioavailability, and has promising clinical application prospects. Summary of the Invention

[0006] On the one hand, the present invention provides a spiroheterocyclic compound represented by formula (I),

[0007]

[0008] (I)

[0009] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts; wherein...

[0010] X is selected from CH2 or C (=O);

[0011] Z1, Z2, Z3, and Z4 are selected from N or CR7;

[0012] R1, R1', R2, and R2' are each independently selected from H, deuterium, C1-C6 alkyl groups optionally substituted with one or more halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups; or, R1 together with R1' or R2 together with R2' and the carbon atoms to which they are attached, forms a C3-C6 cycloalkyl group.

[0013] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, oxo groups, carboxyl groups, or ester groups.

[0014] Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, amino, oxo, carboxyl, or ester group.

[0015] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atom it is attached to, it forms a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group; x and y are each independently selected from 0, 1, 2 or 3;

[0016] R4 is selected from optionally substituted C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 12 cycloalkyl, C6- 14 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic; wherein the C1-C6 alkyl, C3-C 12 cycloalkyl, C6- 14 The aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclic groups are optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups;

[0017] R5 is selected from H, deuterium, and C1-C6 alkyl groups;

[0018] m and n are each independently selected from 1, 2, or 3;

[0019] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and -C(O)R each time they appear. c -C(O)OR c -OC(O) R c , amino, NR d R d';R c R d R d Each is independently selected from H, deuterium, or C1-C6 alkyl groups;

[0020] r is selected from 1, 2, 3, 4, or 5;

[0021] The condition is that when X is CH2, m is 2, n is 2, R3 and R3' are H, and Z1, Z2, Z3 and Z4 are selected from CR7, R4 is selected from any substituted C6- 14 Aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic.

[0022] In some embodiments, the compound of formula (I) provided by the present invention, or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts thereof,

[0023] X is selected from CH2 or C (=O);

[0024] Z1, Z2, Z3, and Z4 are selected from N or CR7;

[0025] R1, R1', R2, and R2' are each independently selected from H, deuterium, or C1-C6 alkyl groups optionally substituted with one or more halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups;

[0026] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, oxo groups, carboxyl groups, or ester groups.

[0027] Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, amino, oxo, carboxyl, or ester group.

[0028] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atom it is attached to, it forms a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group; x and y are each independently selected from 0, 1, 2 or 3;

[0029] R4 is selected from optionally substituted C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 12 cycloalkyl, C6- 14aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic; wherein the C1-C6 alkyl, C3-C 12 cycloalkyl, C6- 14 The aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclic groups are optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups;

[0030] R5 is selected from H, deuterium, and C1-C6 alkyl groups;

[0031] m and n are each independently selected from 1, 2, or 3;

[0032] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and -C(O)R each time they appear. c -C(O)OR c -OC(O) R c , amino, NR d R d ';R c R d R d Each is independently selected from H or C1-C6 alkyl groups;

[0033] r is selected from 1, 2, 3, 4, or 5;

[0034] The condition is that when X is CH2, m is 2, n is 2, R3 and R3' are H, and Z1, Z2, Z3 and Z4 are selected from CR7, R4 is selected from any substituted C6- 14 Aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic.

[0035] In some embodiments, the compound represented by formula (I) provided by the present invention is a compound represented by formula (I') and / or (I'').

[0036]

[0037] (I') (I'')

[0038] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts; wherein X, Z1, Z2, Z3, Z4, R1, R1', R2, R2', R3, R3', Y, R4, R5, m, n, R6, and r are as described above.

[0039] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (II).

[0040]

[0041] (II)

[0042] Or its stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, wherein X, Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, m, n, R6, and r are as defined above.

[0043] In some embodiments, the compound represented by formula (I) provided by the present invention is a compound represented by formula (II') and / or formula (II'').

[0044]

[0045] (II') (II'')

[0046] Or its stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, wherein X, Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, m, n, R6, and r are as defined above.

[0047] In some embodiments, the compounds represented by formulas (I), (I'), (I''), (II), (II'), (II'') provided in this invention, or their stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts,

[0048] X is selected from CH2 or C (=O);

[0049] Z1, Z2, Z3, and Z4 are selected from N or CR7;

[0050] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, oxo groups, carboxyl groups, or ester groups.

[0051] Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, amino, oxo, carboxyl, or ester group.

[0052] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R bTogether with the carbon atoms attached thereto, they form 3-6 membered cycloalkyl groups and 3-6 membered heterocyclic groups;

[0053] R4 is selected from optionally substituted C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 12 cycloalkyl, C6- 14 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic; wherein the C1-C6 alkyl, C3-C 12 cycloalkyl, C6- 14 The aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclic groups are optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups;

[0054] R5 is selected from H, deuterium, and C1-C6 alkyl groups;

[0055] m and n are each independently selected from 1, 2, or 3;

[0056] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and -C(O)R each time they appear. c -C(O)OR c -OC(O) R c , amino, NR d R d ';R c R d R d Each is independently selected from H, deuterium, or C1-C6 alkyl groups;

[0057] r is selected from 1, 2, 3, 4, or 5;

[0058] The condition is that when X is CH2, m is 2, n is 2, R3 and R3' are H, and Z1, Z2, Z3 and Z4 are selected from CR7, R4 is selected from any substituted C6- 14 Aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic.

[0059] In some embodiments, the compounds represented by formulas (I), (I'), (I''), (II), (II'), (II'') provided in this invention, or their stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts,

[0060] X is selected from CH2 or C (=O);

[0061] Z1, Z2, Z3, and Z4 are selected from N or CR7;

[0062] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups.

[0063] Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups;

[0064] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atoms attached thereto, they form 3-6 membered cycloalkyl groups and 3-6 membered heterocyclic groups;

[0065] R4 is selected from optionally substituted C1-C6 alkyl groups, C6- 14 aryl, 5 to 14-membered heteroaryl; wherein the C1-C6 alkyl, C6- 14 The aryl group and the 5- to 14-membered heteroaryl group are optionally substituted with one or more C1-C6 alkyl groups, C1-C6 alkoxy groups, halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups;

[0066] R5 is selected from H, deuterium, and C1-C6 alkyl groups;

[0067] m and n are each independently selected from 1, 2, or 3;

[0068] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and amino when they appear.

[0069] r is selected from 1, 2, 3, 4, or 5;

[0070] The condition is that when X is CH2, m is 2, n is 2, R3 and R3' are H, and Z1, Z2, Z3 and Z4 are selected from CR7, R4 is selected from any substituted C6- 14 Aryl, 5 to 14 heteroaryl groups.

[0071] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IIa).

[0072] (IIa)

[0073] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein X, Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0074] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IIb).

[0075] (IIb)

[0076] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein X, Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0077] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IIc).

[0078] (IIc)

[0079] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein X, Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0080] In some embodiments, the compound represented by formula (IIa) provided by the present invention is a compound represented by formula (IIa') or formula (IIa'').

[0081]

[0082] (IIa') (IIa'')

[0083] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein X, Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0084] In some embodiments, the compound represented by formula (IIb) provided by the present invention is a compound represented by formula (IIb') or formula (IIb'').

[0085]

[0086] (IIb') (IIb'')

[0087] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein X, Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0088] In some embodiments, the compound represented by formula (IIc) provided by the present invention is a compound represented by formula (IIc') or formula (IIc'').

[0089]

[0090] (IIc') (IIc'')

[0091] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein X, Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0092] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IId).

[0093] (IId)

[0094] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0095] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IIe).

[0096] (IIe)

[0097] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0098] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IIf).

[0099] (IIf)

[0100] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0101] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IIg).

[0102] (IIg)

[0103] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0104] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IIh).

[0105] (IIh)

[0106] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0107] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IIi).

[0108] (IIi)

[0109] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0110] In some embodiments, the compound represented by formula (IId) provided by the present invention is a compound represented by formula (IId') or formula (IId'').

[0111]

[0112] (IId') (IId'')

[0113] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0114] In some embodiments, the compound represented by formula (IIe) provided by the present invention is a compound represented by formula (IIe') or formula (IIe'').

[0115]

[0116] (IIe') (IIe'')

[0117] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0118] In some embodiments, the compound represented by formula (IIf) provided by the present invention is a compound represented by formula (IIf') and / or formula (IIf'').

[0119]

[0120] (IIf') (IIf'')

[0121] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0122] In some embodiments, the compound represented by formula (IIg) provided by the present invention is a compound represented by formula (IIg') or formula (IIg'').

[0123]

[0124] (IIg') (IIg'')

[0125] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0126] In some embodiments, the compound represented by formula (IIh) provided by the present invention is a compound represented by formula (IIh') or formula (IIh'').

[0127]

[0128] (IIh') (IIh'')

[0129] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0130] In some embodiments, the compound represented by formula (IIi) provided by the present invention is a compound represented by formula (IIi') or formula (IIi'').

[0131]

[0132] (IIi') (IIi'')

[0133] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined above.

[0134] In some embodiments, the compounds represented by formulas (I), (I'), (I''), (II), (II'), (II''), (IIa) to (IIi), (IIa') to (IIi'), (IIa'') to (IIi'') provided by the present invention, or their stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts,

[0135] Z1, Z2, Z3, and Z4 are selected from N or CR7;

[0136] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more halogens or hydroxyl groups;

[0137] Alternatively, R3, R3' together with the nitrogen atom to which they are attached can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl groups;

[0138] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, or R a R b Together with the carbon atom it is attached to, they form 3-6 membered cycloalkyl groups;

[0139] R4 is selected from optionally substituted C1-C6 alkyl groups, C6- 14 Aryl; wherein the C1-C6 alkyl, C6- 14 The aryl group may optionally be substituted with one or more C1-C6 alkyl groups, C1-C6 alkoxy groups, or halogens;

[0140] R5 is selected from H or deuterium;

[0141] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, and hydroxyl in each occurrence;

[0142] r can be selected from 1, 2, 3, 4 or 5.

[0143] In some embodiments, the compounds represented by formulas (I), (I'), (I''), (II), (II'), (II''), (IIa) to (IIi), (IIa') to (IIi'), (IIa'') to (IIi'') provided by the present invention, or their stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts,

[0144] Z1, Z2, Z3, and Z4 are selected from N or CR7;

[0145] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more halogens or hydroxyl groups;

[0146] Alternatively, R3, R3' together with the nitrogen atom to which they are attached form a 6-membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl groups;

[0147] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C3 alkyl, or R a R b Together with the carbon atoms attached to it, it forms cyclopropane rings and cyclobutane rings;

[0148] R4 is selected from optionally substituted C1-C3 alkyl or phenyl groups; wherein the C1-C3 alkyl or phenyl groups are optionally substituted with one or more C1-C3 alkyl groups, C1-C3 alkoxy groups, or halogens;

[0149] R5 is selected from H or deuterium;

[0150] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, and hydroxyl groups each time they appear;

[0151] r can be selected from 1, 2, 3, 4 or 5.

[0152] In some embodiments, the compounds represented by formula (I) provided by the present invention are compounds represented by formula (IIj), formula (IIk), formula (IIl), formula (IIm), formula (IIin), formula (IIo), formula (IIp), formula (IIq), formula (IIr), formula (IIs), formula (IIt), or formula (IIu).

[0153] (IIj) (IIk), (IIl) (IIm),

[0154] (IIn), (IIo) (IIp) (IIq)

[0155] (IIr), (IIs), (IIt), (IIu),

[0156] Or its stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, wherein R8 is selected from H or C1-C3 alkyl groups, and Z1, Z2, Z3, Z4, R3, R3', Y, R5, R6, and r are as defined above.

[0157] In some embodiments, the compound represented by formula (I) provided by the present invention is a compound represented by formula (IIj'), formula (IIj''), formula (IIk'), formula (IIk''), formula (IIl'), formula (IIl''), formula (IIm'), formula (IIm''), formula (IIIn'), formula (IIIn''), formula (IIo'), formula (IIo''), formula (IIp'), formula (IIp''), formula (IIq'), formula (IIq''), formula (IIr'), formula (IIr''), formula (IIs'), formula (IIs''), formula (IIt'), formula (IIt''), formula (IIu''), or formula (IIu'').

[0158] (IIj'), (IIj'') (IIk'), (IIk'') (IIl'), (IIl''), (IIm'), (IIm'')

[0159] (IIn'), (IIn''), (IIo'), (IIo'') (IIp') (IIp'') (IIq') (IIq'')

[0160] (IIr'), (IIr'') (IIs'), (IIs'') (IIt'), (IIt''), (IIu'), (IIu''),

[0161] Or its stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, wherein R8 is selected from H, deuterium, or C1-C3 alkyl, and Z1, Z2, Z3, Z4, R3, R3', Y, R5, R6, and r are as defined above.

[0162] In some embodiments, the compounds represented by formulas (IIj) to (IIu), (IIj') to (IIu'), (IIj'') to (IIu'') provided in this invention, or their stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, are used.

[0163] Z1, Z2, Z3, and Z4 are selected from N or CR7;

[0164] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more halogens or hydroxyl groups;

[0165] Alternatively, R3, R3' together with the nitrogen atom to which they are attached form a 6-membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C3 alkyl groups;

[0166] Y is selected from , where R a and R b Each is independently selected from H, deuterium, methyl, or R. a R b Together with the carbon atoms it is attached to, it forms a cyclopropane ring;

[0167] R5 is selected from H or deuterium;

[0168] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, and C1-C3 alkyl groups each time they appear;

[0169] r is selected from 1, 2, 3, 4, or 5;

[0170] R8 is selected from H, deuterium, or C1-C3 alkyl groups.

[0171] In some embodiments, the compounds represented by formulas (IIj) to (IIu), (IIj') to (IIu'), (IIj'') to (IIu'') provided in this invention, or their stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, are used.

[0172] Z1, Z2, Z3, and Z4 are selected from N or CR7;

[0173] R3 and R3' are each independently selected from H, deuterium, methyl, ethyl, propyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, propoxy, hydroxymethyl, 2-hydroxyethyl, and 2-hydroxypropyl.

[0174] Alternatively, R3, R3' together with the nitrogen atom they are attached to form a piperazine ring or a piperidine ring; wherein the piperazine ring or piperidine ring is optionally substituted with one or more methyl, ethyl, or propyl groups;

[0175] Y is selected from , where R a and R b Each is independently selected from H, deuterium, methyl, or R. a R b Together with the carbon atoms it is attached to, it forms a cyclopropane ring;

[0176] R5 is selected from H or deuterium;

[0177] R6 and R7 are each independently selected from hydrogen, deuterium, and halogen each time they appear;

[0178] r is selected from 1, 2, 3, 4, or 5;

[0179] R8 is selected from H, deuterium, or C1-C3 alkyl groups.

[0180] In some embodiments, the compound of formula (I) provided by the present invention, or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts thereof,

[0181] X is selected from CH2 or C (=O);

[0182] Z1, Z2, Z3, and Z4 are selected from N or CR7, and at least one of Z1, Z2, Z3, and Z4 is N;

[0183] R1, R1', R2, and R2' are each independently selected from H, deuterium, C1-C6 alkyl groups optionally substituted with one or more halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups; or, R1 together with R1' or R2 together with R2' and the carbon atoms to which they are attached, forms a C3-C6 cycloalkyl group.

[0184] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, oxo groups, carboxyl groups, or ester groups.

[0185] Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, amino, oxo, carboxyl, or ester group.

[0186] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atom it is attached to, it forms a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group; x and y are each independently selected from 0, 1, 2 or 3;

[0187] R4 is selected from optionally substituted C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 12 cycloalkyl, C6- 14 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic; wherein the C1-C6 alkyl, C3-C 12 cycloalkyl, C6- 14 The aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclic groups are optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups;

[0188] R5 is selected from H, deuterium, and C1-C6 alkyl groups;

[0189] m and n are each independently selected from 1, 2, or 3;

[0190] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and -C(O)R each time they appear. c -C(O)OR c -OC(O) R c , amino, NRd R d ';R c R d R d Each is independently selected from H, deuterium, or C1-C6 alkyl groups;

[0191] r can be selected from 1, 2, 3, 4 or 5.

[0192] In some embodiments, the compound of formula (I) provided by the present invention, or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts thereof,

[0193] X is selected from CH2 or C (=O);

[0194] Z1, Z2, Z3, and Z4 are selected from N or CR7, and at least one of Z1, Z2, Z3, and Z4 is N;

[0195] R1, R1', R2, and R2' are each independently selected from H, deuterium, or C1-C6 alkyl groups optionally substituted with one or more halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups;

[0196] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, oxo groups, carboxyl groups, or ester groups.

[0197] Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, amino, oxo, carboxyl, or ester group.

[0198] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atom it is attached to, it forms a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group; x and y are each independently selected from 0, 1, 2 or 3;

[0199] R4 is selected from optionally substituted C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 12 cycloalkyl, C6- 14 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic; wherein the C1-C6 alkyl, C3-C 12 cycloalkyl, C6- 14The aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclic groups are optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups;

[0200] R5 is selected from H, deuterium, and C1-C6 alkyl groups;

[0201] m and n are each independently selected from 1, 2, or 3;

[0202] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and -C(O)R each time they appear. c -C(O)OR c -OC(O) R c , amino, NR d R d ';R c R d R d Each is independently selected from H, deuterium, or C1-C6 alkyl groups;

[0203] r can be selected from 1, 2, 3, 4 or 5.

[0204] In some embodiments, in the compounds represented by formulas (I'), (I''), (II), (II'), and (II'') provided by the present invention, or their stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, Z1, Z2, Z3, and Z4 are selected from N or CR7, and at least one of Z1, Z2, Z3, and Z4 is N, and X, R1, R1', R2, R2', R3, R3', Y, R4, R5, m, n, R6, and r are as described above.

[0205] In some embodiments, the compounds represented by formulas (I'), (I''), (II), (II'), and (II'') provided in this invention, or their stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, are used.

[0206] X is selected from CH2 or C (=O);

[0207] Z1, Z2, Z3, and Z4 are selected from N or CR7, and at least one of Z1, Z2, Z3, and Z4 is N;

[0208] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, oxo groups, carboxyl groups, or ester groups.

[0209] Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, amino, oxo, carboxyl, or ester group.

[0210] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atoms attached thereto, they form 3-6 membered cycloalkyl groups and 3-6 membered heterocyclic groups;

[0211] R4 is selected from optionally substituted C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 12 cycloalkyl, C6- 14 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic; wherein the C1-C6 alkyl, C3-C 12 cycloalkyl, C6- 14 The aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclic groups are optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups;

[0212] R5 is selected from H, deuterium, and C1-C6 alkyl groups;

[0213] m and n are each independently selected from 1, 2, or 3;

[0214] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and -C(O)R each time they appear. c -C(O)OR c -OC(O) R c , amino, NR d R d ';R c R d R d Each is independently selected from H or C1-C6 alkyl groups;

[0215] r can be selected from 1, 2, 3, 4 or 5.

[0216] In some embodiments, the compounds represented by formulas (I'), (I''), (II), (II'), and (II'') provided in this invention, or their stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts,

[0217] X is selected from CH2 or C (=O);

[0218] Z1, Z2, Z3, and Z4 are selected from N or CR7, and at least one of Z1, Z2, Z3, and Z4 is N;

[0219] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups.

[0220] Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups;

[0221] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atoms attached thereto, they form 3-6 membered cycloalkyl groups and 3-6 membered heterocyclic groups;

[0222] R4 is selected from optionally substituted C1-C6 alkyl groups, C6- 14 aryl, 5 to 14-membered heteroaryl; wherein the C1-C6 alkyl, C6- 14 The aryl group and the 5- to 14-membered heteroaryl group are optionally substituted with one or more C1-C6 alkyl groups, C1-C6 alkoxy groups, halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups;

[0223] R5 is selected from H, deuterium, and C1-C6 alkyl groups;

[0224] m and n are each independently selected from 1, 2, or 3;

[0225] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and amino when they appear.

[0226] r can be selected from 1, 2, 3, 4 or 5.

[0227] In some embodiments, among the compounds of formulas (IIa) to (IIi), (IIa') to (IIi'), (IIa'') to (IIi'') provided by the present invention, or their stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, Z1, Z2, Z3, and Z4 are selected from N or CR7, and at least one of Z1, Z2, Z3, and Z4 is N, and X, R3, R3', Y, R4, R5, R6, and r are as described above.

[0228] In some embodiments, the compounds represented by formulas (IIa) to (IIi), (IIa') to (IIi'), (IIa'') to (IIi'') provided in this invention, or their stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts,

[0229] Z1, Z2, Z3, and Z4 are selected from N or CR7, and at least one of Z1, Z2, Z3, and Z4 is N;

[0230] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more halogens or hydroxyl groups;

[0231] Alternatively, R3, R3' together with the nitrogen atom to which they are attached can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl groups;

[0232] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, or R a R b Together with the carbon atom it is attached to, they form 3-6 membered cycloalkyl groups;

[0233] R4 is selected from optionally substituted C1-C6 alkyl groups, C6- 14 Aryl; wherein the C1-C6 alkyl, C6- 14 The aryl group may optionally be substituted with one or more C1-C6 alkyl groups, C1-C6 alkoxy groups, or halogens;

[0234] R5 is selected from H or deuterium;

[0235] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, and hydroxyl in each occurrence;

[0236] r can be selected from 1, 2, 3, 4 or 5.

[0237] In some embodiments, the compounds represented by formulas (IIa) to (IIi), (IIa') to (IIi'), (IIa'') to (IIi'') provided in this invention, or their stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts,

[0238] Z1, Z2, Z3, and Z4 are selected from N or CR7, and at least one of Z1, Z2, Z3, and Z4 is N;

[0239] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more halogens or hydroxyl groups;

[0240] Alternatively, R3, R3' together with the nitrogen atom to which they are attached form a 6-membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl groups;

[0241] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C3 alkyl, or R a R b Together with the carbon atoms attached to it, it forms cyclopropane rings and cyclobutane rings;

[0242] R4 is selected from optionally substituted C1-C3 alkyl or phenyl groups; wherein the C1-C3 alkyl or phenyl groups are optionally substituted with one or more C1-C3 alkyl groups, C1-C3 alkoxy groups, or halogens;

[0243] R5 is selected from H or deuterium;

[0244] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, and hydroxyl groups each time they appear;

[0245] r can be selected from 1, 2, 3, 4 or 5.

[0246] In some embodiments, in the compounds represented by formulas (IIj), (IIk), (IIl), (IIm), (IIin), (IIo), (IIp), (IIq), (IIr), (IIs), (IIt), or (IIu) provided by the present invention, R8 is selected from H or C1-C3 alkyl, Z1, Z2, Z3, and Z4 are selected from N or CR7, and at least one of Z1, Z2, Z3, and Z4 is N, and R3, R3', Y, R5, R6, and r are as defined above.

[0247] In some embodiments, in the compounds of formulas (IIj'), (IIj''), (IIk'), (IIk''), (IIl'), (IIl''), (IIm'), (IIm''), (IIIn'), (IIIn''), (IIo'), (IIo''), (IIp'), (IIp''), (IIq'), (IIq''), (IIr'), (IIr''), (IIs'), (IIs''), (IIt'), (IIt''), (IIu''), or (IIu'') provided by the present invention, or their stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, R8 is selected from H, deuterium or C1-C3 alkyl, Z1, Z2, Z3, Z4 are selected from N or CR7, and at least one of Z1, Z2, Z3, Z4 is N, and R3, R3', Y, R5, R6, r are as defined above.

[0248] In some embodiments, the compounds represented by formulas (IIj) to (IIu), (IIj') to (IIu'), (IIj'') to (IIu'') provided in this invention, or their stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, are used.

[0249] Z1, Z2, Z3, and Z4 are selected from N or CR7, and at least one of Z1, Z2, Z3, and Z4 is N;

[0250] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more halogens or hydroxyl groups;

[0251] Alternatively, R3, R3' together with the nitrogen atom to which they are attached form a 6-membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C3 alkyl groups;

[0252] Y is selected from , where R a and R b Each is independently selected from H, deuterium, methyl, or R. a R b Together with the carbon atoms it is attached to, it forms a cyclopropane ring;

[0253] R5 is selected from H or deuterium;

[0254] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, and C1-C3 alkyl groups each time they appear;

[0255] r is selected from 1, 2, 3, 4, or 5;

[0256] R8 is selected from H, deuterium, or C1-C3 alkyl groups.

[0257] In some embodiments, the compounds represented by formulas (IIj) to (IIu), (IIj') to (IIu'), (IIj'') to (IIu'') provided in this invention, or their stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, are used.

[0258] Z1, Z2, Z3, and Z4 are selected from N or CR7, and at least one of Z1, Z2, Z3, and Z4 is N;

[0259] R3 and R3' are each independently selected from H, deuterium, methyl, ethyl, propyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, propoxy, hydroxymethyl, 2-hydroxyethyl, and 2-hydroxypropyl.

[0260] Alternatively, R3, R3' together with the nitrogen atom they are attached to form a piperazine ring or a piperidine ring; wherein the piperazine ring or piperidine ring is optionally substituted with one or more methyl, ethyl, or propyl groups;

[0261] Y is selected from , where R a and R b Each is independently selected from H, deuterium, methyl, or R. a R b Together with the carbon atoms it is attached to, it forms a cyclopropane ring;

[0262] R5 is selected from H or deuterium;

[0263] R6 and R7 are each independently selected from hydrogen, deuterium, and halogen each time they appear;

[0264] r is selected from 1, 2, 3, 4, or 5;

[0265] R8 is selected from H, deuterium, or C1-C3 alkyl groups.

[0266] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (III).

[0267]

[0268] (III)

[0269] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts; wherein...

[0270] X is selected from CH2 or C (=O);

[0271] R1, R1', R2, and R2' are each independently selected from H, deuterium, C1-C6 alkyl groups optionally substituted with one or more halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups; or, R1 together with R1' or R2 together with R2' and the carbon atoms to which they are attached, forms a C3-C6 cycloalkyl group.

[0272] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, oxo groups, carboxyl groups, or ester groups.

[0273] Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, amino, oxo, carboxyl, or ester group.

[0274] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atom it is attached to, it forms a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group; x and y are each independently selected from 0, 1, 2 or 3;

[0275] R4 is selected from optionally substituted C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 12 cycloalkyl, C6- 14 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic; wherein the C1-C6 alkyl, C3-C 12 cycloalkyl, C6- 14 The aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclic groups are optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups;

[0276] R5 is selected from H, deuterium, and C1-C6 alkyl groups;

[0277] m and n are each independently selected from 1, 2, or 3;

[0278] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and -C(O)R each time they appear. c -C(O)OR c -OC(O) R c , amino, NR d R d';R c R d R d Each is independently selected from H, deuterium, or C1-C6 alkyl groups;

[0279] r is selected from 1, 2, 3, 4, or 5;

[0280] s is selected from 1, 2, 3, or 4;

[0281] The condition is that when X is CH2, m is 2, n is 2, and R3 and R3' are H, R4 is selected from any substituted C6- 14 Aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic.

[0282] In some embodiments, the compound of formula (III) provided by the present invention, or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts thereof,

[0283] X is selected from CH2 or C (=O);

[0284] R1, R1', R2, and R2' are each independently selected from H, deuterium, or C1-C6 alkyl groups optionally substituted with one or more halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups;

[0285] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, oxo groups, carboxyl groups, or ester groups.

[0286] Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, amino, oxo, carboxyl, or ester group.

[0287] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atom it is attached to, it forms a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group; x and y are each independently selected from 0, 1, 2 or 3;

[0288] R4 is selected from optionally substituted C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 12 cycloalkyl, C6- 14 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic; wherein the C1-C6 alkyl, C3-C 12cycloalkyl, C6- 14 The aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclic groups are optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups;

[0289] R5 is selected from H, deuterium, and C1-C6 alkyl groups;

[0290] m and n are each independently selected from 1, 2, or 3;

[0291] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and -C(O)R each time they appear. c -C(O)OR c -OC(O) R c , amino, NR d R d ';R c R d R d Each is independently selected from H or C1-C6 alkyl groups;

[0292] r is selected from 1, 2, 3, 4, or 5;

[0293] s is selected from 1, 2, 3, or 4;

[0294] The condition is that when X is CH2, m is 2, n is 2, and R3 and R3' are H, R4 is selected from any substituted C6- 14 Aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic.

[0295] In some embodiments, the compound represented by formula (I) provided by the present invention is a compound represented by formula (III') or formula (III'').

[0296]

[0297] (III') (III'')

[0298] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts; wherein X, R1, R1', R2, R2', R3, R3', Y, R4, R5, m, n, R6, R7, r, and s are as described above.

[0299] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IV).

[0300]

[0301] (IV)

[0302] Or its stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, wherein X, R3, R3', Y, R4, R5, m, n, R6, R7, r, and s are as defined above.

[0303] In some embodiments, the compound represented by formula (I) provided by the present invention is a compound represented by formula (IV') or formula (IV'').

[0304]

[0305] (IV') (IV'')

[0306] Or its stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, wherein X, R3, R3', Y, R4, R5, m, n, R6, R7, r, and s are as defined above.

[0307] In some embodiments, the compounds represented by formulas (III), (III'), (III''), (IV), (IV'), and (IV'') provided in this invention, or their stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts,

[0308] X is selected from CH2 or C (=O);

[0309] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, oxo groups, carboxyl groups, or ester groups.

[0310] Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, amino, oxo, carboxyl, or ester group.

[0311] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atoms attached thereto, they form 3-6 membered cycloalkyl groups and 3-6 membered heterocyclic groups;

[0312] R4 is selected from optionally substituted C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 12 cycloalkyl, C6- 14aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic; wherein the C1-C6 alkyl, C3-C 12 cycloalkyl, C6- 14 The aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclic groups are optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups;

[0313] R5 is selected from H, deuterium, and C1-C6 alkyl groups;

[0314] m and n are each independently selected from 1, 2, or 3;

[0315] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and -C(O)R each time they appear. c -C(O)OR c -OC(O) R c , amino, NR d R d ';R c R d R d Each is independently selected from H or C1-C6 alkyl groups;

[0316] r is selected from 1, 2, 3, 4, or 5;

[0317] s is selected from 1, 2, 3, or 4;

[0318] The condition is that when X is CH2, m is 2, n is 2, and R3 and R3' are H, R4 is selected from any substituted C6- 14 Aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic.

[0319] In some embodiments, the compounds represented by formulas (III), (III'), (III''), (IV), (IV'), and (IV'') provided in this invention, or their stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts,

[0320] X is selected from CH2 or C (=O);

[0321] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups.

[0322] Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups;

[0323] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atoms attached thereto, they form 3-6 membered cycloalkyl groups and 3-6 membered heterocyclic groups;

[0324] R4 is selected from optionally substituted C1-C6 alkyl groups, C6- 14 aryl, 5 to 14-membered heteroaryl; wherein the C1-C6 alkyl, C6- 14 The aryl group and the 5- to 14-membered heteroaryl group are optionally substituted with one or more C1-C6 alkyl groups, C1-C6 alkoxy groups, halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups;

[0325] R5 is selected from H, deuterium, and C1-C6 alkyl groups;

[0326] m and n are each independently selected from 1, 2, or 3;

[0327] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and amino when they appear.

[0328] r is selected from 1, 2, 3, 4, or 5;

[0329] s is selected from 1, 2, 3, or 4;

[0330] The condition is that when X is CH2, m is 2, n is 2, and R3 and R3' are H, R4 is selected from any substituted C6- 14 Aryl, 5 to 14 heteroaryl groups.

[0331] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IVa).

[0332] (IVa)

[0333] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein X, R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0334] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IVb).

[0335] (IVb)

[0336] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein X, R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0337] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IVc).

[0338] (IVc)

[0339] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein X, R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0340] In some embodiments, the compound represented by formula (IVa) provided by the present invention is a compound represented by formula (IVa') or formula (IVa'').

[0341]

[0342] (IVa') (IVa'')

[0343] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein X, R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0344] In some embodiments, the compound represented by formula (IVb) provided by the present invention is a compound represented by formula (IVb') or formula (IVb'').

[0345]

[0346] (IVb') (IVb'')

[0347] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein X, R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0348] In some embodiments, the compound represented by formula (IVc) provided by the present invention is a compound represented by formula (IVc') or formula (IVc'').

[0349]

[0350] (IVc') (IVc'')

[0351] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein X, R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0352] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IVd).

[0353] (IVd)

[0354] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0355] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IVe).

[0356] (IVe)

[0357] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0358] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IVf).

[0359] (IVf)

[0360] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0361] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IVg).

[0362] (IVg)

[0363] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0364] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IVh).

[0365] (IVh)

[0366] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0367] In some embodiments, the compound represented by formula (I) provided by the present invention is the compound represented by formula (IVi).

[0368] (IVi)

[0369] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0370] In some embodiments, the compound represented by formula (IVd) provided by the present invention is a compound represented by formula (IVd') or formula (IVd'').

[0371]

[0372] (IVd') (IVd'')

[0373] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0374] In some embodiments, the compound represented by formula (IVe) provided by the present invention is a compound represented by formula (IVe') or formula (IVe'').

[0375]

[0376] (IVe') (IVe'')

[0377] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0378] In some embodiments, the compound represented by formula (IVf) provided by the present invention is a compound represented by formula (IVf') or formula (IVf'').

[0379]

[0380] (IVf') (IVf'')

[0381] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0382] In some embodiments, the compound represented by formula (IVg) provided by the present invention is a compound represented by formula (IVg') or formula (IVg'').

[0383]

[0384] (IVg') (IVg'')

[0385] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0386] In some embodiments, the compound represented by formula (IVh) provided by the present invention is a compound represented by formula (IVh') or formula (IVh'').

[0387]

[0388] (IVh') (IVh'')

[0389] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0390] In some embodiments, the compound represented by formula (IVi) provided by the present invention is a compound represented by formula (IVi') or formula (IVi'').

[0391]

[0392] (IVi') (IVi'')

[0393] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein R3, R3', Y, R4, R5, R6, R7, r, and s are as defined above.

[0394] In some embodiments, the compounds represented by formulas (III), (III'), (III''), (IV), (IV'), (IV''), (IVa) to (IVi), (IVa') to (IVi'), (IVa'') to (IVi'') provided in this invention, or their stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts,

[0395] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more halogens or hydroxyl groups;

[0396] Alternatively, R3, R3' together with the nitrogen atom to which they are attached can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl groups;

[0397] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, or R a R b Together with the carbon atom it is attached to, they form 3-6 membered cycloalkyl groups;

[0398] R4 is selected from optionally substituted C1-C6 alkyl groups, C6- 14 Aryl; wherein the C1-C6 alkyl, C6- 14 The aryl group may optionally be substituted with one or more C1-C6 alkyl groups, C1-C6 alkoxy groups, or halogens;

[0399] R5 is selected from H or deuterium;

[0400] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, and hydroxyl in each occurrence;

[0401] r is selected from 1, 2, 3, 4, or 5;

[0402] s is selected from 1, 2, 3 or 4.

[0403] In some embodiments, the compounds represented by formulas (III), (III'), (III''), (IV), (IV'), (IV''), (IVa) to (IVi), (IVa') to (IVi'), (IVa'') to (IVi'') provided in this invention, or their stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts,

[0404] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more halogens or hydroxyl groups;

[0405] Alternatively, R3, R3' together with the nitrogen atom to which they are attached form a 6-membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl groups;

[0406] Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C3 alkyl, or R a R b Together with the carbon atoms attached to it, it forms cyclopropane rings and cyclobutane rings;

[0407] R4 is selected from optionally substituted C1-C3 alkyl or phenyl groups; wherein the C1-C3 alkyl or phenyl groups are optionally substituted with one or more C1-C3 alkyl groups, C1-C3 alkoxy groups, or halogens;

[0408] R5 is selected from H or deuterium;

[0409] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, and hydroxyl groups each time they appear;

[0410] r is selected from 1, 2, 3, 4, or 5;

[0411] s is selected from 1, 2, 3 or 4.

[0412] In some embodiments, the compounds represented by formula (I) provided by the present invention are compounds represented by formulas (IVj), (IVk), (IVl), (IVm), (IVn), (IVo), (IVp), (IVq), (IVr), (IVs), (IVt), and / or (IVu).

[0413] (IVj) (IVk) (IVl) (IVm),

[0414] (IVn) (IVo) (IVp) (IVq)

[0415] (IVr), (IVs) (IVt), (IVu),

[0416] Or its stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, wherein R8 is selected from H or C1-C3 alkyl groups, and R3, R3', Y, R5, R6, R7, r, and s are as defined above.

[0417] In some embodiments, the compounds represented by formula (I) provided by the present invention are compounds represented by formulas (IVj'), (IVj''), (IVk'), (IVk''), (IVl'), (IVl''), (IVm'), (IVm''), (IVn'), (IVn''), (IVo'), (IVo''), (IVp'), (IVp''), (IVq'), (IVq''), (IVr'), (IVr''), (IVs'), (IVs''), (IVt'), (IVt''), (IVu'), and / or (IVu'').

[0418] (IVj') (IVj'') (IVk') (IVk'') (IVl'), (IVl''), (IVm') (IVm'')

[0419] (IVn'), (IVn'') (IVo') (IVo'') (IVp') (IVp'') (IVq') (IVq'')

[0420] (IVr'), (IVr'') (IVs') (IVs'') (IVt') (IVt'') (IVu'), (IVu'')

[0421] Or its stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, wherein R8 is selected from H, deuterium, or C1-C3 alkyl groups, and R3, R3', Y, R5, R6, R7, r, and s are as defined above.

[0422] In some embodiments, the compounds represented by formulas (IVj) to (IVu), (IVj') to (IVu'), (IVj'') to (IVu'') provided in this invention, or their stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts,

[0423] R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more halogens or hydroxyl groups;

[0424] Alternatively, R3, R3' together with the nitrogen atom to which they are attached form a 6-membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C3 alkyl groups;

[0425] Y is selected from , where R a and R b Each is independently selected from H, deuterium, methyl, or R. a R b Together with the carbon atoms it is attached to, it forms a cyclopropane ring;

[0426] R5 is selected from H or deuterium;

[0427] R6 and R7 are each independently selected from hydrogen, deuterium, halogen, and C1-C3 alkyl groups each time they appear;

[0428] r is selected from 1, 2, 3, 4, or 5;

[0429] s is selected from 1, 2, 3, or 4;

[0430] R8 is selected from H, deuterium, or C1-C3 alkyl groups.

[0431] In some embodiments, the compounds represented by formulas (IVj) to (IVu), (IVj') to (IVu'), (IVj'') to (IVu'') provided in this invention, or their stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts,

[0432] R3 and R3' are each independently selected from H, deuterium, methyl, ethyl, propyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, propoxy, hydroxymethyl, 2-hydroxyethyl, and 2-hydroxypropyl.

[0433] Alternatively, R3, R3' together with the nitrogen atom they are attached to form a piperazine ring or a piperidine ring; wherein the piperazine ring or piperidine ring is optionally substituted with one or more methyl, ethyl, or propyl groups;

[0434] Y is selected from , where R a and R b Each is independently selected from H, deuterium, methyl, or R. a R b Together with the carbon atoms it is attached to, it forms a cyclopropane ring;

[0435] R5 is selected from H or deuterium;

[0436] R6 and R7 are each independently selected from hydrogen, deuterium, and halogen each time they appear;

[0437] r is selected from 1, 2, 3, 4, or 5;

[0438] s is selected from 1, 2, 3, or 4;

[0439] R8 is selected from H, deuterium, or C1-C3 alkyl groups.

[0440] In some specific embodiments, the compounds described in this invention include, but are not limited to, the following compounds:

[0441]

[0442]

[0443]

[0444]

[0445]

[0446] Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts.

[0447] On the other hand, the present invention provides a pharmaceutical composition comprising a compound represented by formula (I) according to the present invention, or a stereoisomer, tautomer, isotope label thereof, and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are known to those skilled in the art and include diluents, lubricants, disintegrants, binders, buffers, preservatives, stabilizers, wetting agents, flow aids, emulsifiers, colorants, flavoring agents, sweeteners, etc.

[0448] The pharmaceutical compositions of this invention are suitable for administration via any suitable route, such as oral (including sublingual or sublingual), rectal, nasal, topical (including sublingual, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal injection). Depending on the route of administration, such as oral, parenteral, or rectal administration, the pharmaceutical compositions of this invention can be formulated in solid form (including but not limited to tablets, capsules, pills, granules, powders, suppositories) or liquid form (including but not limited to solutions, suspensions, emulsions, tinctures, and syrups). When the pharmaceutical composition of the present invention is in solid form, the pharmaceutically acceptable carrier typically includes one or more of the following: a) a diluent, such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose, etc.; b) a lubricant, such as silica, talc, stearic acid and its salts (e.g., magnesium stearate, calcium stearate, etc.), polyethylene glycol, etc.; c) a binder, such as magnesium aluminosilicate, gelatinized starch, gelatin, astragalus gum, methylcellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, etc.; d) a disintegrant, such as starch, alginic acid, agar, corn starch; e) a stabilizer, such as an antioxidant like ascorbic acid; f) a flow aid, such as silica; g) a flavoring agent, such as peppermint, methyl salicylate; a sweetener, such as sucrose, saccharin. When the pharmaceutical composition of the present invention is in liquid form, the pharmaceutically acceptable carrier typically includes one or more of the following: a) a diluent, such as water for injection, physiological saline, Ringer's solution, polyethylene glycol, glycerin, propylene glycol, etc.; b) an antioxidant, such as ascorbic acid or sodium bisulfite; c) a buffer, such as acetate, phosphate, etc.

[0449] The effective dose of the compounds of the present invention depends at least on the nature and extent of the condition being treated, the method of delivery, and the pharmaceutical dosage form, and will be ultimately determined by the clinician. A dose of about 0.0001 to about 100 mg per kilogram of body weight per day is anticipated; typically about 0.01 to about 10 mg per kilogram of body weight per day; more typically, about 0.01 to about 5 mg per kilogram of body weight per day; and most typically, about 0.05 to about 0.5 mg per kilogram of body weight per day. For example, a candidate daily dose for an adult weighing about 70 kg would be in the range of 1 mg to 1000 mg, preferably in the range of 5 mg to 500 mg, and could be administered in single or multiple doses.

[0450] In another aspect, the present invention provides the compounds described herein or their stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts for the prevention and / or treatment of growth hormone-related diseases.

[0451] In some embodiments, the present invention provides the compounds described herein, or their stereoisomers, tautomers, isotope-labeled forms, and pharmaceutically acceptable salts, for the prevention and / or treatment of growth hormone-dependent diseases. In some embodiments, the present invention provides the compounds described herein, or their stereoisomers, tautomers, isotope-labeled forms, and pharmaceutically acceptable salts, for the prevention and / or treatment of diseases caused by growth hormone deficiency. In some embodiments, the present invention provides the compounds described herein, or their stereoisomers, tautomers, isotope-labeled forms, and pharmaceutically acceptable salts, for the prevention and / or treatment of diseases including dwarfism, osteoporosis, short stature in children, sexual dysplasia, and developmental delay caused by growth hormone deficiency. In some embodiments, the present invention provides the compounds described herein, or their stereoisomers, tautomers, isotope-labeled forms, and pharmaceutically acceptable salts, for promoting growth hormone secretion or release.

[0452] In another aspect, the present invention provides the use of the compounds described herein or their stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts in the preparation of medicaments for the prevention and / or treatment of growth hormone-related diseases.

[0453] In some embodiments, the present invention provides the use of the compounds described herein, or their stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, in the preparation of medicaments for the prevention and / or treatment of growth hormone-dependent diseases. In some embodiments, the present invention provides the use of the compounds described herein, or their stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, in the preparation of medicaments for the prevention and / or treatment of diseases caused by growth hormone deficiency. In some embodiments, the present invention provides the use of the compounds described herein, or their stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, in the preparation of medicaments for the prevention and / or treatment of diseases including dwarfism, osteoporosis, short stature in children, sexual dysplasia, and developmental delay caused by growth hormone deficiency. In some embodiments, the present invention provides the use of the compounds described herein, or their stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, in the preparation of medicaments for promoting growth hormone secretion or release.

[0454] In another aspect, the present invention provides a method for preventing and / or treating growth hormone-related diseases, comprising administering to an individual in need a therapeutically effective amount of the compound of the present invention or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts thereof.

[0455] In some embodiments, the present invention provides a method for preventing and / or treating growth hormone-dependent diseases, comprising administering to an individual in need a therapeutically effective amount of the compound described herein or its stereoisomers, tautomers, isotope markers, and pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a method for preventing and / or treating diseases caused by growth hormone deficiency, comprising administering to an individual in need a therapeutically effective amount of the compound described herein or its stereoisomers, tautomers, isotope markers, and pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a method for preventing and / or treating diseases including dwarfism, osteoporosis, childhood short stature, sexual dysplasia, and developmental delay caused by growth hormone deficiency, comprising administering to an individual in need a therapeutically effective amount of the compound described herein or its stereoisomers, tautomers, isotope markers, and pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a method for promoting growth hormone secretion or release, comprising administering to an individual in need a therapeutically effective amount of the compound described herein or its stereoisomers, tautomers, isotope markers, and pharmaceutically acceptable salts thereof. Detailed Implementation

[0456] definition

[0457] As used in this specification, unless the context indicates otherwise, the following words and phrases are generally intended to have the meanings set forth below.

[0458] As used herein, the term "alkyl" refers to a monovalent group of a branched or unbranched saturated hydrocarbon chain having 1 to 6 carbon atoms (more typically 1 to 4, or 1 to 3 carbon atoms). The term is exemplified by groups such as methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc.

[0459] As used herein, the term "halogen" includes fluorine, chlorine, bromine, and iodine.

[0460] As used in this article, the term "oxo" refers to =O.

[0461] As used herein, the term "alkoxy" refers to an "alkyl-O-" group, wherein the alkyl group is as defined herein. The term is illustrative of groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0462] As used herein, the term "aryl" refers to an aromatic carbocyclic group having 6 to 14 carbon atoms (more typically 6 to 10 carbon atoms, or 6 carbon atoms) of a monocyclic (e.g., phenyl) or polycyclic (e.g., biphenyl) or multiple fused (fused) rings (e.g., naphthyl, fluorenyl, and anthracene). The term is illustrative of groups such as phenyl, fluorenyl, naphthyl, anthracene, 1,2,3,4-tetrahydronaphthalene (if the linking point is through an aryl group), etc.

[0463] As used herein, the term "cycloalkyl" refers to a monocyclic monomolecular saturated group having 3 to 6 carbon atoms as ring atoms. Examples of cycloalkyl groups include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

[0464] As used herein, the term "heteroaryl" refers to an aromatic cyclic group comprising a monocyclic or multicyclic fused (fused) ring (e.g., comprising two rings) containing 5 to 14 ring atoms, wherein, in addition to a carbon atom, the ring atoms also contain at least one heteroatom selected from oxygen, nitrogen, and / or sulfur. If the ring is aromatic, the sulfur and nitrogen atoms may also be present in oxidized forms. Multicyclic fused (fused) heteroaryl groups are formed by fusing a monocyclic heteroaryl group as defined above with one or more rings selected from the following to form a multicyclic fused ring system: heteroaryl (to form, for example, naphthidyl, such as 1,8-naphthidyl), heterocycle (for example, to form 1,2,3,4-tetrahydronaphthidyl, such as 1,2,3,4-tetrahydro-1,8-naphthidyl), carbocyclic (to form, for example, 5,6,7,8-tetrahydroquinolinyl), and aryl (to form, for example, indazole). It should be understood that the bonding point of the heteroaryl group can be on any suitable atom of the heteroaryl group, including a carbon atom and a heteroatom (e.g., nitrogen). Exemplary heteroaryl groups include, but are not limited to: pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiophenyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzooxazolyl, indazole, quinoxolinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzoimidazolyl, thiaindyl, pyrrolo[2,3-b]pyridyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazoleyl, and 3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopentane[1,2-c]pyrazolyl.

[0465] As used herein, the term "heterocyclic group" refers to a monovalent or divalent saturated or partially unsaturated group having 3 to 8 membered monocyclic or multiple fused (fused) rings, bridged rings, or spirocyclic rings having 3 to 12 ring atoms within the ring, wherein the ring atoms contain at least one nitrogen atom in addition to a carbon atom. Examples of heterocyclic groups include, but are not limited to, azirrocyclopropane rings, azirrocyclobutane rings, tetrahydropyrrole rings, piperidine rings, azirrocycloheptane rings, azirrocyclooctane rings, tetrahydroimidazolium rings, tetrahydropyrazole rings, tetrahydrooxazole rings, tetrahydroisooxazole rings, tetrahydrothiazole rings, tetrahydroisothiazole rings, piperazine rings, morpholine rings, dihydropyridyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazole, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, etc.

[0466] As used in this text, the term "ester group" refers to groups including, but not limited to, RC(O)O-, -C(O)OR, RS(O)2-O-, RP(O)2-O-, etc., where R includes, but is not limited to, alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), cycloalkyl (e.g., C3-C6 cycloalkyl), cycloalkoxy (e.g., C3-C6 cycloalkoxy), aryl (e.g., C6-C...14 aryl), aryloxy (e.g., C6-C) 14 Aryloxy groups, heteroaryl groups (e.g., 5-14 membered heteroaryl groups), heteroaryloxy groups (e.g., 5-14 membered heteroaryloxy groups), etc.

[0467] As used herein, the term "stereoisomer" refers to a compound having the same chemical composition and connectivity, but whose atoms have different spatial orientations that cannot be interchanged by single bond rotation. "Stereoisomer" includes both "diastereomers" and "enantiomers." A "diastereomer" is a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical procedures such as crystallization, electrophoresis, and chromatography. An "enantiomer" is a stereoisomer of a compound that is a non-overlapping mirror image of each other.

[0468] As used herein, the term "tautomer" refers to the coexistence of two (or more) compounds that differ only in the position and electron distribution of one (or more) active atoms, such as keto-enol tautomers.

[0469] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a given compound, and that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts can be derived from inorganic and organic acids. Salts derived from inorganic acids include hydrochlorides, hydrobromicates, sulfates, nitrates, phosphates, carbonates, hydrogen sulfates, hydrogen phosphates, dihydrogen phosphates, bicarbonates, etc. Salts derived from organic acids include formates, acetates, propionates, glycolates, pyruvates, oxalates, malates, malonates, succinates, maleates, fumarates, tartrates, citrates, benzoates, cinnamates, mandelates, methanesulfonates, ethanesulfonates, p-toluenesulfonates, salicylates, etc.

[0470] As used herein, the term “pharmaceutical acceptable” means that the substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or mammals treated with it.

[0471] Any general formula or structure given herein, including general formula I or any general formula disclosed herein, is also intended to represent both unlabeled and isotopically labeled forms of the compound. These forms of the compound may also be referred to as “isotopically labeled”. Isotopically labeled compounds have the structures depicted herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, but not limited to, isotopes of these elements. 2 H (deuterium, D) 3 H (tritium) 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. When the isotope incorporated into the compound of this invention is a hydrogen isotope 2 When H (deuterium, D) isotopic labeling is used, the compound is also called a "deuterated compound". These compounds are synthesized using methods well-known in the field, such as by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0472] Example

[0473] Example 1 (R)-2-amino-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropane-2-yl)-2-methylpropionamide (Example 1)

[0474] Step 1: Synthesis of 1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-carboxylic acid benzyl ester (intermediate 2)

[0475]

[0476] Compound 1 (3.00 g, 9.30 mmol), triethylamine (TEA, 2.82 g, 27.90 mmol), and dichloromethane (35 mL) were added to a 100 mL two-necked flask. Under nitrogen protection, methanesulfonyl chloride (MsCl, 1.58 g, 16.75 mmol) was added dropwise under an ice-water bath, and the reaction was carried out at room temperature for 3 h. TLC (V 石油醚 V 乙酸乙酯=2:1) ​​Monitor the reaction of the starting materials to ensure complete reaction. Quench the reaction mixture with water (50 mL), extract with dichloromethane (100 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (20 g, V 石油醚 V 乙酸乙酯 =3:1), yielding 3.50 g of brown oily intermediate 2, with a yield of 93.9%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.40-7.39 (m, 4H), 7.36-7.30 (m, 2H), 7.29-7.21 (m,2H), 7.07-7.03 (m, 1H), 5.12 (s, 2H), 4.07-4.01 (m, 2H), 3.90 (s, 2H), 3.11-2.98 (m, 5H), 1.81-1.63 (m, 4H).

[0477] Step 2: Synthesis of 1-(methanesulfonyl)spiro[indoline-3,4'-piperidine] (intermediate 3)

[0478]

[0479] Intermediate 2 (3.00 g, 7.49 mmol), 10% Pd / C (300 mg, 10% wt), and ethanol (50 mL) were added to a 250 mL hydrogenation flask. The reaction was carried out overnight at 50 °C under a hydrogen pressure of 40 psi. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction of raw materials until complete, filter the reaction solution through diatomaceous earth, concentrate, and rapidly prepare chromatographically purified solution (20 g, V 二氯甲烷 V 甲醇 =5:1), yielding 1.66 g of brown oily intermediate 3, with a yield of 83.2%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.33-7.16(m, 3H), 7.09-7.03 (m, 1H), 3.84 (s, 2H), 3.03 (s, 3H), 2.99-2.94 (m, 2H),2.74-2.61 (m, 2H), 1.83-1.70 (m, 2H), 1.59 (d, J=9.1 Hz, 2H).

[0480] Step 3: Synthesis of (R)-(3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropane-2-yl)tert-butyl carbamate (intermediate 4)

[0481]

[0482] To a 50 mL single-necked flask, N-Boc-O-benzyl-D-serine (100 mg, 0.34 mmol), intermediate 3 (90 mg, 0.34 mmol), N,N'-dicyclohexylcarbodiimide (DCC, 77 mg, 0.37 mmol), 1-hydroxybenzotriazole (HOBt, 50 mg, 0.37 mmol), isopropyl acetate (IPAC, 3 mL), and water (1.5 mL) were added sequentially. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Quench the reaction mixture with water (20 mL), extract with ethyl acetate (20 mL × 2), combine the organic phases, wash with saturated brine (40 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =100:1), yielding 157 mg of white solid intermediate 4, with a yield of 85.3%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.35-7.20 (m, 7H), 7.15-7.13 (m, 1H), 7.07-6.90 (m, 2H), 4.73-4.68 (m, 1H), 4.54-4.44 (m, 2H), 4.37 (d, J=13.6 Hz,1H), 4.01-3.97 (m, 1H), 3.91 (s, 2H), 3.67-3.63 (m, 1H), 3.59-3.49 (m, 1H),3.25-3.14 (m, 1H), 3.04 (d, J=5.2 Hz, 3H), 2.79 (t, J=12.4 Hz, 1H), 1.67-1.64(m, 4H), 1.38 (s, 9H).

[0483] Step 4: Synthesis of (R)-2-amino-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)prop-1-one (intermediate 5)

[0484]

[0485] Intermediate 4 (150 mg, 0.28 mmol), mesylate (159 mg, 1.65 mmol), and ethanol (6 mL) were added to a 25 mL single-necked flask. After addition, the mixture was reacted overnight at 45 °C under a nitrogen atmosphere. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool to room temperature, quench the reaction mixture with 1 M NaOH (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (40 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =50:1), yielding 105 mg of white solid intermediate 5, yield 86.0%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.37-7.20 (m, 7.5H), 7.06-6.97 (m, 1H), 6.78 (d, J=7.6 Hz,0.5H), 4.49 (d, J=8.8 Hz, 2H), 4.44-4.42 (m, 1H), 4.09-3.96 (m, 2H), 3.89 (d,J=4.8 Hz, 2H), 3.52-3.37 (m, 2H), 3.21-3.09 (m, 1H), 3.04 (s, 3H), 2.79-2.72(m, 1H), 1.82 (s, 2H), 1.68-1.55 (m, 4H).

[0486] Step 5: Synthesis of (R)-(1-((3-benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)carbamate tert-butyl (6)

[0487]

[0488] Intermediate 5 (100 mg, 0.22 mmol), N-tert-butoxycarbonyl-2-methylalanine (51 mg, 0.25 mmol), DCC (51 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol), isopropyl acetate (2 mL), and water (2 mL) were added sequentially to a 25 mL single-necked flask. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇=15:1) Monitor the reaction of the starting materials to ensure complete reaction. Quench the reaction mixture with water (10 mL), extract with ethyl acetate (20 mL × 2), combine the organic phases, wash with saturated brine (40 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =100:1), yielding 132 mg of white solid intermediate 6, with a yield of 95.6%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.59 (d,J=8.4 Hz, 0.5H), 7.48 (d, J=8.4 Hz, 0.5H), 7.38-7.18 (m, 7.5H), 7.05-6.96 (m,2H), 6.87 (d, , 3.64-3.48 (m, 2H),3.20-3.15 (m, 1H), 3.04 (d, J=5.2 Hz, 3H), 2.83-2.75 (m, 1H), 1.66-1.63 (m,4H), 1.36 (s, 9H), 1.29 (d, J=4.0 Hz, 6H).

[0489] Step 6: Synthesis of (R)-2-amino-N-(3-(benzoxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide (intermediate 7)

[0490]

[0491] Intermediate 6 (120 mg, 0.19 mmol), mesylate (110 mg, 1.14 mmol), and ethanol (4 mL) were added to a 25 mL single-necked flask. The mixture was reacted overnight at 45 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool to room temperature, quench the reaction mixture with 1 M NaOH (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (4 g, V 二氯甲烷 V 甲醇=50:1), yielding 70 mg of white solid intermediate 7, with a yield of 69.3%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.30 (s, 1H), 7.38-7.19 (m, 7.5H), 7.06-6.97 (m, 1H), 6.84 (d, J=7.6 Hz, 0.5H), 4.97 (s, 1H), 4.53 (s, 1H), 4.48 (d, J=7.2 Hz, 1H), 4.43-4.38 (m, 1H), 3.98-3.86 (m, 3H), 3.64-3.53 (m, 2H), 3.23-3.11 (m, 1H), 3.04 (d, J=5.2 Hz, 3H), 2.83-2.77 (m,1H), 2.08 (br, 2H), 1.81-1.53 ​​(m, 4H), 1.18 (s, 6H).

[0492] Step 7: Synthesis of (R)-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-2-methyl-2-((2,2,2-trifluoroethyl)amino)propionamide (Example 1)

[0493]

[0494] Intermediate 7 (250 mg, 0.47 mmol), trifluoroacetaldehyde methyl acetal (92 mg, 0.71 mmol), and toluene (5 mL) were added to a 25 mL single-necked flask. The mixture was reacted at 60 °C for 4 h under nitrogen protection. Then, 10% Pd / C (25 mg, 10% wt) and p-toluenesulfonic acid (9 mg, 0.05 mmol) were added, and the mixture was reacted overnight at 60 °C under a hydrogen pressure of 15 psi. TLC (V 石油醚 V 乙酸乙酯 =1:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool the reaction solution to room temperature, filter with diatomaceous earth, add water (30 mL) to the filtrate, extract with ethyl acetate (50 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 石油醚 V 乙酸乙酯 (1:1), yielding 110 mg of the white solid compound of Example 1, with a yield of 34.8%. 1H NMR (400 MHz, CDCl3)δ (ppm): 7.96-7.90 (m, 1H), 7.66 (s, 1H), 7.40-7.29 (m, 6H), 7.23-7.19 (m,1H), 7.13-7.06 (m, 1H), 7.00-6.95 (m, 0.5H), 6.67 (d, J=7.3 Hz, 0.5H), 5.21-5.17 (m, 1H), 4.68-4.51 (m, 3H), 4.12-3.97 (m, 1H), 3.85-3.79 (m, 2H), 3.73-3.64 (m, 2H), 3.17-3.06 (m, 1H), 2.90 (s, 3H), 2.82-2.74 (m, 1H), 1.87-1.54(m, 6H), 1.44 (s, 6H).

[0495] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 172.33 (172.26), 167.49 (167.23), 149.63 (J C-F =36.4 Hz), 141.07, 138.51 (138.32), 138.15(138.03), 128.47, 128.32(128.26), 127.64, 127.59, 127.55, 127.49, 123.54, 123.43, 119.45 (J C-F =277.8Hz), 112.79, 72.35 (72.14), 70.16, 69.27, 65.49 (65.45), 58.28, 49.00(48.59), 42.74 (42.58), 42.24 (42.16), 36.08 (36.02), 35.47 (35.40), 34.32(34.29), 24.94, 24.56.

[0496] HRMS (ESI): m / z [M+H] + C 29 H 38 Calculated value of F3N4O5S: 611.2515; Measured value: 611.2468.

[0497] Example 2 N-((R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropane-2-yl)-2-((2-hydroxypropyl)amino)-2-methylpropionamide (Example 2)

[0498]

[0499] Intermediate 7 from Example 1 (250 mg, 0.47 mmol), EtOH (10 mL), propylene oxide (411 mg, 7.06 mmol), and N,N-diisopropylethylamine (DIPEA, 92 mg, 0.71 mmol) were added sequentially to a 100 mL sealed container. The reaction was carried out overnight at 120 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) After monitoring the reaction to completion, the mixture was cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phase was collected. The mixture was washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a thick preparative plate (V). 二氯甲烷 V 甲醇 The compound was purified by a ratio of 12:1 to obtain 58 mg of the compound from Example 2, with a yield of 26.5%.

[0500] HRMS (ESI): m / z [M+H] + C 30 H 40 Calculated value of D2N4O6S: 587.2903; Measured value: 587.2908.

[0501] Example 3 (R)-2-methyl-N-(1-(1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxo-3-(benzyloxy-d2)prop-2-yl)-2-((2,2,2-trifluoroethyl)amino)propionamide

[0502] Step 1: Synthesis of benzyl 2-((tert-butoxycarbonyl)amino)-2-methylpropionate (Intermediate 2)

[0503]

[0504] 2-(Boc-amino)-2-methylpropionic acid (1, 2.00 g, 9.84 mmol), anhydrous DMF (20 mL), and triethylamine (2.49 g, 24.60 mmol) were added sequentially to a 100 mL single-necked flask, followed by the dropwise addition of benzyl bromide (4.21 g, 24.60 mmol). The reaction was carried out under nitrogen protection at room temperature for 15 h. TLC (V 石油醚 V乙酸乙酯 =10:1) After monitoring the reaction to completion, quench with water (80 mL), extract with ethyl acetate (50 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (50 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (40 g, V 石油醚 V 乙酸乙酯 The mixture was purified at a ratio of 10:1 to obtain 2.84 g of white solid intermediate 2, with a yield of 98.3%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.40-7.28 (m, 5H), 7.27 (s, 1H), 5.06 (s, 2H), 1.34 (s, 15H).

[0505] Step 2: Synthesis of benzyl 2-amino-2-methylpropionate hydrochloride (intermediate 3)

[0506]

[0507] Intermediate 2 (2.84 g, 9.68 mmol), anhydrous dichloromethane (28 mL), and 4 M HCl / dioxane solution (14 mL) were added sequentially to a 100 mL single-necked flask. The reaction was carried out at room temperature for 1 h under nitrogen protection. TLC (V 石油醚 V 乙酸乙酯 =6:1) After monitoring the end of the reaction, the solvent was concentrated and removed. Diethyl ether (25 mL) was added and the mixture was stirred for 30 min. The mixture was filtered, washed with diethyl ether (2 mL × 3), and the filter cake was collected to obtain 2.14 g of white solid intermediate 3, with a yield of 96.4%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.70(br, 2H), 8.54 (br, 1H), 7.53-7.25 (m, 5H), 5.24 (d, J=2.5 Hz, 2H), 1.50 (d,J=4.7 Hz, 6H).

[0508] Step 3: Synthesis of benzyl 2-methyl-2-((2,2,2-trifluoroethyl)amino)propionate (intermediate 4)

[0509]

[0510] Intermediate 3 (1.40 g, 6.09 mmol), anhydrous acetonitrile (28 mL), potassium carbonate (2.52 g, 18.27 mmol), and 2,2,2-trifluoroethyltrifluoromethanesulfonate (2.83 g, 12.18 mmol) were added sequentially to a 100 mL single-necked flask. The reaction was carried out at 80 °C for 19 h under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =20:1) Monitor the end of the reaction, filter, wash with ethyl acetate (50 mL × 3), concentrate the filtrate and perform rapid preparative chromatography (40 g, V 石油醚 V 乙酸乙酯 Purification at a ratio of 10:1 yielded 1.67 g of colorless oily intermediate 4, with a yield of 99.4%. 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.44-7.27 (m, 5H), 5.12 (s, 2H), 3.25-3.12 (m, 2H), 3.01 (t, J=8.2 Hz, 1H), 1.26 (s, 6H).

[0511] Step 4: Synthesis of 2-methyl-2-((2,2,2-trifluoroethyl)amino)propionic acid (intermediate 5)

[0512]

[0513] Intermediate 4 (1.67 g, 6.07 mmol), methanol (30 mL), and 10% Pd / C (334 mg, 20 wt%) were added sequentially to a 100 mL single-necked flask. The reaction was carried out under a hydrogen atmosphere (15 psi) at room temperature for 15 h. TLC (V 石油醚 V 乙酸乙酯 =10:1) After the reaction was completed, the mixture was filtered through a diatomaceous earth bed, washed with methanol (10 mL × 3), and the filtrate was concentrated to give 974 mg of white solid intermediate 5, with a yield of 86.9%. 1 H NMR (400 MHz, CDCl3) δ (ppm): 3.28 (t, J=9.9 Hz, 1H), 3.21-3.15 (m, 2H), 1.19 (s, 6H).

[0514] Step 5: Synthesis of benzyl alcohol-d2 (intermediate 6)

[0515]

[0516] Benzoic acid (2.0 g, 16.4 mmol) and diethyl ether (80 mL) were added to a 250 mL single-necked flask. LiAlD4 (2.06 g, 49.13 mmol) was added under ice bath conditions. The reaction was carried out under nitrogen protection for 2 h. TLC (V 二氯甲烷 V 甲醇 =25:1) Monitor the reaction of the raw materials to ensure complete reaction. Quench the reaction solution with water (80 mL), adjust the pH to 6 with 1M HCl, extract with ether (100 mL × 3), wash with saturated brine (100 mL), dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (40 g, V 二氯甲烷 V 甲醇 =100:1), yielding 1.61 g of colorless oily liquid intermediate 6, with a yield of 88.9%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm):7.32-7.30 (m, 4H), 7.25-7.20 (m, 1H), 5.12 (s, 1H).

[0517] Step 6: Synthesis of (bromomethyl-d2)benzene (intermediate 7)

[0518]

[0519] Intermediate 6 (500 mg, 4.54 mmol) and HBr (5 mL, 40% wt aqueous solution) were added to a 25 mL single-necked flask. The mixture was reacted at 110 °C for 1 h under nitrogen protection. TLC (V 石油醚 V 乙酸乙酯 =10:1) Monitor the reaction of the raw materials to ensure complete reaction. Quench the reaction solution with water (10 mL), extract with dichloromethane (10 mL × 3), wash with saturated brine (10 mL), dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (12 g, V 石油醚 V 乙酸乙酯 =100:1), yielding 420 mg of colorless oily liquid intermediate 7, with a yield of 53.5%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.57-7.28 (m, 5H).

[0520] Step 7: Synthesis of N-(tert-butoxycarbonyl)-O-(benzyl-d2)-D-serine (intermediate 8)

[0521]

[0522] Add 60% NaH (403 mg, 10.07 mmol) and DMF (40 mL) to a 100 mL three-necked flask. Add 8 mL of DMF solution containing Boc-D-serine (984 mg, 4.80 mmol) dropwise under ice bath conditions, and react at room temperature for 1 h. Cool to -40 °C, add 8 mL of DMF solution containing intermediate 7 (830 mg, 4.80 mmol), and incubate overnight. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the raw materials to ensure complete reaction. Add water (40 mL) to the reaction solution to quench the reaction, adjust the pH to 4 with 1 M HCl, extract with ethyl acetate (40 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (20 g, V 二氯甲烷 V 甲醇 =100:1), yielding 695 mg of colorless oily intermediate 8, with a yield of 48.9%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm):12.66 (s, 1H), 7.37-7.26 (m, 5H), 6.95 (d, J=8.4 Hz, 1H), 4.21-4.16 (m, 1H),3.68-3.63 (m, 2H), 1.38 (s, 9H).

[0523] Step 8: Synthesis of (R)-((1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxo-3-(benzyloxy-d2)propane-2-yl))tert-butyl carbamate (intermediate 9)

[0524]

[0525] Intermediate 8 (380 mg, 1.28 mmol), Intermediate 3 from Example 1 (340 mg, 1.28 mmol), DCC (289 mg, 1.40 mmol), HOBt (190 mg, 1.40 mmol), isopropyl acetate (IPAc, 12 mL), and water (6 mL) were added sequentially to a 50 mL single-necked flask. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Add water (30 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (50 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (20 g, V). 二氯甲烷 V 甲醇=100:1), yielding 460 mg of white solid intermediate 9, with a yield of 66.9%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.34-7.28 (m, 5H), 7.28-7.19(m, 3H), 7.14-7.02 (m, 1H), 7.01-6.88 (m, 1H), 4.72-4.68 (m, 1H), 4.37-4.34(m, 1H), 4.00-3.93 (m, 1H), 3.95-3.88 (m, 2H), 3.66-3.62 (m, 1H), 3.59-3.47(m, 1H), 3.23-3.13 (m, 1H), 3.03 (d, J=4.4 Hz, 3H), 2.78 (t, J=12.8 Hz, 1H),1.82-1.79 (m, 1H), 1.67-1.63 (m, 2H), 1.55-1.50 (m, 1H), 1.37 (s, 9H).

[0526] Step 9: Synthesis of (R)-2-amino-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-3-(benzyloxy-d2)prop-1-one (intermediate 10)

[0527]

[0528] Intermediate 9 (460 mg, 0.84 mmol), mesylate (487 mg, 5.04 mmol), and ethanol (19 mL) were added to a 25 mL single-necked flask. After addition, the mixture was reacted overnight at 45 °C under a nitrogen atmosphere. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Quench the reaction solution with 1 M NaOH (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =50:1), yielding 325 mg of white solid intermediate 10, with a yield of 86.9%.

[0529] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.43-7.18 (m, 7.5H), 7.7-6.95 (m,1H), 6.79 (d, J=7.6 Hz, 0.5H), 4.42 (t, J=13.4 Hz, 1H), 4.08-3.92 (m, 2H),3.89 (d, J=5.2 Hz, 2H), 3.52-3.36 (m, 2H), 3.20-3.12 (m, 1H), 3.04 (s, 3H),2.79-2.75 (m, 1H), 1.81 (s, 2H), 1.67-1.49 (m, 4H).

[0530] HRMS (ESI): m / z [M+H] + C 23 H 27 Calculated value of D2N3O4S: 446.2082; Measured value: 446.2047

[0531] Step 10: Synthesis of (R)-2-methyl-N-(1-(1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxo-3-(benzyloxy-d2)prop-2-yl)-2-((2,2,2-trifluoroethyl)amino)propionamide (Example 3)

[0532]

[0533] Intermediate 10 (200 mg, 0.45 mmol), isopropyl acetate (4 mL), water (4 mL), intermediate 5 (93 mg, 0.50 mmol), N,N'-dicyclohexylcarbodiimide (103 mg, 0.50 mmol), and 1-hydroxybenzotriazole (68 mg, 0.50 mmol) were added sequentially to a 25 mL single-necked flask. The reaction was carried out under nitrogen protection at room temperature for 15 h. TLC (V 二氯甲烷 V 甲醇 =20:1) Monitor the reaction to completion, filter, wash with ethyl acetate (2 mL × 3), separate the filtrate, and collect the organic phase. Wash with saturated sodium chloride solution (5 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 The compound was purified by a ratio of 50:1 to give 170 mg of white solid, as described in Example 3, with a yield of 61.6%.

[0534] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.03-7.88 (m, 1H), 7.40-7.15 (m,7.5H), 7.09-6.97 (m, 1H), 6.97-6.89 (m, 0.5H), 5.09-4.97 (m, 1H), 4.46-4.30(m, 1H), 4.02-3.82 (m, 3H), 3.70-3.50 (m, 2H), 3.25-3.04 (m, 4H), 3.03 (s,3H), 2.89-2.73 (m, 1H), 1.79-1.50 (m, 4H), 1.22-1.07 (m, 6H);

[0535] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 175.01, 167.84 (167.73), 141.08,138.48 (138.38), 138.01 (137.95), 128.45, 128.29 (128.25), 127.63 (127.54),125.95 (J C-F =278.5 Hz), 123.40, 112.85 (112.77), 70.13 (69.50), 58.37 (58.27), 48.40 (48.09), 44.78 (J C-F =30.8 Hz), 42.71 (42.62), 42.15, 36.26 (36.07), 35.52, 34.31 (34.26), 25.60 (25.42), 24.85;

[0536] HRMS (ESI): m / z [M+H] + C 29 H 35 Calculated value of D2F3N4O5S: 613.2640; Measured value: 613.2603.

[0537] Example 4 2-((2-hydroxypropyl)amino)-2-methyl-N-((R)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxo-3-(benzoxy-d2)propyl-2-yl)propionamide (Example 4)

[0538]

[0539] Referring to the synthesis method of Example 3, 2-methyl-2-((2,2,2-trifluoroethyl)amino)propionic acid was replaced with 2-((2-hydroxypropyl)amino)-2-methylpropionic acid to obtain 120 mg of the white solid compound of Example 4, with a yield of 43.3%.

[0540] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.21-8.15 (m, 1H), 7.37-7.22 (m,7.5H), 7.06-6.98 (m, 1H), 6.92-6.90 (m, 0.5H), 5.02-4.97 (m, 1H), 4.59-4.51(m, 1H), 4.39 (d, J=13.5 Hz, 1H), 3.98-3.86 (m, 3H), 3.67-3.62 (m, 2H), 3.59-3.57 (m, 1H), 3.20-3.13 (m, 1H), 3.05-3.04 (m, 3H), 2.83-2.76 (m, 1H), 2.37-2.27 (m, 2H), 2.03 (br, 1H), 1.81-1.52 (m, 4H), 1.17 (s, 6H), 1.04 (d, J=4.0Hz, 3H).

[0541] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 169.61 (169.54), 160.98 (160.74), 133.03, 130.00 (129.86), 129.63 (129.60), 120.23, 120.10 (120.04), 119.68(119.63), 119.54 (119.53), 115.39, 115.14 (115.03), 104.89 (104.82), 62.06,61.89, 60.88, 58.98 (58.84), 50.64 (50.48), 50.18 (50.15), 42.66 (42.57), 41.17 (41.08), 40.63 (40.52), 34.78, 34.66 (34.58), 31.31 (31.16), 28.07, 27.34 (27.28), 25.03, 16.38, 16.18 (16.07), 12.04 (11.84).

[0542] HRMS (ESI): m / z [M+H] + C 30 H 40 Calculated value of D2N4O6S: 589.3029; Measured value: 589.2998.

[0543] Example 5 (R)-2-amino-N-(3-(benzoxy)-1-oxo-1-(1-(benzenesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)propyl-2-yl)-2-methylpropionamide

[0544] Step 1: Synthesis of 1-(benzenesulfonyl)spiro[indoline-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (intermediate 2)

[0545]

[0546] To a 100 mL single-necked flask, add spiro[indoline-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (1, 2.0 g, 6.93 mmol), pyridine (1.65 g, 20.8 mmol), benzenesulfonyl chloride (1.35 g, 7.63 mmol), and CH3CN (20 mL). Under nitrogen protection, react at room temperature for 2 h. TLC (V 石油醚 V 乙酸乙酯 =5:1) Monitor the reaction of the starting materials to ensure complete reaction. Quench the reaction mixture with water (80 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (100 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (40 g, V 石油醚 V 乙酸乙酯 =15:1), yielding 2.32 g of white solid intermediate 2, with a yield of 78.1%.

[0547] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.84-7.81 (m, 2H), 7.68 (t, J=8.0Hz, 1H), 7.57 (t, J=7.6 Hz, 2H), 7.50 (d, J=8.0 Hz, 1H), 7.26-7.22 (td, J1=8.8 Hz, J2=1.2 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 7.02 (td, J1=7.6 Hz, J2=1.2Hz, 1H), 3.88 (s, 2H), 3.81-3.78 (m, 2H), 2.82 (br, 2H), 1.55-1.47 (m, 2H),1.39 (s, 9H), 1.05-1.02 (m, 2H).

[0548] Step 2: Synthesis of 1-(phenylsulfonyl)spiro[indoline-3,4'-piperidine] (intermediate 3)

[0549]

[0550] Intermediate 2 (2.32 g, 5.41 mmol) and DCM (30 mL) were added sequentially to a 100 mL single-necked flask. Under nitrogen protection, trifluoroacetic acid (TFA, 15 mL) was added in an ice bath, and the reaction was carried out at room temperature for 1.5 h. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the raw materials to ensure complete reaction. Concentrate the reaction solution, add saturated NaHCO3 solution (40 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (100 mL), dry with anhydrous sodium sulfate, filter, and purify by rapid preparative chromatography (40 g, V 二氯甲烷 V 甲醇 =20:1), yielding 1.85 g of white solid intermediate 3, with a yield of 99.1%.

[0551] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.85-7.82 (m, 2H), 7.68 (t, J=13.2Hz, 1H), 7.57 (t, J=7.6 Hz, 2H), 7.50 (d, J=8.0 Hz, 1H), 7.25 (td, J1=7.6 Hz,J2=1.6 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 7.05 (t, J=7.6 Hz, 1H), 3.88 (s, 2H),2.96-2.88 (m, 2H), 2.70 (t, J=12.8 Hz, 2H), 1.66-1.60 (m, 2H), 1.14-1.01 (m,2H).

[0552] Step 3: Synthesis of (R)-[3-(benzoxy)-1-oxo-1-(1-(benzenesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)propyl-2-yl]carbamate tert-butyl ester (intermediate 4)

[0553]

[0554] To a 50 mL single-necked flask, add intermediate 3 (245 mg, 0.75 mmol), isopropyl acetate (6 mL), water (3 mL), N-Boc-O-benzyl-D-serine (220 mg, 0.75 mmol), HOBt (111 mg, 0.82 mmol), and DCC (169 mg, 0.82 mmol) sequentially. After addition, under nitrogen protection, react overnight at room temperature. TLC (V 石油醚 V 乙酸乙酯 =1:1) Monitor the reaction of the starting materials to ensure complete reaction. Quench with water (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (12 g, V 石油醚 V 乙酸乙酯 =3:1), yielding 319 mg of colorless oily liquid intermediate 4, with a yield of 70.7%.

[0555] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.82 (d, J=7.6 Hz, 2H), 7.68-7.66(m, 1H), 7.57 (t, J=7.6 Hz, 2H), 7.50 (t, J=9.2 Hz, 1H), 7.36-7.23 (m, 6H),7.09-7.02 (m, 1.5H), 6.97 (t, J=8.0 Hz, 1H), 6.79-6.77 (m, 0.5H), 4.68-4.60(m, 1H), 4.51-4.43 (m, 2H), 4.24-4.20 (m, 1H), 3.90-3.94 (m, 2H), 3.84-3.80(m, 1H), 3.66-3.56 (m, 1H), 3.54-3.46 (m, 1H), 3.10 (q, J=12.4 Hz, 1H), 2.68(t, J=12.8 Hz, 1H), 1.63-1.60 (m, 1H), 1.48-1.46 (m, 1H), 1.36 (d, J=20.8 Hz,9H), 1.04-1.00 (m, 2H).

[0556] Step 4: Synthesis of (R)-2-amino-3-(benzoxy)-1-(1-(benzenesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)prop-1-one (intermediate 5)

[0557]

[0558] Intermediate 4 (310 mg, 0.57 mmol), methanesulfonic acid (329 mg, 3.42 mmol), and ethanol (10 mL) were added to a 50 mL single-necked flask, and the reaction was carried out overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Quench the reaction solution with 1 M NaOH solution (40 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =50:1), yielding 192 mg of white solid intermediate 5, with a yield of 74.4%.

[0559] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.82 (d, J=7.2 Hz, 2H), 7.71-7.66 (m, 1H), 7.57 (t, J=7.6 Hz, 2H), 7.52-7.47 (m, 1H), 7.41-7.14 (m, 6.5H), 7.03(t, J=7.2 Hz, 0.5H), 6.94 (t, J=7.2 Hz, 0.5H), 6.66 (d, J=7.2 Hz, 0.5H), 4.49-4.42 (m, 2H), 4.31-4.24 (m, 1H), 3.95-3.87 (m, 4H), 3.48-3.40 (m, 2H),3.12-2.98 (m, 1H), 2.67-2.66 (m, 1H), 1.84-1.70 (m, 2H), 1.67-1.60 (m, 0.5H),1.50-1.36 (m, 1H), 1.30-1.27 (m, 0.5H), 1.13-0.97 (m, 2H).

[0560] Step 5: Synthesis of (R)-[1-([3-(benzoxy)-1-oxo-1-(1-(benzenesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)propyl-2-yl]amino)-2-methyl-1-oxopropyl-2-yl]carbamate tert-butyl ester (intermediate 6)

[0561]

[0562] Intermediate 5 (189 mg, 0.37 mmol), isopropyl acetate (3 mL), water (3 mL), N-tert-butoxycarbonyl-2-methylalanine (84 mg, 0.41 mmol), DCC (85 mg, 0.41 mmol), and HOBt (55 mg, 0.41 mmol) were added sequentially to a 25 mL single-necked flask. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 石油醚 V 乙酸乙酯 =1:1) Monitor the reaction of the starting materials to ensure complete reaction. Add water (10 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (10 mL × 2), combine the organic phases, wash with saturated brine (30 mL), dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (12 g, V 石油醚 V 乙酸乙酯 =5:2), yielding 245 mg of white solid intermediate 6, with a yield of 94.5%.

[0563] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.84-7.80 (m, 1.5H), 7.71-7.66 (m,1H), 7.57 (t, J=11.2 Hz, 2H), 7.50-7.48 (m, 1.5H), 7.38-7.21 (m, 6H), 7.02-6.95 (m, 1.5H), 6.77-6.75 (m, 0.5H), 4.91 (q, J=6.8 Hz, 1H), 4.49-4.42 (m,2H), 4.25 (t, J=15.6 Hz, 1H), 3.98-3.70 (m, 3H), 3.61-3.44 (m, 2H), 3.14-3.02(m, 1H), 2.75-2.60 (m, 1H), 1.71-1.58 (m, 1H), 1.52-1.41 (m, 1H), 1.42-1.19(m, 15H), 1.04-0.94 (m, 2H).

[0564] Step 6: Synthesis of (R)-2-amino-N-(3-(benzoxy)-1-oxo-1-(1-(benzenesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)propyl-2-yl)-2-methylpropionamide (Example 5)

[0565]

[0566] Intermediate 6 (240 mg, 0.35 mmol), mesylate (200 mg, 2.08 mmol), and ethanol (7 mL) were added to a 25 mL single-necked flask. The mixture was reacted overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool to room temperature, quench with 1 M NaOH solution (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =100:1), yielding 160 mg of the white solid compound of Example 5, with a yield of 78.4%.

[0567] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.27 (br, 1H), 7.83-7.80 (m, 2H), 7.69 (t, J=7.6 Hz, 1H), 7.57 (t, J=7.6 Hz, 2H), 7.50 (t, J=8.0 Hz, 1H), 7.40-7.19 (m, 6H), 7.15-7.13 (m, 0.5H), 7.04-6.95 (m, 1H), 6.72 (d, J=7.6 Hz,0.5H), 4.90 (d, J=6.4 Hz, 1H), 4.52-4.44 (m, 2H), 4.31-4.22 (m, 1H), 3.94-3.88 (m, 2H), 3.85-3.81 (m, 1H), 3.61-3.51 (m, 2H), 3.17-3.01 (m, 1H), 2.75-2.67 (m, 1H), 2.01 (br, 2H), 1.63-1.32 (m, 2H), 1.21-1.11 (m, 6H), 1.08-1.00(m, 2H).

[0568] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 176.93 (176.82), 168.00 (167.72), 140.25, 139.09 (138.93), 138.21 (138.00), 136.18, 133.92, 129.53, 128.39(128.28), 127.57 (127.54), 126.98, 124.25 (124.17), 123.43 (123.17), 114.45,72.34 (72.17), 70.47 (69.71), 58.13, 54.25, 48.27 (47.75), 42.97, 42.87, 41.95, 38.91 (38.45), 36.11 (36.01), 35.42, 28.84, 28.57.

[0569] HRMS (ESI): m / z [M+H] + C 32 H 39 Calculated value of N4O5S: 591.2641; Measured value: 591.2603.

[0570] Example 6 2-Amino-N-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxopropane-2-yl)-2-methylpropionamide

[0571] Step 1: Synthesis of spiro[indoline-3,3'-pyrrolidine] (intermediate 2)

[0572]

[0573] Compound 1 (8.91 g, 52.34 mmol), acetonitrile (223 mL), and N-iodosuccinimide (NIS, 12.36 g, 54.96 mmol) were added sequentially to a 1 L single-necked flask. The mixture was reacted at room temperature for 30 min under nitrogen protection. Then, acetonitrile (334 mL) and a borane-amine complex (8.08 g, 261.70 mmol) were added, and the mixture was reacted at room temperature for 2 h under nitrogen protection. TLC (V 石油醚 V 乙酸乙酯 =4:1) After monitoring the reaction to completion, transfer to a 2 L beaker, add 2 M sodium hydroxide solution (1 L), stir at room temperature for 30 min, extract with dichloromethane (1 L × 3), and collect the organic phase. Wash with saturated sodium chloride solution (1 L × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (V... 乙酸乙酯 V 甲醇 V 氨水 The mixture was purified (60:38:2) to give 3.23 g of yellow solid intermediate 2, with a yield of 35.4%.

[0574] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.02 (dd, J1=7.3 Hz, J2=1.3 Hz,1H), 6.90 (td, J1=7.6 Hz, J2=1.3 Hz, 1H), 6.54 (td, J1=7.3 Hz, J2=1.3 Hz, 1H), 6.48 (d, J=7.7 Hz, 1H), 5.44 (br, 1H), 3.33 (d, J=9.0 Hz, 2H), 3.22 (d, J=9.0Hz, 1H), 3.00-2.89 (m, 2H), 2.86 (d, J=10.7 Hz, 1H), 2.67 (d, J=10.7 Hz, 1H),1.95-1.86 (m, 1H), 1.84-1.75 (m, 1H).

[0575] Step 2: Synthesis of spiro[indoline-3,3'-pyrrolidine]-1'-carboxylic acid benzyl ester (intermediate 3)

[0576]

[0577] Intermediate 2 (1.55 g, 8.90 mmol), anhydrous DCM (60 mL), and triethylamine (3.15 g, 31.15 mmol) were added sequentially to a 100 mL single-necked flask. Benzyl chloroformate (1.52 g, 8.90 mmol) was then added dropwise at 0 °C. The reaction was carried out under nitrogen protection at room temperature for 3 h. TLC (V 石油醚 V 乙酸乙酯 =2:1) ​​After monitoring the reaction to completion, quench with water (40 mL), extract with dichloromethane (100 mL × 3), and collect the organic phase. Dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (20 g, V 石油醚 V 乙酸乙酯 The mixture was purified at a ratio of 2:1 to obtain 1.47 g of yellow oily intermediate 3, with a yield of 53.6%.

[0578] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.39 (d, J=4.4 Hz, 2H), 7.35 (d, J=4.4 Hz, 2H), 7.33-7.26 (m, 1H), 7.03 (d, J=7.5 Hz, 1H), 6.96 (td, J1=7.6 Hz,J2=1.3 Hz, 1H), 6.56 (t, J=7.4 Hz, 1H), 6.52 (d, J=7.8 Hz, 1H), 5.60 (br,1H), 5.15-5.03 (m, 2H), 3.64-3.53 (m, 1H), 3.52-3.33 (m, 5H), 2.12-1.92 (m,2H).

[0579] Step 3: Synthesis of 1-(methanesulfonyl)spiro[indoline-3,3'-pyrrolidine]-1'-carboxylic acid benzyl ester (intermediate 4)

[0580]

[0581] Intermediate 3 (1.47 g, 4.77 mmol), anhydrous acetonitrile (30 mL), N,N-diisopropylethylamine (925 mg, 7.16 mmol), and methanesulfonyl chloride (496 mg, 5.25 mmol) were added sequentially to a 100 mL single-necked flask. The reaction was carried out at 50°C for 4 h under nitrogen protection. TLC (V 二氯甲烷 V乙酸乙酯 =4:1) After monitoring the reaction to completion, quench with water (60 mL), extract with ethyl acetate (100 mL × 3), and collect the organic phase. Dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (120 g, V 石油醚 V 乙酸乙酯 After purification at a ratio of 1:1, 1.55 g of white solid intermediate 4 was obtained, with a yield of 84.2%. 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 7.45-7.22 (m, 8H), 7.13-7.02 (m, 1H), 5.18-5.02 (m, 2H), 3.95-3.83 (m,2H), 3.70-3.58 (m, 2H), 3.58-3.42 (m, 2H), 3.05 (s, 3H), 2.22-2.06 (m, 2H).

[0582] Step 4: Synthesis of 1-(methanesulfonyl)spiro[indoline-3,3'-pyrrolidine] (intermediate 5)

[0583]

[0584] Intermediate 4 (1.32 g, 3.42 mmol), anhydrous ethanol (26 mL), and 10% Pd / C (264 mg, 20 wt%) were added sequentially to a 100 mL hydrogenation flask. The reaction was carried out at 55 °C for 5 h under a hydrogen atmosphere (40 psi). TLC (V 石油醚 V 乙酸乙酯 =1:1) After monitoring the reaction to completion, filter under a diatomaceous earth bed, concentrate, and perform rapid preparative chromatography (12 g, V). 二氯甲烷 V 甲醇 Purification at a ratio of 10:1 yielded 772 mg of yellow oily intermediate 5, with a yield of 89.5%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.32 (d,J=7.5 Hz, 1H), 7.29-7.17 (m, 2H), 7.05 (td, J1=7.3 Hz, J2=1.5 Hz, 1H), 3.88(d, J=10.1 Hz, 1H), 3.72 (d, J=10.1 Hz, 1H), 3.07-2.90 (m, 6H), 2.71 (d, J=11.0 Hz, 1H), 2.07-1.91 (m, 2H).

[0585] Step 5: Synthesis of ((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxopropane-2-yl)tert-butyl carbamate (intermediate 6)

[0586]

[0587] Intermediate 5 (390 mg, 1.55 mmol), isopropyl acetate (12 mL), water (6 mL), N-Boc-O-benzyl-D-serine (458 mg, 1.55 mmol), N,N'-dicyclohexylcarbodiimide (353 mg, 1.71 mmol), and 1-hydroxybenzotriazole (231 mg, 1.71 mmol) were added sequentially to a 50 mL single-necked flask. The reaction was carried out at room temperature for 3 h under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) After monitoring the reaction to completion, quench with water (20 mL), extract with ethyl acetate (20 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (20 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 The mixture was purified at a ratio of 20:1 to give 731 mg of white solid intermediate 6, with a yield of 89.0%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.42-7.21 (m, 8H), 7.20-6.92 (m, 2H), 4.59-4.38 (m, 3H), 4.00-3.75 (m, 3H), 3.75-3.39 (m, 5H), 3.08-3.00 (m, 3H), 2.27-2.05 (m, 2H), 1.42-1.30 (m, 9H).

[0588] Step 6: Synthesis of (2R)-2-amino-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)prop-1-one (intermediate 7)

[0589]

[0590] Intermediate 6 (731 mg, 1.38 mmol), anhydrous ethanol (25 mL), and methanesulfonic acid (796 mg, 8.28 mmol) were added sequentially to a 100 mL single-necked flask. The reaction was carried out at 40 °C for 15 h under nitrogen protection. TLC (V 二氯甲烷 V 甲醇=15:1) Monitor the reaction to completion, adjust the pH to 10 with 1 M sodium hydroxide solution, extract with ethyl acetate (50 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (50 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 The mixture was purified at a ratio of 20:1 to obtain 523 mg of white solid intermediate 7, with a yield of 88.2%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm):7.40-7.21 (m, 8H), 7.13-6.91 (m, 1H), 4.54-4.39 (m, 2H), 3.96-3.74 (m, 4H),3.72-3.58 (m, 2H), 3.54-3.34 (m, 5H), 3.06-3.01 (m, 3H), 2.23-2.13 (m, 1H), 2.13-2.03 (m, 1H)

[0591] Step 7: Synthesis of tert-butyl carbamate (intermediate 8)

[0592]

[0593] Intermediate 7 (523 mg, 1.22 mmol), isopropyl acetate (10 mL), water (10 mL), 2-(Boc-amino)-2-methylpropionic acid (272 mg, 1.34 mmol), N,N'-dicyclohexylcarbodiimide (276 mg, 1.34 mmol), and 1-hydroxybenzotriazole (181 mg, 1.34 mmol) were added sequentially to a 100 mL single-necked flask. The reaction was carried out at room temperature for 3 h under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) After monitoring the reaction to completion, quench with water (50 mL), extract with ethyl acetate (50 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (50 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 The mixture was purified at a ratio of 20:1 to obtain 682 mg of white solid intermediate 8, with a yield of 91.0%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.59-7.45 (m, 1H), 7.41-7.21 (m, 8H), 7.20-6.87 (m, 2H), 4.87-4.65 (m, 1H), 4.57-4.39 (m, 2H), 3.97-3.77 (m, 3H), 3.77-3.38 (m, 5H), 3.07-3.02 (m, 3H), 2.24-2.04 (m, 2H), 1.39-1.31 (m, 9H), 1.31-1.25 (m, 6H).

[0594] Step 8 Synthesis of 2-amino-N-((2R)-3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxopropane-2-yl)-2-methylpropionamide (Example 6)

[0595]

[0596] Intermediate 8 (682 mg, 1.11 mmol), anhydrous ethanol (28 mL), and methanesulfonic acid (640 mg, 6.66 mmol) were added sequentially to a 100 mL single-necked flask. The reaction was carried out at 40 °C for 15 h under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction to completion, adjust the pH to 10 with 1 M sodium hydroxide solution, extract with ethyl acetate (50 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (50 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (20 g, V 二氯甲烷 V 甲醇 The compound was purified by a ratio of 20:1 to give 51 mg of white solid, as described in Example 6, with a yield of 8.9%.

[0597] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.25 (br, 1H), 7.42-7.20 (m, 8H), 7.13-6.91 (m, 1H), 4.83-4.62 (m, 1H), 4.58-4.41 (m, 2H), 3.95-3.68 (m, 4H), 3.68-3.35 (m, 6H), 3.08-3.02 (m, 3H), 2.25-2.04 (m, 2H), 1.21-1.11 (m, 6H).

[0598] HRMS (ESI): m / z [M+H] + C 26 H 34 Calculated value of N4O5S: 515.2328; Measured value: 515.2311.

[0599] Example 7 (R)-2-amino-2-methyl-N-(1-oxo-3-(benzyloxy-d2)-1-(1-(benzenesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)propyl-2-yl)propionamide

[0600] Step 1: Synthesis of (R)-[1-oxo-3-(benzoxy-d2)-1-(1-(benzenesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)propyl-2-yl] tert-butyl carbamate (intermediate 1)

[0601]

[0602] Add intermediate 3 (300 mg, 1.01 mmol) from Example 5, isopropyl acetate (4 mL), water (2 mL), intermediate 8 (301 mg, 0.92 mmol) from Example 3, HOBt (136 mg, 1.01 mmol), and DCC (208 mg, 1.01 mmol) to a 50 mL single-necked flask, and react under nitrogen protection at room temperature for 4.5 h. TLC (V 二氯甲烷 V 甲醇 =50:1) Monitor the reaction end. Add water (5 mL), extract with ethyl acetate (5 mL × 2), and collect the organic phase. Wash with saturated sodium chloride solution (5 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (20 g, V). 二氯甲烷 V 甲醇 The mixture was purified at a ratio of 50:1 to obtain 335 mg of colorless oily intermediate 1, with a yield of 59.9%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.83 (d, J=7.8 Hz, 2H), 7.73-7.64 (m, 1H), 7.58 (t, J=7.7 Hz, 2H), 7.51 (t, J=9.1 Hz, 1H), 7.37-7.30 (m, 6H), 7.24-7.21 (m, 0.5H), 7.13-7.06 (m, 1H), 7.05-6.96 (m, 1H), 6.79(d, J=7.5 Hz, 0.5H), 4.65 (br, 1H), 4.23 (d, J=13.2 Hz, 1H), 3.93 (s, 2H), 3.83 (br, 1H), 3.62-3.59 (m, 1H), 3.55-3.50 (m, 1H), 3.15-3.09 (m, 1H), 2.69-2.66 (m, 1H), 1.80-1.67 (m, 1H), 1.64-1.61 (m, 1H), 1.39 (s, 9H), 1.08-1.01(m, 2H).

[0603] Step 2: Synthesis of (R)-2-amino-3-(phenylmethoxy-d2)-1-(1-(benzenesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)prop-1-one (intermediate 2)

[0604]

[0605] Intermediate 1 (331 mg, 0.54 mmol), dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) were added to a 25 mL single-necked flask. The mixture was reacted under nitrogen protection at room temperature for 1.5 h. TLC (V 二氯甲烷 V 甲醇 =50:1) Monitor the reaction for completion. Add 1 M sodium hydroxide solution (5 mL), extract with dichloromethane (5 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (5 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (12 g, V). 二氯甲烷 V 甲醇 The mixture was purified at a ratio of 20:1 to give 150 mg of white solid intermediate 2, with a yield of 54.7%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.84-7.81 (m,2H), 7.71-7.67 (m, 1H), 7.57 (t, J=7.6 Hz, 2H), 7.52-7.47 (m, 1H), 7.38-7.20(m, 6H), 7.16 (d, J=7.5 Hz, 0.5H), 7.05-6.93 (m, 1H), 6.66 (d, J=7.5 Hz,0.5H), 4.31-4.24 (m, 1H), 3.92-3.88 (m, 4H), 3.45-3.41 (m, 2H), 3.12-2.93 (m,1H), 2.67-2.66 (m, 1H), 1.70-1.64 (m, 2H), 1.42-1.30 (m, 2H), 1.11-1.04 (m,2H).

[0606] Step 3: Synthesis of (R)-[2-methyl-1-oxo-1-([1-oxo-3-(benzoxy-d2)-1-(1-(benzenesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)propyl-2-yl]amino)propyl-2-yl] tert-butyl carbamate (intermediate 3)

[0607]

[0608] Intermediate 2 (140 mg, 0.28 mmol), isopropyl acetate (2.5 mL), water (2.5 mL), 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (62 mg, 0.30 mmol), HOBt (41 mg, 0.30 mmol), and DCC (63 mg, 0.30 mmol) were added to a 25 mL single-necked flask. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =30:1) Monitor the reaction end. Add water (5 mL), extract with ethyl acetate (5 mL × 2), and collect the organic phase. Wash with saturated sodium chloride solution (5 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 The mixture was purified at a ratio of 50:1 to obtain 193 mg of white solid intermediate 3, with a yield of 99.5%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.82(d, J=7.8 Hz, 2H), 7.69 (t, J=7.5 Hz, 1H), 7.57 (t, J=7.7 Hz, 2H), 7.53-7.48(m, 2H), 7.40-7.21 (m, 6H), 7.16 (br, 0.5H), 7.03-6.95 (m, 2H), 6.77 (d, J=7.4 Hz, 1H), 4.91 (q, J=6.8 Hz, 1H), 4.25 (t, J=15.2 Hz, 1H), 3.97-3.85 (m,3H), 3.60-3.47 (m, 2H), 3.14-3.02 (m, 1H), 2.75-2.61 (m, 1H), 1.73-1.60 (m,2H), 1.37-1.33 (m, 9H), 1.29-1.23 (m, 6H), 1.11-1.03 (m, 2H).

[0609] Step 4: Synthesis of (R)-2-amino-2-methyl-N-(1-oxo-3-(benzyloxy-d2)-1-(1-(benzenesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)propyl-2-yl)propionamide (Example 7)

[0610]

[0611] Intermediate 3 (190 mg, 0.27 mmol), dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) were added to a 25 mL single-necked flask. The mixture was reacted under nitrogen protection at room temperature for 1 h. TLC (V 二氯甲烷 V 甲醇 =50:1) Monitor the reaction for completion. Add saturated sodium bicarbonate solution (5 mL), extract with dichloromethane (10 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (5 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (12 g, V). 二氯甲烷 V 甲醇 The compound was purified by a ratio of 50:1 to give 120 mg of white solid, as described in Example 7, with a yield of 75.0%.

[0612] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.27 (br, 1H), 7.87-7.76 (m, 2H), 7.69 (t, J=7.4 Hz, 1H), 7.57 (t, J=7.8 Hz, 2H), 7.50 (t, J=7.7 Hz, 1H), 7.42-7.19 (m, 6H), 7.14 (d, J=7.0 Hz, 0.5H), 7.04-6.95 (m, 1H), 6.73 (d, J=7.3 Hz,0.5H), 4.90 (br, 1H), 4.26 (br, 1H), 4.01-3.74 (m, 3H), 3.60-3.50 (m, 2H), 3.16-3.00 (m, 1H), 2.72-2.67 (m, 1H), 2.00 (br, 2H), 1.57-1.42 (m, 2H), 1.18-1.14 (m, 6H), 1.08-1.05 (m, 2H).

[0613] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 177.40 (177.29), 168.47 (168.20), 140.71, 139.56 (139.40), 138.57 (138.36), 136.65, 134.39, 130.00, 128.87,128.74, 128.10, 127.45, 124.70 (124.64), 123.90 (123.64), 114.92, 70.85,70.08, 58.60, 54.72, 48.75, 48.23, 43.44 (43.34), 42.44 (42.38), 39.07(38.91), 36.58 (36.48), 35.89 (35.82), 29.32, 29.04;

[0614] HRMS (ESI): m / z [M+H] + C 32 H 36 Calculated value of D2N4O5S: 593.2767; Measured value: 593.2769.

[0615] Example 8 (R)-N-(3-(benzoxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-2-methyl-2-(4-methylpiperazin-1-yl)propionamide

[0616] Step 1: Synthesis of methyl 2-methyl-2-(4-methylpiperazin-1-yl)propionate (Intermediate 2)

[0617]

[0618] N-methylpiperazine (2.50 g, 24.96 mmol), methyl 2-bromoisobutyrate (1, 5.42 g, 29.95 mmol), potassium carbonate (6.90 g, 49.92 mmol), and acetonitrile (30 mL) were added to a 100 mL single-necked flask. The mixture was reacted overnight at 80 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool to room temperature, quench the reaction mixture with water (50 mL), extract with ethyl acetate (200 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (20 g, V 二氯甲烷 V 甲醇 =10:1), yielding 1.40 g of white solid intermediate 2, yield 28.0%. 1 H NMR (400MHz, CDCl3) δ (ppm): 3.69 (s, 3H), 2.61 (s, 4H), 2.45 (s, 4H), 2.27 (s, 3H), 1.31 (s, 6H).

[0619] Step 2: Synthesis of 2-methyl-2-(4-methylpiperazin-1-yl)propionic acid (intermediate 3)

[0620]

[0621] An aqueous solution (11 mL) of intermediate 2 (1.40 g, 6.99 mmol), methanol (14 mL), and sodium hydroxide (419 mg, 10.48 mmol) was added to a 50 mL single-necked flask, and the reaction was carried out at 45 °C for 5 h. TLC (V1) was then recorded. 二氯甲烷 V 甲醇 =10:1) Monitor the reaction of the raw materials to ensure complete reaction. Filter the reaction solution through filter paper, add water (20 mL), wash with dichloromethane (30 mL × 2), adjust the pH of the aqueous phase to 2 with 1M HCl, and add mixed solvent (V 二氯甲烷 V 甲醇Extracted at a ratio of 5:1 (30 mL × 10), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.00 g of crude pale yellow solid intermediate 3, which was used directly in the next step without purification. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 11.86 (br, 1H), 3.59-3.56 (m, 4H), 3.43 (s 4H), 2.78 (s, 3H), 1.51 (s, 6H).

[0622] Step 3: Synthesis of (R)-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-2-methyl-2-(4-methylpiperazin-1-yl)propionamide (Example 8)

[0623]

[0624] Intermediate 3 (476 mg, 1.07 mmol), Intermediate 5 from Example 1 (200 mg, 1.07 mmol), N,N'-dicyclohexylcarbodiimide (243 mg, 1.18 mmol), 1-hydroxybenzotriazole (159 mg, 1.18 mmol), isopropyl acetate (10 mL), and water (5 mL) were added to a 50 mL single-necked flask. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction of the starting materials to ensure complete reaction. Add water (30 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (50 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (20 g, V 二氯甲烷 V 甲醇 =10:1), yielding 38 mg of the gray solid compound of Example 8, with a two-step yield of 5.8%.

[0625] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.40-7.32 (m, 6H), 7.29-7.23 (m,2H), 7.14-7.04 (m, 2H), 5.36-5.34 (m, 0.5H), 5.24-5.23 (m, 0.5H), 4.59-4.51(m, 2H), 4.38 (t, J=14.3 Hz, 1H), 3.97-3.93 (m, 2H), 3.75-3.70 (m, 1H), 3.54(br, 2H), 3.27-3.24 (m, 1H), 3.06 (s, 3H), 2.85 (q, J=12.4 Hz, 1H), 1.76-1.66(m, 11H), 1.61-1.58 (m, 2H), 1.28-1.26 (m, 6H), 1.09-1.07 (m, 2H).

[0626] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 171.91, 171.51, 141.07, 138.65, 138.48 (138.39), 128.44, 128.37, 127.69, 127.61, 127.52, 123.67, 123.49,123.36, 112.80, 74.05, 73.36, 72.50 (72.27), 58.38, 50.16, 49.57, 42.83(42.71), 42.19 (42.14), 38.79 (38.67), 36.36 (36.25), 35.67 (35.51), 34.35.

[0627] HRMS (ESI): m / z [M+K] + C 32 H 45 Calculated value of KN5O5S: 650.2778; Measured value: 650.3690.

[0628] Example 9 (R)-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-1-(4-methylpiperazin-1-yl)cyclopropane-1-carboxamide

[0629] Step 1: Synthesis of ethyl 1-(4-benzylpiperazin-1-yl)cyclopropane-1-carboxylate (intermediate 2)

[0630]

[0631] To a 50 mL single-necked flask, ethyl 1-aminocyclopropane-1-carboxylate hydrochloride (1, 5.00 g, 30.19 mmol), N-benzyl-bis(o-chloroethylamine) hydrochloride (8.92 g, 33.21 mmol), EtOH (65 mL), and N,N-diisopropylethylamine (39.21 g, 303.41 mmol) were added sequentially. The reaction was carried out at 90 °C for 16 h under nitrogen protection. TLC (V1) was used to record the reaction. 石油醚 V 乙酸乙酯 =4:1) Monitor the reaction to completion, concentrate, pour into water (200 mL), extract with ethyl acetate (150 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (50 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (120 g, V 石油醚 V 乙酸乙酯 The mixture was purified by a ratio of 4:1 to obtain 4.16 g of pale yellow oily intermediate 2, with a yield of 47.8%. 1 H NMR (400 MHz, CDCl3) δ (ppm):7.34-7.22 (m, 5H), 4.13 (q, J=7.1 Hz, 2H), 3.49 (s, 2H), 2.97 (br, 4H), 2.35(br, 4H), 1.28-1.23 (m, 5H), 0.89 (q, J=3.7 Hz, 2H).

[0632] Step 2: Synthesis of ethyl 1-(piperazin-1-yl)cyclopropane-1-carboxylic acid ester hydrochloride (intermediate 3)

[0633]

[0634] Intermediate 2 (4.14 g, 14.42 mmol) and DCM (35 mL) were added sequentially to a 250 mL single-necked flask. Under nitrogen protection, the mixture was cooled to 0 °C, and then 1-chloroethyl chloroformate (3.09 g, 21.63 mmol) was added dropwise. The reaction was carried out at room temperature for 1 h. The mixture was then concentrated, and EtOH (35 mL) was added. Under nitrogen protection, the reaction was carried out overnight at 90 °C. TLC (V1) was performed. 石油醚 V 乙酸乙酯 =3:1) Monitor the reaction to complete, concentrate, and add the residue to a mixed solvent (V2). 乙醇 V 甲基叔丁基醚 =5:1, 10 mL), under nitrogen protection, the mixture was pulped at room temperature for 0.5 h, filtered, the filter cake was collected and dried with an oil pump for 2 h to obtain 2.60 g of white solid intermediate 3, with a yield of 77.2%. 1H NMR (400 MHz, CD3OD) δ (ppm): 4.15 (q, J=7.1 Hz, 2H), 3.37 (t, J=5.2 Hz, 4H), 3.20 (t, J=5.2 Hz, 4H), 1.38 (q, J=4.2 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H), 1.18 (q, J=4.2Hz, 2H).

[0635] Step 3: Synthesis of ethyl 1-(4-methylpiperazin-1-yl)cyclopropane-1-carboxylic acid ester (intermediate 4)

[0636]

[0637] Intermediate 3 (100 mg, 0.43 mmol), sodium bicarbonate (40 mg, 0.47 mmol), paraformaldehyde (150 mg, 5.11 mmol), MeOH (1 mL), water (1 mL), and sodium cyanoborohydride (100 mg, 1.58 mmol) were added sequentially to a 25 mL single-necked flask. The reaction was carried out at room temperature for 16 h under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) After monitoring the reaction to completion, water (20 mL) was added, followed by extraction with dichloromethane (15 mL × 3), and the organic phase was collected. The mixture was washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to rapid preparative chromatography (20 g, V... 二氯甲烷 V 甲醇 The mixture was purified at a ratio of 30:1 to obtain 49 mg of colorless oily intermediate 4, with a yield of 54.4%. 1 H NMR (400 MHz, CD3OD) δ (ppm): 4.12 (q, J=7.1 Hz, 2H), 3.03 (br, 4H), 2.37 (br, 4H), 2.24 (s, 3H), 1.28-1.22 (m, 5H), 0.93 (q, J=3.8 Hz,2H).

[0638] Step 4: Synthesis of 1-(4-methylpiperazin-1-yl)cyclopropane-1-carboxylic acid hydrochloride (intermediate 5)

[0639]

[0640] Intermediate 4 (100 mg, 0.47 mmol) and 6 M HCl solution (1.5 mL) were added sequentially to a 10 mL sealed container. The reaction was carried out at 120 °C for 16 h under nitrogen protection. TLC (V 二氯甲烷V 甲醇 =15:1) After monitoring the reaction to complete, the mixture was concentrated, and the residue was slurried with ethyl acetate (10 mL) for 0.5 h. After filtration, 100 mg of white solid intermediate 5 was obtained, with a yield of 97.1%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.71-10.59 (m, 1H), 3.51-3.41 (m, 2H), 3.32 (d, J=11.2 Hz, 2H), 3.03-2.97 (m, 2H), 2.93-2.82 (m, 2H), 2.69 (s, 3H), 1.22-1.18 (m, 2H), 1.04-0.98 (m, 2H).

[0641] Step 5: Synthesis of (R)-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-1-(4-methylpiperazin-1-yl)cyclopropane-1-carboxamide (Example 9)

[0642]

[0643] Intermediate 5 (70 mg, 0.30 mmol), DMF (5 mg, 0.07 mmol), and DCM (2 mL) were added sequentially to a 25 mL single-necked flask. Under nitrogen protection, the mixture was cooled to 0 °C, and then oxalyl chloride (55 mg, 0.43 mmol) was added dropwise. The reaction was carried out at room temperature for 4 h. TLC (V 二氯甲烷 V 甲醇 =10:1) The reaction was monitored until completion, concentrated, and 75 mg of white solid was obtained. This solid, along with intermediate 5 from Example 1 (100 mg, 0.22 mmol), DCM (5 mL), and triethylamine (114 mg, 1.13 mmol), was added sequentially to a 25 mL single-necked flask. The reaction was carried out under nitrogen protection at room temperature for 16 h. TLC (V 二氯甲烷 V 甲醇 =10:1) After monitoring the reaction to completion, water (20 mL) was added to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3), and the organic phase was collected. The mixture was washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to rapid preparative chromatography (20 g, V... 二氯甲烷 V 甲醇 The compound was purified by a ratio of 50:1 to give 100 mg of white solid, Example 9 compound, with a yield of 72.7%.

[0644] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.50-8.43 (m, 1H), 7.38-7.20 (m, 7.5H), 7.06-6.99 (m, 1H), 6.91-6.89 (m, 0.5H), 5.04-4.99 (m, 1H), 4.54-4.39(m, 3H), 3.98-3.94 (m, 1H), 3.90-3.89 (m, 2H), 3.65-3.62 (m, 2H), 3.23-3.13(m, 1H), 3.04 (s, 3H), 2.85-2.79 (m, 1H), 2.38 (br, 8H), 2.17 (s, 3H), 1.82-1.51 (m, 4H), 1.02-0.98 (m, 2H), 0.96-0.93 (m, 2H).

[0645] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 172.52 (172.43), 168.22 (168.05), 141.53, 138.96 (138.77), 138.63 (138.50), 128.90, 128.77 (128.73), 128.06,127.99 (127.93), 124.03, 123.86, 113.24, 72.82 (72.60), 71.04 (70.12), 58.72,55.76 (55.72), 49.59, 49.45 (49.05), 47.54, 46.16, 43.17 (43.04), 42.70 (42.60), 36.51, 35.96 (35.82), 34.76 (34.73), 11.25.

[0646] HRMS (ESI): m / z [M+H] + C 32 H 43 Calculated N5O5: 610.3063; Measured: 610.3010.

[0647] Example 10 (R)-2-amino-N-(3-(benzyloxy)-1-(1'-(methanesulfonyl)spiro[azazodin-3,3'-indoline]-1-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0648] Step 1: Synthesis of tert-butyl 2-oxoindoline-1-carboxylic acid (intermediate 2)

[0649]

[0650] 2-Indoleone (1, 80.0 g, 0.60 mol), tetrahydrofuran (800 mL), sodium carbonate (223.0 g, 2.10 mol), and di-tert-butyl dicarbonate (328.0 g, 1.50 mol) were added sequentially to a 2 L reaction flask. The reaction was carried out under nitrogen protection at room temperature for 24 h. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction of raw materials until complete, filter the reaction solution through diatomaceous earth, collect the filtrate, concentrate and purify by column chromatography (V 乙酸乙酯 V 石油醚 =1:3), yielding 90.0 g of white solid intermediate 2, with a yield of 64.2%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.68 (d, J=8.4 Hz, 1H), 7.35-7.26 (m, 2H), 7.18-7.09(m, 1H), 3.74 (s, 2H), 1.56 (s, 9H).

[0651] Step 2: Synthesis of tert-butyl 3,3-di(hydroxymethyl)-2-oxoindoline-1-carboxylic acid (intermediate 3)

[0652]

[0653] Intermediate 2 (40.00 g, 171.59 mmol), dioxane (400 mL), sodium carbonate (3.63 g, 34.31 mmol), and 37% wt formaldehyde aqueous solution (34.82 g, 428.98 mmol) were added sequentially to a 1 L reaction flask. The reaction was carried out under nitrogen protection at room temperature for 1 h. TLC (VL) was then used to measure the reaction mixture. 乙酸乙酯 V 石油醚 =1:1) Monitor the reaction of the raw materials to ensure complete reaction, filter the reaction solution, collect the filtrate, quench with water (200 mL), extract with ethyl acetate (500 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (400 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate and dry with a vacuum oil pump to obtain 49 g of light red solid intermediate 3, yield 97.4%. 1H NMR(400 MHz, DMSO-d6) δ (ppm): 87.71 (d, J=8.0 Hz, 1H), 7.42 (dd, J1=7.2 Hz, J2=1.6 Hz, 1H), 7.31 (td, J1=8.0 Hz, J2=1.6 Hz, 1H), 7.18 (td, J1=7.2 Hz, J2=1.6Hz, 1H), 4.90 (t, J=5.2 Hz, 2H), 3.76-3.63 (m, 4H), 1.57 (s, 9H).

[0654] Step 3: Synthesis of 3,3-bis(hydroxymethyl)indoline-2-one (intermediate 4)

[0655]

[0656] Intermediate 3 (49 g, 167.05 mmol) and dichloromethane (500 mL) were added sequentially to a 1 L reaction flask under nitrogen protection. Trifluoroacetic acid (100 mL) was added dropwise under ice bath conditions. After the addition was complete, the reaction was allowed to proceed at room temperature for 1.5 h. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the raw materials to ensure complete reaction. The reaction solution is directly concentrated and dried by a vacuum oil pump for 8 hours to obtain 49 g of crude red oily intermediate 4, which is used directly in the next step without purification. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.18 (s, 1H), 7.28 (dd,J1=7.6 Hz, J2=1.2 Hz, 1H), 7.14 (td, J1=7.6 Hz, J2=1.2 Hz, 1H), 6.93 (td, J1=7.6 Hz, J2=1.2 Hz, 1H), 6.78 (d, J=7.6 Hz, 1H), 4.70 (br, 2H), 3.71 (d, J=10.2 Hz, 2H), 3.58 (d, J=10.3 Hz, 2H).

[0657] Step 4: Synthesis of 3,3'-dihydroxymethylindoline (intermediate 5)

[0658]

[0659] Intermediate 4 (49 g, 253.62 mmol) and tetrahydrofuran (200 mL) were added sequentially to a 2 L three-necked flask under nitrogen protection. Borane dimethyl sulfide complex (507 mL, 1014.48 mmol, 2 M) was added dropwise at -10 °C. The mixture was reacted at 70 °C for 3 h, then cooled to 0 °C, and methanol (507 mL) was added dropwise. The mixture was then heated to 70 °C and reacted for 1 h. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the raw materials to ensure complete reaction. The reaction solution is directly concentrated to remove a large amount of solvent. Water (200 mL) is added to quench the reaction, and ethyl acetate (500 mL × 8) is added for extraction. The organic phases are combined, washed with saturated sodium chloride solution (500 mL × 3), dried with anhydrous sodium sulfate, filtered, concentrated, and dried by vacuum oil pump for 3 h to obtain 40 g of crude product, pale yellow solid intermediate 5, which is used directly in the next step without purification. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.00 (dd, J1=7.2 Hz, J2=1.2 Hz, 1H), 6.89 (td, J1=7.6Hz, J2=1.2 Hz, 1H), 6.47 (td, J1=7.6 Hz, J2=1.2 Hz, 1H), 6.43 (d, J=7.6 Hz, 1H), 5.32 (s, 1H), 4.59 (t, J=5.2 Hz, 2H), 3.56-3.46 (m, 4H), 3.26 (s, 2H).

[0660] Step 5: Synthesis of tert-butyl 3,3-bis(hydroxymethyl)indoline-1-carboxylic acid (intermediate 6)

[0661]

[0662] Intermediate 5 (20 g, 111.60 mmol), tetrahydrofuran (300 mL), and di-tert-butyl dicarbonate (27 g, 122.76 mmol) were added sequentially to a 500 mL reaction flask. The reaction was carried out under nitrogen protection at 35 °C for 16 h. TLC (V1) was then performed. 乙酸乙酯 V 石油醚 =1:1) Monitor the reaction of raw materials until complete, directly mix the reaction solution, concentrate and purify by column chromatography (V 乙酸乙酯 V 石油醚 =1:1), yielding 11.5 g of white solid intermediate 6, with a three-step yield of 49.4%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.68 (br,1H), 7.21 (dd, J1=7.6 Hz, J2=1.2 Hz, 1H), 7.15 (td, J1=7.6 Hz, J2=1.2 Hz, 1H), 6.90 (td, J1=7.6 Hz, J2=1.2 Hz, 1H), 4.82 (t, J=5.2 Hz, 2H), 3.76 (s, 2H), 3.60-3.45 (m, 4H), 1.51 (s, 9H).

[0663] Step 6: Synthesis of 1-diphenylmethylspiro[azacyclobutane-3,3'-indoline]-1'-carboxylic acid tert-butyl ester (intermediate 7)

[0664]

[0665] Intermediate 6 (9.0 g, 32.22 mmol), dichloromethane (120 mL), and DIPEA (20.8 g, 161.10 mmol) were added sequentially to a 500 mL reaction flask under nitrogen protection. The mixture was cooled to -40 °C, and a solution of trifluoromethanesulfonic anhydride (19.89 g, 70.88 mmol) in DCM (40 mL) was added dropwise. The reaction was maintained at this temperature for 1 h. The temperature was then raised to -25 °C, and a solution of diphenylmethane (5.75 g, 31.58 mmol) in dichloromethane (20 mL) was added dropwise. The reaction was maintained at this temperature for 1.5 h, then raised to room temperature and continued for 16 h. TLC (V 乙酸乙酯 V 石油醚 =3:1) Monitor the raw material reaction to ensure complete reaction, directly mix the reaction solution, concentrate and rapidly purify by preparative chromatography (120g, V). 乙酸乙酯 V 石油醚 =1:100), yielding 7.7 g of white solid intermediate 7, with a yield of 55.7%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.78 (d, J=7.6 Hz, 1H), 7.49 (d, J=6.8 Hz, 4H), 7.29 (t, J=7.6 Hz, 5H), 7.22-7.15 (m, 3H), 7.08 (t, J=7.6 LCMS(ESI): m / z [M+H] + C28 H 30 Calculated N2O2 value: 427; Measured value: 427.

[0666] Step 7 Synthesis of 1-diphenylmethylspiro[azacyclobutane-3,3'-indoline] (intermediate 8)

[0667]

[0668] Intermediate 7 (10 g, 23.44 mmol) and HCl / EA solution (100 mL, 4 M) were added to a 500 mL reaction flask. The mixture was reacted at room temperature for 1 h under nitrogen protection. TLC (V1) was then performed. 石油醚 V 乙酸乙酯 =3:1) Monitor the reaction of the raw materials to ensure complete reaction, directly concentrate and evaporate a large amount of HCl / EA solution, dissolve in water (50 mL), adjust pH to 9 with saturated sodium bicarbonate solution, extract with ethyl acetate (300 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (300 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (120 g, V 乙酸乙酯 V 石油醚 =1:5), yielding 6.65 g of pale yellow solid intermediate 8, with a yield of 87.6%. 1 H NMR(400 MHz, DMSO-d6) δ (ppm): 7.48 (d, J=7.6 Hz, 5H), 7.28 (t, J=7.6 Hz, 4H), 7.17 (t, J=7.2 Hz, 2H), 6.95 (td, J1=7.6 Hz, J2=1.2 Hz, 1H), 6.65 (td, J1=7.6Hz, J2=1.2 Hz, 1H), 6.46 (d, J=7.6 Hz, 1H), 4.49 (s, 1H), 4.52 (s, 1H), 3.60 (d, J=1.9 Hz, 2H), 3.23-3.15 (m, 4H).

[0669] Step 8 Synthesis of 1-diphenylmethyl-1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline] (intermediate 9)

[0670]

[0671] Intermediate 8 (6.7 g, 20.52 mmol) and DCM (70 mL) were added to a 250 mL reaction flask. Under nitrogen protection, triethylamine (6.24 g, 61.56 mmol) and methanesulfonyl chloride (3.50 g, 36.94 mmol) were added dropwise sequentially in an ice bath at room temperature for 1 h under nitrogen protection. TLC (V 石油醚 V 乙酸乙酯 =3:1) Monitor the reaction of the raw materials until complete, quench with water (100 mL), extract with dichloromethane (150 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (140 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (120 g, V 乙酸乙酯 V 石油醚 =1:3), yielding 7.4 g of white solid intermediate 9, with a yield of 89.1%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.83 (d, J=6.8 Hz, 1H), 7.53-7.47(m, 4H), 7.33-7.22 (m, 6H), 7.22-7.15 (m, 3H), 4.57 (s, 1H), 4.13 (s, 2H), 3.35 (d, J=7.2 Hz, 2H), 3.26 (d, J=7.2 Hz, 2H), 2.94 (s, 3H).

[0672] Step 9: Synthesis of 1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline] (intermediate 10)

[0673]

[0674] Intermediate 9 (6 g, 14.83 mmol), ethanol (120 mL), ethyl acetate (12 mL), 10% Pd / C (3.00 g, 50% wt), and 10% Pd(OH)₂ / C (3.00 g, 50% wt) were added to a 500 mL hydrogenation flask, and the reaction was carried out at 55°C for 16 h under 70 psi hydrogen pressure. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction of the raw materials to ensure complete reaction. Filter the reaction solution through a diatomaceous earth mat. Wash the filter cake with methanol (500 mL × 2). Collect the filtrate, concentrate it, and purify it by rapid preparative chromatography (120 g, V). 二氯甲烷 V 甲醇 =20:1), yielding 2.6 g of white solid intermediate 10, with a yield of 73.6%. 1H NMR (400 MHz, DMSO-d6) δ (ppm):7.70 (d, J=7.6 Hz, 1H), 7.29-7.23 (m, 2H), 7.15 (td, J1=7.6 Hz, J2=1.6 Hz,1H), 4.13 (s, 2H), 3.75 (d, J=7.8 Hz, 2H), 3.69 (d, J=7.8 Hz, 2H), 2.97 (s,3H). LCMS (ESI): m / z [M+H] + C 11 H 14 Calculated N2O2S value: 239; Measured value: 239.

[0675] Step 10

[0676] (R)-(3-(benzyloxy)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxopropane-2-yl)tert-butyl carbamate

[0677] Synthesis of (Intermediate 11)

[0678]

[0679] Intermediate 10 (300 mg, 1.26 mmol), N-Boc-O-benzyl-D-serine (447 mg, 1.51 mmol), IPAc (8 mL), water (2 mL), DCC (312 mg, 1.51 mmol), and HOBt (204 mg, 1.51 mmol) were added sequentially to a 50 mL reaction flask. The reaction was carried out under nitrogen protection at room temperature for 16 h. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the raw materials until complete, quench with water (20 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (15 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (20 g, V 乙酸乙酯 V 石油醚 =1:1), yielding 540 mg of white solid intermediate 11, with a yield of 83.2%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.49 (d, J=7.6 Hz,0.5H), 7.38-7.19 (m, 8H), 7.13-7.08 (m, 1H), 7.02 (t, J=7.2 Hz, 0.5H), 4.57-4.43 (m, 3.5H), 4.33-4.12 (m, 4.5H), 4.01-3.90 (m, 1H), 3.69-3.53 (m, 2H), 2.99 (d, J=1.2 Hz, 3H), 1.39 (d, J=4.8 Hz, 9H).

[0680] Step 11 Synthesis of (R)-2-amino-3-(benzyloxy)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)propane-1-one (intermediate 12)

[0681]

[0682] Intermediate 11 (540 mg, 1.05 mmol), ethanol (8 mL), and methanesulfonic acid (705 mg, 7.33 mmol) were added to a 50 mL reaction flask. The mixture was reacted at 40 °C for 24 h under nitrogen protection. TLC (V1) was then performed. 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the raw materials until complete, cool the reaction solution to room temperature, add saturated sodium bicarbonate to adjust the pH to 9, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (15 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (20 g, V 二氯甲烷 V 甲醇 =100:1), yielding 310 mg of white solid intermediate 12, yield 73.5%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.55 (d, J=7.6 Hz, 0.5H), 7.38-7.30 (m, 5H), 7.28-7.24 (m,1.5H), 7.24-7.13 (m, 1.5H), 7.01-6.97 (m, 0.5H), 4.52-4.50 (m, 2.5H), 4.46-4.39 (m, 1H), 4.30-4.28 (m, 0.5H), 4.22-4.16 (m, 2.5H), 4.11-4.07 (m, 0.5H), 4.02-3.94 (m, 1H), 3.55-3.51 (m, 1H), 3.48-3.44 (m, 2H), 2.99 (d, J=1.2 Hz,3H).

[0683] Step 12 Synthesis of (R)-[1-[(3-(benzyloxy)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxopropyl-2-yl)amino]-2-methyl-1-oxopropyl-2-yl] tert-butyl carbamate (intermediate 13)

[0684]

[0685] Intermediate 12 (314 mg, 0.76 mmol), N-tert-butoxycarbonyl-2-methylalanine (167 mg, 0.83 mmol), IPAc (5 mL), water (2 mL), DCC (172 mg, 0.83 mmol), and HOBt (112 mg, 0.83 mmol) were added to a 50 mL reaction flask. The mixture was reacted under nitrogen protection at room temperature for 16 h. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the raw materials until complete, quench with water (20 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (15 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (20 g, V 乙酸乙酯 V 石油醚 =1:1), yielding 407 mg of white solid intermediate 13, with a yield of 89.0%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.67-7.51 (m, 1H), 7.44-7.22 (m, 8H), 7.12 (t, J=7.2 Hz, 0.5H), 7.08-6.85 (m, 1.5H), 4.60-4.55(m, 1.5H), 4.50 (d, J=6.8 Hz, 2H), 4.46 (br, 1H), 4.31 (d, J=8.8 Hz, 0.5H), 4.24-4.10 (m, 3H), 4.00-3.95 (m, 1H), 3.66-3.53 (m, 2H), 2.99 (d, J=2.8 Hz,3H), 1.36 (d, J=3.2 Hz, 9H), 1.32-1.27 (m, 6H). HRMS (ESI): m / z [M+H] + C 30 H 40 Calculated value of N4O7S: 601.2696; Measured value: 601.2665.

[0686] Step 13 Synthesis of (R)-2-amino-N-(3-(benzyloxy)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxopropyl-2-yl)-2-methylpropionamide (Example 10)

[0687]

[0688] Intermediate 13 (407 mg, 0.68 mmol), ethanol (8 mL), and methanesulfonic acid (390 mg, 4.06 mmol) were added to a 50 mL reaction flask. The mixture was reacted at 40 °C for 24 h under nitrogen protection. TLC (V1) was then performed. 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the raw materials until complete, cool the reaction solution to room temperature, add saturated sodium bicarbonate to adjust the pH to 9, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (15 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =500:1), yielding 200 mg of the white solid compound of Example 10, with a yield of 59.0%.

[0689] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.26 (br, 1H), 7.51 (d, J=7.6 Hz,0.5H), 7.40-7.22 (m, 7.5H), 7.13 (td, J1=7.6 Hz, J2=1.6 Hz, 0.5H), 7.03 (t, J=7.6 Hz, 0.5H), 4.59-4.42 (m, 4.5H), 4.30 (d, J=8.8 Hz, 0.5H), 4.26-4.16 (m,2.5H), 4.12 (d, J=11.2 Hz, 0.5H), 4.04-3.96 (m, 1H), 3.67-3.60 (m, 2H), 2.99(d, J=3.2 Hz, 3H), 2.30-2.61 (m, 2H), 1.23-1.18 (m, 6H).

[0690] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 177.64 (177.59), 170.12 (170.00), 141.92, 138.58 (138.51), 135.81 (135.67), 129.62 (129.56), 128.83 (128.80),128.11, 128.08, 128.05, 127.95, 124.63, 124.02, 123.68, 113.41 (113.35),72.85 (72.70), 70.29 (69.85), 63.43 (63.35), 61.54 (61.36), 60.43 (60.25), 54.74 (54.72), 49.62 (49.06), 34.85, 29.31 (29.26), 29.04 (28.99).

[0691] HRMS (ESI): m / z [M+H] + C 25 H 32 Calculated value of N4O5S: 501.2172; Measured value: 501.2168.

[0692] Example 11 Synthesis of (R)-2-amino-N-(3-(benzyloxy)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxopropyl-2-yl)-2-methylpropionamide methanesulfonate (Example 11)

[0693]

[0694] Add 200 mg (0.40 mmol) of Compound 10 from Example 10 and 20 mL of ethyl acetate to a 25 mL single-necked flask in sequence. Under nitrogen protection, stir until clear. Then, add dropwise a solution of 42 mg (0.44 mmol) of methanesulfonic acid in ethyl acetate (2 mL). A solid precipitates out, and the reaction is carried out at room temperature for 2 h. Filter, collect the filter cake, and slurry it overnight in low-boiling petroleum ether (15 mL). Filter again, and dry the filter cake under vacuum at 45 °C for 6 h to obtain 180 mg of white solid of Compound 11 from Example 11, yield 75.5%.

[0695] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.61 (d, J=7.6 Hz, 0.5H), 8.26 (d,J=7.6 Hz, 0.5H), 8.14 (br, 3H), 7.48 (d, J=7.6 Hz, 0.5H), 7.42-7.22 (m,7.5H), 7.16 (t, J=7.2 Hz, 1H), 7.06 (t, J=7.2 Hz, 1H), 4.67-4.57 (m, 1H), 4.57-4.43 (m, 3H), 4.37-4.30 (m, 1H), 4.26-4.13 (m, 3H), 4.03-3.99 (m, 1H), 3.78-3.74 (m, 1H), 3.68-3.61 (m, 1H), 3.01 (s, 3H), 2.31 (s, 3H), 1.49 (d, J=2.8 Hz, 3H), 1.47 (s, 3H).

[0696] 13C NMR (101 MHz, DMSO-d6) δ (ppm): 172.12 (172.04), 169.68 (169.45), 141.96 (141.93), 138.56 (138.49), 135.83 (135.59), 129.72 (129.65), 128.82(128.79), 128.07 (127.96), 124.68 (124.61), 123.86 (123.64), 113.42 (113.30),72.84 (72.69), 69.33 (68.96), 63.59 (63.44), 61.37, 60.34 (60.19), 56.97, 49.91 (49.60), 40.99 (40.91), 34.88 (34.85), 24.06 (24.03), 23.71, 22.21, 14.39.

[0697] HRMS (ESI): m / z [M-MsOH+H] + C 26 H 36 Calculated value of N4O8S2: 501.2172; Measured value: 501.2154.

[0698] Example 12 (R)-2-amino-N-(3-(benzyloxy)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxopropyl-2-yl)-2-methylpropionamide hydrochloride

[0699]

[0700] Compound of Example 10 (200 mg, 0.40 mmol) and ethyl acetate (20 mL) were added sequentially to a 25 mL single-necked flask under nitrogen protection and stirred until clear. Then, HCl / EA solution (0.8 mL, 1 mol / L ethyl acetate solution) was slowly added dropwise, resulting in the precipitation of a solid. The reaction was carried out at room temperature for 3 h. The mixture was filtered, and the filter cake was collected and slurried overnight in low-boiling petroleum ether (15 mL). After filtration, the filter cake was dried under vacuum at 45°C for 6 h to obtain 175 mg of white solid of compound of Example 12, with a yield of 81.6%.

[0701] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.65 (d, J=7.6 Hz, 0.5H), 8.59 (d,J=7.6 Hz, 0.5H), 8.27 (br, 3H), 7.49 (d, J=7.6 Hz, 0.5H), 7.39-7.24 (m,7.5H), 7.16 (t, J=7.2 Hz, 0.5H), 7.06 (t, J=7.2 Hz, 0.5H), 4.64-4.58 (m, 1H), 4.55-4.50 (m, 3H), 4.39-4.30 (m, 1H), 4.23-4.19 (m, 3H), 4.03-3.98 (m, 1H), 3.76-3.72 (m, 1H), 3.68-3.63 (m, 1H), 3.01 (s, 3H), 1.51 (s, 3H), 1.49 (s, 3H).

[0702] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 172.19 (172.07), 169.73 (169.49), 141.94, 138.59 (138.53), 135.84 (135.64), 129.68 (129.63), 128.80 (128.77),128.07 (127.98), 124.71 (124.61), 123.87 (123.76), 113.39 (113.31), 72.82(72.69), 69.36 (69.02), 63.60 (63.48), 61.45, 60.31 (60.20), 57.00 (50.11), 49.67, 41.00 (40.91), 34.91, 24.03, 23.70 (23.64).

[0703] HRMS (ESI): m / z [M-HCl+H] + C 25 H 33 Calculated value of ClN4O5S: 501.2172; Measured value: 501.2150.

[0704] Example 13 (R)-2-amino-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0705] Step 1: Synthesis of 1'-benzylspiro[indoline-3,4'-piperidine]-2-one (intermediate 2)

[0706]

[0707] 2-Indolone (1, 2.5 g, 18.8 mmol) and THF (100 mL) were added sequentially to a 500 mL three-necked flask under nitrogen protection. NaHMDS (2 M THF solution, 42 mL, 83.6 mmol) was added dropwise at -78 °C. After incubating for 30 min, N-benzyl-bis(o-chloroethylamine) hydrochloride (5.0 g, 18.8 mmol) was added, and the reaction was carried out overnight at 70 °C. TLC (V 石油醚 V 乙酸乙酯 =1:1) Monitor the reaction of the raw materials to ensure complete reaction. Cool, quench with saturated NH4Cl solution (50 mL), extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated brine (300 mL), dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (80 g, V 石油醚 V 乙酸乙酯 =2:1), yielding 3.10 g of red solid intermediate 2, with a yield of 56.6%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.34 (s, 1H), 7.45 (d, J=6.8 Hz, 1H), 7.38-7.32 (m, 4H), 7.28-7.22 (m, 1H), 7.17 (td, J1=7.6 Hz, J2=1.2 Hz, 1H), 6.94 (td, J1=7.6 Hz,J2=1.2 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 3.61 (s, 2H), 2.86-2.78 (m, 2H),2.60-2.55 (m, 2H), 1.83-1.77 (m, 2H), 1.66-1.60 (m, 2H).

[0708] Step 2: Synthesis of 1'-benzyl-1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-2-one (intermediate 3)

[0709]

[0710] Intermediate 2 (2.46 g, 8.41 mmol) and THF (40 mL) were added to a 100 mL single-necked flask. Under nitrogen protection, NaH (60% wt, 504 mg, 12.62 mmol) was added in portions under ice bath conditions. After reacting for 15 min, methanesulfonyl chloride (1.19 g, 12.62 mmol) was added, and the reaction was carried out at room temperature for 3 h. TLC (V 二氯甲烷 V 甲醇 =25:1) Monitor the reaction of the starting materials to ensure complete reaction. Quench the reaction mixture with water (70 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (100 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (40 g, V 二氯甲烷 V 甲醇 =100:1), yielding 1.47 g of white solid intermediate 3, with a yield of 47.2%. 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.77 (d, J=8.0 Hz, 1H),7.39-7.31 (m, 5H), 7.29-7.26 (m, 2H), 7.20 (td, J1=7.6 Hz, J2=1.2 Hz, 1H),3.66 (s, 2H), 3.40 (s, 3H), 2.91-2.80 (m, 2H), 2.81-2.72 (m, 2H), 2.04-1.89(m, 4H).

[0711] Step 3: Synthesis of 1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-2-one (intermediate 4)

[0712]

[0713] Intermediate 3 (400 mg, 1.08 mmol), 1,2-dichloroethane (8 mL), 1,8-bis(dimethylaminonaphthalene) (108 mg, 0.51 mmol), and 1-chloroethyl chloroformate (250 mg, 1.74 mmol) were added sequentially to a 50 mL single-necked flask. The mixture was reacted at 85 °C for 1.5 h under nitrogen protection. The 1,2-dichloroethane was removed by concentration, and methanol (8 mL) was added. The reaction was then carried out at 65 °C for 0.5 h. TLC (V1) was performed. 二氯甲烷 V 甲醇 =10:1) Monitor the reaction of the raw materials to ensure complete reaction. Concentrate the reaction solution and perform rapid preparative chromatography purification (12 g, V 二氯甲烷 V 甲醇 =10:1), yielding 240 mg of white solid intermediate 4, with a yield of 79.3%. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.47 (br, 1H), 7.68-7.62 (d, J=8.0 Hz, 1H), 7.44-7.36 (m, 2H), 7.29(td, J1=7.6 Hz, J2=1.2 Hz, 1H), 3.57 (s, 3H), 3.34-3.27 (m, 4H), 2.23-2.13 (m, 2H), 2.06-1.98 (m, 2H).

[0714] Step 4: Synthesis of (R)-[3-(benzyloxy)-1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl] tert-butyl carbamate (intermediate 5)

[0715]

[0716] To a 25 mL single-necked flask, add intermediate 4 (230 mg, 0.82 mmol), N-Boc-O-benzyl-D-serine (267 mg, 0.90 mmol), HOBt (122 mg, 0.90 mmol), DCC (186 mg, 0.90 mmol), isopropyl acetate (6 mL), and water (3 mL). After addition, under nitrogen protection, react overnight at room temperature. TLC (V 石油醚 V 乙酸乙酯 =1:1) Monitor the reaction of the starting materials to ensure complete reaction. Quench with water (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (20 g, V 石油醚 V 乙酸乙酯 =2:1), yielding 150 mg of colorless oily intermediate 5, yield 42.6%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.64 (t, J=6.0Hz, 1H), 7.45 (d, J=7.6 Hz, 0.5H), 7.38-7.21 (m, 7H), 7.19-7.11 (m, 1.5H), 4.74 (q, J=7.2 Hz, 1H), 4.55-4.47 (m, 2H), 4.22-4.11 (m, 1H), 3.95-3.89 (m,1H), 3.77-3.63 (m, 2H), 3.57 (d, J=4.8 Hz, 4H), 3.48-3.38 (m, 1H), 1.85-1.77(m, 3H), 1.74-1.70 (m, 1H), 1.38 (s, 9H).

[0717] Step 5: Synthesis of 1'-(O-benzyl-D-serine)-1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-2-one (intermediate 6)

[0718]

[0719] Intermediate 5 (682 mg, 1.22 mmol), mesylate (705 mg, 7.34 mmol), and ethanol (21 mL) were added to a 100 mL single-necked flask. After addition, the mixture was reacted overnight at 40 °C under a nitrogen atmosphere. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction of the raw materials to ensure complete reaction. Adjust the pH to 8 by adding saturated sodium bicarbonate solution (40 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (20 g, V). 二氯甲烷 V 甲醇 =50:1), yielding 425 mg of white solid intermediate 6, with a yield of 76.1%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.64 (t, J=8.4 Hz, 1H), 7.51 (d, J=7.6 Hz, 0.5H), 7.36-7.23(m, 6H), 7.17-7.13 (m, 1H), 7.03 (d, J=7.2 Hz, 0.5H), 4.51 (s, 2H), 4.19 (d,J=13.6 Hz, 1H), 4.03-3.90 (m, 2H), 3.73-3.68 (m, 1H), 3.56 (s, 3H), 3.53-3.44(m, 3H), 2.03-1.98 (m, 1H), 1.85-1.78 (m, 2H), 1.76-1.68 (m, 1H).

[0720] Step 6 Synthesis of tert-butyl(R)-[1-[(3-(benzyloxy)-1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)amino]-2-methyl-1-oxopropyl-2-yl]carbamate (intermediate 7)

[0721]

[0722] Intermediate 6 (200 mg, 0.44 mmol), N-tert-butoxycarbonyl-2-methylalanine (98 mg, 0.48 mmol), DCC (99 mg, 0.48 mmol), HOBt (65 mg, 0.48 mmol), isopropyl acetate (4 mL), and water (4 mL) were added sequentially to a 50 mL single-necked flask. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Quench the reaction mixture with water (20 mL), extract with ethyl acetate (20 mL × 2), combine the organic phases, wash with saturated brine (30 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =200:1), yielding 326 mg of white solid intermediate 7, with a yield of 99.5%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.66-7.52(m, 2.5H), 7.39-7.26 (m, 6H), 7.23-7.14 (m, 1H), 7.09 (d, J=7.6 Hz, 0.5H), 7.01 (br, 1H), 5.57 (d, J=7.6 Hz, 2H), 5.04-4.97 (m, 1H), 4.50 (d, J=10.8 Hz, 2H), 4.23-4.17 (m, 1H), 3.9-3.87 (m, 1H), 3.74-3.68 (m, 1H), 3.56 (d, J=6.0Hz, 3H), 3.49-3.40 (m, 1H), 1.74-1.70 (m, 4H), 1.36 (s, 9H), 1.29 (s, 6H).

[0723] Step 7: Synthesis of (R)-2-amino-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide (Example 13)

[0724]

[0725] Intermediate 7 (325 mg, 0.51 mmol), ethanol (12 mL), and methanesulfonic acid (291 mg, 3.03 mmol) were added to a 50 mL single-necked flask. The mixture was reacted overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction of the raw materials to ensure complete reaction. Add saturated sodium bicarbonate solution (20 mL) to the reaction solution to adjust the pH to 8, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =50:1), yielding 160 mg of the white solid compound of Example 13, with a yield of 58.4%.

[0726] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.34 (br, 1H), 7.64 (t, J=8.0 Hz,1H), 7.51 (d, J=7.6 Hz, 0.5H), 7.38-7.26 (m, 6H), 7.25-7.15 (m, 1H), 7.08 (d,J=7.6 Hz, 0.5H), 4.99 (s, 1H), 4.54-4.51 (m, 2H), 4.22-4.18 (m, 1H), 3.94-3.89 (m, 1H), 3.76-3.72 (m, 1H), 3.67-3.59 (m, 2H), 3.56 (d, J=4.4 Hz, 3H), 3.52-3.41 (m, 1H), 2.21 (br, 2H), 1.95-1.66 (m, 4H), 1.20 (d, J=2.0 Hz, 6H).

[0727] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 177.98 (177.90), 176.77, 168.30(168.10), 138.12, 137.70 (137.66), 132.48 (132.27), 128.40, 128.32 (128.28),127.63, 127.49 (127.41), 124.79 (124.73), 123.68 (123.38), 112.77, 72.40(72.18), 70.40 (69.85), 54.35, 48.37 (48.02), 44.85 (44.67), 41.09, 40.55 (40.44), 37.09 (36.87), 32.92 (32.81), 32.44 (32.18), 28.73 (28.62), 28.46 (28.38).

[0728] HRMS (ESI): m / z [M+H] + C 27 H 35 Calculated value of N4O6S: 543.2277; Measured value: 543.2283.

[0729] Example 14 (R)-2-amino-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide methanesulfonate

[0730]

[0731] Add Example 13 (300 mg, 0.55 mmol) and EA (5 mL) sequentially to a 25 mL single-necked flask. Under nitrogen protection and in an ice bath, add 0.5 mL of EA solution containing methanesulfonic acid (53 mg, 0.55 mmol). Incubate the reaction for 1.5 h, and a large amount of solid precipitates. TLC (V 二氯甲烷 V 甲醇 =10:1) The polarity was monitored and no change was observed. The mixture was filtered, washed with ethyl acetate (10 mL × 3), and the filter cake was collected. It was then distilled with methanol (20 mL) and then slurried with low-boiling petroleum ether (20 mL) at room temperature for 2 h. The mixture was filtered, and the filter cake was dried at 48 °C overnight to obtain 260 mg of white solid compound of Example 14, with a yield of 73.7%.

[0732] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.66-8.63 (m, 1H), 8.13 (br, 3H), 7.65 (t, J=8.0 Hz, 1H), 7.41-7.18 (m, 8H), 5.12-5.06 (m, 1H), 4.55-4.49 (m,2H), 4.21-4.16 (m, 1H), 3.91-3.83 (m, 1H), 3.81-3.62 (m, 3H), 3.58-3.56 (m,3H), 3.50-3.41 (m, 1H), 2.30 (s, 3H), 1.92-1.73 (m, 4H), 1.49 (s, 6H).

[0733] 13C NMR (101 MHz, DMSO-d6) δ (ppm): 177.99, 171.53, 167.84 (167.56), 138.15, 137.73, 132.46 (132.35), 128.53 (128.47), 128.36 (128.33), 127.64(127.55), 124.93 (124.80), 123.58 (123.46), 112.90 (112.82), 72.39 (72.28),69.48 (69.15), 56.54, 49.28 (48.89), 44.82 (44.77), 41.13, 40.59 (40.36), 39.78, 37.34 (36.89), 33.04 (32.77), 32.40 (32.30), 23.64 (23.53), 23.37 (23.33).

[0734] HRMS (ESI): m / z [M-CH3SO3H+H] + C 28 H 38 Calculated value of N4O9S2: 543.2277; Measured value: 543.2263.

[0735] Example 15 (R)-2-amino-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide hydrochloride

[0736]

[0737] Compound 13 (300 mg, 0.55 mmol) and ethyl acetate (3 mL) from Example 13 were added sequentially to a 25 mL single-necked flask. Under nitrogen protection, 1 M HCl / EA solution (0.7 mL, 0.66 mmol) was added dropwise in an ice bath. The reaction was maintained at this temperature for 1.5 h, resulting in the precipitation of a large amount of solid. TLC (V 二氯甲烷 V 甲醇 =10:1) The polarity was monitored and no change was observed. The mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL × 3). The filter cake was collected, dissolved in methanol (20 mL), concentrated, and the residue was slurried with low-boiling petroleum ether (20 mL) at room temperature for 2 h. The mixture was filtered, and the filter cake was dried at 48 °C overnight to obtain 220 mg of white solid compound of Example 15, with a yield of 68.7%.

[0738] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.67-8.65 (m, 1H), 8.23 ​​(br, 3H), 7.65 (t, J=8.0 Hz, 1H), 7.43-7.18 (m, 8H), 5.11-5.05 (m, 1H), 4.55-4.52 (m,2H), 4.20-4.16 (m, 1H), 3.91-3.83 (m, 1H), 3.81-3.61 (m, 3H), 3.58-3.56 (m,3H), 3.49-3.40 (m, 1H), 1.91-1.75 (m, 4H), 1.54-1.49 (m, 6H).

[0739] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 177.99, 171.58 (171.51), 167.86 (167.53), 138.16 (137.70), 132.48 (132.34), 128.48 (128.46), 128.34 (128.30),127.63 (127.61), 127.52, 124.91 (124.78), 123.61 (123.58), 112.83 (112.79),72.39 (72.26), 69.49 (69.16), 56.55, 49.24 (48.90), 44.83 (44.76), 41.14, 40.58 (40.35), 37.31 (36.88), 32.98 (32.78), 32.39 (32.28), 23.60 (23.46), 23.30 (23.27).

[0740] HRMS (ESI): m / z [M-HCl+H] + C 27 H 35 Calculated value of ClN4O6S: 543.2277; Measured value: 543.2264.

[0741] Example 16 (R)-N-(3-((2,4-difluorophenyl)methoxy-d2)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-2-methyl-2-((2,2,2-trifluoroethyl)amino)propionamide

[0742] Step 1: Synthesis of (2,4-difluorophenyl)methanol-d2 (intermediate 2)

[0743]

[0744] 2,4-Difluorobenzoic acid (1, 1.00 g, 6.32 mmol) and diethyl ether (30 mL) were added to a 100 mL single-necked flask. Under nitrogen protection, lithium aluminum deuterated hydride (796 mg, 18.98 mmol) was added in an ice-water bath, and the reaction was carried out at room temperature for 2 h. TLC (V 二氯甲烷 V 甲醇 =20:1) Monitor the reaction of the starting materials to ensure complete reaction. Quench the reaction mixture with water (10 mL), adjust the pH to 6 with 1 M HCl, extract with ether (30 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =100:1), yielding 800 mg of colorless oily intermediate 2, with a yield of 86.7%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.52-7.45 (m, 1H), 7.19-7.13 (m, 1H), 7.09-7.03 (m, 1H), 5.23 (s, 1H).

[0745] Step 2: Synthesis of 1-(bromomethyl-d2)-2,4-difluorobenzene (intermediate 3)

[0746]

[0747] Intermediate 2 (800 mg, 5.47 mmol) and 40% hydrobromic acid solution (80 mL) were added to a 50 mL single-necked flask. The mixture was reacted at 110 °C for 1 h under nitrogen protection. TLC (V1) was then recorded. 石油醚 V 乙酸乙酯 =10:1) Monitor the reaction until complete, cool to room temperature, quench with water (20 mL), extract with dichloromethane (20 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 石油醚 V 乙酸乙酯 =10:1), yielding 750 mg of colorless oily intermediate 3, with a yield of 65.6%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.65-7.58 (m, 1H), 7.32-7.27 (m, 1H), 7.13-7.08 (m, 1H).

[0748] Step 3: Synthesis of N-(tert-butoxycarbonyl)-O-[(2,4-difluorophenyl)methyl-d2]-D-serine (intermediate 4)

[0749]

[0750] Add 60% sodium hydride (301 mg, 7.53 mmol) and N,N-dimethylformamide (3 mL) to a 50 mL two-necked flask. Under ice-water bath conditions, add dropwise a solution of Boc-D-serine (736 mg, 3.59 mmol) in N,N-dimethylformamide (7 mL), and react at room temperature for 1 h. Cool to -40 °C, add dropwise a solution of intermediate 3 (750 mg, 3.59 mmol) in N,N-dimethylformamide (3 mL), and incubate overnight. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction of the starting materials to ensure complete reaction. Add water (30 mL) to the reaction solution to quench the reaction, adjust the pH to 4 with 1 M HCl, extract with ethyl acetate (100 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =10:1), yielding 810 mg of colorless oily intermediate 4, with a yield of 67.7%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.69 (s, 1H), 7.52-7.46 (m,1H), 7.25-7.19 (m, 1H), 7.10-7.05 (m, 1H), 6.93 (d, J=8.3 Hz, 1H), 4.20-4.15(m, 1H), 3.69-3.66 (m, 2H), 1.38 (s, 9H).

[0751] Step 4: Synthesis of (R)-[3-((2,4-difluorophenyl)methoxy-d2)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl]tert-butyl carbamate (intermediate 5)

[0752]

[0753] Intermediate 4 (300 mg, 0.90 mmol), 1-(methanesulfonyl)spiro[indoline-3,4'-piperidine] (240 mg, 0.90 mmol), N,N'-dicyclohexylcarbodiimide (204 mg, 0.99 mmol), 1-hydroxybenzotriazole (34 mg, 0.99 mmol), isopropyl acetate (6 mL), and water (3 mL) were added to a 50 mL single-necked flask. The mixture was reacted under nitrogen protection at room temperature for 3 h. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Add water (30 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (50 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (12 g, V). 二氯甲烷 V 甲醇 =10:1), yielding 450 mg of white solid intermediate 5, yield 86.0%. 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 7.54-7.45 (m, 1H), 7.29-7.19 (m, 4H), 7.11-6.95 (m, 3H), 4.71-4.67 (m,1H), 4.36 (d, J=13.6 Hz, 1H), 3.99-3.95 (m, 1H), 3.91 (s, 2H), 3.69-3.66 (m,1H), 3.59-3.50 (m, 1H), 3.24-3.15 (m, 1H), 3.05 (s, 3H), 2.78 (t, J=12.6 Hz,1H), 1.83-1.65 (m, 4H), 1.37 (s, 9H).

[0754] Step 5: Synthesis of (R)-2-amino-3-((2,4-difluorophenyl)methoxy-d2)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)propane-1-one (intermediate 6)

[0755]

[0756] Intermediate 5 (450 mg, 0.77 mmol), mesylate (520 mg, 5.42 mmol), and ethanol (5 mL) were added to a 25 mL single-necked flask, and the mixture was reacted overnight at 45 °C. TLC (V 二氯甲烷 V 甲醇=15:1) Monitor the reaction of the starting materials to ensure complete reaction. Dilute the reaction solution with water (10 mL) and adjust the pH to 10 with 1 M NaOH. Extract with ethyl acetate (30 mL × 2). Combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =15:1), yielding 300 mg of colorless oily intermediate 6, with a yield of 81.1%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.56-7.47 (m, 1H), 7.25-7.20 (m, 3.5H), 7.12-6.98 (m, 2H), 6.85 (d, J=7.5 Hz, 0.5H), 4.41 (t, J=13.0Hz, 1H), 4.05-3.93 (m, 2H), 3.90 (s, 2H), 3.53-3.37 (m, 2H), 3.41-3.32 (m,2H), 3.15-3.12 (m, 1H), 3.04 (s, 3H), 2.80-2.71 (m, 1H), 1.74-1.64 (m, 2H), 1.59-1.52 (m, 2H).

[0757] Step 6: Synthesis of (R)-N-(3-((2,4-difluorophenyl)methoxy-d2)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-2-methyl-2-((2,2,2-trifluoroethyl)amino)propionamide (Example 16)

[0758]

[0759] Intermediate 6 (200 mg, 0.42 mmol), Intermediate 5 from Example 3 (85 mg, 0.46 mmol), N,N'-dicyclohexylcarbodiimide (95 mg, 0.46 mmol), 1-hydroxybenzotriazole (62 mg, 0.46 mmol), isopropyl acetate (4 mL), and water (2 mL) were added to a 25 mL single-necked flask. The mixture was reacted under nitrogen protection at room temperature for 3.5 h. TLC (V 二氯甲烷 V 甲醇 =20:1) Monitor the reaction of the starting materials to ensure complete reaction. Add water (20 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (30 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =10:1; V 石油醚 V乙酸乙酯 =1:1), yielding 240 mg of the white solid compound of Example 16, with a yield of 88.2%.

[0760] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.99-7.91 (m, 1H), 7.53-7.42 (m,1H), 7.28-7.18 (m, 4H), 7.11-6.97 (m, 3H), 5.02-5.00 (m, 1H), 4.40-4.36 (m,1H), 3.95-3.90 (m, 3H), 3.67-3.54 (m, 2H), 3.21-3.19 (m, 1H), 3.04 (s, 3H),3.03-2.98 (m, 2H), 2.83-2.75 (m, 1H), 1.75-1.66 (m, 4H), 1.19-1.18 (m, 6H).

[0761] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 175.14, 167.77, 141.14, 138.52(138.43), 132.03 (131.74), 128.56, 125.99 (J C-F =278.2 Hz), 123.45 (J C-F =12.2Hz), 121.20, 112.90, 111.43 (J C-F =21.6 Hz), 103.92 (J C-F =25.7 Hz) [103.83 (J C-F =27.1 Hz)], 70.27, 69.73, 58.45, 58.31, 48.25 (J C-F =29.7 Hz), 44.83 (J C-F =31.0Hz), 42.79 (42.68), 42.24, 36.34, 36.13, 35.55, 34.36, 33.43, 25.69 (25.52),25.40, 24.82, 24.55.

[0762] HRMS (ESI): m / z [M+H] + C 29 H 34Calculated value of D2F5N4O5S: 649.2452, measured value: 649.2411.

[0763] Example 17 (R)-2-((ethyl-d5)amino)-2-methyl-N-(1-(1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxo-3-(benzoxy-d2)propyl-2-yl)propionamide

[0764] Step 1: Synthesis of ethane-d5-1-amine hydrochloride (intermediate 2)

[0765]

[0766] Deuterated lithium aluminum hydride (4.28 g, 102.11 mmol) and diethyl ether (140 mL) were added sequentially to a 500 mL three-necked flask. Under nitrogen protection, the mixture was cooled to 0 °C, and then deuterated acetonitrile (3.00 g, 68.07 mmol) was added dropwise. The reaction mixture was kept at this temperature for 2.5 h. Water (4.8 mL), 20 wt% NaOH solution (3.6 mL), and water (16.8 mL) were added dropwise to quench the reaction mixture. The reaction mixture was distilled at 60 °C, and the distillate was passed into a receiving solution of 1 M dilute hydrochloric acid (100 mL). The receiving solution was concentrated, and the residue was dissolved in ethanol (10 mL). Ethyl acetate (200 mL) was added, and the mixture was allowed to stand overnight at room temperature. A large amount of white solid precipitated out. The mixture was filtered, and the filter cake was collected to obtain 4.84 g of white solid intermediate 2, with a yield of 82.0%.

[0767] Step 2: Synthesis of methyl 2-((ethyl-d5)amino)-2-methylpropionate hydrochloride (intermediate 3)

[0768]

[0769] Intermediate 2 (500 mg, 5.78 mmol), methyl 2-bromoisobutyrate (4.19 g, 23.12 mmol), anhydrous acetonitrile (10 mL), potassium carbonate (3.99 g, 28.90 mmol), and potassium iodide (383 mg, 2.31 mmol) were added sequentially to a 100 mL sealed container, and the reaction was carried out at 100 °C for 21 h. TLC (V 二氯甲烷 V 甲醇 =15:1) After monitoring the reaction to completion, filter, wash with ethyl acetate (5 mL × 3), and collect the filtrate. Adjust the pH to 3 with 4 M HCl / dioxane solution, concentrate to remove the solvent, slurry with ethyl acetate (10 mL) for 30 min, filter, collect the filter cake, and obtain 597 mg of off-white solid intermediate 3, yield 55.3%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.65 (br, 2H), 3.76 (s, 3H), 1.53 (s, 6H).

[0770] Step 3: Synthesis of 2-((ethyl-d5)amino)-2-methylpropionic acid (intermediate 4)

[0771]

[0772] Intermediate 3 (597 mg, 3.97 mmol), methanol (12 mL), water (4.8 mL), and lithium hydroxide monohydrate (500 mg, 11.91 mmol) were added sequentially to a 100 mL single-necked flask. The reaction was carried out at room temperature for 15 h under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) After monitoring the reaction to complete, concentrate to remove methanol, adjust the pH to 6 with 1 M dilute hydrochloric acid, concentrate again, and obtain 1.50 g of yellow oily intermediate 4. The crude product is used directly in the next step. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 4.49-4.31 (br,1H), 3.59 (s, 6H).

[0773] Step 4: Synthesis of (R)-2-((ethyl-d5)amino)-2-methyl-N-(1-(1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxo-3-(benzoxy-d2)prop-2-yl)propionamide (Example 17)

[0774]

[0775] Intermediate 10 (200 mg, 0.45 mmol), anhydrous DMF (4 mL), intermediate 4 (270 mg, 1.98 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (205 mg, 0.54 mmol), and N,N-diisopropylethylamine (174 mg, 1.35 mmol) from Example 3 were added sequentially to a 25 mL single-necked flask. The reaction was carried out at room temperature for 19 h under nitrogen protection. TLC (V 乙酸乙酯 V 甲醇 =5:1) After monitoring the reaction to completion, quench with water (20 mL), extract with ethyl acetate (20 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (20 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (12 g, V 乙酸乙酯 V 甲醇The compound was purified by a ratio of 4:1 to give 91 mg of white solid, as described in Example 17, with a two-step yield of 22.6%.

[0776] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.25-8.09 (m, 1H), 7.38-7.17 (m,7.5H), 7.09-6.96 (m, 1H), 6.94-6.85 (m, 0.5H), 5.05-4.94 (m, 1H), 4.49-4.32(m, 1H), 4.03-3.83 (m, 3H), 3.68-3.50 (m, 2H), 3.26-3.11 (m, 1H), 3.09-2.99(m, 3H), 2.89-2.72 (m, 1H), 2.14 (br, 1H), 1.82-1.50 (m, 4H), 1.15 (s, 6H).

[0777] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 175.80, 167.91 (167.80), 141.07,138.48 (138.35), 138.05 (137.97), 128.44, 128.28 (128.25), 127.65 (127.61),127.55, 123.45 (123.39), 112.84 (112.75), 70.40, 69.62, 58.24, 48.30 (47.95),42.67 (42.60), 42.16, 38.77, 36.23 (36.05), 35.52 (35.39), 34.31 (34.26), 25.28.

[0778] HRMS (ESI): m / z [M+H] + C 29 H 33 Calculated value of D7N4O5S: 564.3237; Measured value: 564.3214.

[0779] Example 18 (R)-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-2-(ethoxyamino)-2-methylpropionamide

[0780] Step 1: Synthesis of methyl 2-(ethoxyamino)-2-methylpropionate (intermediate 2)

[0781]

[0782] To a 100 mL sealed container, methyl 2-bromoisobutyrate (1, 5.0 g, 27.6 mmol), acetonitrile (25 mL), ethoxyamine hydrochloride (3.5 g, 35.9 mmol), and Na₂CO₃ (5.81 g, 55.2 mmol) were added sequentially. The reaction was carried out overnight at 120 °C under nitrogen protection. TLC (VL) was performed. 石油醚 V 乙酸乙酯 =5:1) Monitor the reaction of the raw materials to ensure complete reaction. Cool to room temperature, filter the reaction solution through diatomaceous earth, concentrate the filtrate and purify it by rapid preparative chromatography (80 g, V 石油醚 V 乙酸乙酯 =100:7), yielding 920 mg of colorless oily liquid intermediate 2, yield 20.7%. 1 H NMR (400 MHz, CDCl3) δ (ppm): 5.95 (br, 1H), 3.74-3.69 (m, 5H), 1.29 (s, 6H), 1.13 (t, J=6.8 Hz, 3H).

[0783] Step 2: Synthesis of 2-(ethoxyamino)-2-methylpropionic acid (intermediate 3)

[0784]

[0785] Intermediate 2 (920 mg, 5.71 mmol), MeOH (18 mL), H₂O (7.2 mL), and NaOH (342 mg, 8.56 mmol) were added sequentially to a 100 mL single-necked flask. The reaction was carried out overnight at room temperature under nitrogen protection. TLC (V1) was performed. 二氯甲烷 V 甲醇 =10:1) Monitor the reaction of the raw materials to ensure complete reaction. The reaction solution was adjusted to pH 5 with 1M HCl, diluted with water (40 mL), extracted with dichloromethane (4 mL × 10), the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 340 mg of white solid intermediate 3, yield 40.4%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.31 (br, 1H), 3.61 (q, J=7.2 Hz, 2H), 1.15 (s, 6H), 1.04 (t, J=6.8 Hz, 3H).

[0786] Step 3: Synthesis of (R)-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-2-(ethoxyamino)-2-methylpropionamide (Example 18)

[0787]

[0788] To a 50 mL single-necked flask, intermediate 5 (126 mg, 0.28 mmol), intermediate 3 (50 mg, 0.34 mmol), DCC (64 mg, 0.31 mmol), HOBt (42 mg, 0.31 mmol), isopropyl acetate (2.5 mL), and water (2.5 mL) from Example 1 were added sequentially. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Quench the reaction mixture with water (10 mL), extract with ethyl acetate (20 mL × 2), combine the organic phases, wash with saturated brine (40 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (20 g, V 石油醚 V 乙酸乙酯 =1:4), yielding 220 mg of the white solid compound of Example 18, with a yield of 75.6%.

[0789] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.92-7.83 (m, 1H), 7.37-7.20 (m,7.5H), 7.06-7.97 (m, 1H), 6.87 (d, J=7.6 Hz, 0.5H), 6.69 (s, 1H), 5.03-5.01(m, 1H), 4.56-4.45 (m, 2H), 4.46-4.35 (m, 1H), 4.00-3.84 (m, 3H), 3.68-3.52(m, 4H), 3.21-3.16 (m, 1H), 3.04 (d, J=4.4 Hz, 3H), 2.88-2.74 (m, 1H), 1.70-1.63 (m, 4H), 1.14 (d, J=7.2 Hz, 6H), 1.06-0.99 (m, 3H).

[0790] 13C NMR (101 MHz, DMSO-d6) δ (ppm): 174.33, 167.86 (167.63), 141.07,138.51 (138.33), 138.21 (138.08), 128.44, 128.29 (128.25), 127.62 (127.50),123.41, 112.84 (112.76), 72.44 (72.22), 70.44, 69.63, 68.77 (68.70), 61.58,58.28, 48.45 (48.07), 42.71 (42.59), 42.22, 36.20 (36.03), 35.51 (35.41), 34.31 (34.27), 22.78, 14.10.

[0791] HRMS (ESI): m / z [M+H] + C 29 H 41 Calculated value of N4O6S: 573.2747; Measured value: 573.2712.

[0792] Example 19 (R)-2-((ethoxy-d5)amino)-2-methyl-N-(1-(1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-1'-yl)-1-oxo-3-(benzoxy-d2)propyl-2-yl)propionamide

[0793] Step 1: Synthesis of 2-(ethoxy-d5)isoindoline-1,3-dione (intermediate 2)

[0794]

[0795] N-hydroxyphthalimide (1, 5.00 g, 30.65 mmol), anhydrous THF (50 mL), deuterated ethanol (1.60 g, 30.65 mmol), and triphenylphosphine (10.45 g, 39.85 mmol) were added sequentially to a 250 mL single-necked flask. Diethyl azodicarbonate (6.94 g, 39.85 mmol) was added dropwise at 0 °C. The reaction was carried out at room temperature for 18 h under nitrogen protection. TLC (V 石油醚 V 乙酸乙酯 =3:1) Monitor the reaction to completion, concentrate and perform column chromatography (V 石油醚 V 乙酸乙酯 The mixture was purified at a ratio of 10:1 to obtain 10.07 g of white solid intermediate 2, with a yield of 83.7%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.86 (s, 4H).

[0796] Step 2: Synthesis of O-(ethyl-d5)hydroxylamine hydrochloride (intermediate 3)

[0797]

[0798] Intermediate 2 (10.46 g, 53.31 mmol), DCM (105 mL), and hydrazine hydrate (80%, 6.67 g, 106.62 mmol) were added sequentially to a 250 mL single-necked flask. The reaction was carried out at room temperature for 18 h under nitrogen protection. TLC (V 石油醚 V 乙酸乙酯 =10:1) Monitor the reaction to completion, filter, add water (140 mL) to the filtrate, separate the layers, and collect the aqueous phase. Use a mixed solvent (V... 氯仿 V 异丙醇 Extracted at a ratio of 3:1 (140 mL × 3), the organic phase was collected. The extract was dried over anhydrous sodium sulfate, filtered, and 53 mL of 4 M HCl / dioxane solution was added to the filtrate. The mixture was stirred at room temperature for 1 h under nitrogen protection. The solution was concentrated to give 1.69 g of a white solid intermediate 3, with a yield of 30.9%. 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 11.01 (br, 3H).

[0799] Step 3: Synthesis of methyl 2-((ethoxy-d5)amino)-2-methylpropionate (intermediate 4)

[0800]

[0801] Intermediate 3 (1.04 g, 10.14 mmol), anhydrous acetonitrile (7.2 mL), methyl 2-bromoisobutyrate (1.41 g, 7.80 mmol), and sodium carbonate (1.65 g, 15.60 mmol) were added sequentially to a 100 mL sealed container, and the reaction was carried out at 120 °C for 16 h. TLC (V 石油醚 V 乙酸乙酯 =10:1) Monitor the end of the reaction, filter, concentrate the filtrate and perform column chromatography (V) 石油醚 V 乙酸乙酯 The mixture was purified at a ratio of 10:1 to obtain 1.17 g of pale yellow oily intermediate 4, with a yield of 90.0%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 5.95 (br, 1H), 3.73 (s, 3H), 1.29 (s, 6H).

[0802] Step 4: Synthesis of 2-((ethoxy-d5)amino)-2-methylpropionic acid (intermediate 5)

[0803]

[0804] Intermediate 4 (1.70 g, 10.23 mmol), methanol (34 mL), water (13.6 mL), and sodium hydroxide (1.02 g, 25.58 mmol) were added sequentially to a 250 mL single-necked flask. The reaction was carried out at room temperature for 17 h under nitrogen protection. TLC (V 石油醚 V 乙酸乙酯 =10:1) Monitor the reaction to completion, concentrate to remove methanol, add water (50 mL), wash with dichloromethane (50 mL × 3), and collect the aqueous phase. Adjust the pH of the aqueous phase to 5 with 1 M dilute hydrochloric acid, and then use a mixed solvent (V 二氯甲烷 V 甲醇 Extracted with a 5:1 ratio (50 mL × 15 mL), the organic phase was collected. The mixture was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 400 mg of a white solid intermediate 5, yield 25.6%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.33 (br, 1H), 1.15 (s, 6H).

[0805] Step 5: Synthesis of (R)-2-((ethoxy-d5)amino)-2-methyl-N-(1-(1-(1-(methanesulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)-1-oxo-3-(benzoxy-d2)prop-2-yl)propionamide (Example 19)

[0806]

[0807] To a 100 mL single-necked flask, intermediate 10 (400 mg, 0.90 mmol), isopropyl acetate (10 mL), water (10 mL), intermediate 5 (178 mg, 1.17 mmol), N,N'-dicyclohexylcarbodiimide (204 mg, 0.99 mmol), and 1-hydroxybenzotriazole (134 mg, 0.99 mmol) from Example 3 were added sequentially. The reaction was carried out under nitrogen protection at room temperature for 23 h. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction to completion, filter, wash with ethyl acetate (5 mL × 3), separate the filtrate, and collect the organic phase. Wash with saturated sodium chloride solution (5 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇The compound was purified by a ratio of 50:1 to give 269 mg of white solid, Example 19, in a yield of 51.5%.

[0808] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.95-7.78 (m, 1H), 7.37-7.20 (m,7.5H), 7.09-6.96 (m, 1H), 6.91-6.83 (m, 0.5H), 6.67 (br, 1H), 5.08-4.95 (m,1H), 4.47-4.34 (m, 1H), 4.02-3.83 (m, 3H), 3.69-3.49 (m, 2H), 3.23-3.11 (m,1H), 3.08-3.01 (m, 3H), 2.89-2.73 (m, 1H), 1.83-1.49 (m, 4H), 1.18–1.09 (m, 6H).

[0809] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 174.34, 167.87 (167.64), 141.07,138.52 (138.34), 138.10 (137.98), 128.45, 128.30 (128.25), 127.68 (127.62),127.56 (127.51), 123.41, 112.80, 70.34, 69.53, 61.59 (61.56), 58.27, 48.45(48.07), 42.70 (42.58), 42.20, 36.19 (36.02), 35.50 (35.40), 34.31 (34.27), 22.77.

[0810] HRMS (ESI): m / z [M+H] + C 29 H 33 Calculated value of D7N4O6S: 580.3186; Measured value: 580.3163.

[0811] Example 20 (R)-2-amino-N-(3-((4-fluorobenzyl)oxy)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0812] Step 1: Synthesis of N-(tert-butoxycarbonyl)-O-(4-fluorobenzyl)-D-serine (intermediate 2)

[0813]

[0814] Add NaH (60%, 409 mg, 10.2 mmol) and DMF (4 mL) to a 100 mL single-necked flask. Under nitrogen protection, cool to 0 °C, then add dropwise an 8 mL DMF solution of Boc-D-serine (1.00 g, 4.87 mmol). React at room temperature for 1 h. Transfer to -40 °C, add dropwise an 8 mL DMF solution of 4-fluorobenzyl bromide (1, 1.01 g, 5.36 mmol), and incubate overnight. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction to complete. Add water (40 mL) to the reaction solution and adjust the pH to 6 with 1M hydrochloric acid. Extract with ethyl acetate (30 mL × 3) and collect the organic phase. Wash with saturated sodium chloride solution (50 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate and perform rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 The mixture was purified at a ratio of 100:3 to obtain 1.51 g of pale yellow oily intermediate 2, with a yield of 98.7%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.52-7.49 (m, 1H), 7.38-7.34 (m, 1H), 7.22-7.14 (m, 2H), 6.99 (d, J=8.3 Hz, 1H), 4.46 (br, 2H), 4.21-4.16 (m, 1H), 3.69-3.62 (m, 2H), 1.38 (s, 9H).

[0815] Step 2: Synthesis of tert-butyl(R)-[3-((4-fluorobenzyl)oxy)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxopropyl-2-yl]carbamate (intermediate 3)

[0816]

[0817] Intermediate 2 (217 mg, 0.69 mmol), isopropyl acetate (2 mL), water (1 mL), Intermediate 10 (150 mg, 0.63 mmol), HOBt (93 mg, 0.69 mmol), and DCC (142 mg, 0.69 mmol) from Example 10 were added sequentially to a thumb flask. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷V 甲醇 =50:1) Monitor the reaction to complete. Filter under a diatomaceous earth bed, extract the filtrate with ethyl acetate (5 mL × 2), and collect the organic phase. Wash with saturated sodium chloride solution (5 mL × 2), dry to anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (V... 二氯甲烷 V 甲醇 The mixture was purified at a ratio of 50:1 to give 296 mg of white solid intermediate 3, with a yield of 88.1%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.55-7.33 (m, 2.5H), 7.33-7.14 (m,5H), 7.14-6.97 (m, 1.5H), 4.63-4.34 (m, 3.5H), 4.33-4.10 (m, 4.5H), 4.00-3.92(m, 1H), 3.67-3.52 (m, 2H), 3.00 (s, 3H), 1.39 (d, J=4.8 Hz, 9H).

[0818] Step 3: Synthesis of (R)-2-amino-3-((4-fluorobenzyl)oxy)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)propane-1-one (intermediate 4)

[0819]

[0820] Intermediate 3 (290 mg, 0.54 mmol), ethanol (9 mL), and methanesulfonic acid (313 mg, 3.26 mmol) were added to a 50 mL single-necked flask. The mixture was reacted overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction for completion. Cool to room temperature, adjust pH to 8 with saturated sodium bicarbonate solution, extract with dichloromethane (10 mL × 4), and collect the organic phase. Wash with saturated sodium chloride solution (5 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (V... 二氯甲烷 V 甲醇 The mixture was purified at a ratio of 10:1 to obtain 178 mg of white solid intermediate 4, with a yield of 73.6%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.55 (d, J=6.8 Hz, 0.5H), 7.41-7.37 (m, 2H), 7.34-7.22 (m, 2H), 7.21-7.14 (m, 3H), 7.01-6.97 (m, 0.5H), 4.52-4.48 (m, 2.5H), 4.46-4.40 (m, 1H), 4.28-4.26 (m, 0.5H), 4.22-4.17 (m, 2.5H), 4.11-4.08 (m, 0.5H), 4.02-4.00 (m, 0.5H), 3.96-3.94 (m,0.5H), 3.55-3.49 (m, 1H), 3.47-3.42 (m, 2H), 2.99 (s, 3H), 1.71 (br, 2H).

[0821] Step 4: Synthesis of (R)-[1-[(3-((4-fluorobenzyl)oxy)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxopropyl-2-yl)amino]-2-methyl-1-oxopropyl-2-yl] tert-butyl carbamate (intermediate 5)

[0822]

[0823] Intermediate 4 (175 mg, 0.39 mmol), isopropyl acetate (3 mL), water (3 mL), N-tert-butoxycarbonyl-2-methylalanine (87 mg, 0.43 mmol), HOBt (58 mg, 0.43 mmol), and DCC (89 mg, 0.43 mmol) were added sequentially to a thumb flask. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =30:1) Monitor the reaction to complete. Filter under a diatomaceous earth bed, extract the filtrate with ethyl acetate (5 mL × 2), and collect the organic phase. Wash with saturated sodium chloride solution (5 mL × 2), dry to anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (V... 二氯甲烷 V 甲醇 The mixture was purified at a ratio of 25:1 to obtain 242 mg of white solid intermediate 5, with a yield of 95.4%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.64-7.53 (m, 1H), 7.42-7.32(m, 3H), 7.31-7.11 (m, 5H), 7.03 (t, J=7.0 Hz, 1H), 4.56-4.53 (m, 1.5H),4.52-4.42 (m, 3H), 4.30-4.20 (m, 1H), 3.99-3.95 (m, 2.5H), 3.99-3.95 (m, 1H),3.64-3.51 (m, 2H), 2.99 (d, J=2.8 Hz, 3H), 1.36 (d, J=4.1 Hz, 9H), 1.29 (br,6H).

[0824] Step 5: Synthesis of (R)-2-amino-N-(3-((4-fluorobenzyl)oxy)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxopropyl-2-yl)-2-methylpropionamide (Example 20)

[0825]

[0826] Intermediate 5 (238 mg, 0.38 mmol), ethanol (8 mL), and methanesulfonic acid (221 mg, 2.31 mmol) were added to a 50 mL single-necked flask. The mixture was reacted overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction for completion. Cool to room temperature, adjust pH to 8 with saturated sodium bicarbonate solution, extract with dichloromethane (20 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (5 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and pass through a preparative plate (V). 二氯甲烷 V 甲醇 The compound was purified by a ratio of 10:1 to obtain 123 mg of white solid, Example 20 compound, with a yield of 62.4%.

[0827] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.25 (br, 1H), 7.51 (d, J=6.9Hz,0.5H), 7.42-7.36 (m, 2H), 7.31-7.16 (m, 4H), 7.15-7.01 (m, 1.5H), 4.60-4.34(m, 4.5H), 4.31-4.09 (m, 3.5H), 4.04-3.98 (m, 1H), 3.68-3.50 (m, 2H), 2.99(d, J=3.1 Hz, 3H), 2.05 (br, 2H), 1.20-1.18 (m, 6H).

[0828] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 177.67 (177.61), 170.09 (169.98), 162.14 (J C-F =243.9 Hz) [162.10 (J C-F =244.0 Hz)], 141.94, 135.80 (135.65), 134.81 (134.74), 134.77, 130.22 (J C-F =20.4 Hz) [130.14 (J C-F =21.1 Hz)], 129.62(129.57), 124.59 (124.51), 124.01, 123.62, 115.60 (J C-F =21.1 Hz) [115.57 (J C-F =21.1 Hz)], 113.42 (113.35), 72.06 (71.92), 70.23 (69.82), 63.43 (63.36), 61.53 (61.33), 60.43 (60.25), 54.73, 49.57 (49.04), 41.07 (40.91), 34.86(34.83), 29.31 (29.26), 29.05 (29.00).

[0829] HRMS (ESI): m / z [M+H] + C 25 H 31 Calculated value of FN4O5S: 519.2077; Measured value: 519.2088.

[0830] Example 21 (R)-2-amino-N-(3-((4-chlorobenzyl)oxy)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0831] Step 1: Synthesis of N-(tert-butoxycarbonyl)-O-(4-chlorobenzyl)-D-serine (intermediate 2)

[0832]

[0833] Add 60% sodium hydroxide (818 mg, 20.4 mmol) and DMF (15 mL) sequentially to a 250 mL three-necked flask. Under nitrogen protection, add a 15 mL solution of Boc-D-serine (2.00 g, 9.7 mmol) in DMF dropwise under an ice-water bath. After the addition is complete, react at room temperature for 1 h. Then, add a 15 mL solution of 4-chlorobenzyl bromide (1, 2.00 g, 9.7 mmol) in DMF dropwise at -40 °C and react overnight. TLC (V 二氯甲烷 V 甲醇 =20:1) Monitor the reaction of the raw materials until complete, quench with water (100 mL), adjust the pH to 4 by adding 3 mol / L dilute hydrochloric acid, extract with ethyl acetate (70 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (70 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (20 g, V 二氯甲烷 V 甲醇 =100:1), yielding 1.15 g of colorless oily intermediate 2, with a yield of 35.8%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.67 (br, 1H), 7.42-7.32 (m,4H), 7.00 (d, J=8.4 Hz, 1H), 4.50-4.44 (m, 2H), 4.24-4.13 (m, 1H), 3.67-3.65(m, 2H), 1.38(s, 9H).

[0834] Step 2: Synthesis of (R)-[3-((4-chlorobenzyl)oxy)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxopropyl-2-yl]tert-butyl carbamate (intermediate 3)

[0835]

[0836] To a 25 mL single-necked flask, add intermediate 2 (282 mg, 0.86 mmol), intermediate 10 from Example 10 (170 mg, 0.71 mmol), isopropyl acetate (4 mL), water (1 mL), HOBt (116 mg, 0.86 mmol), and DCC (176 mg, 0.86 mmol). After addition, under nitrogen protection, react overnight at room temperature. TLC (V 二氯甲烷 V 甲醇 =20:1) Monitor the reaction of the starting materials to ensure complete reaction. Dilute with water (15 mL), extract with ethyl acetate (25 mL × 3), combine the organic phases, wash successively with saturated sodium bicarbonate solution (25 mL × 3) and saturated sodium chloride solution (20 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 石油醚 V 乙酸乙酯 =1:1), yielding 350 mg of white solid intermediate 3, with a yield of 90.1%. 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 7.47 (d, J=7.6 Hz, 0.5H), 7.43-7.34 (m, 4H), 7.31-7.22 (m, 3H), 7.10(t, J=7.6 Hz, 1H), 7.03 (t, J=7.6 Hz, 0.5H), 4.57-4.43 (m, 3.5H), 4.33-4.12(m, 4.5H), 4.00-3.92 (m, 1H), 3.66-3.54 (m, 2H), 3.00 (d, J=1.6 Hz, 3H), 1.39(d, J=4.8 Hz, 9H).

[0837] Step 3: Synthesis of (R)-2-amino-3-((4-chlorobenzyl)oxy)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)propane-1-one (intermediate 4)

[0838]

[0839] Intermediate 3 (350 mg, 0.64 mmol), ethanol (5 mL), and methanesulfonic acid (428 mg, 4.45 mmol) were added to a 50 mL single-necked flask. After addition, the mixture was reacted overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇=15:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool to room temperature, quench with saturated sodium bicarbonate solution (15 mL), extract with ethyl acetate (25 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (40 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =30:1), yielding 235 mg of white solid intermediate 4, with a yield of 82.1%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.55 (d, J=7.6 Hz, 0.5H), 7.45-7.33 (m, 4H), 7.32-7.22 (m,2H), 7.17-7.14 (m, 1H), 7.02-6.95 (m, 0.5H), 4.52-4.49 (m, 2.5H), 4.44-4.43(m, 1H), 4.26 (d, J=8.8 Hz, 0.5H), 4.22-4.17 (m, 2.5H), 4.11 (d, J=11.2 Hz,0.5H), 4.01 (d, J=9.6 Hz, 0.5H), 3.95 (d, J=9.6 Hz, 0.5H), 3.54-3.52 (m, 1H), 3.50-3.40 (m, 2H), 2.99 (d, J=2.4 Hz, 3H), 1.84 (s, 2H).

[0840] Step 4: Synthesis of (R)-[1-[(3-((4-chlorobenzyl)oxy)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxopropyl-2-yl)amino]-2-methyl-1-oxopropyl-2-yl] tert-butyl carbamate (intermediate 5)

[0841]

[0842] To a 25 mL single-necked flask, add intermediate 4 (235 mg, 0.52 mmol), isopropyl acetate (4 mL), water (1.5 mL), N-tert-butoxycarbonyl-2-methylalanine (118 mg, 0.57 mmol), DCC (119 mg, 0.57 mmol), and HOBt (78 mg, 0.57 mmol) sequentially. After addition, under nitrogen protection, react overnight at room temperature. TLC (V 二氯甲烷 V 甲醇=15:1) Monitor the reaction of the starting materials to ensure complete reaction. Quench with water (15 mL), extract with ethyl acetate (25 mL × 3), combine the organic phases, wash successively with saturated sodium bicarbonate solution (25 mL × 3) and saturated sodium chloride solution (20 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 石油醚 V 乙酸乙酯 =1:1), yielding 315 mg of white solid intermediate 5, with a yield of 95.0%. 1 H NMR(400 MHz, DMSO-d6) δ (ppm): 7.59-7.57 (m, 1H), 7.43-7.39 (m, 2.5H), 7.37-7.34(m, 2H), 7.29-7.23 (m, 2.5H), 7.12 (t, J=7.6 Hz, 0.5H), 7.06-6.91 (m, 1.5H), 4.57-4.55 (m, 1.5H), 4.52-4.43 (m, 3H), 4.29-4.27 (m, 0.5H), 4.24-4.13 (m, 3H), 4.00-3.93 (m, 1H), 3.64-3.53 (m, 2H), 2.99 (d, J=3.6 Hz, 3H), 1.35 (d, J=4.4 Hz, 9H), 1.29 (d, J=1.6 Hz, 6H).

[0843] Step 5: Synthesis of (R)-2-amino-N-(3-((4-chlorobenzyl)oxy)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxopropyl-2-yl)-2-methylpropionamide (Example 21)

[0844]

[0845] Intermediate 5 (315 mg, 0.50 mmol), ethanol (5 mL), and methanesulfonic acid (286 mg, 3.00 mmol) were added to a 25 mL single-necked flask. After addition, the mixture was reacted overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool to room temperature, quench with saturated sodium bicarbonate solution (15 mL), extract with ethyl acetate (25 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (40 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇=30:1), yielding 220 mg of the white solid compound of Example 21, with a yield of 82.9%.

[0846] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.26 (br, 1H), 7.52-7.50 (m, 0.5H), 7.44-7.42 (m, 2H), 7.39-7.35 (m, 2H), 7.31-7.25 (m, 2H), 7.22-7.21 (m, 1H),7.16-7.10 (m, 0.5H), 7.05-7.01 (m, 0.5H), 4.57-4.55 (m, 0.5H), 4.53-4.50 (m,3H), 4.46-4.44 (m, 1H), 4.28-4.26 (m, 0.5H), 4.25-4.17 (m, 2.5H), 4.15-4.12(m, 0.5H), 4.04-3.96 (m, 1H), 3.65-3.59 (m, 2H), 2.99 (d, J=4.0 Hz, 3H), 2.09(br, 2H), 1.19-1.20 (m, 6H).

[0847] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 177.65 (177.59), 170.05 (169.94), 141.95, 137.65 (137.58), 135.78 (135.66), 132.68 (132.60), 129.95 (129.74),129.62 (129.56), 128.83 (128.79), 124.58 (124.51), 124.01, 123.62, 113.42(113.35), 71.96 (71.81), 70.32 (69.92), 63.44 (63.39), 61.54 (61.30), 60.43 (60.26), 54.74 (54.72), 49.57 (49.00), 34.87 (34.85), 29.32 (29.26), 29.05 (29.00).

[0848] HRMS (ESI): m / z [M+H] + C 25 H 31Calculated value of ClN4O5S: 535.1578; Measured value: 535.1777.

[0849] Example 22 (R)-2-amino-N-(3-((4-fluorophenyl)methoxy-d2)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0850] Step 1: Synthesis of (4-fluorophenyl)-d2 methanol (intermediate 2)

[0851]

[0852] p-Fluorobenzoic acid (1, 2.00 g, 14.27 mmol) and diethyl ether (60 mL) were added to a 250 mL single-necked flask. Under nitrogen protection, lithium aluminum deuterated hydride (1.79 g, 42.82 mmol) was added in an ice-water bath, and the reaction was carried out at room temperature for 2 h. TLC (V 二氯甲烷 V 甲醇 =20:1) Monitor the reaction of the starting materials to ensure complete reaction. Quench the reaction mixture with water (30 mL), adjust the pH to 6 with 1 M HCl, extract with ether (30 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =100:1), yielding 1.72 g of colorless oily intermediate 2, with a yield of 94.1%. 1 H NMR (400 MHz, DMSO-d6)δ (ppm): 7.36-7.31 (m, 2H), 7.15-7.10 (m, 2H), 5.17 (s, 1H).

[0853] Step 2: Synthesis of 1-(bromomethyl-d2)-4-fluorobenzene (intermediate 3)

[0854]

[0855] Intermediate 2 (1.42 g, 11.08 mmol) and 40% hydrobromic acid solution (14 mL) were added to a 50 mL single-necked flask. The mixture was reacted at 110 °C for 1 h under nitrogen protection. TLC (V1) was then recorded. 石油醚 V 乙酸乙酯 =10:1) Monitor the reaction of the raw materials to ensure complete reaction, add water (20 mL) to quench the reaction mixture, extract with dichloromethane (20 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 石油醚 V 乙酸乙酯=10:1), yielding 1.50 g of colorless oily intermediate 3, with a yield of 70.9%. 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 7.52-7.48 (m, 2H), 7.21-7.16 (m, 2H).

[0856] Step 3: Synthesis of N-(tert-butoxycarbonyl)-O-[(4-fluorophenyl)methyl-d2]-D-serine (intermediate 4)

[0857]

[0858] Add 60% sodium hydride (795 mg, 19.89 mmol) and N,N-dimethylformamide (8 mL) to a 150 mL two-necked flask. Add a solution of Boc-D-serine (1.94 g, 9.47 mmol) in N,N-dimethylformamide (20 mL) dropwise under ice-water bath conditions. React at room temperature for 1 h. Cool to -40 °C, add intermediate 3 (1.81 g, 9.47 mmol) in N,N-dimethylformamide (5 mL) dropwise, and incubate overnight. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction of the starting materials to ensure complete reaction. Add water (30 mL) to the reaction solution to quench the reaction, adjust the pH to 4 with 1 M HCl, extract with ethyl acetate (150 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (20 g, V 二氯甲烷 V 甲醇 =10:1), yielding 2.05 g of colorless oily intermediate 4, with a yield of 68.8%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.68 (br, 1H), 7.38-7.34 (m,2H), 7.18-7.13 (m, 2H), 6.98 (d, J=8.4 Hz, 1H), 4.21-4.16 (m, 1H), 3.68-3.61(m, 2H), 1.38(s, 9H).

[0859] Step 4: Synthesis of (R)-[3-((4-fluorophenyl)methoxy-d2)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxopropyl-2-yl]tert-butyl carbamate (intermediate 5)

[0860]

[0861] Intermediate 4 (293 mg, 0.93 mmol), Intermediate 10 from Example 10 (185 mg, 0.78 mmol), N,N'-dicyclohexylcarbodiimide (176 mg, 0.85 mmol), 1-hydroxybenzotriazole (114 mg, 0.85 mmol), isopropyl acetate (6 mL), and water (3 mL) were added to a 50 mL single-necked flask. The mixture was reacted at room temperature for 3 h under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Add water (30 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (50 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (12 g, V). 二氯甲烷 V 甲醇 =15:1), yielding 390 mg of white solid intermediate 5, with a yield of 93.5%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.46 (d, J=7.2Hz, 0.5H), 7.42-7.37 (m, 2H), 7.32-7.23 (m, 3H), 7.20-7.14 (m, 2H), 7.13-7.09(m, 1H), 7.02 (t, J=8.0 Hz, 0.5H), 4.51-4.44 (m, 1H), 4.37-4.34 (m, 0.5H), 4.31-4.26 (m, 1H), 4.24-4.12 (m, 3.5H), 3.96 (dd, J1=20.1 Hz, J2=10.0 Hz, 1H),3.65-3.57 (m, 2H), 3.00 (s, 3H), 1.40-1.38 (m, 9H).

[0862] Step 5: Synthesis of (R)-2-amino-3-((4-fluorophenyl)methoxy-d2)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)propane-1-one (intermediate 6)

[0863]

[0864] Intermediate 5 (390 mg, 0.73 mmol), mesylate (489 mg, 5.09 mmol), and ethanol (5 mL) were added to a 25 mL single-necked flask, and the mixture was reacted overnight at 40 °C. TLC (V 二氯甲烷 V 甲醇=15:1) Monitor the reaction of the starting materials to ensure complete reaction. Dilute the reaction solution with water (10 mL) and adjust the pH to 10 with 1 M NaOH. Extract with ethyl acetate (30 mL × 2). Combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =15:1), yielding 245 mg of colorless oily intermediate 6, with a yield of 77.3%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.55 (d, J=7.9 Hz, 0.5H), 7.41-7.36 (m, 2H), 7.32-7.24 (m, 2H), 7.20-7.15 (m, 3H), 6.99 (t, J=7.4 Hz,0.5H), 4.50 (d, J=9.0 Hz, 0.5H), 4.45-4.40 (m, 1H), 4.26 (d, J=8.8 Hz, 0.5H), 4.19-4.16 (m, 2.5H), 4.12-4.07 (m, 1.5H), 3.97 (dd, J1=24.5 Hz, J2=9.9 Hz,1H), 3.46-3.44 (m, 2H), 2.99 (s, 3H), 1.74 (br, 2H).

[0865] Step 6: Synthesis of (R)-[1-[(3-((4-fluorophenyl)methoxy-d2)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxopropyl-2-yl)amino]-2-methyl-1-oxopropyl-2-yl] tert-butyl carbamate (intermediate 7)

[0866]

[0867] 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (125 mg, 0.62 mmol), intermediate 6 (245 mg, 0.56 mmol), N,N'-dicyclohexylcarbodiimide (127 mg, 0.62 mmol), 1-hydroxybenzotriazole (84 mg, 0.62 mmol), isopropyl acetate (5 mL), and water (2 mL) were added to a 25 mL single-necked flask. The mixture was reacted under nitrogen protection at room temperature for 3 h. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Add water (30 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (50 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (12 g, V二氯甲烷 V 甲醇 =10:1), yielding 320 mg of white solid intermediate 7, with a yield of 92.2%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.60 (br, 0.5H), 7.56 (d, J=7.9 Hz, 0.5H), 7.42-7.34 (m, 2.5H), 7.31-7.23 (m, 2.5H), 7.19-7.10 (m, 3H), 7.03 (t, J=8.0 Hz, 0.5H), 6.97 (br,0.5H), 4.58-4.53 (m, 1.5H), 4.46 (s, 1H), 4.29-4.27 (m, 0.5H), 4.22-4.21 (m,0.5H), 4.19-4.11 (m, 2.5H), 3.99-3.95 (m, 1H), 3.63-3.52 (m, 2H), 2.99 (d, J=3.0 Hz, 3H), 1.36-1.34 (m, 9H), 1.30-1.29 (m, 6H).

[0868] Step 7: Synthesis of (R)-2-amino-N-(3-((4-fluorophenyl)methoxy-d2)-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxopropyl-2-yl)-2-methylpropionamide (Example 22)

[0869]

[0870] Intermediate 7 (320 mg, 0.52 mmol), mesylate (347 mg, 3.61 mmol), and ethanol (5 mL) were added to a 25 mL single-necked flask, and the mixture was reacted overnight at 40 °C. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Dilute the reaction solution with water (10 mL) and adjust the pH to 9 with saturated NaHCO3. Extract with ethyl acetate (40 mL × 2). Combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =15:1), yielding 175 mg of the white solid compound of Example 22, with a yield of 64.8%.

[0871] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.25 (br, 1H), 7.51 (d, J=7.5 Hz,0.5H), 7.42-7.36 (m, 2H), 7.30-7.11 (m, 5H), 7.03 (t, J=6.6 Hz, 0.5H), 4.55(d, J=8.9 Hz, 0.5H), 4.50-4.45 (m, 2H), 4.29-4.19 (m, 3H), 4.12 (d, J=11.1Hz, 0.5H), 3.99 (dd, J1=22.0 Hz, J2=9.8 Hz, 1H), 3.64-3.55 (m, 2H), 2.99 (d, J=3.3 Hz, 3H), 2.05 (br, 2H), 1.20-1.18 (m, 6H).

[0872] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 177.21 (177.15), 169.63 (169.53),161.70 (J C-F =243.9 Hz) [161.65 (J C-F =244.0 Hz)], 141.48, 135.34, 135.19,134.21, 134.20 (J C-F =7.2 Hz), 129.81 (J C-F =20.3 Hz) [129.73 (J C-F =20.3 Hz)],129.17 (129.11), 124.13 (124.06), 123.55 (123.15), 115.14 (J C-F =21.3 Hz)[115.11 (J C-F =21.3 Hz)], 112.96 (112.89), 69.68 (69.26), 62.97 (62.90), 61.06(60.87), 59.96 (59.79), 54.27 (54.25), 49.12, 48.59, 40.61 (40.44), 34.40(34.38), 28.85 (28.81), 28.59 (28.54).

[0873] MS (ESI): m / z [M+H] + C 25 H30 Calculated value of D2FN4O5S: 521.2203; Measured value: 521.2192.

[0874] Example 23 (R)-2-amino-N-(3-((2,4-difluorobenzyl)oxy)-1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide

[0875] Step 1: Synthesis of N-(tert-butoxycarbonyl)-O-(2,4-difluorobenzyl)-D-serine (intermediate 2)

[0876]

[0877] Add 60% NaH (1.22 g, 30.43 mmol) and DMF (14 mL) to a 250 mL three-necked flask. Add a 28 mL solution of Boc-D-serine (2.97 g, 14.49 mmol) in DMF dropwise under ice bath conditions, and react at room temperature for 1 h. Cool to -40 °C, add a 28 mL solution of 2,4-difluorobenzyl bromide (1, 3.0 g, 14.49 mmol) in DMF dropwise, and incubate overnight. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Add water (100 mL) to the reaction solution to quench the reaction, adjust the pH to 5 with 1 M HCl, extract with ethyl acetate (70 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (80 g, V 二氯甲烷 V 甲醇 =100:1.5), yielding 2.51 g of colorless oily intermediate 2, yield 52.1%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.69 (s, 1H), 7.49 (q, J=8.0 Hz, 1H), 7.23 (td, J1=9.6 Hz, J2=2.4 Hz, 1H), 7.08 (td, J1=8.4 Hz, J2=2.4 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 4.50 (t, J=12.8 Hz, 2H), 4.20-4.15 (m, 1H), 3.68-3.65 (m, 2H), 1.37 (s, 9H).

[0878] Step 2: Synthesis of (R)-[3-((2,4-difluorobenzyl)oxy)-1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl] tert-butyl carbamate (intermediate 3)

[0879]

[0880] Intermediate 2 (500 mg, 1.51 mmol), Intermediate 4 (423 mg, 1.51 mmol), DCC (343 mg, 1.66 mmol), HOBt (224 mg, 1.66 mmol), isopropyl acetate (10 mL), and water (2.5 mL) were added sequentially to a 50 mL single-necked flask. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =20:1) Monitor the reaction of the raw materials to ensure complete reaction. Quench the reaction mixture with water (30 mL), extract with ethyl acetate (30 mL × 2), combine the organic phases, wash successively with saturated sodium bicarbonate solution (30 mL) and saturated brine (30 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (20 g, V 石油醚 V 乙酸乙酯 =1:1), yielding 200 mg of colorless oily liquid intermediate 3, with a yield of 22.3%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.64 (d, J=8.0 Hz, 1H), 7.55-7.41 (m, 2H), 7.36 (t, J=8.0 Hz, 1H), 7.27-7.20 (m, 2H), 7.15-7.08 (m, 2H), 4.73-4.71 (m, 1H), 4.54-4.50 (m, 2H), 4.21-4.10 (m, 1H), 3.94-3.87 (m, 1H), 3.72-3.67 (m, 2H), 3.57(d, J=3.2 Hz, 4H), 3.50-3.37 (m, 1H), 1.90-1.67 (m, 4H), 1.37 (s, 9H).

[0881] Step 3: Synthesis of 1'-(O-(2,4-difluorobenzyl)-D-serine)-1-(methanesulfonyl)spiro[indoline-3,4'-piperidine]-2-one (intermediate 4)

[0882]

[0883] Intermediate 3 (190 mg, 0.32 mmol), mesylate (185 mg, 1.92 mmol), and ethanol (5 mL) were added to a 50 mL single-necked flask. The mixture was reacted overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool to room temperature, quench with saturated sodium bicarbonate solution (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (30 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =50:1), yielding 120 mg of white solid intermediate 4, with a yield of 75.9%. 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 7.67-7.60 (m, 1H), 7.57-7.50 (m, 1.5H), 7.35 (t, J=8.0 Hz, 1H), 7.28-7.16 (m, 2H), 7.12-7.07 (m, 1.5H), 4.53 (s, 2H), 4.22-4.14 (m, 1H), 3.98-3.89(m, 2H), 3.74-3.68 (m, 1H), 3.56 (s, 3H), 3.52 (t, J=8.0 Hz, 1H), 3.49-3.39(m, 2H), 1.95-1.67(m, 6H).

[0884] Step 4: Synthesis of (R)-[1-[(3-((2,4-difluorobenzyl)oxy)-1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)-1-oxopropyl-2-yl)amino]-2-methyl-1-oxopropyl-2-yl] tert-butyl carbamate (intermediate 5)

[0885]

[0886] Intermediate 4 (300 mg, 0.61 mmol), isopropyl acetate (5 mL), water (5 mL), N-tert-butoxycarbonyl-2-methylalanine (136 mg, 0.67 mmol), DCC (138 mg, 0.67 mmol), and HOBt (90 mg, 0.67 mmol) were added sequentially to a 50 mL single-necked flask. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 石油醚 V 乙酸乙酯=1:1) Monitor the reaction of the starting materials to ensure complete reaction. Add water (20 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (30 mL × 2), combine the organic phases, wash with saturated brine (40 mL), dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (12 g, V 石油醚 V 乙酸乙酯 =5:3), yielding 345 mg of white solid intermediate 5, with a yield of 83.6%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm):7.65-7.44 (m, 3.5H), 7.35 (t, J=8.4 Hz, 1H), 7.27-7.17 (m, 2.5H), 7.09 (td,J1=8.4 Hz, J2=2.8 Hz, 1H), 6.99 (br, 1H), 5.02-4.94 (m, 1H), 4.54-4.51 (m,2H), 4.22-4.15 (m, 1H), 3.96-3.85 (m, 1H), 3.74-3.68 (m, 1H), 3.66-3.62 (m,1H), 3.59-3.52 (m, 4H), 3.48-3.35 (m, 1H), 1.93-1.68 (m, 4H), 1.36 (s, 9H), 1.28 (s, 6H).

[0887] Step 5: Synthesis of (R)-2-amino-N-(3-((2,4-difluorobenzyl)oxy)-1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-2-methylpropionamide (Example 23)

[0888]

[0889] Intermediate 5 (340 mg, 0.51 mmol), methanesulfonic acid (297 mg, 3.09 mmol), and ethanol (8 mL) were added to a 50 mL single-necked flask. The mixture was reacted overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool to room temperature, quench with saturated sodium bicarbonate solution (40 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =100:1), yielding 200 mg of the white solid compound of Example 23, with a yield of 69.2%.

[0890] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.32 (br, 1H), 7.64 (d, J=8.0 Hz,1H), 7.55-7.45 (m, 1.5H), 7.36 (t, J=8.0 Hz, 1H), 7.28-7.14 (m, 2.5H), 7.10(td, J1=8.8 Hz, J2=2.8 Hz, 1H), 4.99-4.97 (m, 1H), 4.55 (d, J=10.8 Hz, 2H),4.21-4.17 (m, 1H), 3.91-3.88 (d, 1H), 3.74-3.67 (m, 1H), 3.65-3.60 (m, 2H),3.57 (d, J=3.2 Hz, 3H), 3.47-3.40 (m, 1H), 2.05 (br, 2H), 1.88-1.70 (m, 4H),1.18 (s, 6H).

[0891] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 177.96 (177.88), 177.01 (176.93),168.19, 167.97, 163.36-158.96 (m), 137.70, 132.40 (J C-F =17.7 Hz), 132.08-131.45 (m), 131.97, 131.56, 128.41, 124.78 (124.67), 123.46 (J C-F =43.5 Hz),121.41-121.18 (m), 112.79, 111.56-111.24 (m), 103.85 (J 1C-F =26.2 Hz, J 2C-F =7.2Hz), 70.46 (69.99), 65.81 (65.53), 54.28, 48.26 (47.90), 44.82 (44.65),41.08, 40.49 (40.40), 37.05 (36.84), 32.91 (32.83), 32.40 (32.15), 28.83(28.57).

[0892] HRMS (ESI): m / z [M+H] + C27 H 33 Calculated value of F2N4O6S: 579.2089; Measured value: 579.2051

[0893] Example 24 Synthesis of (R)-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropyl-2-yl)-2-methyl-2-((2,2,2-trifluoroethyl)amino)propionamide (Example 24)

[0894]

[0895] To a 25 mL single-necked flask, intermediate 6 of Example 13 (200 mg, 0.44 mmol), isopropyl acetate (4 mL), water (4 mL), intermediate 5 of Example 3 (89 mg, 0.48 mmol), N,N'-dicyclohexylcarbodiimide (99 mg, 0.48 mmol), and 1-hydroxybenzotriazole (65 mg, 0.48 mmol) were added sequentially. The mixture was reacted under nitrogen protection at room temperature for 16 h. TLC (V 二氯甲烷 V 甲醇 =20:1) Monitor the reaction to completion, filter, wash with ethyl acetate (5 mL × 3), separate the filtrate, and collect the organic phase. Wash with saturated sodium chloride solution (5 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (20 g, V 二氯甲烷 V 甲醇 The compound was purified by a ratio of 50:1 to give 187 mg of white solid, as described in Example 24, with a yield of 68.0%.

[0896] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.04-7.93 (m, 1H), 7.68-7.59 (m,1H), 7.49-7.42 (m, 0.5H), 7.39-7.26 (m, 6H), 7.26-7.21 (m, 0.5H), 7.20-7.13(m, 1H), 5.11-5.01 (m, 1H), 4.60-4.44 (m, 2H), 4.25-4.11 (m, 1H), 3.97-3.83(m, 1H), 3.79-3.59 (m, 3H), 3.59-3.54 (m, 3H), 3.53-3.40 (m, 1H), 3.18-2.98(m, 3H), 1.97-1.66 (m, 4H), 1.22-1.15 (m, 6H).

[0897] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 177.99 (177.91), 175.08, 168.16(168.11), 138.08, 137.74 (137.69), 132.48 (132.32), 128.42, 128.29 (128.26),127.59, 127.50, 127.40, 125.95 (J C-F =278.3 Hz), 124.80 (124.73), 123.51,112.81, 72.30 (72.12), 70.10 (69.67), 58.37, 48.50 (48.16), 44.83 (44.72),44.78 (J C-F =31.4 Hz), 41.08, 40.53 (40.35), 37.18 (36.87), 32.92 (32.78), 32.41 (32.21), 25.58 (25.38), 24.92 (24.79).

[0898] HRMS (ESI): m / z [M+H] + C 29 H 35 Calculated value of F3N4O6S: 625.2307; Measured value: 625.2282.

[0899] Example 25 (R)-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropane-2-yl)-2-((ethyl-d5)amino)-2-methylpropionamide

[0900] Step 1: Synthesis of 2-((ethyl-d5)amino)-2-methylpropionate (Intermediate 1)

[0901]

[0902] Intermediate 3 from Example 17 (1.74 g, 9.34 mmol), MeOH (35 mL), water (14 mL), and lithium hydroxide monohydrate (1.18 g, 28.03 mmol) were added sequentially to a 100 mL single-necked flask. The mixture was reacted under nitrogen protection at room temperature for 16 h. TLC (V 二氯甲烷 V 甲醇=15:1) After monitoring the reaction to complete, the methanol was removed by concentration, the pH was adjusted to 5 with 1 M dilute hydrochloric acid, and the mixture was concentrated to obtain 4.89 g of off-white solid intermediate 1. The crude product was used directly in the next step. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 4.28-4.24 (m, 2H), 3.59 (d, J=4.0 Hz, 6H).

[0903] Step 2: Synthesis of (R)-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropane-2-yl)-2-((ethyl-d5)amino)-2-methylpropionamide (Example 25)

[0904]

[0905] Intermediate 6 (200 mg, 0.44 mmol), DMF (4 mL), Intermediate 1 (298 mg, 2.19 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (200 mg, 0.52 mmol), and N,N-diisopropylethylamine (170 mg, 1.31 mmol) from Example 13 were added sequentially to a 25 mL single-necked flask. The mixture was reacted under nitrogen protection at room temperature for 16 h. TLC (V 乙酸乙酯 V 甲醇 =5:1) After monitoring the reaction to completion, quench with water (20 mL), extract with ethyl acetate (20 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (20 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (12 g, V 乙酸乙酯 V 甲醇 The compound was purified by a ratio of 5:1 to give 118 mg of white solid, compound of Example 25, with a two-step yield of 36.0%.

[0906] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.24-8.19 (m, 1H), 7.64 (t, J=7.7Hz, 1H), 7.47 (d, J=8.0 Hz, 0.5H), 7.38-7.16 (m, 7.5H), 5.05-5.00 (m, 1H),4.57-4.47 (m, 2H), 4.20-4.15 (m, 1H), 3.94-3.87 (m, 1H), 3.75-3.60 (m, 3H),3.57-3.56 (m, 3H), 3.49-3.42 (m, 1H), 1.90-1.68 (m, 4H), 1.16 (s, 6H).

[0907] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 177.96 (177.90), 175.76, 168.22(168.10), 138.11, 137.72 (137.67), 132.46 (132.29), 128.41, 128.28 (128.25),127.59 (127.49), 127.39, 124.77 (124.75), 123.58 (123.46), 112.79, 72.36(72.18), 70.32 (69.85), 58.30, 48.44 (48.07), 44.84 (44.72), 41.08, 40.50 (40.39), 37.70 (36.89), 32.93 (32.80), 32.43 (32.20), 25.35, 25.18.

[0908] HRMS (ESI): m / z [M+H] + C 29 H 33 Calculated value of D5N4O6S: 576.2904; Measured value: 576.2864.

[0909] Example 26 (R)-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropane-2-yl)-2-methyl-2-((methyl-d3)amino)propionamide

[0910] Step 1: Synthesis of methyl-d3 2-((tert-butoxycarbonyl)amino)-2-methylpropionate (intermediate 2)

[0911]

[0912] N-tert-butoxycarbonyl-2-methylalanine (1, 2.00 g, 9.84 mmol), dimethyl sulfoxide (10 mL), potassium hydroxide (1.67 g, 29.52 mmol), and deuterated iodomethane (4.28 g, 29.52 mmol) were added sequentially to a 100 mL sealed tube. The reaction was carried out at room temperature for 16 h under nitrogen protection. TLC (V 石油醚 V 乙酸乙酯 =4:1) After monitoring the reaction to completion, quench with water (100 mL), extract with petroleum ether (100 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (50 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (40 g, V 石油醚 V 乙酸乙酯 The mixture was purified by a ratio of 4:1 to obtain 2.03 g of colorless oily intermediate 2, with a yield of 93.5%. 1 H NMR (400 MHz, CDCl3) δ (ppm): 2.55 (s, 1H), 1.36 (s, 15H).

[0913] Step 2: Synthesis of methyl-d3 2-((tert-butoxycarbonyl)(methyl-d3)amino)-2-methylpropionate (intermediate 3)

[0914]

[0915] Intermediate 2 (2.03 g, 9.22 mmol), DMF (20 mL), and deuterated iodomethane (5.34 g, 36.9 mmol) were added sequentially to a 100 mL single-necked flask. Under nitrogen protection, 60% NaH (737 mg, 18.4 mmol) was added in three portions, and the reaction was allowed to proceed at room temperature for 3.5 h. TLC (V 石油醚 V 乙酸乙酯 =6:1) After monitoring the reaction to completion, quench with ice water (20 mL), extract with petroleum ether (15 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (5 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (40 g, V 石油醚 V 乙酸乙酯 Purification at a ratio of 10:1 yielded 1.67 g of colorless oily intermediate 3, with a yield of 76.3%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 1.35 (s, 15H).

[0916] Step 3: Synthesis of 2-((tert-butoxycarbonyl)(methyl-d3)amino)-2-methylpropionic acid (intermediate 4)

[0917]

[0918] To a 100 mL single-necked flask, intermediate 3 (1.67 g, 7.04 mmol), 1,4-dioxane (16 mL), methanol (5 mL), and an aqueous solution of lithium hydroxide monohydrate (1.48 g, 35.2 mmol) (37 mL) were added sequentially. The reaction was carried out overnight at 50 °C under nitrogen protection. TLC (V 石油醚 V 乙酸乙酯 (6:1 ratio) Monitor the remaining feed to approximately 20%, cool to room temperature, adjust pH to 7 with 1 M hydrochloric acid, and concentrate. Wash with ethyl acetate (15 mL × 2), collect the aqueous phase. Adjust pH to 2 with 1 M hydrochloric acid, extract with ethyl acetate (10 mL × 5), collect the organic phase. Dry with anhydrous sodium sulfate, filter, and concentrate to obtain 348 mg of white solid intermediate 4, yield 22.5%. 1 HNMR (400 MHz, DMSO-d6) δ (ppm): 12.09 (s, 1H), 1.36 (s, 9H), 1.32 (s, 6H).

[0919] Step 4: Synthesis of (R)-((1-((3-(benzyloxy)-1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)(methyl-d3))tert-butyl carbamate (intermediate 5)

[0920]

[0921] To a 50 mL single-necked flask, intermediate 6 (400 mg, 0.87 mmol), intermediate 4 (249 mg, 1.13 mmol), IPAc (10 mL), water (10 mL), HOBt (153 mg, 1.13 mmol), and DCC (233 mg, 1.13 mmol) from Example 13 were added sequentially. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =20:1) After monitoring the reaction of the raw materials to complete, quench with ice water (2 mL), extract with ethyl acetate (10 mL × 3), and collect the organic phase. Wash with saturated sodium bicarbonate solution (5 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (40 g, V 石油醚 V 乙酸乙酯The mixture was purified at a ratio of 2:3 to obtain 347 mg of white solid intermediate 5, with a yield of 22.5%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.66-7.60 (m, 2H),7.47-7.25 (m, 7H), 7.20-7.07 (m, 1H), 5.05-4.97 (m, 1H), 4.52-4.49 (m, 2H),4.22-4.19 (m, 1H), 3.93-3.90 (m, 1H), 3.77-3.63 (m, 2H), 3.57-3.56 (m, 4H),3.44-3.39 (m, 1H), 1.90-1.65 (m, 4H), 1.40 (s, 9H), 1.34-1.32 (m, 6H).

[0922] Step 5: Synthesis of (R)-N-(3-(benzyloxy)-1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-yl)-1-oxopropane-2-yl)-2-methyl-2-((methyl-d3)amino)propionamide (Example 26)

[0923]

[0924] Intermediate 5 (347 mg, 0.53 mmol), ethanol (16 mL), and methanesulfonic acid (306 mg, 3.18 mmol) were added to a 50 mL single-necked flask. The mixture was reacted overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =20:1) Monitor the reaction to completion, then concentrate. Adjust the pH to 8 with saturated sodium bicarbonate solution, extract with dichloromethane (20 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (5 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and pass through rapid preparative chromatography (40 g, V). 二氯甲烷 V 甲醇 The compound was purified by a ratio of 50:1 to give 190 mg of white solid, as described in Example 26, with a yield of 64.0%.

[0925] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.16-8.13 (m, 1H), 7.64 (t, J=7.7Hz, 1H), 7.48 (d, J=8.0 Hz, 0.5H), 7.38-7.27 (m, 6H), 7.25-7.20 (m, 0.5H),7.18-7.14 (m, 1H), 5.03 (q, J=6.5 Hz, 1H), 4.59-4.45 (m, 2H), 4.21-4.16 (m,1H), 3.90 (br, 1H), 3.78-3.59 (m, 3H), 3.57-3.56 (m, 3H), 3.51-3.41 (m, 1H),2.01-1.61 (m, 4H), 1.15 (s, 6H).

[0926] 13 C NMR (101 MHz, DMSO) δ (ppm): 178.44 (178.37), 176.11, 172.60, 168.75 (168.60), 138.59, 138.20 (138.15), 132.94 (132.76), 128.88, 128.76(128.73), 128.07, 127.96, 127.88, 125.26 (125.19), 124.05 (123.92), 113.26,72.81 (72.63), 70.78 (70.28), 58.91, 48.84 (48.46), 45.31 (45.19), 41.55, 40.99 (40.86), 37.57 (37.34), 33.42 (33.26), 32.91 (32.66), 25.39 (25.30), 25.16, 21.68.

[0927] HRMS (ESI): m / z [M+H] + C 28 H 33 Calculated value of D3N4O6S: 560.2622; Measured value: 560.2608.

[0928] Example 27 (R)-2-amino-2-methyl-N-(1-(1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)-1-oxo-3-((phenyl-d5)methoxy)propane-2-yl)propionamide

[0929] Step 1: Synthesis of (phenyl-d5)methanol (intermediate 2)

[0930]

[0931] Deuterated benzoic acid (1, 2.00 g, 15.7 mmol) and diethyl ether (80 mL) were added to a 250 mL single-necked flask. Under nitrogen protection, lithium aluminum hydride (1.79 g, 47.2 mmol) was added in portions under an ice-water bath, and the reaction was carried out at room temperature for 2 h. TLC (V 二氯甲烷 V 甲醇 =20:1) Monitor the reaction of the raw materials to ensure complete reaction, pour the reaction solution into ice water (100 mL) to quench, add 3 mol / L dilute hydrochloric acid to adjust the pH to 4, extract with ether (100 mL × 2), combine the organic phases, wash with saturated sodium chloride solution (100 mL), dry with anhydrous sodium sulfate, filter, concentrate, and obtain 2.10 g of colorless oily intermediate 2, which can be used directly in the next step without purification. 1 H NMR (400 MHz, CDCl3) δ (ppm): 4.71 (s, 2H).

[0932] Step 2: Synthesis of 1-(bromomethyl)benzene-2,3,4,5,6-d5 (intermediate 3)

[0933]

[0934] Intermediate 2 (2.10 g, 18.6 mmol) and hydrobromic acid (20 mL, 40% wtin H2O) were added sequentially to a 100 mL single-necked flask. The mixture was reacted at 110 °C for 1 h under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =20:1) Monitor the reaction of the starting materials until complete, cool to room temperature, dilute with water (20 mL), extract with dichloromethane (20 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (30 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (40 g, V 石油醚 =1), yielding 2.20 g of colorless oily intermediate 3, with a two-step yield of 79.4%. 1 H NMR (400 MHz, CDCl3) δ (ppm): 4.51 (s, 2H).

[0935] Step 3: Synthesis of N-(tert-butoxycarbonyl)-O-((phenyl-d5)methyl)-D-serine (intermediate 4)

[0936]

[0937] Add 60% sodium hydroxide (1.05 g, 26.2 mmol) and DMF (20 mL) sequentially to a 250 mL three-necked flask. Under nitrogen protection, add a 20 mL solution of Boc-D-serine (2.56 g, 12.5 mmol) in DMF dropwise under an ice-water bath and react at room temperature for 1 h. Add a 20 mL solution of intermediate 3 (2.20 g, 12.5 mmol) in DMF dropwise at -40°C and react overnight. TLC (V 二氯甲烷 V 甲醇 =20:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool to room temperature, quench with water (100 mL), adjust pH to 3 by adding 3 mol / L dilute hydrochloric acid, extract with ethyl acetate (70 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (70 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (40 g, V 二氯甲烷 V 甲醇 =100:1), yielding 1.80 g of colorless oily intermediate 4, with a yield of 47.9%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.68 (s, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.51-4.45 (m, 2H), 4.22-4.17 (m, 1H), 3.67-3.65 (m, 2H), 1.38(s, 9H).

[0938] Step 4: Synthesis of (R)-((1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-yl)-1-oxo-3-((phenyl-d5)methoxy)propane-2-yl))tert-butyl carbamate (intermediate 5)

[0939]

[0940] Intermediate 4 (800 mg, 2.66 mmol), Intermediate 4 from Example 13 (747 mg, 2.66 mmol), isopropyl acetate (15 mL), water (7.5 mL), HOBt (396 mg, 2.93 mmol), and DCC (604 mg, 2.93 mmol) were added to a 25 mL single-necked flask. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇=15:1) Monitor the reaction of the starting materials until complete, dilute with water (15 mL), extract with ethyl acetate (25 mL × 3), combine the organic phases, wash successively with saturated sodium bicarbonate solution (25 mL × 3) and saturated sodium chloride solution (20 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (20 g, V 石油醚 V 乙酸乙酯 =3:2), yielding 440 mg of white solid intermediate 5, yield 29.4%. 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 7.66-7.62 (m, 1H), 7.48-7.31 (m, 2H), 7.26-7.18 (m, 1H), 7.18-7.12 (m,1H), 4.75-4.73 (m, 1H), 4.55-4.48 (m, 2H), 4.22-4.09 (m, 1H), 3.92-3.88 (m,1H), 3.76-3.64 (m, 2H), 3.60-3.52 (m, 4H), 3.48-3.38 (m, 1H), 1.80-1.70 (m,4H), 1.38 (s, 9H).

[0941] Step 5: Synthesis of 1-(methanesulfonyl)-1'-(O-((phenyl-d5)methyl)-D-seryl)spiro[indoline-3,4'-piperidine]-2-one (intermediate 6)

[0942]

[0943] Intermediate 5 (440 mg, 0.78 mmol), ethanol (8 mL), and methanesulfonic acid (450 mg, 4.69 mmol) were added to a 50 mL single-necked flask. The mixture was reacted overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool to room temperature, quench with saturated sodium bicarbonate solution (15 mL), extract with ethyl acetate (25 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (30 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =100:1), yielding 290 mg of white solid intermediate 6, with a yield of 80.2%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.64 (t, J=9.2 Hz, 1H), 7.52 (d, J=7.6 Hz, 0.5H), 7.34 (q, J=8.0Hz, 1H), 7.24 (d, J=7.6 Hz, 0.5H), 7.14 (t, J=7.6 Hz, 0.5H), 7.02 (d, J=7.6Hz, 0.5H), 4.54-4.47 (m, 2H), 4.21-4.18 (m, 1H), 4.05-3.88 (m, 2H), 3.76-3.67(m, 1H), 3.57-3.56 (m, 3H), 3.54-3.39 (m, 3H), 2.02-1.63 (m, 6H).

[0944] Step 6: Synthesis of (R)-(2-methyl-1-((1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-yl)-1-oxo-3-((phenyl-d5)methoxy)propane-2-yl)amino)-1-oxopropane-2-yl)carbamate tert-butyl ester (intermediate 7)

[0945]

[0946] Intermediate 6 (290 mg, 0.63 mmol), isopropyl acetate (5 mL), water (5 mL), N-tert-butoxycarbonyl-2-methylalanine (140 mg, 0.69 mmol), DCC (142 mg, 0.69 mmol), and HOBt (93 mg, 0.69 mmol) were added sequentially to a 50 mL single-necked flask. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Quench with water (15 mL), extract with ethyl acetate (25 mL × 3), combine the organic phases, wash successively with saturated sodium bicarbonate solution (25 mL × 3) and saturated sodium chloride solution (20 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 石油醚 V 乙酸乙酯 =1:1), yielding 380 mg of white solid intermediate 7, with a yield of 93.6%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.68-7.48 (m, 2.5H), 7.34 (q, J=7.6 Hz, 1H), 7.23-7.14 (m,1H), 7.09 (d, J=7.6 Hz, 0.5H), 7.01 (br, 1H), 5.06-4.95 (m, 1H), 4.50 (d, J=10.8 Hz, 2H), 4.23-4.16 (m, 1H), 4.00-3.85 (m, 1H), 3.77-3.67 (m, 1H), 3.65-3.57 (m, 2H), 3.56 (d, J=6.0 Hz, 3H), 3.48-3.34 (m, 1H), 1.95-1.70 (m, 4H), 1.36 (s, 9H), 1.30 (s, 6H).

[0947] Step 7: Synthesis of (R)-2-amino-2-methyl-N-(1-(1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)-1-oxo-3-((phenyl-d5)methoxy)propane-2-yl)propionamide (Example 27)

[0948]

[0949] Intermediate 7 (380 mg, 0.59 mmol), ethanol (6 mL), and methanesulfonic acid (338 mg, 3.51 mmol) were added to a 25 mL single-necked flask. The mixture was reacted overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool to room temperature, quench with saturated sodium bicarbonate solution (15 mL), extract with ethyl acetate (25 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (40 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =100:1), yielding 260 mg of the white solid compound of Example 27, with a yield of 80.9%.

[0950] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.34 (br, 1H), 7.64 (t, J=8.4 Hz,1H), 7.51 (d, J=7.6 Hz, 0.5H), 7.35 (q, J=7.2 Hz, 1H), 7.23 (t, J=7.6 Hz,0.5H), 7.16 (t, J=7.6 Hz, 0.5H), 7.07 (d, J=7.6 Hz, 0.5H), 5.00 (br, 1H), 4.57-4.47 (m, 2H), 4.22-4.19 (m, 1H), 3.97-3.86 (m, 1H), 3.78-3.67 (m, 1H),3.67-3.58 (m, 2H), 3.56 (d, J=5.6 Hz, 3H), 3.51-3.40 (m, 1H), 2.05 (br, 2H),1.92-1.68 (m, 4H), 1.19 (d, J=2.0 Hz, 6H).

[0951] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 177.97 (177.89), 176.98 (176.89), 168.32 (168.11), 137.93 (137.70), 132.48 (132.26), 128.39, 128.01 (127.78),127.52, 127.21, 126.97, 124.78 (124.72), 123.69 (123.38), 112.76, 72.33(72.10), 70.43 (69.87), 54.28, 48.34 (47.98), 44.85 (44.67), 41.08, 40.54 (40.43), 37.07 (36.86), 32.91 (32.80), 32.44 (32.17), 28.88 (28.84), 28.59.

[0952] HRMS (ESI): m / z [M+H] + C 27 H 29 Calculated value of D5N4O6S: 548.2591; Measured value: 548.2568.

[0953] Example 28 (R)-2-amino-2-methyl-N-(1-(1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)-1-oxo-3-((phenyl-d5)methoxy-d2)propane-2-yl)propionamide

[0954] Step 1: Synthesis of 1-(bromomethyl-d2)benzene-2,3,4,5,6-d5 (intermediate 2)

[0955]

[0956] Deuterated toluene (1,500 mg, 4.99 mmol), carbon tetrachloride (10 mL), tert-butyl peroxide (290 mg, 1.49 mmol), and NBS (888 mg, 4.99 mmol) were added sequentially to a 50 mL single-necked flask. The mixture was reacted at 90 °C for 2 h under nitrogen protection. TLC (VL) was then recorded. 石油醚 V 乙酸乙酯 =10:1) Monitor the reaction of raw materials until complete. Filter the reaction solution through diatomaceous earth, collect the filtrate, concentrate it, and purify it by rapid preparative chromatography (20 g, V). 乙酸乙酯 V 石油醚 =1:100), yielding 580 mg of colorless oily intermediate 2, yield 65.3%.

[0957] Step 2: Synthesis of N-(tert-butoxycarbonyl)-O-((phenyl-d5)methyl-d2)-D-serine (intermediate 3)

[0958]

[0959] Add 60% sodium hydroxide (273 mg, 6.85 mmol) and DMF (5 mL) sequentially to a 50 mL double-necked flask. Under nitrogen protection, add a 3 mL solution of Boc-D-serine (668 mg, 3.26 mmol) in DMF dropwise over an ice bath. Incubate at room temperature for 1 h. Cool to -40°C and add a 2 mL solution of intermediate 2 (580 mg, 0.60 mol) in DMF dropwise. Incubate under nitrogen protection for 16 h. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the raw materials until complete, quench with water (10 mL) in an ice bath, adjust the pH to 4 with dilute hydrochloric acid (1 M), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (40 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (20 g, V 二氯甲烷 V 甲醇 =100:1), yielding 520 mg of colorless oily intermediate 3, with a yield of 52.8%.1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.68 (s, 1H), 6.97 (d, J=8.4Hz, 1H), 4.22-4.12 (m, 1H), 3.66-3.63 (m, 2H), 1.38 (s, 9H).

[0960] Step 3: Synthesis of (R)-((1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-yl)-1-oxo-3-((phenyl-d5)methoxy-d2)propane-2-yl))tert-butyl carbamate (intermediate 4)

[0961]

[0962] Compound intermediate 3 (520 mg, 1.72 mmol), intermediate 4 from Example 13 (482 mg, 1.72 mmol), IPAc (8 mL), water (2 mL), DCC (390 mg, 1.89 mmol), and HOBt (256 mg, 1.89 mmol) were added sequentially to a 50 mL reaction flask. The mixture was reacted under nitrogen protection at room temperature for 16 h. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the raw materials until complete, quench with water (20 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (15 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (20 g, V 乙酸乙酯 V 石油醚 =1:1), yielding 220 mg of white solid intermediate 4, yield 22.3%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.64 (t, J=7.2 Hz,1H), 7.47-7.31 (m, 2H), 7.20-7.08 (m, 2H), 4.74 (q, J=7.2 Hz, 1H), 4.22-4.10(m, 1H), 3.95-3.88 (m, 1H), 3.77-3.59 (m, 3H), 3.57 (d, J=4.8 Hz, 3H), 3.50-3.39 (m, 1H), 1.91-1.78 (m, 3H), 1.76-1.61 (m, 1H), 1.38 (s, 9H).

[0963] Step 4: Synthesis of 1-(methanesulfonyl)-1'-(O-((phenyl-d5)methyl-d2)-D-seryl)spiro[indoline-3,4'-piperidine]-2-one (intermediate 5)

[0964]

[0965] Compound intermediate 4 (220 mg, 0.39 mmol), ethanol (5 mL), and methanesulfonic acid (225 mg, 2.34 mmol) were added to a 50 mL reaction flask. The mixture was reacted at 40 °C for 24 h under nitrogen protection. TLC (V1) was then performed. 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool the reaction solution to room temperature, adjust the pH to 9 with saturated sodium bicarbonate, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (15 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =100:1), yielding 130 mg of white solid intermediate 5, yield 71.8%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.64 (t, J=8.8 Hz, 1H), 7.51 (d, J=7.6 Hz, 0.5H), 7.38-7.32(m, 1H), 7.25-7.13 (m, 1H), 7.03 (d, J=7.6 Hz, 0.5H), 4.19 (d, J=13.6 Hz,1H), 4.03-3.93 (m, 2H), 3.73-3.70 (m, 1H), 3.56 (s, 3H), 3.53-3.42 (m, 3H), 1.98-1.58 (m, 4H).

[0966] Step 5: Synthesis of (R)-(2-methyl-1-((1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)-1-oxo-3-((phenyl-d5)methoxy-d2)propane-2-yl)amino)-1-oxopropane-2-yl)tert-butyl carbamate (intermediate 6)

[0967]

[0968] Compound intermediate 5 (130 mg, 0.28 mmol), N-tert-butoxycarbonyl-2-methylalanine (63 mg, 0.31 mmol), IPAc (2.5 mL), water (2.5 mL), DCC (64 mg, 0.31 mmol), and HOBt (42 mg, 0.31 mmol) were added to a 50 mL reaction flask. The mixture was reacted under nitrogen protection at room temperature for 16 h. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the raw materials until complete, quench with water (15 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (15 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (4 g, V 乙酸乙酯 V 石油醚 =2:3), yielding 180 mg of white solid intermediate 6, with a yield of 93.5%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.66-7.55(m, 2.5H), 7.35 (q, J=7.2 Hz, 1H), 7.23-7.15 (m, 1H), 7.09 (d, J=7.6 Hz,0.5H), 7.01 (br, 1H), 5.57 (d, J=8.0 Hz, 1H), 5.02-4.98 (m, 1H), 4.23-4.16(m, 1H), 3.98-3.87 (m, 1H), 3.75-3.70 (m, 1H), 3.65-3.60 (m, 1H), 3.56 (d, J=6.0 Hz, 3H), 3.50-3.38 (m, 1H), 1.85-1.83 (m, 2H), 1.74-1.70 (m, 2H), 1.36 (s, 9H), 1.30 (s, 6H).

[0969] Step 6: Synthesis of (R)-2-amino-2-methyl-N-(1-(1-(1-(methanesulfonyl)-2-oxospiro[indoline-3,4'-piperidin]-1'-yl)-1-oxo-3-((phenyl-d5)methoxy-d2)propane-2-yl)propionamide (Example 28)

[0970]

[0971] Intermediate 6 (170 mg, 0.26 mmol), ethanol (4 mL), and methanesulfonic acid (151 mg, 1.57 mmol) were added to a 50 mL reaction flask. The mixture was reacted at 40 °C for 24 h under nitrogen protection. TLC (V1) was then performed.二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool the reaction solution to room temperature, adjust the pH to 9 with saturated sodium bicarbonate, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (15 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (4 g, V 二氯甲烷 V 甲醇 =100:1), yielding 100 mg of the white solid compound of Example 28, with a yield of 69.5%.

[0972] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.34 (br, 1H), 7.64 (t, J=8.0 Hz,1H), 7.51 (d, J=7.6 Hz, 0.5H), 7.35 (q, J=7.2 Hz, 1H), 7.25-7.15 (m, 1H),7.07 (d, J=7.6 Hz, 0.5H), 4.99 (br, 1H), 4.22-4.18 (m, 1H), 3.93-3.89 (m,1H), 3.74-3.66 (m, 1H), 3.65-3.53 (m, 5H), 3.49-3.41 (m, 1H), 2.14 (br, 2H),1.92-1.69 (m, 4H), 1.19 (s, 6H).

[0973] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 178.46 (178.37), 177.44 (177.36), 168.80 (168.60), 138.30 (138.16), 132.96 (132.74), 128.87, 128.50 (128.26),128.01, 127.74 (127.51), 125.26 (125.20), 124.17 (123.85), 113.24, 70.83(70.26), 54.76, 48.83 (48.47), 45.33 (45.15), 41.56, 37.55 (37.33), 33.40 (33.28), 32.92 (32.65), 29.35 (29.31), 29.06.

[0974] HRMS (ESI): m / z [M+H] + C27 H 27 Calculated value of D7N4O6S: 550.2717; Measured value: 550.2689.

[0975] Example 29 (R)-2-amino-N-(3-(benzyloxy)-1-oxo-1-(2-oxo-1-toluenesulfonylspiro[indoline-3,4'-piperidine]-1'-yl)propane-2-yl)-2-methylpropionamide

[0976] Step 1: Synthesis of 1'-benzyl-1-toluenesulfonylspiro[indoline-3,4'-piperidine]-2-one (Intermediate 2)

[0977]

[0978] Compound 1 (1.50 g, 5.13 mmol) and tetrahydrofuran (25 mL) were added to a 100 mL single-necked flask. Under nitrogen protection, 60% sodium hydride (307 mg, 7.69 mmol) was added in an ice-water bath. The reaction was maintained at this temperature for 30 min, followed by the addition of p-toluenesulfonyl chloride (1.47 g, 7.69 mmol), and the reaction was continued at room temperature for 2 h. TLC (V 石油醚 V 乙酸乙酯 =3:1) Monitor the reaction of the starting materials to ensure complete reaction. Quench the reaction mixture with ice water (10 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (12 g, V 石油醚 V 乙酸乙酯 =3:1), yielding 1.79 g of gray solid intermediate 2, with a yield of 78.2%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.89 (d, J=8.3 Hz, 2H), 7.79 (d, J=8.1 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.40-7.30 (m,5H), 7.25-7.21 (m, 2H), 3.56 (s, 2H), 2.67-2.59 (m, 4H), 2.38 (s, 3H), 1.82-1.73 (m, 2H), 1.65-1.62 (m, 2H).

[0979] Step 2: Synthesis of 1-toluenesulfonylspiro[indoline-3,4'-piperidine]-2-one hydrochloride (intermediate 3)

[0980]

[0981] Intermediate 2 (1.79 g, 5.02 mmol), 1-chloroethyl chloroformate (1.16 g, 8.13 mmol), 1,8-bis(dimethylaminonaphthalene) (505 mg, 2.36 mmol), and 1,2-dichloroethane (34 mL) were added to a 100 mL single-necked flask. The mixture was reacted at 85 °C for 1.5 h under nitrogen protection. The solution was concentrated to a solid state, and methanol (34 mL) was added. The reaction was then carried out at 65 °C for 1 h. TLC (V1) was performed. 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of raw materials to ensure complete reaction. Concentrate the reaction solution and rapidly purify it by preparative chromatography (20 g, V). 二氯甲烷 V 甲醇 =10:1), yielding 1.21 g of gray solid intermediate 3, with a yield of 84.7%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.03 (br, 2H),7.93 (d, J=12.9 Hz, 2H), 7.80 (d, J=8.3 Hz, 1H), 7.48 (d, J=7.8 Hz, 2H),7.45-7.41 (m, 1H), 7.39-7.37 (m, 1H), 7.32-7.28 (m, 1H), 3.27-3.24 (m, 4H), 2.40 (s, 3H), 2.19-2.12 (m, 2H), 1.86-1.81 (m, 2H).

[0982] Step 3: Synthesis of (R)-((3-(benzyloxy)-1-oxo-1-(2-oxo-1-toluenesulfonylspiro[indoline-3,4'-piperidine]-1'-yl)propane-2-yl))tert-butyl carbamate (intermediate 4)

[0983]

[0984] Intermediate 3 (965 mg, 2.71 mmol), N-Boc-O-benzyl-D-serine (800 mg, 2.71 mmol), N,N'-dicyclohexylcarbodiimide (614 mg, 2.98 mmol), 1-hydroxybenzotriazole (402 mg, 2.98 mmol), isopropyl acetate (20 mL), and water (10 mL) were added to a 100 mL single-necked flask. The mixture was reacted under nitrogen protection at room temperature for 3 h. TLC (V 二氯甲烷 V 甲醇=20:1) Monitor the reaction of the starting materials to ensure complete reaction. Add water (50 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (100 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (20 g, V). 二氯甲烷 V 甲醇 =20:1), yielding 800 mg of white solid intermediate 4, yield 46.6%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.91(t, J=7.3 Hz, 2H), 7.80-7.79 (m, 1H), 7.48-7.46 (m, 2H), 7.43-7.38 (m, 1H),7.34-7.28 (m, 7H), 7.11-7.09 (m, 1H), 4.70-4.68 (m, 1H), 4.50-4.48 (m, 2H), 4.12-4.09 (m, 0.5H), 4.02-3.99 (m, 0.5H), 3.86-3.79 (m, 1H), 3.67-3.61 (m,3H), 3.57-3.50 (m, 1H), 3.29 (s, 3H), 1.73-7.70 (m, 4H), 1.38-1.36 (m, 9H).

[0985] Step 4: Synthesis of 1'-(O-benzyl-D-seryl)-1-toluenesulfonylspiro[indoline-3,4'-piperidine]-2-one (intermediate 5)

[0986]

[0987] Intermediate 4 (800 mg, 1.26 mmol), mesylate (849 mg, 8.84 mmol), and ethanol (10 mL) were added to a 50 mL single-necked flask, and the mixture was reacted overnight at 40 °C. TLC (V 二氯甲烷 V 甲醇 =20:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool to room temperature, dilute the reaction solution with water (10 mL), adjust the pH to 9 with saturated NaHCO3, extract with ethyl acetate (50 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (20 g, V 二氯甲烷 V 甲醇 =15:1), yielding 320 mg of colorless oily intermediate 5, with a yield of 47.6%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.92-7.87(m, 2H), 7.79 (t, J=8.8 Hz, 1H), 7.47 (d, J=8.0 Hz, 2H), 7.42-7.16 (m, 8H),4.51-4.48 (m, 1.5H), 4.49-4.42 (m, 0.5H), 4.11-4.08 (m, 1H), 4.01-3.98 (m,1H), 3.89-3.82 (m, 1H), 3.66-3.59 (m, 1H), 3.50-3.46 (m, 1.5H), 3.42-3.37 (m,1.5H), 2.39 (s, 3H), 1.84-1.72 (m, 1H), 1.67-1.59 (m, 3H).

[0988] Step 5: Synthesis of (R)-((1-((3-(benzyloxy)-1-oxo-1-(2-oxo-1-toluenesulfonylspiro[indoline-3,4'-piperidine]-1'-yl)propane-2-yl)amino)-2-methyl-1-oxopropane-2-yl))tert-butyl carbamate (intermediate 6)

[0989]

[0990] 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (134 mg, 0.66 mmol), intermediate 5 (320 mg, 0.59 mmol), N,N'-dicyclohexylcarbodiimide (136 mg, 0.66 mmol), 1-hydroxybenzotriazole (89 mg, 0.66 mmol), isopropyl acetate (6 mL), and water (3 mL) were added to a 50 mL single-necked flask. The mixture was reacted under nitrogen protection at room temperature for 4 h. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Add water (30 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (50 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (20 g, V). 二氯甲烷 V 甲醇 =15:1), yielding 300 mg of white solid intermediate 6, with a yield of 69.6%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.90 (t, J=7.3 Hz, 2H), 7.78 (t, J=8.7 Hz, 1H), 7.58-7.56 (m,1H), 7.48-7.46 (m, 2H), 7.41-7.28 (m, 8H), 7.15-7.09 (m, 1H), 4.50-4.95 (m,1H), 4.49-4.47 (m, 2H), 4.43-4.41 (m, 0.5H), 3.85-3.78 (m, 1.5H), 3.67-3.51(m, 4H), 2.39 (s, 3H), 1.74-1.71 (m, 1H), 1.65-1.62 (m, 3H), 1.34 (s, 9H), 1.28-1.26 (m, 6H).

[0991] Step 6: Synthesis of (R)-2-amino-N-(3-(benzyloxy)-1-oxo-1-(2-oxo-1-toluenesulfonylspiro[indoline-3,4'-piperidin]-1'-yl)propane-2-yl)-2-methylpropionamide (Example 29)

[0992]

[0993] Intermediate 6 (300 mg, 0.42 mmol), mesylate (280 mg, 2.92 mmol), and ethanol (5 mL) were added to a 50 mL single-necked flask, and the mixture was reacted overnight at 40 °C. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool to room temperature, dilute the reaction solution with water (10 mL), adjust the pH to 9 with saturated NaHCO3, extract with ethyl acetate (50 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (20 g, V 二氯甲烷 V 甲醇 =15:1), yielding 135 mg of the off-white solid compound of Example 29, with a yield of 52.1%.

[0994] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.32 (br, 1H), 7.91 (t, J=7.5 Hz,2H), 7.78 (t, J=8.0 Hz, 1H), 7.50-7.46 (m, 2H), 7.39-7.15 (m, 7H), 7.17 (d, J=7.9 Hz, 0.5H), 7.06 (d, J=7.1 Hz, 0.5H), 4.95 (br, 1H), 4.51-4.45 (m, 2H), 4.10-4.08 (m, 1H), 3.84-3.81 (m, 1H), 3.64-3.56 (m, 3H), 3.43-3.38 (m, 1H),2.39 (s, 3H), 2.02 (br, 2H), 1.83-1.72 (m, 1H), 1.67-1.55 (m, 3H), 1.16-1.18(m, 6H).

[0995] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 177.08 (177.02), 176.95 (176.87), 168.28 (168.10), 145.95, 138.10, 137.03 (136.98), 134.47 (134.43), 132.45,132.24, 130.21, 128.71, 128.27, 127.60, 127.48, 127.41, 127.29, 125.22(125.20), 123.83 (123.51), 113.07, 72.35 (72.17), 70.35, 69.85, 54.28, 48.33, 47.98, 44.92 (44.79), 40.43 (40.34), 36.96 (36.81), 32.87, 32.34 (32.17), 28.81 (28.78), 28.55, 21.18.

[0996] MS (ESI): m / z [M+H] + C 33 H 39 Calculated value of N4O6S: 619.2590; Measured value: 619.2572.

[0997] Example 30 (R)-2-amino-2-methyl-N-(1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxo-3-((phenyl-d5)methoxy-d2)propane-2-yl)propionamide

[0998] Step 1: Synthesis of (R)-((1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxo-3-((phenyl-d5)methoxy-d2)propane-2-yl))tert-butyl carbamate (intermediate 1)

[0999]

[1000] To a 100 mL single-necked flask, intermediate 3 (490 mg, 1.62 mmol), isopropyl acetate (7.5 mL), water (2 mL), intermediate 10 (300 mg, 1.26 mmol), N,N'-dicyclohexylcarbodiimide (338 mg, 1.62 mmol), and 1-hydroxybenzotriazole (222 mg, 1.62 mmol) were added sequentially. The reaction was carried out overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =20:1) After monitoring the reaction to complete, quench the reaction mixture with saturated sodium bicarbonate solution (50 mL), filter, extract the filtrate with ethyl acetate (30 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (30 mL), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (40 g, V 二氯甲烷 V 甲醇 The mixture was purified at a ratio of 100:1 to give 580 mg of white solid intermediate 1, with a yield of 88.1%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.49 (d, J=7.2 Hz,0.5H), 7.33-7.19 (m, 3H), 7.13-7.01 (m, 1.5H), 4.56-4.44 (m, 1.5H), 4.32-4.12(m, 4.5H), 4.05-3.92 (m, 1H), 3.66-3.55 (m, 2H), 3.00 (s, 3H), 1.40-1.39 (m,9H).

[1001] Step 2: Synthesis of (R)-2-amino-1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-3-((phenyl-d5)methoxy-d2)prop-1-one (intermediate 2)

[1002]

[1003] Intermediate 1 (580 mg, 1.11 mmol), EtOH (12 ml), and methanesulfonic acid (640 mg, 6.65 mmol) were added to a 100 mL single-necked flask. The reaction was carried out overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction to complete. Quench the reaction mixture with saturated sodium bicarbonate solution (50 mL), extract with ethyl acetate (30 mL × 3), and collect the organic phase. Wash with saturated brine (30 mL), dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (40 g, V 二氯甲烷 V 甲醇 =20:1), yielding 453 mg of white solid intermediate 2, with a yield of 96.6%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm):7.55 (d, J=7.2 Hz, 0.5H), 7.33-7.14 (m, 3H), 7.01-6.97 (m, 0.5H), 4.51 (d, J=8.8 Hz, 0.5H), 4.46-4.40 (m, 1H), 4.29 (d, J=8.8 Hz, 0.5H), 4.22-4.16 (m,2.5H), 4.30 (d, J=10.8 Hz, 0.5H), 4.04-3.94 (m, 1H), 3.55-3.51 (m, 1H), 3.47-3.42 (m, 2H), 2.99 (s, 3H), 1.71 (br, 2H).

[1004] Step 3: Synthesis of (R)-((2-methyl-1-((1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxo-3-((phenyl-d5)methoxy-d2)propane-2-yl)amino)-1-oxopropane-2-yl))tert-butyl carbamate (intermediate 3)

[1005]

[1006] Intermediate 2 (453 mg, 1.07 mmol), isopropyl acetate (14 mL), water (7 mL), N-tert-butoxycarbonyl-2-methylalanine (240 mg, 1.18 mmol), N,N'-dicyclohexylcarbodiimide (243 mg, 1.18 mmol), and 1-hydroxybenzotriazole (159 mg, 1.18 mmol) were added sequentially to a 100 mL single-necked flask. The reaction was carried out overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =20:1) After monitoring the reaction to complete, quench the reaction mixture with saturated sodium bicarbonate solution (50 mL), filter, extract the filtrate with ethyl acetate (30 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (30 mL), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (40 g, V 石油醚 V 乙酸乙酯 The solution was purified by a ratio of 1:1 to obtain 626 mg of white solid intermediate 3, with a yield of 96.0%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.61 (br, 0.5H), 7.56-7.54 (m, 0.5H), 7.41 (d, J=8.0 Hz, 0.5H), 7.32-7.23 (m, 2.5H), 7.14-7.10 (m,0.5H), 7.05-7.01 (m, 1H), 6.97 (br, 0.5H), 4.59-4.53 (m, 1.5H), 4.46 (br,1H), 4.30 (d, J=8.8 Hz, 0.5H), 4.23-4.12 (m, 3H), 4.00-3.95 (m, 1H), 3.63-3.53 (m, 2H), 2.99-2.98 (m, 3H), 1.36-1.35 (m, 9H), 1.30-1.29 (m, 6H).

[1007] Step 4: Synthesis of (R)-2-amino-2-methyl-N-(1-(1'-(methanesulfonyl)spiro[azacyclobutane-3,3'-indoline]-1-yl)-1-oxo-3-((phenyl-d5)methoxy-d2)propane-2-yl)propionamide (Example 30)

[1008]

[1009] Intermediate 3 (626 mg, 1.03 mmol), EtOH (14 mL), and methanesulfonic acid (594 mg, 6.18 mmol) were added to a 100 mL single-necked flask. The reaction was carried out overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction for completion. Cool to room temperature, quench the reaction mixture with saturated sodium bicarbonate solution (50 mL), extract with ethyl acetate (30 mL × 3), and collect the organic phase. Wash with saturated brine (30 mL), dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (40 g, V 二氯甲烷 V 甲醇 =50:1), yielding 432 mg of the white solid compound of Example 30, with a yield of 82.6%.

[1010] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.26 (br, 1H), 7.51 (d, J=7.6 Hz,0.5H), 7.32-7.23 (m, 2.5H), 7.13 (t, J=8.0 Hz, 0.5H), 7.03 (t, J=8.0 Hz,0.5H), 4.57-4.45 (m, 2.5H), 4.30 (d, J=8.8 Hz, 0.5H), 4.24-4.19 (m, 2.5H), 4.11 (d, J=11.2 Hz, 0.5H), 4.00 (dd, J1=24.0 Hz, J2=12.0 Hz, 1H), 3.66-3.56(m, 2H), 2.99-2.98 (d, J=3.3 Hz, 3H), 2.01 (br, 2H), 1.20 (s, 1.4H), 1.18 (s,4.6H).

[1011] 13C NMR (101 MHz, DMSO-d6) δ (ppm): 177.17 (177.12), 169.65 (169.54), 141.46, 137.82 (137.75), 135.34 (135.20), 129.14 (129.08), 128.07 (127.83),127.59 (127.46), 127.35 (127.22), 127.10 (126.99), 126.86, 124.16 (124.13),123.55 (123.11), 112.93 (112.88), 69.74 (69.30), 62.95 (62.87), 61.07 (60.89), 59.96 (59.78), 54.26 (54.24), 49.15 (48.59), 40.59 (40.44), 34.38, 28.86 (28.82), 28.60 (28.55).

[1012] HRMS (ESI): m / z [M+H] + C 25 H 25 Calculated value of D7N4O5S: 508.2611; Measured value: 508.2569.

[1013] Example 31

[1014] (R)-2-amino-N-(3-(benzyloxy)-1-(1'-(methanesulfonyl)-2'-oxo-1',2'-dihydrospiro[piperidin-4,3'-pyrrolo[3,2-c]pyridine]-1-yl)-1-oxopropane-2-yl)-2-methylpropionamide

[1015] Step 1 Synthesis of 3,3,7-tribromo-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (intermediate 2)

[1016]

[1017] 5-azaindole (1, 11.00 g, 93.11 mmol), tert-butanol (660 mL), and water (660 mL) were added sequentially to a 2 L single-necked flask. Under nitrogen protection, bromine (59.52 g, 372.44 mmol) was added dropwise, and the reaction was carried out at room temperature for 1 h. TLC (V 二氯甲烷 V 甲醇(20:1) After monitoring the reaction to complete, saturated sodium bicarbonate solution was added dropwise to adjust the pH to 7, resulting in the precipitation of a large amount of solid. The mixture was filtered, and the filter cake was washed with water (20 mL × 5). The filter cake was collected and dried overnight at 48°C with forced air to obtain 27.50 g of yellow solid intermediate 2, with a yield of 79.6%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.25 (br, 1H), 8.70 (s, 1H), 8.59 (s, 1H).

[1018] Step 2 Synthesis of 1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (intermediate 3)

[1019]

[1020] Intermediate 2 (6.80 g, 18.34 mmol), acetic acid (41 mL), and zinc powder (12.09 g, 183.37 mmol) were added sequentially to a 250 mL single-necked flask. The reaction was carried out at room temperature for 4 h under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction to completion, filter through diatomaceous earth, and wash the filter cake with a mixed solvent (V 二氯甲烷 V 甲醇 The solution was washed with a 5:1 ratio (30 mL × 3), the filtrate was concentrated and subjected to rapid preparative chromatography (40 g, V...). 二氯甲烷 V 甲醇 The mixture was purified at a ratio of 10:1 to give 1.60 g of off-white solid intermediate 3, with a yield of 65.1%. 1 H NMR(400 MHz, DMSO-d6) δ (ppm): 10.96 (br, 1H), 8.33 (d, J=5.5 Hz, 1H), 8.28 (s,1H), 6.97-6.94 (m, 1H), 3.60 (s, 2H).

[1021] Step 3 Synthesis of 1-benzylspiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-2'(1'H)-one (intermediate 4)

[1022]

[1023] Intermediate 3 (1.50 g, 11.18 mmol) and tetrahydrofuran (30 mL) were added sequentially to a 250 mL single-necked flask. Under nitrogen protection, the temperature was lowered to -78 °C, and LiHMDS (1 M in THF, 33.6 mL, 33.55 mmol) was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 15 min, then slowly heated to 0 °C. N-Benzyl-N,N-bis(2-chloroethyl)amine hydrochloride (3.00 g, 11.18 mmol) was added, and the reaction was carried out at 70 °C for 16 h under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction to completion, place in an ice bath, quench with 10% wt ammonium chloride solution (25 mL), filter through diatomaceous earth, wash the filter cake with ethyl acetate (10 mL × 3), and collect the filtrate. Dilute with water (100 mL), extract with ethyl acetate (100 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (100 mL), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (40 g, V 二氯甲烷 V 甲醇 The mixture was purified at a ratio of 20:1 to give 1.00 g of off-white solid intermediate 4, with a yield of 30.6%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.81 (br, 1H),8.58 (s, 1H), 8.32 (d, J=5.2 Hz, 1H), 7.38-7.32 (m, 4H), 7.28-7.24 (m, 1H),6.89 (d, J=5.2 Hz, 1H), 3.64 (s, 2H), 2.85-2.80 (m, 2H), 2.59-2.53 (m, 2H), 1.91-1.83 (m, 2H), 1.67-1.61 (m, 2H).

[1024] Step 4 Synthesis of spiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-2'(1'H)-one (intermediate 5)

[1025]

[1026] Intermediate 4 (2.00 g, 6.82 mmol), methanol (73 mL), and 10% Pd / C (1.40 g, 70% wt) were added sequentially to a 250 mL hydrogenation flask. The reaction was carried out under a hydrogen atmosphere (50 psi) at 50 °C for 16 h. TLC (V 二氯甲烷 V 甲醇=10:1) After the reaction was completed, the mixture was filtered through diatomaceous earth, the filter cake was washed with methanol (10 mL × 3), and the filtrate was concentrated to obtain 1.25 g of off-white solid intermediate 5, with a yield of 90.6%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.59 (s, 1H), 8.33 (d, J=5.2 Hz, 1H), 6.90 (d, J=5.2 Hz, 1H), 3.13-3.08 (m, 2H), 2.99-2.93 (m, 2H),1.81-1.74 (m, 2H), 1.59-1.53 ​​(m, 2H).

[1027] Step 5: Synthesis of tert-butyl 2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-1-carboxylate (intermediate 6)

[1028]

[1029] Intermediate 5 (1.25 g, 6.15 mmol), methanol (53 mL), and di-tert-butyl dicarbonate (1.61 g, 7.38 mmol) were added sequentially to a 250 mL single-necked flask. The reaction was carried out at room temperature for 3 h under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the end of the reaction, concentrate and perform rapid preparative chromatography (20 g, V) (V 二氯甲烷 V 甲醇 The mixture was purified at a ratio of 20:1 to obtain 1.52 g of white solid intermediate 6, with a yield of 81.5%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.86 (br, 1H), 8.60 (s, 1H), 8.34 (d, J=5.2 Hz, 1H), 6.90 (d, J=5.2 Hz, 1H), 3.81-3.75 (m, 2H), 3.56-3.51 (m, 2H), 1.75-1.63 (m, 4H), 1.44 (s, 9H).

[1030] Step 6: Synthesis of tert-butyl 1'-(methanesulfonyl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-1-carboxylate (intermediate 7)

[1031]

[1032] Intermediate 6 (1.51 g, 4.98 mmol), dichloromethane (76 mL), TEA (1.21 g, 11.95 mmol), DMAP (12 mg, 0.10 mmol), and methanesulfonyl chloride (1.37 g, 11.95 mmol) were added sequentially to a 250 mL single-necked flask. The reaction was carried out under nitrogen protection at room temperature for 16 h. TLC (V 二氯甲烷 V 甲醇 =10:1) After monitoring the reaction to completion, quench with water (30 mL), extract with dichloromethane (30 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (50 mL), dry with anhydrous sodium sulfate, filter, concentrate, and pass through rapid preparative chromatography (40 g, V 二氯甲烷 V 甲醇 The mixture was purified at a ratio of 30:1 to obtain 1.45 g of white solid intermediate 7, with a yield of 76.4%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.76 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 7.59 (d, J=5.5 Hz, 1H), 3.74 (m, 2H), 3.61 (s, 3H), 3.57 (br, 2H), 1.91-1.88(m, 4H), 1.45(s, 9H).

[1033] Step 7 Synthesis of 1'-(methanesulfonyl)spiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-2'(1'H)-keto hydrochloride (intermediate 8)

[1034]

[1035] Intermediate 7 (1.45 g, 3.80 mmol), dichloromethane (28 mL), and HCl / dioxane (4 M, 8.7 mL) were added sequentially to a 100 mL single-necked flask. The reaction was carried out at room temperature for 0.5 h under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =10:1) After monitoring the reaction to complete, filter, wash the filter cake with dichloromethane (2 mL × 3), and collect the filter cake. Distill methanol (10 mL × 3) three times, then slurry with low-boiling-point petroleum ether (20 mL) at room temperature for 2 h, filter, collect the filter cake, and obtain 1.26 g of white solid intermediate 8, which can be used directly in the next step. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.47-9.41 (m, 2H), 8.97 (s, 1H), 8.83(br, 1H), 7.98 (d, J=5.9 Hz, 1H), 3.73 (s, 3H), 3.38 (br, 4H), 2.42-2.36 (m,2H), 2.39-2.23 (m, 2H).

[1036] Step 8: Synthesis of tert-butyl (R)-(3-(benzyloxy)-1-(1'-(methanesulfonyl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-1-yl)-1-oxopropane-2-yl)carboxylate (intermediate 9)

[1037]

[1038] Intermediate 8 (630 mg, 1.99 mmol), isopropyl acetate (24 mL), water (12 mL), N-Boc-O-benzyl-D-serine (646 mg, 2.19 mmol), DCC (533 mg, 2.58 mmol), and HOBt (349 mg, 2.58 mmol) were added sequentially to a 100 mL single-necked flask. The reaction was carried out overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =10:1) After monitoring the reaction to complete, quench the reaction mixture with saturated sodium bicarbonate solution (10 mL), filter, extract the filtrate with ethyl acetate (20 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (20 mL), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (40 g, V 石油醚 V 乙酸乙酯 Purification (1:10) yielded 288 mg of white solid intermediate 9, with a two-step yield of 27.2%. 1H NMR(400 MHz, DMSO-d6) δ (ppm): 8.64 (br, 0.5H), 8.57 (br, 0.5H), 8.53 (d, J=5.5Hz, 1H), 7.59 (d, J=5.7 Hz, 1H), 7.37-7.26 (m, 5H), 7.20-7.10 (m, 1H), 4.76-4.72 (m, 1H), 4.55-4.46 (m, 2H), 4.13-3.89 (m, 2H), 3.83-3.65 (m, 2H), 3.62-3.61 (m, 3H), 3.57-3.51 (m, 2H), 2.03-1.90 (m, 4H), 1.39 (s, 9H).

[1039] LCMS (ESI): m / z [M+H] + C 27 H 34 Calculated value of N4O7S: 559, Measured value: 559.

[1040] Step 9 Synthesis of 1-(O-benzyl-D-serineyl)-1'-(methanesulfonyl)spiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-2'(1'H)-one (intermediate 10)

[1041]

[1042] Intermediate 9 (570 mg, 1.02 mmol), ethanol (20 mL), and methanesulfonic acid (588 mg, 6.12 mmol) were added to a 100 mL single-necked flask. The reaction was carried out overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction to completion, place in an ice bath, adjust the pH to 8 with saturated sodium bicarbonate solution, dilute with water (20 mL), extract with ethyl acetate (30 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (15 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate at 25 °C until about 5 mL of ethyl acetate remains, add isopropyl acetate (15 mL), concentrate at 25 °C to about 15 mL, and obtain an isopropyl acetate solution of intermediate 10, which can be used directly in the next step.

[1043] Step 10: Synthesis of (R)-(1-((3-(benzyloxy)-1-(1'-(methanesulfonyl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-1-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)tert-butyl formate (intermediate 11)

[1044]

[1045] To a 100 mL single-necked flask, add approximately 15 mL of isopropyl acetate solution of intermediate 10, 6 mL of water, 2-(Boc-amino)-2-methylpropionic acid (219 mg, 1.08 mmol), DCC (223 mg, 1.08 mmol), and HOBt (146 mg, 1.08 mmol) sequentially. React overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) After monitoring the reaction to complete, quench the reaction mixture with saturated sodium bicarbonate solution (20 mL), filter, extract the filtrate with ethyl acetate (30 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (30 mL), dry with anhydrous sodium sulfate, filter, concentrate at 25 °C, and perform rapid preparative chromatography (20 g, V) 二氯甲烷 V 甲醇 The mixture was purified by a ratio of 50:1 to obtain 378 mg of white solid intermediate 11, with a two-step yield of 57.5%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.71 (br, 0.5H), 8.48 (br, 0.5H), 8.52 (d, J=5.5 Hz,1H), 7.59-7.57 (m, 2H), 7.40-7.26 (m, 5H), 7.05 (br, 0.5H), 6.97 (br, 0.5H),5.02-4.99 (m, 1H), 4.52-4.49 (m, 2H), 4.10-4.07 (m, 1H), 3.96-3.92 (m, 1H),3.83-3.63 (m, 2H), 3.62-3.60 (m, 3H), 3.57-3.52 (m, 2H), 1.94-1.83 (m, 4H), 1.36 (s, 9H), 1.30 (s, 6H).

[1046] LCMS (ESI): m / z [M+H] + C 31 H 41Calculated value of N5O8S: 644, Measured value: 644.

[1047] Step 11 Synthesis of (R)-2-amino-N-(3-(benzyloxy)-1-(1'-(methanesulfonyl)-2'-oxo-1',2'-dihydrospiro[piperidin-4,3'-pyrrolo[3,2-c]pyridine]-1-yl)-1-oxopropane-2-yl)-2-methylpropionamide (Example 31)

[1048]

[1049] Intermediate 11 (370 mg, 0.58 mmol), ethanol (15 mL), and methanesulfonic acid (332 mg, 3.45 mmol) were added sequentially to a 50 mL single-necked flask. The reaction was carried out overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction to completion, and cool the reaction solution to 0℃. Adjust the pH to 8 with saturated sodium bicarbonate solution, extract with ethyl acetate (100 mL × 2), and collect the organic phase. Wash with saturated sodium chloride solution (5 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate at 25℃, and perform rapid preparative chromatography (wet method, 20 g, V) 二氯甲烷 V 甲醇 =20:1) Purified, pulped with petroleum ether (10 mL) overnight, filtered, and the filter cake was vacuum dried at room temperature for 4 h to give 35 mg of white solid of the compound in Example 31, yield 11.1%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm):8.71 (s, 0.5H), 8.52 (d, J=5.5 Hz, 1H), 8.48 (s, 0.5H), 8.36 (br, 1H), 7.58(d, J=5.5 Hz, 1H), 7.36-7.28 (m, 5H), 5.00 (br, 1H), 4.57-4.48 (m, 2H), 4.061-4.00 (m, 1H), 3.91-3.84 (m, 1H), 3.79-3.76 (m, 1H), 3.66-3.64 (m, 1H),3.62-3.58 (m, 5H), 2.33 (br, 2H), 1.97-1.84 (m, 4H), 1.20 (s, 6H).

[1050] HRMS (ESI): m / z [M+Na] + C 26 H 33Calculated value of N5O6S: 566.2044, measured value: 566.2045.

[1051] Example 32 (R)-2-amino-N-(3-(benzyloxy)-1-(1'-(methanesulfonyl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-c]pyridine]-1-yl)-1-oxopropane-2-yl)-2-methylpropionamide

[1052]

[1053] Following the synthetic method of Example 31, the compound of Example 32 was prepared using 1H-pyrrolo[2,3-C]pyridine-2(3H)-keto hydrochloride (CAS: 295327-22-9, purchased from Shanghai BIDE Pharmaceutical Technology Co., Ltd.) as a starting material. LCMS: m / z [M+H] + C 26 H 33 Calculated value of N5O6S: 544, Measured value: 544.

[1054] Example 33 (R)-2-amino-N-(3-(benzyloxy)-1-(1'-(methanesulfonyl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridine]-1-yl)-1-oxopropane-2-yl)-2-methylpropionamide

[1055]

[1056] Following the synthetic method of Example 31, the compound of Example 33 was prepared using 2-oxospiro[1H-pyrrolo[3,2-b]pyridine-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (CAS: 1290625-80-7, purchased from Nanjing Yaoshi Technology Co., Ltd.) as the starting material. LCMS: m / z [M+H] + C 26 H 33 Calculated value of N5O6S: 544, Measured value: 544.

[1057] Example 34 (R)-2-amino-N-(3-(benzyloxy)-1-(1'-(methanesulfonyl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1-yl)-1-oxopropane-2-yl)-2-methylpropionamide

[1058]

[1059] Following the synthetic method of Example 31, the compound of Example 34 was prepared using 1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-2'-one dihydrochloride (CAS: 883984-94-9, purchased from Shanghai Haohong Biomedical Technology Co., Ltd.) as a starting material. LCMS: m / z [M+H] + C 26 H 33 Calculated value of N5O6S: 544, Measured value: 544.

[1060] Example 35 (R)-2-amino-N-(3-(benzyloxy)-1-(1'-(methanesulfonyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-1-yl)-1-oxopropane-2-yl)-2-methylpropionamide

[1061] Step 1: Synthesis of 1-benzyl-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine] (intermediate 2)

[1062]

[1063] Add intermediate 4 (150 mg, 0.51 mmol) from Example 31 and tetrahydrofuran (3 mL) to a 25 mL single-necked flask. Under nitrogen protection, add lithium aluminum hydride solution (1 M in THF, 2 mL, 2.04 mmol) dropwise under an ice-water bath, and then reflux for 2 h. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction of the raw materials to ensure completeness. Add water (0.7 mL), 15% wt sodium hydroxide solution (0.7 mL), and water (2.1 mL) dropwise under an ice-water bath, stirring for 10 min. Filter through diatomaceous earth, collect the filtrate, concentrate, and perform rapid preparative chromatography (4 g, V... 乙酸乙酯 V 甲醇 V 三乙胺 Purification was performed using a mixture of 10:1:0.02 to obtain 95 mg of colorless oily intermediate 2, with a yield of 66.9%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.98 (s, 1H), 7.91 (d, J=5.6 Hz, 1H), 7.34-7.30 (m, 4H), 7.27-7.22 (m, 1H), 6.45 (br, 1H), 6.37 (d, J=5.6 Hz, 1H), 3.48(s, 2H), 3.37 (s, 2H), 2.74-2.71 (m, 2H), 2.09-2.04 (m, 2H), 1.81-1.77 (m, 2H), 1.62-1.59 (m, 2H).

[1064] LCMS (ESI): m / z [M+H] + C 18 H 21 Calculated N3 value: 280, Measured value: 280.

[1065] Step 2 Synthesis of 1-benzyl-1'-(methanesulfonyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine] (intermediate 3)

[1066]

[1067] Intermediate 2 (50 mg, 0.18 mmol), dichloromethane (1.5 mL), TEA (36 mg, 0.36 mmol), and DMAP (2 mg, 0.02 mmol) were added to a 25 mL two-necked flask. Under nitrogen protection, a solution of MsCl (31 mg, 0.27 mmol) in dichloromethane (0.5 mL) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 1 h. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction of the raw materials to ensure complete reaction. Dilute the reaction solution with dichloromethane (30 mL), wash with saturated saline (15 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (4 g, V 二氯甲烷 V 甲醇 =10:1), yielding 30 mg of white solid intermediate 3, with a yield of 46.8%. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.45 (s, 1H), 8.34 (d, J=5.6 Hz, 1H), 7.37-7.30 (m, 4H), 7.29-7.23 (m, 1H), 7.18 (d, J=5.6 Hz, 1H), 3.86 (s,2H), 3.52 (s, 2H), 3.16 (s, 3H), 2.81-2.78 (m, 2H), 2.12-2.06 (m, 2H), 1.95-1.89 (m, 2H), 1.75-1.68 (m, 2H).

[1068] Step 3: Synthesis of 1'-(methanesulfonyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine] (intermediate 4)

[1069]

[1070] Intermediate 3 (100 mg, 0.28 mmol), ethanol (10 mL), 10% Pd / C (30 mg, 30% w / w), and 10% Pd(OH)2 / C (30 mg, 30% w / w) were added sequentially to a 50 mL hydrogenation flask. The reaction was carried out overnight at 55 °C under a hydrogen atmosphere (70 psi). TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction of the raw materials to ensure complete reaction. Cool to room temperature, filter through diatomaceous earth, and concentrate to obtain 70 mg of white solid intermediate 4, which was used directly in the next step without purification.

[1071] Step 4: Synthesis of tert-butyl (R)-(3-(benzyloxy)-1-(1'-(methanesulfonyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-1-yl)-1-oxopropane-2-yl)carboxylate (intermediate 5)

[1072]

[1073] Intermediate 4 (70 mg, 0.26 mmol), N-Boc-O-benzyl-D-serine (77 mg, 0.26 mmol), isopropyl acetate (2 mL), water (2 mL), HOBt (47 mg, 0.34 mmol), and DCC (70 mg, 0.34 mmol) were added to a 25 mL single-necked flask. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇=20:1) Monitor the reaction of the starting materials to ensure complete reaction. Dilute with water (15 mL), extract with ethyl acetate (25 mL × 3), combine the organic phases, wash successively with saturated sodium bicarbonate solution (25 mL × 3) and saturated sodium chloride solution (20 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =50:1), yielding 105 mg of white solid intermediate 5, yield 73.6%. 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.36-8.34 (m, 2H, 1.5H), 8.19 (s, 0.5H), 7.35-7.28 (m, 5H), 7.21-7.19(m, 1H), 7.13 (d, J=8.4 Hz, 0.5H), 7.02 (d, J=8.4 Hz, 0.5H), 4.72-4.70 (m,1H), 4.52-4.48 (m, 2H), 4.36-4.33 (m, 1H), 3.99-3.98 (m, 3H), 3.67-3.63 (m,1H), 3.58-3.52 (m, 1H), 3.23-3.18 (m, 4H), 2.86-2.80 (m, 1H), 1.74-1.65 (m,4H), 1.38 (s, 9H).

[1074] HRMS (ESI): m / z [M+H] + C 27 H 36 Calculated value of N4O6S: 545.2428, measured value: 545.2416.

[1075] Step 5: Synthesis of (R)-2-amino-3-(benzyloxy)-1-(1'-(methanesulfonyl)-1',2'-dihydrospiro[piperidin-4,3'-pyrrolo[3,2-c]pyridin]-1-yl)propane-1-one (intermediate 6)

[1076]

[1077] Intermediate 5 (100 mg, 0.18 mmol), ethanol (2 mL), and methanesulfonic acid (106 mg, 1.10 mmol) were added to a 25 mL single-necked flask. The mixture was reacted overnight at 40°C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇=15:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool to room temperature, quench with saturated sodium bicarbonate solution (15 mL), extract with ethyl acetate (25 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (30 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (4 g, V 二氯甲烷 V 甲醇 =10:1), yielding 60 mg of white solid intermediate 6, with a yield of 73.5%. 1 H NMR (400 MHz, DMSO-d6) δ(ppm): δ 8.42-8.34 (m, 1.5H), 8.10 (s, 0.5H), 7.36-7.28 (m, 5H), 7.20 (s,1H), 4.52-4.48 (m, 2H), 4.40-4.38 (m, 1H), 4.01-3.97 (m, 4H), 3.50-3.44 (m,2H), 3.22-3.18 (m, 4H), 2.84-2.80 (m, 1H), 2.11 (br, 2H), 1.90-1.67 (m, 4H).

[1078] Step 6: Synthesis of (R)-(1-((3-(benzyloxy)-1-(1'-(methanesulfonyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-1-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)tert-butyl formate (intermediate 7)

[1079]

[1080] To a 25 mL single-necked flask, intermediate 6 (60 mg, 0.13 mmol), isopropyl acetate (2 mL), water (2 mL), N-tert-butoxycarbonyl-2-methylalanine (33 mg, 0.16 mmol), DCC (33 mg, 0.16 mmol), and HOBt (22 mg, 0.16 mmol) were added sequentially. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Quench with water (15 mL), extract with ethyl acetate (25 mL × 3), combine the organic phases, wash successively with saturated sodium bicarbonate solution (25 mL × 3) and saturated sodium chloride solution (20 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =50:1), yielding 70 mg of white solid intermediate 7, with a yield of 82.4%. 1H NMR (400 MHz, CD3OD) δ(ppm): 8.44 (br, 0.5H), 8.32 (d, J=5.6 Hz, 1H), 7.93 (s, 0.5H), 7.37-7.28 (m,6H), 5.17-5.16 (m, 1H), 4.56-4.47 (m, 3H), 4.18-3.98 (m, 3H), 3.72-3.66 (m,2H), 3.25-3.18 (m, 1H), 3.12 (s, 1.5H), 3.10 (s, 1.5H), 2.93-2.83 (m, 1H),1.94-1.69 (m, 4H), 1.43 (s, 9H), 1.40 (s, 6H).

[1081] Step 7 Synthesis of (R)-2-amino-N-(3-(benzyloxy)-1-(1'-(methanesulfonyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-c]pyridine]-1-yl)-1-oxopropane-2-yl)-2-methylpropionamide (Example 35)

[1082]

[1083] Intermediate 7 (70 mg, 0.11 mmol), ethanol (2 mL), and methanesulfonic acid (64 mg, 0.66 mmol) were added to a 25 mL single-necked flask. The mixture was reacted overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool to room temperature, quench with saturated sodium bicarbonate solution (15 mL), extract with ethyl acetate (25 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (40 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =10:1), yielding 40 mg of the white solid compound of Example 35, with a yield of 67.9%. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.36 (s, 0.5H), 8.32 (d, J=5.6 Hz, 1H), 7.94 (s, 0.5H), 7.38-7.29 (m, 6H), 5.12-5.10 (m, 1H), 4.58-4.49 (m, 3H), 4.12-3.97 (m, 3H), 3.74-3.70 (m, 2H), 3.27-3.19 (m, 1H), 3.12 (s, 1.5H), 3.10 (s, 1.5H), 2.99-2.86(m, 1H), 2.02-1.70 (m, 4H), 1.34-1.32 (m, 6H).

[1084] HRMS (ESI): m / z [M+H] + C 26 H 35 Calculated N5O5S value: 530.2432, measured value: 530.2429.

[1085] Example 36 (R)-2-amino-N-(3-(benzyloxy)-1-(1'-(methanesulfonyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-c]pyridine]-1-yl)-1-oxopropane-2-yl)-2-methylpropionamide

[1086]

[1087] Following the synthetic method of Example 35, the compound of Example 36 was prepared using 1H,2H,3H-pyrrolo[2,3-c]pyridin-2-one hydrochloride (CAS: 295327-22-9, purchased from Shanghai BIDE Pharmaceutical Technology Co., Ltd.) as a starting material. LCMS: m / z [M+H] + C 26 H 35 Calculated N5O5S value: 530, Measured value: 530.

[1088] Example 37 (R)-2-amino-N-(3-(benzyloxy)-1-(1'-(methanesulfonyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridine]-1-yl)-1-oxopropane-2-yl)-2-methylpropionamide

[1089] Step 1: Synthesis of tert-butyl 1'-(methanesulfonyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate (intermediate 1)

[1090]

[1091] To a 25 mL two-necked flask, add 1.00 g (3.46 mmol, CAS: 1251008-17-9, purchased from Nantong Hanfang Biotechnology Co., Ltd.), dichloromethane (20 mL), TEA (699 mg, 6.91 mmol), and DMAP (43 mg, 0.35 mmol). Under nitrogen protection, add dropwise a solution of MsCl (594 mg, 5.18 mmol) in dichloromethane (5 mL) under ice-water bath. Incubate at room temperature for 2 h. TLC (V 二氯甲烷 V 甲醇 =20:1) Monitor the reaction of the raw materials to ensure complete reaction. Dilute the reaction solution with dichloromethane (40 mL), wash with saturated sodium chloride solution (30 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate, and purify by rapid preparative chromatography (20 g, V 二氯甲烷 V 甲醇 =20:1), yielding 600 mg of white solid intermediate 1, yield 47.3%. LCMS (ESI): m / z [M+H] + C 17 H 25 Calculated value of N3O4S: 368, Measured value: 368.

[1092] Step 2: Synthesis of 1'-(methanesulfonyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridine] hydrochloride (intermediate 2)

[1093]

[1094] Intermediate 1 (500 mg, 1.36 mmol), ethyl acetate (10 mL), and HCl / ethyl acetate solution (5 mL, 4 M) were added to a 25 mL single-necked flask. The mixture was reacted under nitrogen protection at room temperature for 2 h. TLC (V 二氯甲烷 V 甲醇 =10:1) Monitor the reaction of the starting materials to ensure complete reaction. Concentrate directly, slurry with ethyl acetate (10 mL) for 2 h, filter, and dry under vacuum at room temperature for 3 h using an oil pump to obtain 350 mg of white solid intermediate 2, yield 84.7%. LCMS (ESI): m / z [M-HCl+H) + C 12 H 18 Calculated value of ClN3O2S: 268, Measured value: 268.

[1095] Step 3: Synthesis of tert-butyl (R)-(3-(benzyloxy)-1-(1'-(methanesulfonyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridine]-1-yl)-1-oxopropane-2-yl)carboxylate (intermediate 3)

[1096]

[1097] Intermediate 2 (350 mg, 1.15 mmol), N-Boc-O-benzyl-D-serine (408 mg, 1.38 mmol), isopropyl acetate (10 mL), water (10 mL), HOBt (186 mg, 1.38 mmol), and DCC (285 mg, 1.38 mmol) were added to a 25 mL single-necked flask. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =20:1) Monitor the reaction of the starting materials to ensure complete reaction. Dilute with water (10 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash successively with saturated sodium bicarbonate solution (20 mL × 3) and saturated sodium chloride solution (20 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (20 g, V 二氯甲烷 V 甲醇 =50:1), yielding 300 mg of white solid intermediate 3, yield 47.8%. LCMS (ESI): m / z [M+H] + C 27 H 36 Calculated value of N4O6S: 545, Measured value: 545.

[1098] Step 4: Synthesis of (R)-2-amino-3-(benzyloxy)-1-(1'-(methanesulfonyl)-1',2'-dihydrospiro[piperidin-4,3'-pyrrolo[3,2-b]pyridin]-1-yl)propane-1-one (intermediate 4)

[1099]

[1100] Intermediate 3 (300 mg, 0.55 mmol), ethanol (4 mL), and methanesulfonic acid (318 mg, 3.30 mmol) were added to a 25 mL single-necked flask. The mixture was reacted overnight at 40°C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool to room temperature, quench with saturated sodium bicarbonate solution (15 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (30 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V二氯甲烷 V 甲醇 =10:1), yielding 180 mg of white solid intermediate 4, yield 73.5%. LCMS (ESI): m / z [M+H] + C 22 H 28 Calculated value of N4O4S: 445, Measured value: 445.

[1101] Step 5: Synthesis of (R)-(1-((3-(benzyloxy)-1-(1'-(methanesulfonyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridine]-1-yl)-1-oxopropane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)tert-butyl formate (intermediate 5)

[1102]

[1103] Intermediate 4 (180 mg, 0.40 mmol), isopropyl acetate (5 mL), water (5 mL), N-tert-butoxycarbonyl-2-methylalanine (99 mg, 0.48 mmol), DCC (99 mg, 0.48 mmol), and HOBt (66 mg, 0.48 mmol) were added sequentially to a 25 mL single-necked flask. The mixture was reacted overnight at room temperature under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the raw materials to ensure complete reaction. Quench with water (10 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash successively with saturated sodium bicarbonate solution (20 mL × 3) and saturated sodium chloride solution (20 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (12 g, V 二氯甲烷 V 甲醇 =50:1), yielding 130 mg of white solid intermediate 5, yield 51.0%. LCMS (ESI): m / z [M+H] + C 31 H 43 Calculated value of N5O7S: 630, Measured value: 630.

[1104] Step 6: Synthesis of (R)-2-amino-N-(3-(benzyloxy)-1-(1'-(methanesulfonyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[3,2-b]pyridine]-1-yl)-1-oxopropane-2-yl)-2-methylpropionamide (Example 37)

[1105]

[1106] Intermediate 5 (130 mg, 0.21 mmol), ethanol (3 mL), and methanesulfonic acid (119 mg, 1.24 mmol) were added to a 25 mL single-necked flask. The mixture was reacted overnight at 40 °C under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =15:1) Monitor the reaction of the starting materials to ensure complete reaction. Cool to room temperature, quench with saturated sodium bicarbonate solution (15 mL), extract with ethyl acetate (15 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (20 mL), dry with anhydrous sodium sulfate, filter, concentrate and purify by rapid preparative chromatography (4 g, V 二氯甲烷 V 甲醇 =15:1), yielding 65 mg of the white solid compound of Example 37, in a yield of 59.5%. LCMS (ESI): m / z [M+H] + C 26 H 35 Calculated N5O5S value: 530, Measured value: 530.

[1107] Example 38 (R)-2-amino-N-(3-(benzyloxy)-1-(1'-(methanesulfonyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine]-1-yl)-1-oxopropane-2-yl)-2-methylpropionamide

[1108]

[1109] Following the synthetic method of Example 37, the compound of Example 38 was prepared using 1-benzyl-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine] (CAS: 845552-76-3, purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.) as a starting material. LCMS: m / z [M+H] + C 26 H 35 Calculated N5O5S value: 530, Measured value: 530.

[1110] Example 39 (R)-2-amino-N-(3-(benzyloxy)-1-(1'-(methanesulfonyl)-1',2'-dihydrospiro[azacyclobutane-3,3'-pyrrolo[3,2-b]pyridine]-1-yl)-1-oxopropane-2-yl)-2-methylpropionamide

[1111] Step 1: Synthesis of tert-butyl 3-((2-bromopyridin-3-yl)carbamoyl)azacyclobutane-1-carboxylate (Intermediate 1)

[1112]

[1113] 2-Bromo-3-aminopyridine (7.20 g, 41.62 mmol), acetonitrile (100 mL), TCFH (14.65 g, 52.22 mmol), 1-methylimidazole (7.36 g, 89.69 mmol), and 1-Boc-azacyclobutane-3-carboxylic acid (8.37 g, 41.62 mmol) were added sequentially to a 250 mL single-necked flask. The reaction was carried out overnight at 45 °C under nitrogen protection. TLC (V 石油醚 V 乙酸乙酯 =2:1) ​​Monitor the reaction until completion, cool to room temperature, add water (50 mL), extract with ethyl acetate (50 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (50 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (120 g, V 石油醚 V 乙酸乙酯 The mixture was purified at a ratio of 3:1 to give 10.84 g of a white solid intermediate 1, with a yield of 73.1%. LCMS (ESI): m / z [M+H] + C 14 H 18 Calculated value of BrN3O3: 356, Measured value: 356.

[1114] Step 2: Synthesis of 3-((2-bromopyridin-3-yl)(4-methoxybenzyl)carbamoyl)azacyclobutane-1-carboxylic acid tert-butyl ester (intermediate 2)

[1115]

[1116] Intermediate 1 (8.05 g, 22.6 mmol), N,N-dimethylformamide (80 mL), and cesium carbonate (14.73 g, 45.2 mmol) were added sequentially to a 250 mL single-necked flask. Under nitrogen protection, p-methoxybenzyl chloride (PMBCl, 4.25 g, 27.12 mmol) was added dropwise at 0 °C, and the mixture was then transferred to 60 °C and reacted overnight. TLC (V 石油醚 V 乙酸乙酯 =3:1) Monitor the reaction until completion, cool to room temperature, quench with water (200 mL), extract with ethyl acetate (50 mL × 3), and collect the organic phase. Wash with saturated sodium chloride solution (100 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and perform rapid preparative chromatography (120 g, V 石油醚 V 乙酸乙酯 The mixture was purified at a ratio of 5:1 to give 7.01 g of a white solid intermediate 2, with a yield of 65.1%. LCMS (ESI): m / z [M+H] + C 22 H 26Calculated value of BrN3O4: 476, Me...

Claims

1. The compound shown in formula (I), （I） Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts; wherein... X is selected from CH2 or C (=O); Z1, Z2, Z3, and Z4 are selected from N or CR7; R1, R1', R2, and R2' are each independently selected from H, deuterium, C1-C6 alkyl groups optionally substituted with one or more halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups; or, R1 together with R1' or R2 together with R2' and the carbon atoms to which they are attached, forms a C3-C6 cycloalkyl group. R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, oxo groups, carboxyl groups, or ester groups. Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, amino, oxo, carboxyl, or ester group. Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atom it is attached to, it forms a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group; x and y are each independently selected from 0, 1, 2 or 3; R4 is selected from optionally substituted C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 12 cycloalkyl, C6- 14 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic; wherein the C1-C6 alkyl, C3-C 12 cycloalkyl, C6- 14 The aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclic groups are optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups; R5 is selected from H, deuterium, and C1-C6 alkyl groups; m and n are each independently selected from 1, 2, or 3; R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and -C(O)R each time they appear. c -C(O)OR c -OC(O) R c , amino, NR d R d ';R c R d R d Each is independently selected from H or C1-C6 alkyl groups; r is selected from 1, 2, 3, 4, or 5; The condition is that when X is CH2, m is 2, n is 2, R3 and R3' are H, and Z1, Z2, Z3 and Z4 are selected from CR7, R4 is selected from an arbitrarily substituted C6- 14 Aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic.

2. The compound of formula (I) according to claim 1, or its stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, wherein, X is selected from CH2 or C (=O); Z1, Z2, Z3, and Z4 are selected from N or CR7; R1, R1', R2, and R2' are each independently selected from H, deuterium, or C1-C6 alkyl groups optionally substituted with one or more halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups; R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, oxo groups, carboxyl groups, or ester groups. Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, amino, oxo, carboxyl, or ester group. Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atom it is attached to, it forms a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group; x and y are each independently selected from 0, 1, 2 or 3; R4 is selected from optionally substituted C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 12 cycloalkyl, C6- 14 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic; wherein the C1-C6 alkyl, C3-C 12 cycloalkyl, C6- 14 The aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclic groups are optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups; R5 is selected from H, deuterium, and C1-C6 alkyl groups; m and n are each independently selected from 1, 2, or 3; R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and -C(O)R each time they appear. c -C(O)OR c -OC(O) R c , amino, NR d R d ';R c R d R d Each is independently selected from H or C1-C6 alkyl groups; r is selected from 1, 2, 3, 4, or 5; The condition is that when X is CH2, m is 2, n is 2, R3 and R3' are H, and Z1, Z2, Z3 and Z4 are selected from CR7, R4 is selected from any substituted C6- 14 Aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic.

3. The compound of formula (I) according to claim 1, characterized in that, The compound is the compound shown in formula (II). (II) Or its stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, wherein X, Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, m, n, R6, and r are as defined in claim 1.

4. The compound of formula (II) according to claim 3, or its stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, wherein, X is selected from CH2 or C (=O); Z1, Z2, Z3, and Z4 are selected from N or CR7; R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, oxo groups, carboxyl groups, or ester groups. Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, amino, oxo, carboxyl, or ester group. Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atoms attached thereto, they form 3-6 membered cycloalkyl groups and 3-6 membered heterocyclic groups; R4 is selected from optionally substituted C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 12 cycloalkyl, C6- 14 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic; wherein the C1-C6 alkyl, C3-C 12 cycloalkyl, C6- 14 The aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclic groups are optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups; R5 is selected from H, deuterium, and C1-C6 alkyl groups; m and n are each independently selected from 1, 2, or 3; R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and -C(O)R each time they appear. c -C(O)OR c -OC(O) R c , amino, NR d R d ';R c R d R d Each is independently selected from H or C1-C6 alkyl groups; r is selected from 1, 2, 3, 4, or 5; The condition is that when X is CH2, m is 2, n is 2, R3 and R3' are H, and Z1, Z2, Z3 and Z4 are selected from CR7, R4 is selected from any substituted C6- 14 Aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic.

5. The compound of formula (II) according to claim 3, or its stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, wherein, X is selected from CH2 or C (=O); Z1, Z2, Z3, and Z4 are selected from N or CR7; R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups. Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups; Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atoms attached thereto, they form 3-6 membered cycloalkyl groups and 3-6 membered heterocyclic groups; R4 is selected from optionally substituted C1-C6 alkyl groups, C6- 14 aryl, 5 to 14-membered heteroaryl; wherein the C1-C6 alkyl, C6- 14 The aryl group and the 5- to 14-membered heteroaryl group are optionally substituted with one or more C1-C6 alkyl groups, C1-C6 alkoxy groups, halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups; R5 is selected from H, deuterium, and C1-C6 alkyl groups; m and n are each independently selected from 1, 2, or 3; R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and amino when they appear. r is selected from 1, 2, 3, 4, or 5; The condition is that when X is CH2, m is 2, n is 2, R3 and R3' are H, and Z1, Z2, Z3 and Z4 are selected from CR7, R4 is selected from any substituted C6- 14 Aryl, 5 to 14 heteroaryl groups.

6. The compound according to any one of claims 3-5, characterized in that, The compound is a compound of formula (IIa), formula (IIb) or formula (IIc). (IIa)、 (IIb)、 (IIc) Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein X, Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined in claims 3-5.

7. The compound according to claim 6, characterized in that, The compound is a compound represented by formula (IId), formula (IIe), formula (IIIf), formula (IIg), formula (IIh), or formula (IIi). (IId)、 (IIe) (IIf)、 (IIg)、 (IIh)、 (IIi) Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein Z1, Z2, Z3, Z4, R3, R3', Y, R4, R5, R6, and r are as defined in claim 6.

8. The compound according to claim 7, or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein, Z1, Z2, Z3, and Z4 are selected from N or CR7; R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more halogens or hydroxyl groups; Alternatively, R3, R3' together with the nitrogen atom to which they are attached form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl groups; Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, or R a R b Together with the carbon atom it is attached to, they form 3-6 membered cycloalkyl groups; R4 is selected from optionally substituted C1-C6 alkyl groups, C6- 14 Aryl; wherein the C1-C6 alkyl, C6- 14 The aryl group may optionally be substituted with one or more C1-C6 alkyl groups, C1-C6 alkoxy groups, or halogens; R5 is selected from H or deuterium; R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, and hydroxyl groups each time they appear; r can be selected from 1, 2, 3, 4 or 5.

9. The compound according to claim 8, or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein, Z1, Z2, Z3, and Z4 are selected from N or CR7; R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more halogens or hydroxyl groups; Alternatively, R3, R3' together with the nitrogen atom to which they are attached form a 6-membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl groups; Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C3 alkyl, or R a R b Together with the carbon atoms attached to it, it forms cyclopropane rings and cyclobutane rings; R4 is selected from optionally substituted C1-C3 alkyl or phenyl groups; wherein the C1-C3 alkyl or phenyl groups are optionally substituted with one or more C1-C3 alkyl groups, C1-C3 alkoxy groups, or halogens; R5 is selected from H or deuterium; R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, and hydroxyl groups each time they appear; r can be selected from 1, 2, 3, 4 or 5.

10. The compound according to any one of claims 7-9, characterized in that, The compound is a compound represented by formula (IIj), formula (IIk), formula (IIl), formula (IIm), formula (IIin), formula (IIo), formula (IIp), formula (IIq), formula (IIr), formula (IIs), formula (IIt), or formula (IIu). (IIj)、 (IIk)、 (IIl)、 (IIm)、 (IIn)、 (IIo)、 (IIp)、 (IIq)、 (IIr)、 (IIs)、 (IIt)、 (IIu)、 Or its stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, wherein R8 is selected from H, deuterium, or C1-C3 alkyl, Z1, Z2, Z3, Z4, R3, R3', Y, R5, R6, and r as defined in any one of claims 7-9.

11. The compound according to claim 10, or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein, Z1, Z2, Z3, and Z4 are selected from N or CR7; R3 and R3' are each independently selected from H, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more halogens or hydroxyl groups; Alternatively, R3, R3' together with the nitrogen atom to which they are attached form a 6-membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C3 alkyl groups; Y is selected from , where R a and R b Each is independently selected from H, deuterium, methyl, or R. a R b Together with the carbon atoms it is attached to, it forms a cyclopropane ring; R5 is selected from H or deuterium; R6 and R7 are each independently selected from hydrogen, deuterium, halogen, and C1-C3 alkyl groups each time they appear; r is selected from 1, 2, 3, 4, or 5; R8 is selected from H, deuterium, or C1-C3 alkyl groups.

12. The compound according to claim 10, or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein, Z1, Z2, Z3, and Z4 are selected from N or CR7; R3 and R3' are each independently selected from H, deuterium, methyl, ethyl, propyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, propoxy, hydroxymethyl, 2-hydroxyethyl, and 2-hydroxypropyl. Alternatively, R3, R3' together with the nitrogen atom they are attached to form a piperazine ring or a piperidine ring; wherein the piperazine ring or piperidine ring is optionally substituted with one or more methyl, ethyl, or propyl groups; Y is selected from , where R a and R b Each is independently selected from H, deuterium, methyl, or R. a R b Together with the carbon atoms it is attached to, it forms a cyclopropane ring; R5 is selected from H or deuterium; R6 and R7 are each independently selected from hydrogen, deuterium, and halogen each time they appear; r is selected from 1, 2, 3, 4, or 5; R8 is selected from H, deuterium, or C1-C3 alkyl groups.

13. The compound according to any one of claims 1-12, or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein, Z1, Z2, Z3, and Z4 are selected from N or CR7, and at least one of Z1, Z2, Z3, and Z4 is N.

14. The compound of formula (I) according to claim 1, characterized in that, The compound is the compound shown in formula (III). (III) Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein, X is selected from CH2 or C (=O); R1, R1', R2, and R2' are each independently selected from H, deuterium, C1-C6 alkyl groups optionally substituted with one or more halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups; or, R1 together with R1' or R2 together with R2' and the carbon atoms to which they are attached, forms a C3-C6 cycloalkyl group. R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, oxo groups, carboxyl groups, or ester groups. Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, amino, oxo, carboxyl, or ester group. Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atom it is attached to, it forms a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group; x and y are each independently selected from 0, 1, 2 or 3; R4 is selected from optionally substituted C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 12 cycloalkyl, C6- 14 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic; wherein the C1-C6 alkyl, C3-C 12 cycloalkyl, C6- 14 The aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclic groups are optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups; R5 is selected from H, deuterium, and C1-C6 alkyl groups; m and n are each independently selected from 1, 2, or 3; R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and -C(O)R each time they appear. c -C(O)OR c -OC(O) R c , amino, NR d R d ';R c R d R d Each is independently selected from H or C1-C6 alkyl groups; r is selected from 1, 2, 3, 4, or 5; s is selected from 1, 2, 3, or 4; The condition is that when X is CH2, m is 2, n is 2, and R3 and R3' are H, R4 is selected from any substituted C6- 14 Aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic.

15. The compound of formula (III) according to claim 14, or its stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, wherein, X is selected from CH2 or C (=O); R1, R1', R2, and R2' are each independently selected from H, deuterium, or C1-C6 alkyl groups optionally substituted with one or more halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups; R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, oxo groups, carboxyl groups, or ester groups. Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, amino, oxo, carboxyl, or ester group. Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atom it is attached to, it forms a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group; x and y are each independently selected from 0, 1, 2 or 3; R4 is selected from optionally substituted C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 12 cycloalkyl, C6- 14 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic; wherein the C1-C6 alkyl, C3-C 12 cycloalkyl, C6- 14 The aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclic groups are optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups; R5 is selected from H, deuterium, and C1-C6 alkyl groups; m and n are each independently selected from 1, 2, or 3; R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and -C(O)R each time they appear. c -C(O)OR c -OC(O) R c , amino, NR d R d ';R c R d R d Each is independently selected from H, deuterium, or C1-C6 alkyl groups; r is selected from 1, 2, 3, 4, or 5; s is selected from 1, 2, 3, or 4; The condition is that when X is CH2, m is 2, n is 2, and R3 and R3' are H, R4 is selected from any substituted C6- 14 Aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic.

16. The compound of formula (III) according to claim 14, characterized in that, The compound is the compound shown in formula (IV). (IV) Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein X, R3, R3', Y, R4, R5, m, n, R6, R7, r, and s are as defined in claim 14.

17. The compound of formula (IV) according to claim 16, or its stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, wherein, X is selected from CH2 or C (=O); R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, oxo groups, carboxyl groups, or ester groups. Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, amino, oxo, carboxyl, or ester group. Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atoms attached thereto, they form 3-6 membered cycloalkyl groups and 3-6 membered heterocyclic groups; R4 is selected from optionally substituted C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 12 cycloalkyl, C6- 14 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic; wherein the C1-C6 alkyl, C3-C 12 cycloalkyl, C6- 14 The aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclic groups are optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups; R5 is selected from H, deuterium, and C1-C6 alkyl groups; m and n are each independently selected from 1, 2, or 3; R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and -C(O)R each time they appear. c -C(O)OR c -OC(O) R c , amino, NR d R d ';R c R d R d Each is independently selected from H, deuterium, or C1-C6 alkyl groups; r is selected from 1, 2, 3, 4, or 5; s is selected from 1, 2, 3, or 4; The condition is that when X is CH2, m is 2, n is 2, and R3 and R3' are H, R4 is selected from any substituted C6- 14 Aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclic.

18. The compound of formula (IV) according to claim 16, or its stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, wherein, X is selected from CH2 or C (=O); R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups. Alternatively, R3, R3' together with the nitrogen atom attached to them can form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, mercapto, cyano, or amino groups; Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, halogen, or R. a R b Together with the carbon atoms attached thereto, they form 3-6 membered cycloalkyl groups and 3-6 membered heterocyclic groups; R4 is selected from optionally substituted C1-C6 alkyl groups, C6- 14 aryl, 5 to 14-membered heteroaryl; wherein the C1-C6 alkyl, C6- 14 The aryl group and the 5- to 14-membered heteroaryl group are optionally substituted with one or more C1-C6 alkyl groups, C1-C6 alkoxy groups, halogens, hydroxyl groups, mercapto groups, cyano groups, or amino groups; R5 is selected from H, deuterium, and C1-C6 alkyl groups; m and n are each independently selected from 1, 2, or 3; R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, mercapto, C1-C6 alkylthio, cyano, nitro, and amino when they appear. r is selected from 1, 2, 3, 4, or 5; s is selected from 1, 2, 3, or 4; The condition is that when X is CH2, m is 2, n is 2, and R3 and R3' are H, R4 is selected from any substituted C6- 14 Aryl, 5 to 14 heteroaryl groups.

19. The compound according to any one of claims 16-18, characterized in that, The compound is a compound of formula (IVa), formula (IVb) or formula (IVc). (IVa)、 (IVb)、 (IVc) Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein X, R3, R3', Y, R4, R5, R6, R7, r, and s are as defined in claims 16-18.

20. The compound according to claim 19, characterized in that, The compound is a compound represented by formula (IVd), formula (IVe), formula (IVf), formula (IVg), formula (IVh), or formula (IVi). (IVd)、 (IVe) (IVf)、 (IVg)、 (IVh)、 (iv) Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein R3, R3', Y, R4, R5, R6, R7, r, and s are as defined in claim 19.

21. The compound according to claim 20, or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein, R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more halogens or hydroxyl groups; Alternatively, R3, R3' together with the nitrogen atom to which they are attached form a 4-6 membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl groups; Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C6 alkyl, or R a R b Together with the carbon atom it is attached to, they form 3-6 membered cycloalkyl groups; R4 is selected from optionally substituted C1-C6 alkyl groups, C6- 14 Aryl; wherein the C1-C6 alkyl, C6- 14 The aryl group may optionally be substituted with one or more C1-C6 alkyl groups, C1-C6 alkoxy groups, or halogens; R5 is selected from H or deuterium; R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, and hydroxyl groups each time they appear; r is selected from 1, 2, 3, 4, or 5; s is selected from 1, 2, 3 or 4.

22. The compound according to claim 21, or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein, R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more halogens or hydroxyl groups; Alternatively, R3, R3' together with the nitrogen atom to which they are attached form a 6-membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C6 alkyl groups; Y is selected from , where R a and R b Each is independently selected from H, deuterium, C1-C3 alkyl, or R a R b Together with the carbon atoms attached to it, it forms cyclopropane rings and cyclobutane rings; R4 is selected from optionally substituted C1-C3 alkyl or phenyl groups; wherein the C1-C3 alkyl or phenyl groups are optionally substituted with one or more C1-C3 alkyl groups, C1-C3 alkoxy groups, or halogens; R5 is selected from H or deuterium; R6 and R7 are each independently selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, and hydroxyl groups each time they appear; r is selected from 1, 2, 3, 4, or 5; s is selected from 1, 2, 3 or 4.

23. The compound according to any one of claims 20-22, characterized in that, The compound is a compound represented by formula (IVj), (IVk), (IVl), (IVm), (IVn), (IVo), (IVp), (IVq), (IVr), (IVs), (IVt), or (IVu). (IVj)、 (IVk)、 (IVl)、 (IVm)、 (IVn) (IVo) (IVp) (IVq) (IVr)、 (IVs)、 (IVt)、 (IVu)、 Or its stereoisomers, tautomers, isotopic labels, and pharmaceutically acceptable salts, wherein R8 is selected from H, deuterium, or C1-C3 alkyl, and R3, R3', Y, R5, R6, R7, r, and s are as defined in any one of claims 20-22.

24. The compound according to claim 23, or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein, R3 and R3' are each independently selected from H, deuterium, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more halogens or hydroxyl groups; Alternatively, R3, R3' together with the nitrogen atom to which they are attached form a 6-membered, optionally substituted heterocyclic group; wherein the heterocyclic group is optionally substituted by one or more C1-C3 alkyl groups; Y is selected from , where R a and R b Each is independently selected from H, deuterium, methyl, or R. a R b Together with the carbon atoms it is attached to, it forms a cyclopropane ring; R5 is selected from H or deuterium; R6 and R7 are each independently selected from hydrogen, deuterium, halogen, and C1-C3 alkyl groups each time they appear; r is selected from 1, 2, 3, 4, or 5; s is selected from 1, 2, 3, or 4; R8 is selected from H, deuterium, or C1-C3 alkyl groups.

25. The compound according to claim 23, or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts, wherein, R3 and R3' are each independently selected from H, deuterium, methyl, ethyl, propyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, propoxy, hydroxymethyl, 2-hydroxyethyl, and 2-hydroxypropyl. Alternatively, R3, R3' together with the nitrogen atom they are attached to form a piperazine ring or a piperidine ring; wherein the piperazine ring or piperidine ring is optionally substituted with one or more methyl, ethyl, or propyl groups; Y is selected from , where R a and R b Each is independently selected from H, deuterium, methyl, or R. a R b Together with the carbon atoms it is attached to, it forms a cyclopropane ring; R5 is selected from H or deuterium; R6 and R7 are each independently selected from hydrogen, deuterium, and halogen each time they appear; r is selected from 1, 2, 3, 4, or 5; s is selected from 1, 2, 3, or 4; R8 is selected from H or C1-C3 alkyl groups.

26. The compound of formula (I) according to claim 1, characterized in that: The compound is selected from: Or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts.

27. A pharmaceutical composition comprising the compound or stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts of any one of claims 1-26, and a pharmaceutically acceptable carrier.

28. Use of the compound or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts according to any one of claims 1-26 in the preparation of a medicament for the prevention and / or treatment of growth hormone-dependent diseases.

29. Use of the compound or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts according to any one of claims 1-26 in the preparation of a medicament for the prevention and / or treatment of diseases caused by growth hormone deficiency.

30. The use according to claim 28 or 29, wherein the growth hormone-dependent disease or disease caused by growth hormone deficiency is selected from dwarfism, osteoporosis, childhood short stature, sexual organ dysplasia, and growth retardation caused by growth hormone deficiency.

31. Use of the compound or its stereoisomers, tautomers, isotopic markers, and pharmaceutically acceptable salts according to any one of claims 1-26 in the preparation of a medicament for promoting the secretion or release of growth hormone.

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