Compound with SMARCA2 inhibition effect and application thereof

Abstract

The invention discloses a compound for inhibiting SMARCA2 or pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorphic substance, solvate, metabolite, isotope labeled compound or prodrug of the compound, and a pharmaceutical composition containing the compound and the pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorphic substance, solvate, metabolite, isotope labeled compound or prodrug. The compound and the pharmaceutical composition are used for preventing or treating diseases, symptoms or disorders related to SMARCA2.

Description

Technical Field

[0001] This disclosure relates to compounds that inhibit SMARCA2 or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs, and pharmaceutical compositions comprising the thereof, for use in the prevention or treatment of diseases, conditions or disorders associated with SMARCA2. Background Technology

[0002] The SWI / SNF complex is one of the four major families of chromatin regulatory factors. It utilizes ATP hydrolysis to regulate the sliding of DNA along histones, either making the DNA denser and hindering transcription, or loosening it and promoting transcription. Subunit mutations in SWI / SNF occur in various types of cancer.

[0003] SMARCA2, a core member of the SWI / SNF complex, is an ATPase subunit that hydrolyzes ATP to obtain energy, altering and reshaping the interaction between histones and DNA in nucleosomes. This influences the chromatin openness in specific regions of the genome, thereby regulating gene expression. SMARCA2 and SMARCA4 have independent functional relationships; when SMARCA4 undergoes a LOF mutation, SMARCA2 gene transcription significantly increases. Under normal physiological function, SMARCA2 participates in regulating DNA repair, replication, and cell differentiation. SMARCA4 LOF leads to genomic instability and abnormal cell proliferation. SMARCA4 LOF mutations induce increased expression of proto-oncogenes and their target genes, promoting tumor development and progression. Single-gene mutations in SMARCA4 can directly induce various types of tumors.

[0004] The mechanism of SMARCA2 targeting in the synthesis of SMARCA4 LOF mutant cells is well understood, and there is a high unmet clinical need, making it necessary to develop new SMARCA2 inhibitors. Invention Overview

[0005] This invention provides compounds that can be used as inhibitors targeting SMARCA2. The compounds of this invention belong to the PROTAC family, with one end binding to the target protein and the other end having a high-affinity ligand that recruits the target protein to an E3 ubiquitin ligase, leading to inhibition of the SMARCA2 protein. The compounds of this invention can be used to treat and / or prevent SMARCA2-related cancers or conditions.

[0006] On the one hand, the present invention provides compounds or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, said compounds having the structure of formula (I):

[0007]

[0008] in,

[0009] Dashed lines indicate the presence or absence of a key;

[0010] - / - indicates forward or reverse, as mentioned above include or mixtures thereof;

[0011] X 1 Selected from CH2, NH, O, or S;

[0012] R 1 Selected from -C 1～8 Alkyl, -C 0～4 Alkylene-NHC 0～4 Alkyl, -C 0～4 Alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3 to 12-membered heterocyclic groups; the R 1 The alkyl, heterocyclic, and cycloalkyl groups in the R group may optionally be replaced by R. x Replaced 1 to 3 times; R 1 Replaced by A1, where A1 is the key between the connector and L;

[0013] R 2 Selected from hydrogen, -C 1～6 Alkyl, -C 0～3 Alkylene-C 3～6 cycloalkyl, -C 0～3 alkylene-3- to 6-membered heterocyclic groups, aryl groups, and 5- to 6-membered heteroaryl groups; the R 2 The alkyl, heterocyclic, cycloalkyl, aryl, and heteroaryl groups in the R group may optionally be replaced by R. x Replace 1 to 3 times;

[0014] R 3 Independently selected from halogen, cyano, oxo, hydroxyl, C 1～3 Alkyl, C 1～3 Alkoxy and C 1～3 Halogenated alkyl groups;

[0015] R 4 Independently selected from hydrogen and C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～6 Cycloalkyl, 3-6 membered heterocyclic, aryl, and 5-6 membered heteroaryl; the R 4 The alkyl, heterocyclic, cycloalkyl, aryl, and heteroaryl groups in the R group may optionally be replaced by R. x Replace 1 to 3 times;

[0016] n is 0, 1, 2, or 3;

[0017] m can be 0, 1, 2, or 3;

[0018] R x Independently selected from halogen, cyano, oxo, hydroxyl, amino, C 1～3 Alkyl, C 1～3 Alkoxy and C 3～6 cycloalkyl; the R x The alkyl, alkoxy, and cycloalkyl groups in the alkyl group may optionally be substituted with halogens 1 to 3 times;

[0019] L is A1-L 1 -L 2 -L 3 -L 4 -A2;

[0020] A1 is the bond between the linker and the toxin; A2 is the bond between the degradation portion and the linker;

[0021] L 1 Selected from -O-, -S-, -C(O)-, -NR 1a -、C 1-6 Alkylene, C 3-6 Cycloalkylene and 3-10 heteroalkylene groups, wherein each of the alkylene, cycloalkylene, heterocyclic group and heteroalkylene group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0022] L 2 It is a covalent bond, or selected from -C(O)-, C 1-6 Alkylene;

[0023] L 3 It is a covalent bond, or selected from -O-, -NR 3a -、C 1-6 Alkylene, -OC 1-6 Alkylene, C 1-6 Alkylene-O-, C 3-6 Cycloalkylene and 3-10-membered heterocyclic groups, wherein each of the alkylene, cycloalkylene, and heterocyclic group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0024] L 4 It is a covalent bond, or selected from -O-, -S-, -NR. 4a -、C 1-6 Alkylene, -OC 1-6 Alkylene-, C 1-6 Alkylene-O-, C 3-6Cycloalkylene, -C(O)-, -C(O)-N(R) 4a )- and 3-10-membered heterocyclic groups, wherein each of the alkylene, cycloalkylene, and heterocyclic groups is optionally composed of one or more groups selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0025] R 1a R 3a and R 4a Each is independently selected from hydrogen and C. 1-6 alkyl;

[0026] M can be M1, M2, or M3 as shown in the following formula:

[0027] M1, Y 1 Selected from C(O) or CR Y1-1 R Y1-2 ;

[0028] R Y1-1 R Y1-2 Selected from H or optionally substituted C 1-6 alkyl;

[0029] M 1-1 M 1-2 M 1-3 and M 1-4 Each of the following is independently H, A2, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C2-C9 heterocyclic, optionally substituted C6-C 10 A combination of aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted -O-C3-C6 cycloalkyl, hydroxyl, and thioalkyl groups to form an optionally substituted C6-C10 aryl, optionally substituted C3-C10 cycloalkyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclic group, any one of which is optionally substituted by A2 or optionally substituted amino; or M 1-1 and M 1-2 M 1-2 and M 1-3 , and / or M 1-3 and M 1-4 They merge together with their respective connected carbon atoms to form and C6-C as an optional substitute 10 Aryl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclic, any one of which may be substituted by A2.

[0030] Where M 1-1 M 1-2 M 1-3 and M 1-4 One of them is A2, or can be replaced by A2; and

[0031] A2 is the bond between the degradation portion and the linker;

[0032] M 1-5 H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; in M2,

[0033] M 2-1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-12 membered heterocyclic groups;

[0034] M 2-1 It is replaced by A2, where A2 is the bond between the degradation portion and L;

[0035] M 2-2 Each of the following is independently a halogen, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted C2-C9 heterocyclic, an optionally substituted C6-C10 aryl, an optionally substituted C2-C9 heteroaryl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 heteroalkenyl, a hydroxyl, a thioalkyl, or an optionally substituted amino.

[0036] M 2-3 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are each optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0037] M 2-4 H, or optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl-C3-C 10 Cycloalkyl or optionally substituted C1-C6 alkyl-C6-C 10 Aryl;

[0038] v2 is 0, 1, 2, 3 or 4;

[0039] A2 is the bond between the degradation portion and the linker;

[0040] In M3, ring M3-A is a C3-C10 cycloalkyl group, a 3-9 membered heterocyclic group, or a C6-C cycloalkyl group. 12 Aryl or 5-12 heteroaryl groups;

[0041] M3-1 is a halogen, cyano, hydroxyl, amino, C1-C3 alkyl, or C1-C3 haloalkyl;

[0042] P can be 0, 1, 2, or 3;

[0043] A2 is the bond between the degradation portion and the linker.

[0044] On the other hand, this disclosure provides pharmaceutical compositions comprising preventive and / or therapeutically effective amounts of the compound of this disclosure or its pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers.

[0045] On the other hand, this disclosure provides a kit containing a compound of the disclosure or a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically labeled compound, a metabolite or a prodrug, or a pharmaceutical composition comprising the present invention.

[0046] On the other hand, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or pharmaceutical compositions of the disclosure that target the SMARCA2 protein and are used to inhibit or degrade the SMARCA2 protein.

[0047] On the other hand, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or pharmaceutical compositions of the disclosure for the prevention and / or treatment of SMARCA2-mediated diseases.

[0048] In some embodiments, the disease is a tumor (e.g., cancer), including solid tumors and hematologic malignancies. In some embodiments, the tumor or cancer is selected from non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal-gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, hematologic malignancies, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumors, uterine sarcoma, gastrointestinal stromal tumors, central nervous system cancers, thymic tumors, adrenocortical carcinoma, appendix cancer, small bowel cancer, or penile cancer.

[0049] On the other hand, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof, their stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or pharmaceutical compositions of this disclosure in the preparation of medicaments for the prevention and / or treatment of SMARCA2-mediated related diseases.

[0050] On the other hand, this disclosure provides methods for preventing and / or treating SMARCA2-mediated related diseases, comprising administering to an individual in need of such prevention and / or treatment an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof, its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or pharmaceutical compositions of the disclosure.

[0051] On the other hand, this disclosure provides a method for preparing the compounds disclosed herein. Invention Details

[0053] compound

[0054] This disclosure provides compounds or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, said compounds having the structure of formula (I):

[0055]

[0056] The dashed lines indicate the presence or absence of a key.

[0057] - / - indicates forward or reverse, as mentioned above include or mixtures thereof;

[0058] X 1 Selected from CH2, NH, O, or S;

[0059] R1 Selected from -C 1～8 Alkyl, -C 0～4 Alkylene-NHC 0～4 Alkyl, -C 0～4 Alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3 to 12-membered heterocyclic groups; the R 1 The alkyl, heterocyclic, and cycloalkyl groups in the R group may optionally be replaced by R. x Replaced 1 to 3 times; R 1 Replaced by A1, where A1 is the key between the connector and L;

[0060] R 2 Selected from hydrogen, -C 1～6 Alkyl, -C 0～3 Alkylene-C 3～6 cycloalkyl, -C 0～3 alkylene-3- to 6-membered heterocyclic groups, aryl groups, and 5- to 6-membered heteroaryl groups; the R 2 The alkyl, heterocyclic, cycloalkyl, aryl, and heteroaryl groups in the R group may optionally be replaced by R. x Replace 1 to 3 times;

[0061] R 3 Independently selected from halogen, cyano, oxo, hydroxyl, C 1～3 Alkyl, C 1～3 Alkoxy and C 1～3 Halogenated alkyl groups;

[0062] R 4 Independently selected from hydrogen and C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～6 Cycloalkyl, 3-6 membered heterocyclic, aryl, and 5-6 membered heteroaryl; the R 4 The alkyl, heterocyclic, cycloalkyl, aryl, and heteroaryl groups in the R group may optionally be replaced by R. x Replace 1 to 3 times;

[0063] n is 0, 1, 2, or 3;

[0064] m can be 0, 1, 2, or 3;

[0065] R x Independently selected from halogen, cyano, oxo, hydroxyl, amino, C 1～3 Alkyl, C 1～3 Alkoxy and C 3～6 cycloalkyl; the R x The alkyl, alkoxy, and cycloalkyl groups in the alkyl group may optionally be substituted with halogens 1 to 3 times;

[0066] L is A1-L 1 -L 2 -L3 -L 4 -A2;

[0067] A1 is the bond between the linker and the toxin; A2 is the bond between the degradation portion and the linker;

[0068] L 1 Selected from -O-, -S-, -C(O)-, -NR 1a -、C 1-6 Alkylene, C 1-6 alkylene-3-10-membered heteroaryl, C 3-6 Cycloalkylene and 3-10-membered heterocyclic groups, wherein the alkylene, cycloalkylene, heterocyclic group and heteroaryl group are each optionally composed of one or more elements selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0069] L 2 It is a covalent bond, or selected from -C(O)-, C 1-6 Alkylene;

[0070] L 3 It is a covalent bond, or selected from -O-, -NR 3a -、C 1-6 Alkylene, -OC 1-6 Alkylene, C 1-6 Alkylene-O-, C 3-6 Cycloalkylene and 3-10-membered heterocyclic groups, wherein each of the alkylene, cycloalkylene, and heterocyclic group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0071] L 4 It is a covalent bond, or selected from -O-, -S-, -NR. 4a -、C 1-6 Alkylene, -OC 1-6 Alkylene-, C 1-6 Alkylene-O-, C 3-6 Cycloalkylene, -C(O)-, -C(O)-N(R) 4a )-、-C(O)-C 1-6 Alkylene, and 3-10-membered heterocyclic groups, wherein each of the alkylene, cycloalkylene, and heterocyclic groups is optionally composed of one or more elements selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 The alkyl halide is substituted; the alkylene, cycloalkylene, and heteroalkylene groups are each optionally replaced by one or more groups selected from halogen, hydroxyl, cyano, C. 1-6 Alkyl and C 1-6Substituents of haloalkyl groups;

[0072] R 1a R 3a and R 4a Each is independently selected from hydrogen and C. 1-6 alkyl;

[0073] M can be M1, M2, or M3 as shown in the following formula:

[0074] M1, Y 1 Selected from C(O) or CR Y1-1 R Y1-2 ;

[0075] R Y1-1 R Y1-2 Selected from H or optionally substituted C 1-6 alkyl;

[0076] M 1-1 M 1-2 M 1-3 and M 1-4 Each of the following is independently H, A2, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C2-C9 heterocyclic, optionally substituted C6-C 10 A combination of aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted -O-C3-C6 cycloalkyl, hydroxyl, and thioalkyl groups to form an optionally substituted C6-C10 aryl, optionally substituted C3-C10 cycloalkyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclic group, any one of which is optionally substituted by A2 or optionally substituted amino; or M 1-1 and M 1-2 M 1-2 and M 1-3 , and / or M 1-3 and M 1-4 They merge together with their respective connected carbon atoms to form and C6-C as an optional substitute 10 Aryl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclic, any one of which may be substituted by A2.

[0077] Where M 1-1 M 1-2 M 1-3 and M 1-4 One of them is A2, or can be replaced by A2; and

[0078] A2 is the bond between the degradation portion and the linker;

[0079] M 1-5 H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; in M2,

[0080] M 2-1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-12 membered heterocyclic groups;

[0081] M 2-1 It is replaced by A2, where A2 is the bond between the degradation portion and L;

[0082] M 2-2 Each of the following is independently a halogen, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted C2-C9 heterocyclic, an optionally substituted C6-C10 aryl, an optionally substituted C2-C9 heteroaryl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 heteroalkenyl, a hydroxyl, a thioalkyl, or an optionally substituted amino.

[0083] M 2-3 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are each optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0084] M 2-4 H, or optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl-C3-C 10 Cycloalkyl or optionally substituted C1-C6 alkyl-C6-C 10 Aryl;

[0085] v2 is 0, 1, 2, 3 or 4;

[0086] A2 is the bond between the degradation portion and the linker;

[0087] In M3, ring M3-A is a C3-C10 cycloalkyl group, a 3-9 membered heterocyclic group, or a C6-C cycloalkyl group. 12 Aryl or 5-12 heteroaryl groups;

[0088] M3-1 is a halogen, cyano, hydroxyl, amino, C1-C3 alkyl, or C1-C3 haloalkyl;

[0089] P can be 0, 1, 2, or 3;

[0090] A2 represents the bond between the degradation portion and the connector.

[0091] In some embodiments, the compound of formula (I) is a compound of formula (I-1):

[0092]

[0093] in,

[0094] Indicates a single bond or a double bond;

[0095] X1 is selected from CH2, NH or S;

[0096] R 1 Selected from -C 0～4 Alkylene-NHC 0～4 Alkyl, -C 0～4 Alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3 to 12-membered heterocyclic groups; the R 1 The heterocyclic, cycloalkyl, and amino groups in R can optionally be replaced by R x Replace 1 to 3 times;

[0097] R2 is selected from hydrogen, -C 1～6 Alkyl groups; the alkyl, heterocyclic, and cycloalkyl groups in R2 may optionally be replaced by R x Replace 1 to 3 times;

[0098] R3 is independently selected from halogen, cyano, oxo, and C. 1～3 Alkyl and C 1～3 Halogenated alkyl groups;

[0099] R4 is independently selected from hydrogen, C 1～3 Alkyl, C 1～3 Halogenated alkyl and cyclopropyl;

[0100] R x Independently selected from halogen, cyano, hydroxyl, amino, C 1～3 Alkyl, C 1～3 Alkoxy and C 3～6 cycloalkyl; the R x The alkyl, alkoxy, and cycloalkyl groups in the alkyl group may optionally be substituted with halogens 1 to 3 times;

[0101] The rest of the definitions are the same as in Equation I.

[0102] In some embodiments, the compound of formula (I) is a compound of formula (I-2):

[0103]

[0104] in,

[0105] X1 is selected from CH2, NH or S;

[0106] R 1 Selected from -C 0～4 Alkylene-NHC 0～4 Alkyl, -C 0～4 Alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3 to 12-membered heterocyclic groups; the R 1 The alkyl, heterocyclic, cycloalkyl, and amino groups in R can optionally be replaced by R x Replace 1 to 3 times;

[0107] R2 is selected from hydrogen, -C 1～6 Alkyl; the alkyl group in R2 may optionally be replaced by R x Replace 1 to 3 times;

[0108] R3 is independently selected from halogen, cyano, oxo, and C. 1～3 Alkyl and C 1～3 Halogenated alkyl groups;

[0109] R4 is independently selected from hydrogen, C 1～3 Alkyl, C 1～3 Halogenated alkyl and cyclopropyl;

[0110] R x Independently selected from halogen, cyano, hydroxyl, amino, C 1～3 Alkyl, C 1～3 Alkoxy and C 3～6 cycloalkyl; the R x The alkyl, alkoxy, and cycloalkyl groups can optionally be substituted with halogens 1 to 3 times.

[0111] In other embodiments, in formula I-1, the compound of formula (I) is a compound of formula (I-1-1), formula (I-1-2), or formula (I-1-3):

[0112]

[0113]

[0114] The rest of the definitions are the same as those for (Ii).

[0115] In other embodiments, in formula (I-2), the compound of formula (I) is a compound of formula (I-2-1) or formula (I-2-2):

[0116]

[0117] The rest of the definitions are the same as those in equation (I-2).

[0118] In some preferred embodiments, R1 is independently selected from -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH2NHCH3, -CH2CH2NH2, -CH2NHCH3, -CH2CH2NHCH2CH3, -CH2NHCH2CH3, -CH2CH2CH2NH2, -CH2CH2CH2NHCH3; the alkyl, heterocyclic, cycloalkyl, and amino groups in R1 may optionally be replaced by R x Replace 1 to 3 times.

[0119] In some preferred embodiments, R2 is independently selected from -H, -CH3, -CH2CH3, -CH2CH(CH3)2, -CH(CH3)2, The alkyl and heterocyclic groups in R2 may optionally be substituted with halogens 1 to 3 times.

[0120] In some preferred embodiments, R3 is independently selected from -F, -Cl, -Br, =O, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2Cl, CCl3, -CHCl2, -CH2CH2Cl, -CH2CCl3, -CH2F, -CF3, -CHF2, -CH2CH2F, and -CH2CF3.

[0121] In some preferred embodiments, R4 is independently selected from -H, -F, -Cl, -Br, -CH3, -CH2CH3, -CH(CH3)2, -CH2F, -CF3, -CHF2, and -CH2CF3.

[0122] In some preferred embodiments, X1 is selected from NH or S.

[0123] In some preferred embodiments, R1 is independently selected from -CH2CH2NHCH3、

[0124] In some preferred embodiments, R2 is independently selected from -H, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2,

[0125] In some preferred embodiments, R3 is independently selected from -F, -Cl, and -CH3.

[0126] In some preferred embodiments, R4 is independently selected from -H and -CH3.

[0127] In some preferred embodiments, in formula (I-1), the compound of formula (I) is

[0128]

[0129] In some preferred embodiments, in formula (I-2), the compound of formula I is

[0130]

[0131] In some implementation schemes, M 1-5 It is H or methyl. In some embodiments, M 1-5 For H.

[0132] In some implementations, each M 1-1 M 1-2 M 1-3 and M 1-4 Independently, it is either H or A2.

[0133] In some implementation schemes, M 1-1 It is A2, and each M 1-2 M 1-3 and M 1-4 It is H or halogen.

[0134] In some implementation schemes, M 1-2 It is A2, and each M 1-1 M 1-3 and M 1-4 It is H or halogen.

[0135] In some implementation schemes, M 1-3 It is A2, and each M 1-1 M 1-2 and M 1-4 It is H or halogen.

[0136] In some implementation schemes, M 1-4 It is A2, and each M 1-1 M 1-2 and M 1-3 It is H or halogen.

[0137] In some implementations, Y1-1 is H. In some implementations, Y1-2 is H.

[0138] In some preferred embodiments, the M includes formula M 1-1 Structure:

[0139] In some preferred embodiments, M is

[0140] In some preferred embodiments, M includes the structure of formula M1-2:

[0141] In some preferred embodiments, M is

[0142] In some preferred embodiments, M includes the structure of formulas M1-3:

[0143] In some preferred embodiments, M is

[0144] In some preferred embodiments, M includes the structure of formulas M1-4:

[0145] In some preferred embodiments, M is

[0146] In some preferred embodiments, M includes the structure of formulas M1-5:

[0147] In some preferred embodiments, M is

[0148] In some preferred embodiments, M includes the structure of formulas M1-6:

[0149] In some preferred embodiments, M is

[0150]

[0151] In some implementations, M has the structure of formula M2:

[0152]

[0153] in

[0154] M 2-1 for

[0155] R B3 Optionally substituted C1-C6 alkyl, Optionally substituted C1-C6 heteroalkyl, Optionally substituted C3-C10 cycloalkyl, Optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl-C3-C 10 Cycloalkyl or optionally substituted C1-C6 alkyl-C6-C10 Aryl;

[0156] M 2-2 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0157] M 2-3 It is H or an optional substituted C1-C6 alkyl group; and

[0158] M 2-4 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-12 membered heterocyclic groups.

[0159] In some preferred embodiments, M has the structure of formula M2-1:

[0160] In some preferred embodiments, M is Preferred

[0161] In some embodiments, cycloM3-A is a C3-C10 cycloalkyl group, preferably a C3-6 cycloalkyl group, and more preferably a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

[0162] In some embodiments, ring M3-A is a 3-9 membered heterocyclic group, preferably pyridyl, quinolinyl, phenothiazinyl, benzodiazepine, furanyl, pyrazoloneyl, or pyrimidinyl, with pyridyl, quinolinyl, or phenothiazinyl being the most preferred.

[0163] In some implementations, ring M3-A is C6-C. 10 Aryl, preferably phenyl or naphthyl.

[0164] In some embodiments, ring M3-A is a 3-9 membered heteroaryl group, preferably a pyridine ring, pyrimidine ring, pyrazine ring, or pyridazine ring; for example...

[0165] In some implementations, M has the structure of formula M3:

[0166] in,

[0167] M3-A is selected from phenyl, naphthyl, pyridine ring, pyrimidine ring, pyrazine ring, and pyridazine ring; for example...

[0168] M 3-1 Selected from halogens, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0169] In some implementations, M3 is

[0170] In some implementations, L, L 1 Selected from -C(O)-, C 1-6 Alkylene, C 1-6 Alkylene-3-10-membered heteroarylene, wherein the alkylene, heterocyclic and heteroarylene groups are each optionally separated by one or more elements selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; preferably L 1 It is a covalent bond, or selected from -C(O)-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH(CH3)-, -CH(pyridyl group).

[0171] In some implementations, L, L 2 It is a covalent bond, or selected from -C(O)- or C 1-6 Alkylene; preferably L 2 It is a covalent bond, or selected from -C(O)-, -CH2-.

[0172] In some implementation schemes, L, 3 It is a covalent bond, or selected from C 3-6 Cycloalkylene and 3-10-membered heterocyclic groups, wherein each of the cycloalkylene and heterocyclic groups is optionally composed of one or more elements selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; preferably L 3 It is a covalent bond, or selected from

[0173] In some implementations, L, L 4 It is a covalent bond, or selected from -O-, -NR 4a -、C 1-6 Alkylene, -C(O)-, -C(O)-N(R) 4a )-、-C(O)-C 1-6 Alkylene; preferably L 4 It is a covalent bond, or selected from -O-, -N(CH3)-, -C(O)-, -C(O)-NH-, C(O)-N(CH3)-, methylene, -C(O)-CH3-.

[0174] In some preferred embodiments, L is -C(O)-C 1-6 Alkylene -O-, -C(O)-C1-6 Alkylene-NR 4a -、C 1-6 Alkylene-NR 4a -、C 1-6 Alkylene-NR 4a C(O)-、-C 1-6 alkylene-3-10-membered heterocyclic-C(O)-, C 1-6 Alkyl-3-10-membered heterocyclic-, -3-10-membered heterocyclic-, -C(O)-C 1-6 alkylene-3-10-membered heterocyclic-,-C(O)-10-membered heterocyclic-C 1-6 alkylene-, -C 1-6 alkylene-3-10-membered cycloene-NR 4a C(O)-, C 1-6 Alkylene-3-10-membered heterocyclic-3-10-membered heterocyclic-C(O)-.

[0175] In some preferred embodiments, the L has the following structure:

[0176]

[0177] In another aspect, the present invention also provides compounds of formula Ii, their optical isomers, and pharmaceutically acceptable salts thereof.

[0178]

[0179] Among them, R 1 Selected from -C 1～8 Alkyl, -C 0～4 Alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3 to 12-membered heterocyclic groups; the R 1 The alkyl, heterocyclic, and cycloalkyl groups in the R group may optionally be replaced by R. x Replace 1 to 3 times; preferred R 1 Selected from -C 0～4 Alkyl-3 to 12-membered heterocyclic groups;

[0180] R2 is selected from hydrogen, -C 1～6 alkyl;

[0181] Ring M 3-A Selected from C3-C 10 Cycloalkyl, 3-9 membered heterocyclic, C6-C 10 Aryl or 3-9 quinone heteroaryl;

[0182] M 3-1 It can be halogen, cyano, hydroxyl, amino, C1-C3 alkyl, or C1-C3 haloalkyl;

[0183] L is A1-L 1 -L 2 -L 3 -L 4 -A2;

[0184] L 1 Selected from -O-, -S-, -C(O)-, -NR 1a -、C 1-6 Alkylene, C 1-6 alkylene-3-10-membered aromatic ring group, C 3-6 Cycloalkylene and 3-10-membered heterocyclic groups, wherein the alkylene, cycloalkylene, heterocyclic group and heteroaryl group are each optionally composed of one or more elements selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0185] L 2 It is a covalent bond, or selected from -C(O)- or C 1-6 Alkylene;

[0186] L 3 It is a covalent bond, or selected from -O-, -NR 3a -、C 1-6 Alkylene, -OC 1-6 Alkylene, C 1-6 Alkylene-O-, C 3-6 Cycloalkylene and 3-10-membered heterocyclic groups, wherein each of the alkylene, cycloalkylene, and heterocyclic group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0187] L 4 It is a covalent bond, or selected from -O-, -S-, -NR. 4a -、C 1-6 Alkylene, -OC 1-6 Alkylene-, C 1-6 Alkylene-O-, C 3-6 Cycloalkylene, -C(O)-, -C(O)-N(R) 4a )-、-C(O)-C 1-6 Alkylene, and 3-10-membered heterocyclic groups, wherein each of the alkylene, cycloalkylene, and heterocyclic groups is optionally composed of one or more elements selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 The alkyl halide is substituted; the alkylene, cycloalkylene, and heteroalkylene groups are each optionally replaced by one or more groups selected from halogen, hydroxyl, cyano, C. 1-6 Alkyl and C 1-6Substituents of haloalkyl groups;

[0188] R 1a R 3a and R 4a Each is independently selected from hydrogen and C. 1-6 alkyl.

[0189] In some preferred embodiments, R1 is independently selected from Preferably, Further optimization

[0190] In some preferred embodiments, ring M 3-A For phenyl, Phenyl is preferred.

[0191] In some preferred embodiments, the connector L has the following structure:

[0192] Preferably, the connector L has the following structure: More preferably, the connector L has the following structure:

[0193] In some preferred embodiments, the present invention also provides that in formula Ii, the compound represented by formula Ii is formula Ii-1.

[0194]

[0195] In another aspect, the present invention also provides compounds of formulas I-ii, their optical isomers, and their pharmaceutically acceptable salts.

[0196]

[0197] Among them, R 1 Selected from -C 1～8 Alkyl, -C 0～4 Alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3 to 12-membered heterocyclic groups; the R 1 The alkyl, heterocyclic, cycloalkyl, and amino groups in R can optionally be replaced by R x Replace 1 to 3 times; preferred R 1 Selected from -C 0～4 Alkylene-C 3～8 cycloalkyl;

[0198] R2 is selected from hydrogen, -C 1～6 alkyl;

[0199] R x Independently selected from halogen, cyano, hydroxyl, amino, C 1～3 Alkyl, C 1～3 Alkoxy;

[0200] Y 1 for or CR Y1-1 R Y1-2 ;

[0201] M 1-5 H, or optionally substituted C1-C6 alkyl;

[0202] M 1-1 M 1-2 M 1-3 and M 1-4 Each is independently H, A2, or halogen.

[0203] L is A1-L 1 -L 2 -L 3 -L 4 -A2;

[0204] L 1 Selected from -O-, -S-, -C(O)-, -NR 1a -、C 1-6 Alkylene, C 1-6 alkylene-3-10-membered heteroaryl, C 3-6 Cycloalkylene and 3-10-membered heterocyclic groups, wherein the alkylene, cycloalkylene, heterocyclic group and heteroaryl group are each optionally composed of one or more elements selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0205] L 2 It is a covalent bond, or selected from -C(O)- or C 1-6 Alkylene;

[0206] L 3 It is a covalent bond, or selected from -O-, -NR 3a -、C 1-6 Alkylene, -OC 1-6 Alkylene, C 1-6 Alkylene-O-, C 3-6 Cycloalkylene and 3-10-membered heterocyclic groups, wherein each of the alkylene, cycloalkylene, and heterocyclic group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl and C1-6 Substituents of haloalkyl groups;

[0207] L 4 It is a covalent bond, or selected from -O-, -S-, -NR. 4a -、C 1-6 Alkylene, -OC 1-6 Alkylene-, C 1-6 Alkylene-O-, C 3-6 Cycloalkylene, -C(O)-, -C(O)-N(R) 4a )-、-C(O)-C 1-6 Alkylene, and 3-10-membered heterocyclic groups, wherein each of the alkylene, cycloalkylene, and heterocyclic groups is optionally composed of one or more elements selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 The alkyl halide is substituted; the alkylene, cycloalkylene, and heteroalkylene groups are each optionally replaced by one or more groups selected from halogen, hydroxyl, cyano, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0208] R 1a R 3a and R 4a Each is independently selected from hydrogen and C. 1-6 Alkyl group. In some preferred embodiments, R1 is independently selected from... Further optimization

[0209] In some preferred embodiments, the L has the following structure:

[0210]

[0211] Preferably, the L-connector has the following structure

[0212] In another aspect, the present invention also provides compounds of formulas I-iii, their optical isomers, and their pharmaceutically acceptable salts.

[0213]

[0214] Among them, R 1 Selected from -C 1～8 Alkyl, -C 0～4 Alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3 to 12-membered heterocyclic groups; the R 1 The alkyl, heterocyclic, and cycloalkyl groups in the R group may optionally be replaced by R. xReplace 1 to 3 times; preferred R 1 Selected from -C 0～4 Alkylene-C 3～8 cycloalkyl;

[0215] R2 is selected from hydrogen, -C 1～6 alkyl;

[0216] R x Independently selected from halogen, cyano, hydroxyl, amino, C 1～3 Alkyl, C 1～3 Alkoxy;

[0217] M2-3 is H or an optional substituted C1-C6 alkyl group;

[0218] L is A1-L 1 -L 2 -L 3 -L 4 -A2;

[0219] L 1 Selected from -O-, -S-, -C(O)-, -NR 1a -、C 1-6 Alkylene, C 1-6 alkylene-3-10-membered heterocyclic group, C 3-6 Cycloalkylene and 3-10-membered heterocyclic groups, wherein the alkylene, cycloalkylene, heterocyclic group and heteroaryl group are each optionally composed of one or more elements selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0220] L 2 It is a covalent bond, or selected from -C(O)- or C 1-6 Alkylene;

[0221] L 3 It is a covalent bond, or selected from -O-, -NR 3a -、C 1-6 Alkylene, -OC 1-6 Alkylene, C 1-6 Alkylene-O-, C 3-6 Cycloalkylene and 3-10-membered heterocyclic groups, wherein each of the alkylene, cycloalkylene, and heterocyclic group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0222] L 4 It is a covalent bond, or selected from -O-, -S-, -NR. 4a -、C 1-6 Alkylene, -OC 1-6Alkylene-, C 1-6 Alkylene-O-, C 3-6 Cycloalkylene, -C(O)-, -C(O)-N(R) 4a )-、-C(O)-C 1-6 Alkylene, and 3-10-membered heterocyclic groups, wherein each of the alkylene, cycloalkylene, and heterocyclic groups is optionally composed of one or more elements selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 The alkyl halide is substituted; the alkylene, cycloalkylene, and heteroalkylene groups are each optionally replaced by one or more groups selected from halogen, hydroxyl, cyano, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0223] R 1a R 3a and R 4a Each is independently selected from hydrogen and C. 1-6 alkyl.

[0224] In some preferred embodiments, R1 is independently selected from Further optimization

[0225] In some preferred embodiments, the L has the following structure:

[0226] -CH2-、 Preferably, the L has the following structure: -CH2- or

[0227] In another aspect, the present invention also provides compounds of formulas I-iv, their optical isomers, and their pharmaceutically acceptable salts.

[0228]

[0229] in,

[0230] Among them, R 1 Selected from -C 1～8 Alkyl, -C 0～4 Alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3 to 12-membered heterocyclic groups; the R 1 The alkyl, heterocyclic, and cycloalkyl groups in the R group may optionally be replaced by R. x Replace 1 to 3 times; preferred R 1 Selected from -C 0～4 Alkylene-C 3～8 cycloalkyl;

[0231] R2 is selected from hydrogen, -C 1～6 alkyl;

[0232] R x Independently selected from halogen, cyano, hydroxyl, amino, C 1～3 Alkyl, C 1～3 Alkoxy and C 3～6 cycloalkyl; the R x The alkyl, alkoxy, and cycloalkyl groups in the alkyl group may optionally be substituted with halogens 1 to 3 times;

[0233] Ring M 3-A It is a C3-C10 cycloalkyl group, a 3-9 membered heterocyclic group, or a C6-C... 10 Aryl or 3-9 quinone heteroaryl;

[0234] M 3-1 It can be halogen, cyano, hydroxyl, amino, C1-C3 alkyl, or C1-C3 haloalkyl;

[0235] L is A1-L 1 -L 2 -L 3 -L 4 -A2;

[0236] L 1 Selected from -O-, -S-, -C(O)-, -NR 1a -、C 1-6 Alkylene, C 1-6 alkylene-3-10-membered heterocyclic group, C 3-6 Cycloalkylene and 3-10-membered heterocyclic groups, wherein the alkylene, cycloalkylene, heterocyclic group and heteroaryl group are each optionally composed of one or more elements selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0237] L 2 It is a covalent bond, or selected from -C(O)- or C 1-6 Alkylene;

[0238] L 3 It is a covalent bond, or selected from -O-, -NR 3a -、C 1-6 Alkylene, -OC 1-6 Alkylene, C 1-6 Alkylene-O-, C 3-6 Cycloalkylene and 3-10-membered heterocyclic groups, wherein each of the alkylene, cycloalkylene, and heterocyclic group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0239] L 4 It is a covalent bond, or selected from -O-, -S-, -NR. 4a -、C 1-6 Alkylene, -OC 1-6 Alkylene-, C 1-6 Alkylene-O-, C 3-6 Cycloalkylene, -C(O)-, -C(O)-N(R) 4a )-、-C(O)-C 1-6 Alkylene, and 3-10-membered heterocyclic groups, wherein each of the alkylene, cycloalkylene, and heterocyclic groups is optionally composed of one or more elements selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 The alkyl halide is substituted; the alkylene, cycloalkylene, and heteroalkylene groups are each optionally replaced by one or more groups selected from halogen, hydroxyl, cyano, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0240] R 1a R 3a and R 4a Each is independently selected from hydrogen and C. 1-6 alkyl.

[0241] In some implementations, ring M3-A is a benzene ring. Phenyl is preferred.

[0242] In some preferred embodiments, R1 is independently selected from The alkyl, heterocyclic, cycloalkyl, and amino groups in R1 may optionally be substituted with halogens; preferably, R1 is independently selected from... -CH2CH2CH3, more preferably R1 is independently selected -CH2CH2CH3, further optimized

[0243] In some preferred embodiments, the L has the following structure:

[0244] -CH2-、 Preferably, the connector L has the following structure:

[0245]

[0246] Further optimization Further optimization

[0247] In another aspect, the present invention also provides compounds of formula Iv, their optical isomers, and pharmaceutically acceptable salts thereof.

[0248]

[0249] Among them, R 1 Selected from -C 1～8 Alkyl, -C 0～4 Alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3 to 12-membered heterocyclic groups; the R 1 The alkyl, heterocyclic, and cycloalkyl groups in the R group may optionally be replaced by R. x Replace 1 to 3 times; preferred R 1 Selected from -C 0～4 Alkyl-3 to 12-membered heterocyclic groups;

[0250] R2 is selected from hydrogen, -C 1～6 alkyl;

[0251] R x Independently selected from halogen, cyano, hydroxyl, amino, C 1～3 Alkyl, C 1～3 Alkoxy and C 3～6 cycloalkyl; the R x The alkyl, alkoxy, and cycloalkyl groups in the alkyl group may optionally be substituted with halogens 1 to 3 times;

[0252] Y 1 for or CR Y1-1 R Y1-2 ;

[0253] M 1-5 H, or optionally substituted C1-C6 alkyl;

[0254] M 1-1 M 1-2 M 1-3 and M 1-4 Each is independently H, A2, or halogen.

[0255] L is A1-L 1 -L 2 -L 3 -L 4 -A2;

[0256] Wherein, A1 is the bond between the connector and ring system A; A2 is the bond between the degraded portion and the connector;

[0257] L 1 Selected from -O-, -S-, -C(O)-, -NR 1a -、C 1-6 Alkylene, C 1-6 alkylene-3-10-membered heterocyclic group, C 3-6 Cycloalkylene and 3-10-membered heterocyclic groups, wherein the alkylene, cycloalkylene, heterocyclic group and heteroaryl group are each optionally composed of one or more elements selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0258] L 2 It is a covalent bond, or selected from -C(O)- or C 1-6 Alkylene;

[0259] L 3 It is a covalent bond, or selected from -O-, -NR 3a -、C 1-6 Alkylene, -OC 1-6 Alkylene, C 1-6 Alkylene-O-, C 3-6 Cycloalkylene and 3-10-membered heterocyclic groups, wherein each of the alkylene, cycloalkylene, and heterocyclic group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0260] L 4 It is a covalent bond, or selected from -O-, -S-, -NR. 4a -、C 1-6 Alkylene, -OC 1-6 Alkylene-, C 1-6 Alkylene-O-, C 3-6 Cycloalkylene, -C(O)-, -C(O)-N(R) 4a )-、-C(O)-C 1-6 Alkylene, and 3-10-membered heterocyclic groups, wherein each of the alkylene, cycloalkylene, and heterocyclic groups is optionally composed of one or more elements selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 The alkyl halide is substituted; the alkylene, cycloalkylene, and heteroalkylene groups are each optionally replaced by one or more groups selected from halogen, hydroxyl, cyano, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0261] R 1a R 3a and R 4a Each is independently selected from hydrogen and C.1-6 alkyl.

[0262] In some preferred embodiments, R1 is independently selected from The alkyl, heterocyclic, cycloalkyl, and amino groups in R1 may optionally be replaced by R x Replacement 1 to 3 times; preferably R1 is independently selected -CH2CH2CH3, with higher priority for R1 to be selected independently -CH2CH2CH3, further optimized

[0263] In some preferred embodiments, the L has the following structure:

[0264] -CH2-、 Preferably, the L has the following structure: Further optimization

[0265] In some preferred embodiments, the L has the following structure:

[0266] Preferably, the L has the following structure: Further optimization

[0267] In another aspect, the present invention also provides compounds of formulas I-vi, their optical isomers, and their pharmaceutically acceptable salts.

[0268]

[0269] Among them, R 1 Selected from -C 1～8 Alkyl, -C 0～4 Alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3 to 12-membered heterocyclic groups; the R 1 The alkyl, heterocyclic, and cycloalkyl groups in the R group may optionally be replaced by R. x Replace 1 to 3 times; preferred R 1 Selected from -C 0～4 Alkylene-C 3～8 cycloalkyl;

[0270] R2 is selected from hydrogen, -C 1～6 alkyl;

[0271] R x Independently selected from halogen, cyano, hydroxyl, amino, C 1～3 Alkyl, C 1～3 Alkoxy and C 3～6 cycloalkyl; the R x The alkyl, alkoxy, and cycloalkyl groups in the alkyl group may optionally be substituted with halogens 1 to 3 times;

[0272] M2-3 is H or an optional substituted C1-C6 alkyl group;

[0273] L is A1-L 1 -L 2 -L 3 -L 4 -A2;

[0274] L 1 Selected from -O-, -S-, -C(O)-, -NR 1a -、C 1-6 Alkylene, C 1-6 alkylene-3-10-membered heterocyclic group, C 3-6 Cycloalkylene and 3-10-membered heterocyclic groups, wherein each of the alkylene, cycloalkylene, and heterocyclic group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0275] L 2 It is a covalent bond, or selected from -C(O)- or C 1-6 Alkylene;

[0276] L 3 It is a covalent bond, or selected from -O-, -NR 3a -、C 1-6 Alkylene, -OC 1-6 Alkylene, C 1-6 Alkylene-O-, C 3-6 Cycloalkylene and 3-10-membered heterocyclic groups, wherein each of the alkylene, cycloalkylene, and heterocyclic group is optionally selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0277] L 4 It is a covalent bond, or selected from -O-, -S-, -NR. 4a -、C 1-6 Alkylene, -OC 1-6 Alkylene-, C 1-6 Alkylene-O-, C 3-6 Cycloalkylene, -C(O)-, -C(O)-N(R) 4a)-、-C(O)-C 1-6 Alkylene, and 3-10-membered heterocyclic groups, wherein each of the alkylene, cycloalkylene, and heterocyclic groups is optionally composed of one or more elements selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 The alkyl halide is substituted; the alkylene, cycloalkylene, and heteroalkylene groups are each optionally replaced by one or more groups selected from halogen, hydroxyl, cyano, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0278] R 1a R 3a and R 4a Each is independently selected from hydrogen and C. 1-6 alkyl.

[0279] In some preferred embodiments, R1 is independently selected from The alkyl, heterocyclic, cycloalkyl, and amino groups in R1 may optionally be replaced by R x Replacement 1 to 3 times; preferably R1 is independently selected -CH2CH2CH、 Further optimization

[0280] In some preferred embodiments, the L has the following structure:

[0281] -CH2-、 Preferred -CH2- Further optimization of -CH2-.

[0282] In another aspect, the present invention also provides compounds of the following formula, their optical isomers, and pharmaceutically acceptable salts thereof, selected from...

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295] In another aspect of the invention, this disclosure provides pharmaceutical compositions comprising a preventive and / or therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

[0296] In another aspect of the invention, this disclosure provides a kit comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically labeled compound, a metabolite or a prodrug, or a pharmaceutical composition comprising the invention.

[0297] In another aspect of the invention, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or pharmaceutical compositions of the disclosure that target the SMARCA2 protein and are used to inhibit or degrade the SMARCA2 protein.

[0298] In another aspect of the invention, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or pharmaceutical compositions of the disclosure for the prevention and / or treatment of SMARCA2-mediated diseases.

[0299] In some embodiments, the disease is a tumor (e.g., cancer), including solid tumors and hematologic malignancies. In some embodiments, the tumor or cancer is selected from non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal-gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, hematologic malignancies, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumors, uterine sarcoma, gastrointestinal stromal tumors, central nervous system cancers, thymic tumors, adrenocortical carcinoma, appendix cancer, small bowel cancer, or penile cancer.

[0300] In another aspect of the invention, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or pharmaceutical compositions of this disclosure in the preparation of medicaments for the prevention and / or treatment of SMARCA2-mediated related diseases.

[0301] In another aspect of the invention, this disclosure provides a method for preventing and / or treating SMARCA2-mediated related diseases, comprising administering to an individual in need of such prevention and / or treatment an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, or a pharmaceutical composition of the present disclosure. Detailed Implementation

[0302] The present application is described in detail below with reference to embodiments, but this does not imply any adverse limitations on the present application. The present application has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific implementations of the present application without departing from the spirit and scope thereof.

[0303] The following abbreviations are used in this disclosure:

[0304]

[0305]

[0306] Definitions and Explanations

[0307] Terminology Definition

[0308] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0309] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps (i.e., these terms also cover the terms “consistently made up of” and “comprises of”).

[0310] As used in this article, the term "alkane" refers to a straight-chain or branched saturated aliphatic hydrocarbon.

[0311] As used herein, the term "alkyl" refers to a straight-chain or branched monovalent saturated aliphatic hydrocarbon, which can be considered as a group obtained by losing one hydrogen atom from an alkane. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, as used herein, the term "C 1-8 "Alkyl" refers to a straight-chain or branched group with 1 to 8 carbon atoms, including "C". 1-6 Alkyl", C 2-6 Alkyl", C 2-5 Alkyl", C 1-4 "alkyl" and "C" 1-2 Alkyl group. "C" 1-6 Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. The alkyl group is optionally substituted with one or more (such as one to three) suitable substituents such as halogens (in which case the group is called "haloalkyl", for example CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C" 1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0312] As used herein, the term "alkylene" refers to a straight-chain or branched divalent saturated aliphatic hydrocarbon. In some embodiments, the alkylene has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0313] As used herein, the terms “cycloalkyl,” “cycloalkyl,” and “cycloalkylene” refer to a monocyclic or polycyclic fused hydrocarbon having, for example, 3 to 10 (suitably 3 to 8, more preferably 3 to 7, 3 to 6, 4 to 6, or 5 to 6) cyclic carbon atoms, either saturated (i.e., “cycloalkyl” and “cycloalkylene”) or partially unsaturated (i.e., having one or more double bonds (i.e., “cycloalkenyl” and “cycloalkenylene”) and / or triple bonds within the ring). Cyclic rings, including but not limited to (cyclo-propyl), (cyclo-butyl), (cyclo-pentyl), (cyclo-hexyl), (cyclo-heptyl), (cyclo-octyl), (cyclo-nonyl), (cyclo-butenyl), (cyclo-pentenyl), (cyclo-hexenyl), (cyclo-heptenyl), (cyclo-octenyl), and (cyclo-nonenyl).

[0314] As used in this article, the term "fusion" means that two or more ring structures share two adjacent atoms with each other.

[0315] As used herein, the terms “cycloalkyl” and “cycloalkylene” refer to saturated monocyclic or polycyclic (such as bicyclic) fused hydrocarbon rings (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl), or bicyclic, such as… The cycloalkyl and cycloalkylene groups have 3 to 10 carbon atoms, suitably 3 to 8, such as 3 to 7, 3 to 6, 4 to 6, or 5 to 6. The cycloalkyl and cycloalkylene groups are optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g., methyl or halogen), such as methyl-substituted cyclopropyl.

[0316] As used herein, the terms "cycloalkenyl" and "cycloalkyleneide" refer to a monocyclic or polycyclic (such as bicyclic) fused hydrocarbon ring having one or more double bonds within the ring (e.g., monocyclic, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or bicyclic). The cycloalkenyl and "cycloalkyleneide" have 3 to 10 carbon atoms, suitably 3 to 8, for example 3 to 7, 3 to 6, 4 to 6, or 5 to 6. The cycloalkenyl and cycloalkyleneide are optionally substituted with one or more suitable substituents (e.g., 1 to 3), such as methyl-substituted cyclopentenyl.

[0317] As used herein, the terms “heterocyclic,” “heterocyclic,” and “hemiecyclic” refer to a saturated (i.e., “hemiecyclic alkyl” and “hemiecyclic alkyl”) or partially unsaturated (e.g., having one or more double bonds within the ring, i.e., “hemiecyclic alkenyl” and “hemiecyclic alkenyl”) monovalent monocyclic or bicyclic fused cyclic structure having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatom-containing groups selected from O, S, S(=O), S(=O)2, and NR’, wherein R’ is a hydrogen atom or C 1-6 Alkyl or halogenated -C 1-6 Alkyl group. The heterocyclic group may be attached to the remainder of the molecule by any one of the carbon atoms or a nitrogen atom (if present). In particular, a 3-10 membered heterocyclic group is a group having 3-10 (e.g., 3-8, 3-7, 3-6, 4-6, or 5-6) carbon atoms and heteroatoms in the ring. The heterocyclic group is optionally substituented by one or more (e.g., 1 to 3) suitable substituents (e.g., halogen, OH, NH2, oxo (=O), C). 1-6 Alkyl, C 1-6(Halogenated alkyl) substitution. Examples that can be listed include, but are not limited to, ethylene oxide, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolinyl, pyrrolyl, pyrrolidone, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrazolyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, hexahydropyrimidinyl, triazine, morpholinyl, dithianyl, thiomorpholinyl, piperazine, trithianyl, azetidinyl, dihydropyrrolyl, dihydroimidazolyl, and azetidinyl.

[0318] As used herein, the term "aryl" refers to a fully carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, the term "C 6-14 "Aryl" refers to an aromatic group containing 6 to 14 (e.g., 6 to 12) carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituented with one or more (e.g., 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C). 1-6 Alkyl groups, etc., are substituted.

[0319] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 5 to 14 ring atoms, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and 1, 2, 3, 4, or 5 identical or different heteroatoms independently selected from N, O, S, and S(O)₂. One or more ring carbon atoms in the heteroaryl group may be replaced by C(O). Heteroaryl groups may be benzofused. Examples of heteroaryl groups include, but are not limited to: pyridinyl, pyridoneyl, pyrimidinyl, pyrimidinoneyl, pyrazinyl, pyridazinyl, thiazolyl, thiopheneyl, oxazolyl, furanyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazoleyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzoisothiazolyl, imidazole-pyridinyl, quinolinyl, indolyl, pyrrolopyridazinyl, benzo[] Furanyl, benzothiopheneyl, indazoleyl, benzoxazolyl, benzoisoxazolyl, quinazolinyl, pyrrolopyridyl, pyrazolopyrimidinyl, imidazopyridazinyl, pyrazolopyridyl, triazolopyridyl, isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, cenolinyl, indoleyl, phthalazinyl, isoindolyl, pteridinyl, purinyl, furazanyl, benzofurazanyl, quinoxalinyl, naphridinyl, or furanolopyridinyl. The heteroaryl group may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0320] As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br, or I.

[0321] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0322] If a group is described as “optionally substituted with” or “optionally substituted,” then the group may be: (1) unsubstituted or (2) substituted. If the carbon of a group is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on that carbon (to the extent that any hydrogens are present) may be substituted individually and / or together with independently selected optional substituents. If the nitrogen of a group is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on that nitrogen (to the extent that any hydrogens are present) may each be substituted with independently selected optional substituents. If a substituent is described as “independently selected from” a group, then each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0323] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0324] When a substituent is shown to be a bond that passes through the ring and connects two atoms (“floating bond”), such a substituent may be bonded to any cyclic atom in the substituted ring, unless otherwise stated. In cases where a substituted hydrogen atom is shown to be carried by a substituted ring member, the substituted hydrogen atom is substantially substituted (i.e., not present) when the floating bond is bonded to that substituted ring member.

[0325] The compounds and pharmaceutically acceptable salts disclosed herein may exist in chiral forms, i.e., S-configuration or R-configuration. The compounds and pharmaceutically acceptable salts disclosed herein may also exist in achiral forms. When the structure of a compound is exemplified by one of its configurations, it also indicates that the structure of another configuration or achiral form is disclosed.

[0326] The compounds described in this disclosure include stereoisomers of the compounds. Stereoisomers described in this disclosure refer to enantiomers produced when a compound of Formula I or II contains an asymmetric carbon atom; cis-trans isomers produced when a compound contains a carbon-carbon double bond or a cyclic structure; and tautomers produced when a compound contains a ketone or oxime. In some embodiments, the stereoisomers described in this disclosure include, but are not limited to: enantiomers, diastereomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof.

[0327] The compounds disclosed herein may exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure.

[0328] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium (D, ...). 2 H), tritium (T), 3 H); carbon isotopes (e.g., H); 11 C 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes ... 32 P); and isotopes of sulfur (e.g. 35 S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6. In some embodiments, the isotopically labeled compounds of the present invention are deuterated.

[0329] The term "stereoisomer" refers to isomers formed due to at least one asymmetric center, having the same chemical composition but different spatial arrangements of atoms or groups. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can occur. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It should be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0330] A diastereomer is a stereoisomer that has 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 properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography.

[0331] "Enantiomers" refer to two stereoisomers of a compound that are non-overlapping mirror images of each other.

[0332] The term "chirality" refers to molecules that have mirror pairs that are not overlapping, while the term "chirality" refers to molecules that can overlap on their mirror pairs.

[0333] The compounds of the present invention can be prepared in racemic form, or a single enantiomer can be prepared by enantioselective synthesis or by resolution.

[0334] As used herein, the terms “cis-trans isomers” or “geometric isomers” arise from the fact that the single bonds of double bonds or cyclic carbon atoms cannot rotate freely. The compounds presented herein include all cis, trans, syn, anti, engegen (E), and zusammen (Z) isomers and their corresponding mixtures. The - / - designation may be used herein to indicate cis, trans isomers, and their corresponding mixtures.

[0335] Solid lines (-) and solid wedges can be used in this article. Or virtual wedge The chemical bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) are included at that carbon atom. Solid or imaginary wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and imaginary wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0336] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to cover the various derivative forms of the compounds described above.

[0337] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0338] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0339] When the number of a substituent is 0, it means that the substituent does not exist. For example, -A-(R)0 means that the structure is actually -A.

[0340] When a substituent is vacant, it means that the substituent does not exist. For example, if X is vacant in AX, it means that the structure is actually A.

[0341] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0342] When a substituent can be cross-bonded to two or more atoms on a ring, this substituent can bond to any atom on that ring, for example, a structural unit. This indicates that the substituent R can be substituted at any position on either pyridazine or 1H-pyrrole. When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, a pyridinyl group as a substituent can be attached to the substituted group through any carbon atom on the pyridine ring.

[0343] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linker group L is -MW-. In this case, -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form a ring. Alternatively, rings A and B can be connected in the opposite direction to the left-to-right reading order to form a ring. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0344] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with the corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds ( / ) or straight dashed line bonds. or wavy line Indicated. As used in this article, waveform lines This represents the connection point between a substituent and another group.

[0345] The term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components constituting the formulation and / or the mammals treated with it.

[0346] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.

[0347] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate / carbonate, bisulfate / sulfate, fumarate, glucohepanoate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodate / iodide, maleate, malonate, methyl sulfate, naphthylcarbamate, nicotinate, nitrate, orotate, oxalate, palmitate, and other similar salts.

[0348] Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, diethylamine salts, lysine salts, magnesium salts, meglumine salts, potassium salts, and other similar salts.

[0349] For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts for the compounds of the present invention are known to those skilled in the art.

[0350] As used herein, the term "ester" means an ester derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (the compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves also be esters.

[0351] This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0352] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0353] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0354] This invention further includes, within its scope, prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity, which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that readily convert in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987 (edited by EBR, American Pharmaceutical Association). The prodrugs of the invention can be prepared, for example, by replacing suitable functional groups present in the compounds of the invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0355] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in *Protective Groups in Organic Chemistry*, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P. ​​G.W. Uts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art. The term "protecting group" includes, but is not limited to, "amino protecting group," "hydroxyl protecting group," or "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (B℃); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenemethoxycarbonyl (Fm℃); arylmethyl, such as benzyl (Bn), triphenylmethyl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanolyl groups (e.g., acetyl); arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (diphenylmethyl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc.

[0356] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the examples listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples below.

[0357] The compounds described in this disclosure are named according to their chemical structural formulas. If the name of a compound representing the same compound differs from its chemical structural formula, the chemical structural formula shall prevail.

[0358] Compound purification and preparation method 1:

[0359]

[0360] Preparation of intermediates

[0361] 1. Preparation of intermediate 1

[0362]

[0363] Step 1

[0364] 3-Amino-4-bromo-6-chloropyridazine (10.0 g, 48.3 mmol) and tributyl(1-ethoxyethylene)tin (22.67 g, 62.79 mmol) were dissolved in Dioxane (100 mL) at room temperature. Pd(PPh3)4 (5.58 g, 4.83 mmol) was added, and the reaction mixture was stirred at 85 °C for 12 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was filtered and concentrated under vacuum to obtain a crude product. Purification was performed by silica gel chromatography (petroleum ether: ethyl acetate = 50%) to give intermediate 1a (3 g, yield: 31.1%). LC-MS (ESI) m / z: [M+H] + =200.1.

[0365] Step 2

[0366] Intermediate 1a (3 g, 15 mmol) was dissolved in Dioxane / H₂O (v / v: 10 / 1) (30 mL) at room temperature. 2-hydroxyphenylboronic acid (4.14 g, 30 mmol), X-phos Pd G₃ (1.26 g, 1.5 mmol), and cesium carbonate (9.78 g, 30 mmol) were added. The reaction mixture was stirred at 95 °C under nitrogen protection for 12 hours. LC-MS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-30%) yielded intermediate 1b (1.2 g, yield: 30.7%). LC-MS (ESI) m / z: [M+H] + =258.1.

[0367] Step 3

[0368] Intermediate 1b (1.2 g, 4.6 mmol) was dissolved in ethanol (20 mL) at room temperature, and a reaction solution of 4 M HCl / Dioxane (1 mL) was added. The mixture was stirred at room temperature for 4 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction solution was concentrated under vacuum, then dissolved in ethyl acetate (20 mL), saturated NaHCO3 (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Intermediate 1c (320 mg, yield: 8.7%) was purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-50%). LCMS (ESI) m / z: [M+H] + =229.9.

[0369] Step 4

[0370] Intermediate 1c (158 mg, 0.62 mmol) was dissolved in MeOH (5 mL) at room temperature. Compound 1d (401.76 mg, 1.86 mmol) and HOAc (37.2 mg, 0.62 mmol) were added, and the reaction mixture was heated under reflux and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain a crude product, which was purified by silica gel chromatography (petroleum ether: ethyl acetate = 30%-50%) to obtain 150 mg of crude product. The product was then prepared by HPLC (compound HPLC purification preparation method 1). Freeze-drying yielded intermediate 1e (62 mg, yield: 22.7%). LCMS (ESI) m / z: [M+H] + =428.1.

[0371] Step 5

[0372] Intermediate 1e (62 mg, 0.144 mmol) was dissolved in DCM (2 mL), and 4 M HCl / Dioxane (0.1 mL) was added. The mixture was stirred at room temperature for 3 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction solution was concentrated under vacuum, and the solid was slurried with diethyl ether (2 mL), filtered, and freeze-dried to obtain intermediate 1 (30.02 mg). LCMS (ESI) m / z: [M+H] + =327.98. 1 H NMR(400MHz,CD3OD)δ8.67(s,1H),7.70(dd,J=8.0,1.7Hz,1H),7.43–7.36(m,1H),7.03-7.00(m,2H),4.80– 4.76(m,1H),3.39-3.30(m,2H),3.28-3.22(m,2H),2.49-2.43(m,3H),2.33-2.22(m,2H),2.12-2.05(m,2H).

[0373] 2. Preparation of intermediate 2

[0374]

[0375] Step 1

[0376] N-hydroxyphthalimide (150 mg, 0.92 mmol), triphenylphosphine (310 mg, 1.2 mmol), and N-Boc-4-piperidinemethanol (200 mg, 0.92 mmol) were dissolved in anhydrous THF (10 mL) at room temperature. After three nitrogen purgings, DIAD (242 mg, 1.2 mmol) was slowly added under ice bath conditions. The temperature was slowly raised from the ice bath to room temperature, and the reaction was carried out overnight. LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was then quenched, extracted three times with dichloroisocyanuric acid, and the organic phase was collected, dried, concentrated, and purified by column chromatography at EA:PE = 50% to give intermediate 2a (125 mg, 40% yield). LC-MS (ESI) m / z: [M+H] + =360.2.

[0377] Step 2

[0378] Intermediate 2a (125 mg, 0.36 mmol) was dissolved in ethanol (5 mL) at room temperature, and 0.5 mL (1 M) of hydrazine hydrate was added. After reacting at room temperature for 30 min, a solid was formed. The solid was filtered, and the filtrate was evaporated to dryness. Methyl tert-butyl ether was added and the mixture was stirred. The filtrate was then collected and evaporated to dryness for later use. No purification was required in this step to obtain intermediate 2b (78 mg, 0.36 mmol). LCMS (ESI) m / z: [M+H] + =230.3.

[0379] Step 3

[0380] Intermediate 2b (78 mg, 0.36 mmol), intermediate 1e (74 mg, 0.35 mmol), and acetic acid (10 mg, 0.1 mmol) were dissolved in methanol (5 mL) at room temperature. The mixture was heated under reflux at 60°C for 16 h. LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was then quenched, extracted three times with dichloroisocyanuric acid, and the organic phase was collected, dried, concentrated, and purified by column chromatography (methanol:dichloroisocyanuric acid = 10%) to give intermediate 2c (64 mg, 45% yield). LC-MS (ESI) m / z: [M+H] + =441.2.

[0381] Step 4

[0382] Intermediate 2c (64 mg, 0.14 mmol) was added to a reaction flask, followed by 1 mL (4 M) of dioxane hydrochloride solution. The mixture was stirred at room temperature for 1 h. LC-MS analysis confirmed the reaction was complete. The reaction solution was then evaporated to dryness and purified with saturated sodium bicarbonate to obtain crude intermediate 2 (E or Z). LC-MS (ESI) m / z: [M+H] + =341.2.

[0383] 3. Preparation of intermediate 3

[0384]

[0385] Step 1

[0386] Intermediate 3a (500 mg, 3.3 mmol) was dissolved in 10 mL of DCM at room temperature. Anhydrous aluminum trichloride (1.08 g, 8.14 mmol) was added, and the reaction mixture was stirred at 25 °C for 0.5 h. Isovaleryl chloride (1.96 g, 8.14 mmol) was added to the reaction mixture, and the mixture was stirred at 25 °C for 3 days. The product was detected by LCMS. The reaction mixture was cooled to 0 °C, and the reaction was quenched by adding 30 mL of MeOH dropwise. The pH of the system was adjusted to weakly alkaline by adding 7 MNH3 / MeOH, and then evaporated to dryness. 20 mL of tetrahydrofuran was added to dissolve the product. Di-tert-butyl dicarbonate (852.7 mg, 3.91 mmol) and triethylamine (988.4 mg, 9.77 mmol) were added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 h. LCMS showed that most of the reactants were converted and the product was detected. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (100 mL × 3), washed with saturated brine (100 mL × 3), and dried over anhydrous sodium sulfate. The filtrate was dried under vacuum and concentrated to obtain the crude product. Purification was performed by silica gel chromatography (petroleum ether:ethyl acetate = 10:1) to give intermediate 3b (300 mg, yield: 27%). LCMS (ESI) m / z: [M+H]+ = 338.2.

[0387] Step 2

[0388] Intermediate 3b (300 mg, 0.89 mmol) was dissolved in Dioxane / H₂O (5 / 1) (10 mL) at room temperature. 2-hydroxyphenylboronic acid (147.6 mg, 1.07 mmol), X-phos Pd G₃ (76.2 mg, 0.09 mmol), and cesium carbonate (724.9 mg, 2.22 mmol) were added. The reaction mixture was stirred at 95 °C under nitrogen protection for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was obtained by vacuum concentration. Intermediate 3c (40 mg, yield: 15.7%) was obtained by HPLC (compound purification method 1). LCMS (ESI) m / z: [M+H]⁺ = 296.1.

[0389] Step 3

[0390] Intermediate 3c (40 mg, 0.14 mmol) was dissolved in MeOH (2 mL) at room temperature. Intermediate 3d (35.3 mg, 0.16 mmol) and HOAc (8.13 mg, 0.13 mmol) were added, and the reaction mixture was heated under reflux and stirred for 12 hours. The product was detected by LCMS. The reaction mixture was concentrated under vacuum to obtain a crude product, which was purified by prep-TLC (petroleum ether: ethyl acetate = 1:1) to obtain intermediate 3e (50 mg, yield: 64.3%). LCMS (ESI) m / z S: [M+H]+ = 494.1.

[0391] Step 4

[0392] Intermediate 3e (50 mg, 0.09 mmol) was dissolved in DCM (2 mL), and 4 M dioxane hydrochloride (2 mL) was added. The mixture was stirred at room temperature for 3 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction solution was concentrated under vacuum to obtain the crude product. Intermediate 3 (38.72 mg, yield: 98%) was obtained by HPLC (compound purification preparation method 1). LCMS(ESI)m / z:[M+H]+=394.3.1H NMR (400MHz, CD3OD) δ9.00(s,1H),8.47(s,1H),7.76(dd,J=8.1,1.5Hz,1H),7.44–7.34(m,1H),7.06–7.03(m,2H),4.66–4.54( m,1H),3.40–3.32(m,2H),3.28–3.24(m,2H),2.81(d,J=7.5Hz,2H),2.31–2.22(m,2H),2.20–2.12(m,3H),1.05(d,J=6.7Hz,6H)

[0393] Preparation of intermediate V-1

[0394]

[0395] Step 1

[0396] [(S)-1-(4-bromophenyl)ethyl] tert-butyl carbamate (5 g, 16.66 mmol) was dissolved in DMF (50 mL) at room temperature. 4-methylthiazole (3.30 g, 33.32 mmol), potassium carbonate (3.27 g, 33.32 mmol), and palladium acetate (0.094 g, 0.42 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen atmosphere. LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was filtered and concentrated under vacuum to obtain the crude product. Purification was performed by silica gel chromatography (petroleum ether: ethyl acetate = 0-24%) to give compound V-1a (5.1 g, yield: 96.16%).

[0397] LCMS(ESI)m / z:[M+H] + =319.1.

[0398] Step 2

[0399] Compound V-1a (6.9 g, 15.99 mmol) was dissolved in dichloromethane (30 mL) at room temperature, and trifluoroacetic acid (30 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give crude compound V-1b (5.88 g).

[0400] LCMS(ESI)m / z:[M+H] + =219.0.

[0401] Step 3

[0402] Compound V-1b (3.5 g, 16.03 mmol) was dissolved in dichloromethane (100 mL) at room temperature. Boc-L-hydroxyproline (4.45 g, 19.24 mmol), HATU (9.14 g, 24.05 mmol), and triethylamine (8.11 g, 80.15 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification by silica gel chromatography (methanol:dichloromethane = 0-5%) yielded compound V-1c (6.9 g, yield: 99.73%).

[0403] LCMS(ESI)m / z:[M+H] + =432.2.

[0404] Step 4

[0405] Compound V-1c (6.9 g, 15.99 mmol) was dissolved in dichloromethane (30 mL) at room temperature, and dioxane hydrochloride (20 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 30 minutes. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was dissolved in dichloromethane (100 mL), and the organic phase was separated by saturated sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give crude compound V-1 (5.88 g).

[0406] LCMS(ESI)m / z:[M+H] + =332.2.

[0407] 4. Preparation of intermediate Linker-1

[0408]

[0409] Step 1

[0410] Benzyloxyacetaldehyde (10.0 g, 67 mmol) was dissolved in 200 mL of EtOH / H₂O = 1 / 3 at room temperature. Hydroxylamine hydrochloride (5.08 g, 73.3 mmol) was added, and sodium hydroxide (6.67 g, 167 mmol) was added to the reaction solution at 0 °C. The mixture was stirred at 0 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was cooled to 0 °C, and the pH was adjusted to 2 with 1 N hydrochloric acid. Extraction was performed with ethyl acetate (150 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether:ethyl acetate = 0-50%) to give Linker-1a (9.8 g, yield: 89%).

[0411] LCMS(ESI)m / z:[M+H] + =166.1.

[0412] Step 2

[0413] Linker-1a (9.8 mg, 59.3 mmol) was dissolved in DMF (80 mL) at room temperature. NCS (11.88 g, 89.00 mmol) was added at room temperature, and the reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed the starting material disappeared. The reaction mixture was poured into water (500 mL), and then extracted with ethyl acetate (300 mL x 3). The organic layer was washed with saturated sodium chloride solution (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0-30%) to obtain Linker-1b (11.6 g, yield: 80.1%).

[0414] Step 3

[0415] Linker-1b (11.6 g, 58.1 mmol) was dissolved in ethyl acetate (150 mL) at room temperature. 3-Butyn-1-ol (6.11 g, 87.1 mmol) was added, followed by slow addition of potassium carbonate (20.1 g, 145 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (200 mL). The combined organic phases were concentrated under vacuum to obtain a crude product, which was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0-30%) to give Linker-1c (5.2 g, yield: 38.3%).

[0416] LCMS(ESI)m / z:[M+H] + =234.2.

[0417] Step 4

[0418] Compound Linker-1c (5.2 g, 22.3 mmol) was dissolved in acetone / water = 10 / 1 (66 mL), and chromium trioxide (4.46 g, 44.6 mmol) was added. Concentrated sulfuric acid was slowly added at 0 °C, and the mixture was stirred at room temperature for 4 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was poured into water (100 mL), and then extracted with ethyl acetate (100 mL * 3). The organic layer was washed with saturated sodium chloride solution (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give crude compound Linker-1d (5.1 g).

[0419] LCMS(ESI)m / z:[M+H] + =248.3.

[0420] Step 5

[0421] The compound Linker-1d (5.1 g, 20.6 mmol) was dissolved in EtOH (40 mL), and concentrated sulfuric acid (2.6 mL) was added. The reaction mixture was heated to 70 °C and stirred for 12 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum and poured into water (100 mL). It was then extracted with ethyl acetate (100 mL x 3). The organic layer was washed with saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-30%) to obtain the compound Linker-1f (3.9 g, yield: 68.7%).

[0422] LCMS(ESI)m / z:[M+H]+ =276.3.

[0423] Step 6

[0424] Linker-1f (3.9 g, 14.2 mmol) was dissolved in THF (40 mL), and 1 M potassium tert-butoxide (21.3 mL) was added at 0 °C, followed by 2-iodopropane. The reaction mixture was heated to 25 °C and stirred for 6 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum and poured into water (50 mL), then extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-20%) to obtain Linker-1f (3.1 g, yield: 68.9%).

[0425] LCMS(ESI)m / z:[M+H] + =318.2.

[0426] Step 7

[0427] Linker-1 g (3.1 g, 9.8 mmol) was dissolved in dichloromethane (30 mL), and 1 M boron tribromide (15.6 mL) was added under nitrogen protection at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was heated to 0 °C, quenched with water (30 mL), and then extracted with dichloromethane (30 mL x 3). The organic layer was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-30%) to obtain Linker-1 h (1.8 g, yield: 81.1%).

[0428] LCMS(ESI)m / z:[M+H] + =228.4.

[0429] Step 8

[0430] The compound Linker-1h (1.8 g, 7.4 mmol) was dissolved in dichloromethane (20 mL). DMAP (90.0 mg, 0.74 mmol) and TEA (2.26 g, 22.4 mmol) were added at 0 °C, followed by p-toluenesulfonyl chloride (1.7 g, 8.9 mmol). The reaction mixture was heated to 25 °C and stirred for 12 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum and poured into water (20 mL). Extraction was then performed with dichloromethane (20 mL x 3). The organic layer was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-15%) to obtain the compound Linker-1 (1.7 g, yield: 57.5%).

[0431] LCMS(ESI)m / z:[M+H] + =382.4.

[0432] Example

[0433] Example 1: Preparation of compound C001

[0434]

[0435] Step 1.

[0436] Compound V-1 (832 mg, 2.51 mmol), DIPEA (973.2 mg, 7.53 mmol), and HATU (1427.8 mg, 3.77 mmol) were added to a solution of compound 1a (500 mg, 2.51 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was washed with saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 94:6) to give compound 1b (670 mg, yield: 52.2%).

[0437] LCMS(ESI)m / z:[M+H] + =513.2.

[0438] Step 2

[0439] Compound 1b (670 mg, 1.31 mmol) was added to an aqueous solution of 33% hydrobromic acid (5 mL), and the reaction was carried out at 60 °C under nitrogen protection for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was concentrated under vacuum to give the crude product. Purification was carried out by reverse-phase chromatography (acetonitrile:trifluoroacetic acid 0.1% = 28-33%) to give compound 1c (500 mg, yield: 68.7%).

[0440] LCMS:[M+H] + =499.2.

[0441] Step 3

[0442] To compound 1c (500 mg, 1.00 mmol) and potassium carbonate (415.8 mg, 3.00 mmol) in acetonitrile (10 mL), tert-butyl bromoacetate (293.4 mg, 1.50 mmol) was added, and the reaction mixture was stirred at 60 °C under a nitrogen atmosphere for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (20 mL), and then extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. Purification by silica gel chromatography (dichloromethane:methanol = 94:6) yielded compound 1d (260 mg, yield: 42%).

[0443] LCMS(ESI)m / z:[M+H] + =613.3.

[0444] Step 4

[0445] A solution of dioxane in hydrochloric acid (2 mL, 4 M) was added to a 260 mg (0.42 mmol) solution of compound 1d in dichloromethane (2 mL), and the mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was concentrated under vacuum to give crude compound 1e (180 mg).

[0446] LCMS(ESI)m / z:[M+H] + =557.3.

[0447] Step 5

[0448] Intermediate 1 (80 mg, 0.24 mmol), DIPEA (126.4 mg, 0.98 mmol), and HBTU (139 mg, 0.37 mmol) were added to a solution of compound 1e (180 mg, 0.32 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (100 mL * 3). The organic layer was washed with saturated sodium chloride solution (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by prep-HPLC (compound HPLC purification preparation method 1) to obtain compound C001 (9.42 mg, yield: 4.2%).

[0449] LCMS(ESI)m / z:[M+H] + =866.4.

[0450] 1 H NMR(400MHz,MeOD)δ8.88(d,J=8.2Hz,1H),8.60(d,J=4.0Hz,1H),7.77–7.65(m,1H),7.4 5–7.33(m,6H),7.01(t,J=7.0Hz,2H),6.17–6.02(m,1H),5.05–4.97(m,2H),4.76–4.66( m,2H),4.60–4.49(m,1H),4.00–3.40(m,8H),2.52–2.45(m,3H),2.43(d,J=6.9Hz,3H),2 .24–1.73(m,7H),1.50(dd,J=15.3,7.1Hz,3H),1.06(d,J=6.6Hz,3H),0.94–0.86(m,3H).

[0451] Example 2: Preparation of compound C002

[0452]

[0453] Step 1

[0454] Compound 2b (1050 mg, 2.36 mmol), DIPEA (913.4 mg, 7.07 mmol), and HATU (1072 mg, 2.83 mmol) were added to a solution of compound 2a (704 mg, 2.83 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was washed with saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 98:2) to give compound 2c (1.08 g, yield: 60.8%).

[0455] LCMS(ESI)m / z:[M+H] + =627.3.

[0456] Step 2

[0457] Compound 2c (1.08 g, 1.72 mmol) and triethylamine (523 mg, 5.17 mmol) were added dropwise to dichloromethane (10 mL) under nitrogen protection at 0 °C, followed by slow recovery to room temperature for 2 h. LC-MS showed complete conversion of the reactants and detection of the product. The reaction was quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane (50 mL x 3). The organic layer was washed with saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (dichloromethane:methanol = 98:2) yielded compound 2d (800 mg, yield: 59.3%).

[0458] LCMS(ESI)m / z:[M+H] + =705.3.

[0459] Step 3

[0460] Compound 2e (550 mg, 0.78 mmol) was added to acetonitrile (10 mL) containing compound 2d (203.4 mg, 0.94 mmol) and N,N-diisopropylethylamine (302.5 mg, 2.34 mmol). The reaction mixture was stirred at 70 °C under a nitrogen atmosphere for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (20 mL), and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. Purification was achieved by silica gel chromatography (dichloromethane:methanol = 94:6) to give compound 2f (560 mg, yield: 72.3%).

[0461] LCMS(ESI)m / z:[M+H] + =825.7.

[0462] Step 4

[0463] A solution of dioxane in hydrochloric acid (2 mL, 4 M) was added to a 2 mL solution of compound 2f (560 mg, 0.68 mmol) in dichloromethane, and the mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was concentrated under vacuum and slurried with diethyl ether to give 2 g (450 mg) of compound.

[0464] LCMS(ESI)m / z:[M+H] + =611.3.

[0465] Step 5

[0466] Intermediate 3d (169 mg, 0.57 mmol) and acetic acid (34.4 mg, 0.57 mmol) were added to a methanol (5 mL) solution of 2 g (350 mg, 0.57 mmol). The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 16 hours. LC-MS showed conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain the crude product. Compound C002 was purified by silica gel chromatography (dichloromethane:methanol = 90:10) and Prep-HPLC (compound HPLC purification preparation method 1) to obtain compound C002.

[0467] (60.45 mg, yield: 11.7%).

[0468] LCMS(ESI)m / z:[M+H] + =888.3.

[0469] 1H NMR (400MHz, MeOD) δ9.00–8.93(m,1H),8.89–8.80(m,1H),8.60–8.54(m,0.3H),8.44(d,J=5.0Hz,0.3H),8.16–8.07(m,1H),7. 89(t,J=7.2Hz,0.3H),7.85–7.74(m,1H),7.44(d,J=3.7Hz,2H),7.31–7.26(m,2H),7.02–6.98(m,2H),6.49–6.38(m,1H),5.11– 4.93(m,1H),4.61–4.53(m,1H),4.44(s,1H),3.93–3.81(m,2H),3.75–3.62(m,4H),2.83–2.68(m,4H),2.49(s,3H),2.39(s,1H ),2.23–2.11(m,4H),2.02–1.90(m,4H),1.59–1.40(m,4H),1.09(d,J=6.7Hz,3H),1.02(t,J=5.9Hz,6H),0.97(t,J=7.1Hz,3H).

[0470] Example 3: Preparation of compound C003

[0471]

[0472] Step 1

[0473] Compound 1,2-dibromoethane (414.5 mg, 2.21 mmol) was added to acetonitrile (5 mL) containing compound 1e (550 mg, 1.10 mmol) and potassium carbonate (457.4 mg, 3.3 mmol). The reaction mixture was stirred at 60 °C under a nitrogen atmosphere for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification by silica gel chromatography (dichloromethane:methanol = 92:8) yielded compound 3a (200 mg, yield: 26.4%).

[0474] LCMS(ESI)m / z:[M+H] + =604.9.

[0475] Step 2

[0476] Compound 3a (180 mg, 0.30 mmol) was added to acetonitrile (5 mL) containing compound 2e (97 mg, 0.45 mmol) and N,N-diisopropylethylamine (115.3 mg, 0.89 mmol). The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (20 mL), and then extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification by silica gel chromatography (dichloromethane:methanol = 92:8–90:10) yielded compound 3b (190 mg, yield: 86.7%).

[0477] LCMS(ESI)m / z:[M+H] + =741.5.

[0478] Step 3

[0479] A solution of dioxane in hydrochloric acid (2 mL, 4 M) was added to a 2 mL solution of compound 3b (190 mg, 0.26 mmol) in dichloromethane, and the mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was concentrated under vacuum and slurried with diethyl ether to give compound 3c (150 mg).

[0480] LCMS(ESI)m / z:[M+H] + =641.4.

[0481] Step 4

[0482] Intermediate 3d (161.3 mg, 0.55 mmol) and acetic acid (32.8 mg, 0.55 mmol) were added to a methanol (5 mL) solution of compound 3c (350 mg, 0.55 mmol). The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 16 hours. LC-MS showed conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain a crude product. Compound C003 (67.02 mg, yield: 13.1%) was purified by silica gel chromatography (dichloromethane:methanol = 85:15) and Prep-HPLC (compound HPLC purification preparation method 1) to obtain compound C003.

[0483] LCMS(ESI)m / z:[M+H] + =918.4.

[0484] 1HNMR(400MHz,MeOD)δ8.98(d,J=3.9Hz,1H),8.89–8.84(m,1H),8.57(d,J=6.2Hz,0.3H),8.43(d,J=2.2Hz,0.3H),8.13(d,J=3.8Hz,1H),7.91 –7.87(m,0.3H),7.85–7.79(m,1H),7.46–7.41(m,2H),7.35–7.30(m,2 H),7.28–7.00(m,2H),6.06–5.98(m,1H),5.09–4.96(m,1H),4.62–4.52 (m,1H),4.48–4.36(m,4H),4.32–4.23(m,1H),3.87–3.76(m,1H),3.73 –3.62(m,2H),2.89–2.83(m,4H),2.75–2.72(m,2H),2.49(s,2H),2.45 (s,2H),2.24–2.12(m,4H),2.04–1.92(m,4H),1.63–1.45(m,4H),1.08–1.05(d,J=6.6Hz,3H),1.03(dd,J=6.6,3.1Hz,6H),0.96–0.91(m,3H).

[0485] Example 4: Preparation of compound C004

[0486]

[0487] Step 1

[0488] Intermediate 1 (200 mg, 0.61 mmol) was dissolved in DMSO (2 mL) at room temperature. 1-BOC-4-methanesulfonyloxymethylpiperidine (357 mg, 1.22 mmol) and N,N-diisopropylethylamine (236 mg, 1.83 mmol) were added, and the reaction mixture was stirred at 90 °C for 12 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain a crude product. Purification by silica gel chromatography (MeOH:DCM = 10%) gave compound 4a (172 mg, yield: 54.1%).

[0489] LCMS(ESI)m / z:[M+H] + =525.3.

[0490] Step 2

[0491] Compound 4a (172 mg, 0.33 mmol) was added to DCM (2 mL), followed by TFA (0.2 mL), and stirred at room temperature for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The mixture was concentrated under vacuum to give compound 4b (130 mg).

[0492] LCMS(ESI)m / z:[M+H] + =425.2.

[0493] Step 3

[0494] Compound 4b (130 mg, 0.31 mmol) was added to DMSO (4 mL), followed by 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (83 mg, 0.31 mmol), DIPEA (120 mg, 0.93 mmol), and HBTU (235 mg, 0.62 mmol). The mixture was stirred at room temperature for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The product was concentrated under vacuum and purified by silica gel chromatography (MeOH:DCM = 10%) to obtain a crude product, which was then purified by pre-HPLC (compound HPLC purification preparation method 1) to obtain compound C004 (38.9 mg, yield: 18.4%).

[0495] LCMS(ESI)m / z:[M+H] + =675.3.

[0496] 1H NMR(400MHz,MeOD)δ8.52(s,1H),7.77(dd,J=8.1,1.5Hz,1H),7.69(d,J=8.2Hz,1H),7 .56(d,J=1.9Hz,1H),7.46(d,J=8.5Hz,1H),7.41–7.34(m,1H),7.04–6.99(m,2H),4.70 (s,2H),3.83-3.79(m,4H),3.59-3.50(m,1H),3.24-3.17(m,2H),3.17-3.45(m,3H),2. 99–2.82(m,3H),2.54–2.37(m,5H),2.25-2.24(m,2H),2.09-1.89(m,3H),1.37(s,2H).

[0497] Example 5: Preparation of compound C005

[0498]

[0499] Step 1

[0500] To a dimethyl sulfoxide solution (2 mL) of compound 5a (60 mg, 0.14 mmol) and 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (78 mg, 0.28 mmol), N,N-diisopropylethylamine (54 mg, 0.42 mmol) was added, and the mixture was reacted at 80 °C under a nitrogen atmosphere for 3 h. LC-MS showed conversion of the reactants and detection of the product. The reaction mixture was poured into water (10 mL), and then extracted with ethyl acetate (50 mL * 3). The organic layer was washed with saturated sodium chloride solution (50 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by Prep-HPLC (compound HPLC purification preparation method 1) to obtain compound C005 (22 mg, yield: 22.8%).

[0501] LCMS(ESI)m / z:[M+H] + =681.5.

[0502] 1 H NMR(400MHz,MeOD)δ8.21(s,1H),7.86(d,J=7.2Hz,1H),7.68(d,J=8.4Hz,1H), 7.37(d,J=2.0Hz,1H),7.33–7.19(m,2H),6.99-6.96(m,2H),5.10-5.06(m,1H), 4.45(s,1H),4.09-4.06(m,2H),3.06-3.0(m,2H),2.92–2.67(m,5H),2.46(s,3 H),2.37-2.35(m,3H),2.13-2.11(m,3H),1.95-1.93(m,5H),1.35-1.32(m,2H).

[0503] Example 6: Preparation of compound C006

[0504]

[0505] Step 1

[0506] Intermediate 1 (300 mg, 0.92 mmol) was dissolved in DMF (3 mL) at room temperature, and tert-butyl 3-(methanesulfonyloxymethyl)azabutane-1-carboxylic acid (488.14 mg, 1.83 mmol) and DIPEA (236.89 mg, 1.83 mmol) were added. The reaction mixture was stirred at 90 °C for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and the crude product was purified by silica gel chromatography (methanol:dichloromethane = 0-5%) to give compound 6a (200 mg, yield: 43.5%).

[0507] LCMS(ESI)m / z:[M+H] + =497.2.

[0508] Step 2

[0509] Compound 6a (200 mg, 0.40 mmol) was dissolved in DCM (2 mL) at room temperature, and TFA (1 mL, 10%) was added. The mixture was stirred at room temperature for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The mixture was concentrated under vacuum to give 6b (160 mg).

[0510] LCMS(ESI)m / z:[M+H] + =397.2.

[0511] Step 3

[0512] Compound 6b (150 mg, 0.38 mmol) was dissolved in DMSO (2 mL), and 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (156.74 mg, 0.57 mmol) and DIPEA (142.1 mg, 1.13 mmol) were added. The mixture was heated to 80 °C and stirred for 3 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction solution was poured into water (20 mL), and then extracted with ethyl acetate (20 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by HPLC (HPLC purification method 1) to give C006 (43.6 mg, yield: 18.4%).

[0513] LCMS(ESI)m / z:[M+H] + =653.2.

[0514] 1H NMR (400MHz, DMSO) δ11.07(s,1H),9.66(s,1H),8.30(d,J=5.6Hz,1H),7.88(d,J=7.6Hz,2H),7.69(d,J=8.4Hz,1H),7.31(t,J=7. 6Hz,1H),7.00–6.87(m,2H),6.82(d,J=1.6Hz,1H),6.69(d,J=8.4Hz,1H),5.06(dd,J=12.8,5.2Hz,1H),4.75(s,1H),4.59(s,1H) ,4.26(t,J=8.4Hz,2H),3.85(d,J=6.4Hz,2H),3.56(s,3H),3.40(d,J=10.8Hz,1H),3.32–3.24(m,1H),3.12(s,2H),2.94–2.80(m ,1H),2.70–2.55(m,2H),2.46(s,2H),2.35(d,J=18.0Hz,2H),2.19(d,J=13.6Hz,1H),2.12–1.97(m,2H),1.84(d,J=11.2Hz,1H).

[0515] Example 7: Preparation of compound C007

[0516]

[0517] Step 1

[0518] Methylsulfonyl chloride (144.5 mg, 1.26 mmol) was slowly added dropwise to a dichloromethane solution (5 mL) of tert-butyl 3-hydroxypropyl methylcarbamate (200 mg, 1.05 mmol) and triethylamine (319 mg, 3.15 mmol) under nitrogen protection at 0 °C, and the mixture was stirred at room temperature for two hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution (10 mL), followed by extraction with dichloromethane (30 mL x 3). The organic layer was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give crude compound 7a (300 mg), which was used directly in the next step.

[0519] LCMS(ESI)m / z:[M-55] + =212.0.

[0520] Step 2

[0521] Compound 7a (300 mg, 1.12 mmol) was added to a solution of intermediate 1 (183 mg, 0.56 mmol), sodium iodide (16.8 mg, 0.11 mmol), and N,N-diisopropylethylamine (433 mg, 3.35 mmol) in N,N-dimethylformamide (4 mL), and reacted at 90 °C under nitrogen protection for 16 h. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (100 mL x 3), the organic layer was washed with saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. Compound 7b (160 mg, yield: 57%) was purified by silica gel chromatography (MeOH:DCM = 2-4%).

[0522] LCMS(ESI)m / z:[M+H] + =499.3.

[0523] Step 3

[0524] A 4M hydrochloric acid / dioxane solution (2 mL) was added to a 2 mL solution of compound 7b (160 mg, 0.32 mmol) in dichloromethane, and the mixture was stirred at room temperature for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was concentrated under vacuum to give compound 7c (150 mg).

[0525] LCMS(ESI)m / z:[M+H] + =399.3.

[0526] Step 4

[0527] To a dimethyl sulfoxide solution (2 mL) of compound 7c (130 mg, 0.3 mmol) and 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (143 mg, 0.49 mmol), N,N-diisopropylethylamine (126.5 mg, 0.98 mmol) was added, and the mixture was reacted at 80 °C under a nitrogen atmosphere for 3 h. LC-MS showed conversion of the reactants and detection of the product. The reaction mixture was poured into water (10 mL), and then extracted with ethyl acetate (50 mL * 3). The organic layer was washed with saturated sodium chloride solution (50 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by Prep-HPLC (compound HPLC purification preparation method 1) to obtain compound C007 (63.34 mg, yield: 28.2%).

[0528] LCMS(ESI)m / z:[M+H] + =655.4.

[0529] 1 H NMR (400MHz, MeOD) δ8.48(s,1H),8.17(s,1H),7.82(d,J=8.1Hz,1H),7.68–7.57(m,1H),7.29(dt,J=22.6,7.5Hz,3H),6.95(t,J=6.9Hz,2H),5.11(dd ,J=12.5,5.4Hz,1H),4.55(s,1H),3.63–3.45(m,2H),3.14(s,2H),3.05(s, 3H),3.00–2.82(m,5H),2.76–2.70(m,2H),2.43(s,3H),2.25–1.95(m,7H).

[0530] Example 8: Preparation of compound C008

[0531]

[0532] Step 1

[0533] Compound 8a (50 mg, 0.13 mmol) was dissolved in DMSO (3 mL) at room temperature. Compound DIPEA (84.01 mg, 0.65 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Then, compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (39.5 mg, 0.14 mmol) was added to the reaction mixture, and the mixture was stirred at 80 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was extracted with water (15 mL) and ethyl acetate (15 mL x 3), washed with saturated brine (20 mL x 2), and the organic layer was dried over anhydrous Na₂SO₄. The mixture was filtered and concentrated under vacuum to obtain the crude product. The crude product was purified by Pre-HPLC (compound HPLC purification preparation method 1) to obtain compound C008 (4.69 mg, yield: 5.4%).

[0534] LCMS(ESI)m / z:[M+H] + =626.7.

[0535] Example 9: Preparation of compound C009

[0536]

[0537] Step 1

[0538] Intermediate 1 (73 mg, 0.22 mmol) was dissolved in methanol (10 mL) at room temperature. Tert-butyl methyl (3-oxopropyl)carbamate (41 mg, 0.22 mmol) and acetic acid (6.6 mg, 0.11 mmol) were added. The reaction mixture was stirred at room temperature for 30 min, followed by the addition of sodium borohydride acetate (140 mg, 0.66 mmol) and stirring for 12 h. LC-MS showed complete conversion of the reactants and detection of the product. After quenching the reaction with water (30 mL), extraction was performed using DCM (20 mL x 3). The organic phase was collected, dried, concentrated, and purified by silica gel chromatography (MeOH:DCM = 0-10%) to give compound 9a (72 mg, yield: 65.7%). LC-MS (ESI) m / z: [M+H] + =498.2.

[0539] Step 2

[0540] Compound 9a (72 mg, 0.15 mmol) was dissolved in 10 mL of MeOH at room temperature, and 2 mL of dioxane hydrochloride solution was added. The reaction mixture was stirred at room temperature for 0.5 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was then evaporated to dryness for later use. No purification was required for this step, yielding crude compound 9b (58 mg). LC-MS (ESI) m / z: [M+H] + =398.2.

[0541] Step 3

[0542] Reactant 9b (20 mg, 0.05 mmol), 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (28 mg, 0.1 mmol), and DIPEA (20 mg, 0.15 mmol) were added sequentially to a reaction flask. Then, DMSO (3 mL) was added, and the reaction was carried out at 80 °C for 2 h. LCMS analysis confirmed the reaction was complete. The reaction was quenched with water (30 mL), and the mixture was extracted with DCM (20 mL x 3). The organic phase was collected, dried, concentrated, and purified by preparative chromatography to give compound C009 (10.55 mg, yield 32%). LCMS (ESI) m / z: [M+H] + =640.3.

[0543] 1H NMR (500MHz, DMSO-d6) δ13.14(s,1H),11.07(s,1H),8.19(s,1H),7.98(dd,J=8.3,1.7Hz,1H),7.64(d,J=8.5Hz,1 H),7.51(s,2H),7.27(td,J=7.6,1.6Hz,1H),7.14(d,J=2.4Hz,1H),7.02(dd,J=8.7,2.4Hz,1H),6.976.90(m,2H) ,5.06(dd,J=12.9,5.4Hz,1H),4.38(t,J=5.4Hz,1H),3.57(d,J=6.9Hz,2H),2.92–2.84(m,1H),2.71–2.62(m,2H) ,2.61–2.55(m,1H),2.39(s,3H),2.31(t,J=6.7Hz,2H),2.26–2.18(m,2H),2.04–1.94(m,3H),1.80–1.67(m,4H).

[0544] Example 10: Preparation of compound C010

[0545]

[0546] Step 1

[0547] Compound 8a (50 mg, 0.13 mmol) was dissolved in DMSO (3 mL) at room temperature. Compound DIPEA (84.01 mg, 0.65 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 min. Compound 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (39.5 mg, 0.14 mmol) was added to the reaction mixture, and the mixture was stirred at 80 °C for 2 h. LCMS showed complete conversion of the reactants and detection of the product. The reaction mixture was extracted with water (15 mL) using EA (15 mL * 3), washed with saturated brine (20 mL * 2), dried over anhydrous sodium sulfate (Na₂SO₄), filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by pre-HPLC (compound HPLC purification preparation method 1) to obtain compound C010 (5.6 mg, yield: 6.5%).

[0548] LCMS(ESI)m / z:[M+H] + =626.7.

[0549] Example 11: Preparation of compound C011

[0550]

[0551] Step 1

[0552] Intermediate 1 (150 mg, 0.42 mmol) was dissolved in DCM / DMSO at room temperature in a 1:1 ratio (20 mL). Methyl (2-oxyethyl) tert-butyl carbamate (143 mg, 0.84 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Sodium triacetoxyborohydride (350 mg, 1.65 mmol) was then added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether: ethyl acetate = 0-70%) to give compound 11a (150 mg, yield: 75%).

[0553] Step 2

[0554] Compound 11a (150 mg, 0.31 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 11b (160 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =385.3.

[0555] Step 3

[0556] Compound 11b (160 mg, 0.30 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (123.2 mg, 0.46 mmol), HATU (172 mg, 0.33 mmol), and DIPA (215 mg, 0.9 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture, and extracted with DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The product was prepared by HPLC. Lyophilization yielded compound C011 (18 mg, yield: 6.4%). LCMS (ESI) m / z: [M+H] + =635.2.

[0557] Example 12: Preparation of compound C012

[0558]

[0559] Step 1

[0560] Intermediate 1 (150 mg, 0.42 mmol) was dissolved in DCM / DMSO at room temperature (1:1, 20 mL). Compound N-tert-butoxycarbonyl-4-piperidinone (140 mg, 0.84 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Sodium triacetoxyborohydride (350 mg, 1.65 mmol) was then added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water, and the mixture was extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification by silica gel chromatography (petroleum ether:ethyl acetate = 0-70%) yielded compound 12a (110 mg, yield: 75%).

[0561] Step 2

[0562] Compound 12a (110 mg, 0.22 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was obtained by vacuum concentration. Compound 12b (90 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =410.5.

[0563] Step 3

[0564] Compound 12b (90 mg, 0.22 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (66.6 mg, 0.24 mmol) and DIPA (113.4 mg, 0.88 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC preparation (compound HPLC purification preparation method 1) was then performed. Freeze-drying yielded compound C012 (9.3 mg, yield: 6.4%). LCMS (ESI) m / z: [M+H] + =666.7.

[0565] Example 13: Preparation of compound C013

[0566]

[0567] Step 1

[0568] Intermediate 1 (150 mg, 0.42 mmol) was dissolved in DCM / DMSO at room temperature (1:1, 20 mL). Compound N-tert-butoxycarbonyl-4-piperidinone (140 mg, 0.84 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Sodium triacetoxyborohydride (350 mg, 1.65 mmol) was then added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water, and the mixture was extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether:ethyl acetate = 0-70%) to give compound 013a (110 mg, yield: 75%).

[0569] Step 2

[0570] Compound 13a (110 mg, 0.22 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was obtained by vacuum concentration. Compound 13b (90 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =410.5.

[0571] Step 3

[0572] Compound 13b (90 mg, 0.22 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (66.6 mg, 0.24 mmol) and DIPA (113.4 mg, 0.88 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC preparation (compound HPLC purification preparation method 1) was then performed. Freeze-drying yielded compound C013 (10.1 mg, yield: 6.9%). LCMS (ESI) m / z: [M+H] + =666.7.

[0573] Example 14: Preparation of compound C014

[0574]

[0575] Step 1

[0576] Intermediate 3 (100 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL) at room temperature. TEA (78.9 mg, 0.78 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Tetraisopropyl titanate (147.8 mg, 0.52 mmol) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (67.5 mg, 0.39 mmol) were added, and the mixture was reacted for 1 hour. Sodium triacetoxyborohydride (110 mg, 0.52 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. After the reaction was completed, saturated ammonium chloride aqueous solution (10 mL) was added, followed by extraction with dichloromethane (2 x 10 mL). The organic phases were combined and washed with saturated brine (2 x 20 mL). The organic layer was collected, dried with anhydrous Na2SO4, filtered, and rotary evaporated. The crude product was purified by Pre-TLC (dichloromethane / methanol = 10:1) to obtain compound 14a (98 mg, yield: 62.9%).

[0577] LCMS(ESI)m / z:[M+H] + =550.7.

[0578] Step 2

[0579] Compound 14a (98 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, and HCl / dioxane (0.5 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give compound 14b (75 mg, yield: 88.9%).

[0580] LCMS(ESI)m / z:[M+H] + =450.6.

[0581] Step 3

[0582] Compound 14b (30 mg, 0.067 mmol) was dissolved in DMSO (3 mL) at room temperature. Compound DIPEA (43.3 mg, 0.34 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Then, 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (18.5 mg, 0.067 mmol) was added to the reaction mixture, and the mixture was stirred at 25 °C for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was extracted with water (15 mL) and ethyl acetate (15 mL x 3), washed with saturated brine (20 mL x 2), and the organic layer was dried over anhydrous Na₂SO₄. The mixture was filtered and concentrated under vacuum to obtain the crude product. The crude product was purified by pre-HPLC (compound HPLC purification preparation method 1) to obtain compound C014 (4.38 mg, yield: 8.8%).

[0583] LCMS (ESI) m / z: [M+H]+=706.8.

[0584] Example 15: Preparation of compound C015

[0585]

[0586] Step 1

[0587] Crude intermediate 1 (38 mg, 0.12 mmol) was dissolved in methanol (10 mL) at room temperature. 1-Boc-3-azacyclobutanone (20 mg, 0.11 mmol) and acetic acid (6.6 mg, 0.11 mmol) were added. The reaction mixture was stirred at room temperature for 30 min, followed by the addition of sodium borohydride acetate (70 mg, 0.33 mmol) and stirring for 12 h. LC-MS showed complete conversion of the reactants and detection of the product. After quenching the reaction with water, the mixture was extracted three times with DCM. The organic phase was collected, dried, concentrated, and purified by silica gel chromatography (MeOH:DCM = 0-10%) to give compound 15a (19 mg, yield: 33.9%). LC-MS (ESI) m / z: [M+H] + =482.3.

[0588] Step 2

[0589] Compound 15a (19 mg, 0.039 mmol) was dissolved in 5 mL of MeOH at room temperature, and 2 mL of dioxane hydrochloride solution was added. The reaction mixture was stirred at 25 °C for 0.5 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was then evaporated to dryness for later use. No purification was required for this step, yielding crude compound 15b (15 mg).

[0590] LCMS(ESI)m / z:[M+H] + =382.2.

[0591] Step 3

[0592] Reactant 15b (15 mg, 0.039 mmol), 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (28 mg, 0.1 mmol), and DIPEA (20 mg, 0.15 mmol) were added sequentially to a reaction flask, followed by the addition of 3 mL of DMSO. The reaction was carried out at 80 °C for 2 h, and LCMS analysis confirmed complete reaction. The reaction was quenched with water, and the mixture was extracted three times with dichloroisocyanurate. The organic phase was collected, dried, concentrated, and then purified using Pre-HPLC (Compound HPLC Purification Preparation Method 1) to obtain compound C015 (12.23 mg, yield: 38%). LCMS (ESI) m / z: [M+H] + =638.3.

[0593] 1 H NMR(500MHz,DMSO-d6)δ13.14(s,1H),11.07(s,1H),8.19(s,1H),8.00–7.94(m,1H),7.58(dd,J=8.5,7.0Hz, 1H),7.50(s,2H),7.30–7.22(m,1H),7.13(d,J=7.0Hz,1H),6.94(d,J=7.7Hz,2H),6.81(d,J=8.5Hz,1H),5.0 5(dd,J=12.7,5.5Hz,1H),4.41(s,1H),4.30(s,2H),3.96(d,J=8.1Hz,2H),3.22-3.28(m,2H),2.90–2.80(m, 1H),2.62(d,J=17.9Hz,2H),2.39(s,3H),2.22(s,2H),2.07–1.94(m,3H),1.72(d,J=9.8Hz,2H),1.24(s,1H).

[0594] Example 16: Preparation of compound C016

[0595]

[0596] Step 1

[0597] Intermediate 1 (73 mg, 0.22 mmol) was dissolved in methanol (10 mL) at room temperature. Then, tert-butyl methyl (3-oxopropyl)carbamate (41 mg, 0.22 mmol) and AcOH (6.6 mg, 0.11 mmol) were added. The reaction mixture was stirred at room temperature for 30 min, followed by the addition of sodium triacetylborohydride (140 mg, 0.66 mmol) and stirring for 12 h. LC-MS showed complete conversion of the reactants and detection of the product. After quenching the reaction with water (30 mL), extraction was performed using DCM (20 mL x 3). The organic phase was collected, dried, concentrated, and purified by silica gel chromatography (MeOH:DCM = 0-10%) to give compound 16a (40 mg, yield: 37%). LC-MS (ESI) m / z: [M+H] + =498.3.

[0598] Step 2

[0599] Compound 16a (40 mg, 0.08 mmol) was dissolved in methanol (10 mL) at room temperature, and dioxane hydrochloride solution (2 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was then evaporated to dryness for later use. No purification was required for this step, yielding crude compound 16b (20 mg). LC-MS (ESI) m / z: [M+H] + =398.2.

[0600] Step 3

[0601] Reactant 16b (20 mg, 0.05 mmol), 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (12 mg, 0.045 mmol), and DIPEA (20 mg, 0.15 mmol) were dissolved in DMSO (3 mL). Finally, HBTU (21 mg, 0.055 mmol) was added. After reacting at room temperature for 2 h, LCMS analysis showed the reaction was complete. The reaction was quenched with water (30 mL), and extracted with DCM (20 mL * 3). The organic phase was collected, dried, concentrated, and purified by Pre-HPLC (compound HPLC purification preparation method 1) to obtain compound C016 (18.03 mg, yield 32%). LCMS (ESI) m / z: [M+H] + =632.2.

[0602] 1H NMR (500MHz, DMSO-d6) δ13.13(s,1H),10.51(s,1H),8.19(s,1H),7.97(dd,J=8.3,1.7Hz,1H),7.64(d,J=8.2Hz,1H),7.57(d ,J=16.0Hz,1H),7.50(s,2H),7.41(d,J=8.3Hz,1H),7.27(td,J=7.6,1.6Hz,1H),6.98–6.90(m,2H),4.35(d,J=49.8Hz,1H), 3.84–3.70(m,2H),3.62(s,2H),3.47(s,2H),2.95(d,J=23.4Hz,3H),2.75(q,J=7.6,6.8Hz,2H),2.54(s,1H),2.45(s,1H),2 .38(d,J=6.6Hz,3H),2.19(s,1H),2.02(s,1H),1.88-2.00(m,2H),1.87(s,1H),1.68-1.78(m,2H),1.67(s,1H),1.54(s,1H).

[0603] Example 17: Preparation of compound C017

[0604]

[0605] Step 1

[0606] Compound 15b (26 mg, 0.06 mmol) was dissolved in DMSO (3 mL), and 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (13 mg, 0.05 mmol), DIPEA (20 mg, 0.15 mmol), and HBTU (21 mg, 0.056 mmol) were added. The reaction was allowed to proceed at room temperature for 2 h, and LCMS analysis confirmed complete reaction. The reaction was quenched with water (30 mL), and the mixture was extracted with DCM (20 mL x 3). The organic phase was collected, dried, concentrated, and purified by Pre-HPLC (compound HPLC purification preparation method 1) to obtain compound C017 (4.99 mg, yield 13.3%). LCMS (ESI) m / z: [M+H] + =632.

[0607] 1H NMR (500MHz, DMSO-d6) δ13.13(s,1H),10.52(s,1H),8.19(s,1H),7.97(dd,J=8.4,1.7Hz,1H),7.79(d,J= 1.8Hz,1H),7.68–7.60(m,2H),7.50(s,2H),7.30–7.23(m,1H),6.97–6.89(m,2H),4.45–4.29(m,2H),4.2 6–4.04(m,3H),3.88(dd,J=10.5,5.1Hz,1H),3.78(s,1H),3.61(dt,J=11.9,6.0Hz,1H),3.22–3.15(m,1H ), 2.75(dt,J=14.5,6.7Hz,3H),2.38(s,3H),1.99(s,3H),1.71(d,J=8.9Hz,2H),1.26(d,J=29.1Hz,1H).

[0608] Example 18: Preparation of compound C018

[0609]

[0610] Step 1

[0611] Intermediate 1 (150 mg, 0.42 mmol) was dissolved in DCM / DMSO at room temperature (1:1, 20 mL). Compound N-tert-butoxycarbonyl-4-piperidinone (140 mg, 0.84 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Sodium triacetoxyborohydride (350 mg, 1.65 mmol) was then added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water, and the mixture was extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification by silica gel chromatography (petroleum ether:ethyl acetate = 0-70%) yielded compound 18a (110 mg, yield: 75%).

[0612] Step 2

[0613] Compound 18a (110 mg, 0.22 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 18b (90 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =410.5.

[0614] Step 3

[0615] Compound 18b (90 mg, 0.22 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (66.6 mg, 0.23 mmol), HATU (172 mg, 0.33 mmol), and DIPEA (215 mg, 0.9 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture, and extracted with DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC preparation (compound HPLC purification preparation method 1) was then performed. The product was freeze-dried to obtain compound C018 (20 mg, yield: 13.8%). LCMS (ESI) m / z: [M+H] + =661.2.

[0616] Example 19: Preparation of compound C019

[0617]

[0618] Step 1

[0619] Intermediate 1 (300 mg, 0.84 mmol) was dissolved in DCM / DMSO at room temperature (1:1, 20 mL). Compound 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (280 mg, 1.68 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Sodium triacetoxyborohydride (700 mg, 3.30 mmol) was added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture, and extracted with DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-70%) to obtain compound 19a (250 mg, yield: 82%).

[0620] Step 2

[0621] Compound 19a (110 mg, 0.22 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 19b (100 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =424.3.

[0622] Step 3

[0623] Compound 19b (100 mg, 0.24 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (73.2 mg, 0.27 mmol), HATU (172 mg, 0.33 mmol), and DIPEA (215 mg, 0.9 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture, and extracted with DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC preparation (compound HPLC purification preparation method 1) was then performed. The product was freeze-dried to obtain compound C019 (20 mg, yield: 13.7%). LCMS (ESI) m / z: [M+H] + =675.2.

[0624] Example 20: Preparation of compound CO20

[0625]

[0626] Step 1

[0627] Intermediate 1 (38 mg, 0.118 mmol) was dissolved in DMSO (10 mL) at room temperature. 1-Boc-4-piperidinic acid (20 mg, 0.11 mmol), DIEA (20 mg, 0.33 mmol), and HATU (41 mg, 0.11 mmol) were added at room temperature, and the reaction mixture was stirred at room temperature for 2 h. LC-MS showed complete conversion of the reactants and detection of the product. After quenching the reaction with water (30 mL), extraction was performed using DCM (20 mL * 3). The organic phase was collected, dried, concentrated, and purified by silica gel chromatography (MeOH:DCM = 0-10%) to give compound 20a (17 mg).

[0628] LCMS(ESI)m / z:[M+H] + =538.3.

[0629] Step 2

[0630] Compound 20a (17 mg, 0.03 mmol) was dissolved in 5 mL of MeOH at room temperature, and 2 mL of dioxane hydrochloride solution was added. The reaction mixture was stirred at 25 °C for 0.5 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was then evaporated to dryness for later use. No purification was required for this step, yielding crude compound 20b (17 mg).

[0631] LCMS(ESI)m / z:[M+H] + =438.3.

[0632] Step 3

[0633] Compound 20b (17 mg, 0.03 mmol) was dissolved in DMSO (3 mL) at room temperature. 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (11 mg, 0.02 mmol), DIPEA (20 mg, 0.15 mmol), and HBTU (16 mg, 0.03 mmol) were added, and the mixture was reacted at room temperature for 2 h. The reaction was confirmed to be complete by LCMS. After quenching the reaction with water (30 mL), the mixture was extracted with DCM (20 mL * 3), and the organic phase was collected, dried, concentrated, and purified by Pre-HPLC (compound HPLC purification preparation method 1) to obtain compound C020 (6.68 mg, yield 32%). LCMS (ESI) m / z: [M+H] + =688.3.

[0634] Example 21: Preparation of compound CO21

[0635]

[0636] Step 1

[0637] Intermediate 1 (300 mg, 0.84 mmol) was dissolved in DCM / DMSO at room temperature in a 1:1 ratio (20 mL). Compound 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (280 mg, 1.68 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Sodium triacetoxyborohydride (700 mg, 3.30 mmol) was then added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water, and the mixture was extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether:ethyl acetate = 0-70%) to give compound 21a (250 mg, yield: 82%).

[0638] Step 2

[0639] Compound 21a (110 mg, 0.22 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 21b (100 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =424.3.

[0640] Step 3

[0641] Compound 21b (100 mg, 0.24 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (66.6 mg, 0.24 mmol) and DIPEA (113.4 mg, 0.88 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC preparation (compound HPLC purification preparation method 1) was then performed. Freeze-drying yielded compound C021 (10.1 mg, yield: 6.8%). LCMS (ESI) m / z: [M+H] + =680.8.

[0642] Example 22: Preparation of compound CO22

[0643]

[0644] Step 1

[0645] Reactant 22a (29 mg, 0.054 mmol) was dissolved in DMSO (3 mL), and 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (18 mg, 0.048 mmol) and DIPEA (20 mg, 0.15 mmol) were added at room temperature. The reaction was carried out at 80 °C for 2 h. LCMS analysis confirmed the reaction was complete. After quenching the reaction with water (30 mL), the mixture was extracted with DCM (20 mL * 3), and the organic phase was collected, dried, concentrated, and purified by Pre-HPLC to give compound CO22 (7.26 mg, yield 17%). LCMS (ESI) m / z: [M + H] + =694.3.

[0646] Example 23: Preparation of compound CO23

[0647]

[0648] Step 1

[0649] Intermediate 1 (300 mg, 0.84 mmol) was dissolved in DCM / DMSO at room temperature in a 1:1 ratio (20 mL). Compound 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (280 mg, 1.68 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Sodium triacetoxyborohydride (700 mg, 3.30 mmol) was then added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether:ethyl acetate = 0-70%) to give compound 23a (250 mg, yield: 82%).

[0650] Step 2

[0651] Compound 23a (110 mg, 0.22 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 23b (100 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =424.3.

[0652] Step 3

[0653] Compound 23b (100 mg, 0.24 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (66.6 mg, 0.24 mmol) and DIPEA (113.4 mg, 0.88 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding water (30 mL), and extracted with DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. It was then prepared by pre-HPLC (compound HPLC purification preparation method 1). Freeze-drying yielded compound C023 (10.1 mg, yield: 6.8%). LCMS (ESI) m / z: [M+H] + =680.8.

[0654] Example 24: Preparation of compound CO24

[0655]

[0656] Step 1

[0657] Compound 24a (32 mg, 0.055 mmol) was dissolved in DMSO (3 mL), and 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (18 mg, 0.048 mmol) and DIPEA (20 mg, 0.15 mmol) were added at room temperature. The reaction mixture was stirred at 80 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (20 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC purification (compound HPLC purification preparation method 1) yielded compound C024 (7.88 mg, yield 18%).

[0658] LCMS(ESI)m / z:[M+H] + =694.4.

[0659] Example 25: Preparation of compound C025

[0660]

[0661] Step 1

[0662] Intermediate 1 (150 mg, 0.46 mmol) was dissolved in dichloromethane (5 mL) at room temperature. Triethylamine (190 mg, 1.84 mmol) was added, and the reaction mixture was stirred at 25 °C for 1 hour. Tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (164 mg, 0.69 mmol) and tetraisopropyl titanate (260 mg, 0.92 mmol) were added to the reaction mixture, and the reaction was carried out at room temperature for 1 hour. Sodium triacetoxyborohydride (240 mg, 1.15 mmol) was added, and the mixture was stirred at 25 °C for 12 hours. LC-MS showed complete conversion of the reactants and detection of the product. After the reaction was completed, saturated ammonium chloride aqueous solution and dichloromethane (10 mL) were added. The mixture was filtered, and the filter cake was washed with dichloromethane. The organic phases were combined and washed with saturated brine (2*20 mL). The organic layer was taken, dried with Na2SO4, filtered, and rotary evaporated. The crude product was purified by silica gel chromatography (dichloromethane / methanol = 10:1) to obtain compound 25a (128 mg, yield: 48.2%).

[0663] LCMS(ESI)m / z:[M+H] + =550.7.

[0664] Step 2

[0665] Compound 25a (128 mg, 0.048 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, and HCl / dioxane (0.5 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give compound 25b (105 mg).

[0666] LCMS(ESI)m / z:[M+H] + =450.6.

[0667] Step 3

[0668] Compound 25b (35 mg, 0.078 mmol) was dissolved in DMSO (3 mL) at room temperature. Compound DIPEA (50 mg, 0.39 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (15.15 mg, 0.094 mmol) and HATU (33.3 mg, 0.11 mmol) were added to the reaction mixture, and the reaction was carried out at 25 °C for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was added to the aqueous phase, and ethyl acetate (3 x 20 mL) was added. The organic layers were combined and washed with saturated NaCl solution (3 x 20 mL). The combined organic layers were dried with Na2SO4, filtered, and rotary evaporated. The crude product was purified by Pre-HTLC (compound HPLC purification preparation method 1) to obtain compound C025 (22.56 mg, yield: 39.35%).

[0669] LCMS(ESI)m / z:[M+H] + =701.2.

[0670] Example 26: Preparation of compound C026

[0671]

[0672] Step 1

[0673] Compound 25b (35 mg, 0.078 mmol) was dissolved in DMSO (3 mL) at room temperature. Compound DIPEA (30.24 mg, 0.23 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Then, compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (21.5 mg, 0.078 mmol) was added to the reaction mixture, and the mixture was stirred at 80 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was added to water (15 mL), extracted with ethyl acetate (15 mL * 3), washed with saturated brine (20 mL * 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain the crude product. The crude product was prepared by Pre-HPLC (compound HPLC purification preparation method 1) to obtain compound C026 (13.25 mg, yield: 26.17%).

[0674] LCMS(ESI)m / z:[M+H] + =706.8.

[0675] Example 27: Preparation of compound C027

[0676]

[0677] Step 1

[0678] Compound 25b (35 mg, 0.078 mmol) was dissolved in DMSO (3 mL) at room temperature. Compound DIPEA (30.24 mg, 0.23 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Then, compound 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (21.5 mg, 0.078 mmol) was added to the reaction mixture, and the mixture was stirred at 80 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was added to water (15 mL), extracted with ethyl acetate (15 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain the crude product. The crude product was prepared by Pre-HPLC to obtain compound C027 (8.56 mg).

[0679] LCMS(ESI)m / z:[M+H] + =706.8.

[0680] Example 28: Preparation of compound C028

[0681]

[0682] Step 1

[0683] Intermediate 1 (200 mg, 0.61 mmol) was dissolved in DMSO (10 mL) at room temperature. Compound 1-tert-butoxycarbonyl-4-piperidineacetic acid (163.5 mg, 0.67 mmol), HATU (278.8 mg, 0.74 mmol), and DIPA (450 mg, 1.8 mmol) were added, and the reaction mixture was stirred for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether: ethyl acetate = 0-70%) to give compound 28a (300 mg, yield: 88.9%).

[0684] Step 2

[0685] Compound 28a (100 mg, 0.18 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 28b (110 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =452.7.

[0686] Step 3

[0687] Compound 28b (110 mg, 0.18 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (73.9 mg, 0.28 mmol), HATU (103 mg, 0.20 mmol), and DIPA (130 mg, 0.54 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding water (30 mL), and extracted with DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC preparation (compound HPLC purification preparation method 1) yielded compound C028 (18 mg, yield: 6.4%). LCMS (ESI) m / z: [M+H] + =703.2.

[0688] Example 29: Preparation of compound C029

[0689]

[0690] Step 1

[0691] Intermediate 1 (200 mg, 0.61 mmol) was dissolved in DMSO (10 mL) at room temperature. Compound 1-tert-butoxycarbonyl-4-piperidineacetic acid (163.5 mg, 0.67 mmol), HATU (278.8 mg, 0.74 mmol), and DIPA (450 mg, 1.8 mmol) were added, and the reaction mixture was stirred for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether: ethyl acetate = 0-70%) to give compound 29a (300 mg, yield: 88.9%).

[0692] Step 2

[0693] Compound 29a (100 mg, 0.18 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 29b (110 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =452.7.

[0694] Step 3

[0695] Compound 29b (100 mg, 0.24 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (66.6 mg, 0.24 mmol) and DIPEA (113.4 mg, 0.88 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC preparation (compound HPLC purification preparation method 1) was then performed. Freeze-drying yielded compound C029 (10.1 mg, yield: 6.8%). LCMS (ESI) m / z: [M+H] + =708.8.

[0696] Example 30: Preparation of compound CO30

[0697]

[0698] Step 1

[0699] Intermediate 1 (200 mg, 0.61 mmol) was dissolved in DMSO (10 mL) at room temperature. Compound 1-tert-butoxycarbonyl-4-piperidineacetic acid (163.5 mg, 0.67 mmol), HATU (278.8 mg, 0.74 mmol), and DIPEA (450 mg, 1.8 mmol) were added, and the reaction mixture was stirred for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether: ethyl acetate = 0-70%) to obtain compound 30a (300 mg, yield: 88.9%).

[0700] Step 2

[0701] Compound 30a (100 mg, 0.18 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was obtained by vacuum concentration. Compound 30b (110 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =452.7.

[0702] Step 3

[0703] Compound 30b (100 mg, 0.24 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (66.6 mg, 0.24 mmol) and DIPEA (113.4 mg, 0.88 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC preparation (compound HPLC purification preparation method 1) was then performed. Freeze-drying yielded compound C030 (10.1 mg, yield: 6.8%). LCMS (ESI) m / z: [M+H] + =708.8.

[0704] Example 31: Preparation of compound C031

[0705]

[0706] Step 1

[0707] Compound 31a (55 mg, 0.17 mmol) was dissolved in DCM (50, 3 mL) at room temperature. Compound 31b (54 mg, 0.26 mmol) and tetraisopropyl titanate (96 mg, 0.34 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. Then, sodium triacetylborohydride (180.15 mg, 0.85 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into a sodium bicarbonate solution (20 mL), and extracted with dichloromethane (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was performed by silica gel chromatography (methanol:dichloromethane = 0.1%, ammonia) to obtain compound 31c (35 mg, yield: 39.86%). LC-MS (ESI) m / z: [M+H] + =523.4.

[0708] Step 2

[0709] Compound 31c (35 mg, 0.067 mmol) was dissolved in dioxane hydrochloride (2 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. LCMS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain crude compound 31d (28 mg), which was used directly in the next step without purification. LCMS (ESI) m / z: [M+H]+=423.3.

[0710] Step 3

[0711] Compound 31d (28 mg, 0.066 mmol) was dissolved in DMSO (10 mL) at room temperature. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (18 mg, 0.067 mmol), DIPEA (42.65 mg, 0.33 mmol), and HATU (27.60 mg, 0.073 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC purification (compound HPLC purification preparation method 1) yielded compound C031 (16.01 mg, yield: 34.81%). LC-MS (ESI) m / z: [M+H] + =673.4.

[0712] 1HNMR(500MHz,DMSO-d6)δ13.16(s,1H),10.52(s,1H),8.18(s,2H),7.97(dd,J=8.3,1.5Hz,1H),7.63(d,J=8.4Hz,2H),7.48(d,J=1 3.5Hz,2H),7.44–7.38(m,1H),7.27(td,J=7.6,1.5Hz,1H),6.97–6.88(m,2H),4.35(dq,J=8.5,4.2Hz,1H),3.95(t,J=11.3Hz,1H) ,3.80–3.74(m,1H),3.70–3.67(m,1H),3.63–3.59(m,1H),3.29(dd,J=6.4,2.1Hz,1H),2.74(q,J=6.9,6.4Hz,4H),2.37(s,3H),2. 29(tt,J=12.6,7.7Hz,4H),2.02–1.92(m,2H),1.69(dq,J=13.2,8.5,6.3Hz,2H),1.46(dq,J=11.6,3.6Hz,3H),0.72–0.63(m,1H).

[0713] Example 32: Preparation of compound CO32

[0714]

[0715] Step 1

[0716] Intermediate 3 (30 mg, 0.076 mmol) was dissolved in dichloromethane (50 mL, 3 mL) at room temperature. Compound 32a (24 mg, 0.11 mmol) and tetraisopropyl titanate (43 mg, 0.15 mmol) were added, and the reaction mixture was stirred at 50 °C for 2 hours. Then, sodium triacetylborohydride (81 mg, 0.38 mmol) was added, and the mixture was stirred at 50 °C for another 1 hour. LCMS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (30 mL), and then extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was performed by silica gel chromatography (methanol:dichloromethane = 0-3%) to give compound 32b (30 mg, yield: 66.83%). LCMS (ESI) m / z: [M+H] + =589.5.

[0717] Step 2

[0718] Compound 32b (30 mg, 0.051 mmol) was dissolved in dioxane hydrochloride (3 mL, 4 M) at room temperature and stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction solution was concentrated under vacuum to obtain crude compound 32c (24 mg), which was used directly in the next step without purification. LCMS (ESI) m / z: [M+H] + =489.3.

[0719] Step 3

[0720] Compound 32c (24 mg, 0.049 mmol) was dissolved in DMSO (5 mL) at room temperature. 4-Chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (13 mg, 0.048 mmol), DIPEA (32 mg, 0.25 mmol), and HATU (23 mg, 0.060 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. LCMS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound C032 (5.51 mg, yield 14.99%) was obtained by pre-HPLC (HPLC purification preparation method 1). LCMS (ESI) m / z: [M+H] + =739.4.

[0721] Example 33: Preparation of compound CO33

[0722]

[0723] Step 1

[0724] Intermediate 1 (100 mg, 0.31 mmol) was dissolved in dichloromethane (5 mL) at room temperature. Triethylamine (131 mg, 1.24 mmol) was added, and the reaction mixture was stirred at 25 °C for 1 hour. Compound 4-N-Boc-aminocyclohexanone (66.1 mg, 0.31 mmol) and tetraisopropyl titanate (180 mg, 0.62 mmol) were added to the reaction mixture, and the reaction was carried out at room temperature for 1 hour. Sodium triacetoxyborohydride (160 mg, 0.78 mmol) was added, and the mixture was stirred at 25 °C for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. After the reaction was completed, saturated ammonium chloride aqueous solution and dichloromethane (10 mL) were added. The mixture was filtered, and the filter cake was washed with dichloromethane. The organic phases were combined and washed with saturated brine (2*20 mL). The organic layer was taken, dried with Na2SO4, filtered, and rotary evaporated. The crude product was purified by silica gel chromatography (dichloromethane / methanol = 0-10%) to obtain compound 33a (36 mg, yield: 21.8%).

[0725] LCMS(ESI)m / z:[M+H] + =524.3.

[0726] Step 2

[0727] Compound 33a (36 mg, 0.069 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, and HCl / dioxane (0.5 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give compound 33b (30.1 mg, yield: 92%).

[0728] LCMS(ESI)m / z:[M+H] + =424.5.

[0729] Step 3

[0730] Compound 33b (30 mg, 0.071 mmol) was dissolved in DMSO (3 mL) at room temperature. Compound DIPEA (27.5 mg, 0.21 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (22.9 mg, 0.085 mmol) and HATU (34.2 mg, 0.11 mmol) were added to the reaction mixture, and the reaction was carried out at 25 °C for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was added to water (20 mL) and ethyl acetate (3 x 20 mL). The organic layers were combined and washed with saturated saline solution (3 x 20 mL). The combined organic layers were dried with Na2SO4, filtered, and rotary evaporated. The crude product was prepared by Pre-HTLC (compound HPLC purification preparation method 1) to obtain compound C033 (5.6 mg, yield: 6.5%).

[0731] LCMS(ESI)m / z:[M+H] + =675.2.

[0732] Example 34: Preparation of compound C034

[0733]

[0734] Step 1

[0735] Intermediate 3 (30 mg, 0.08 mmol) was dissolved in DCM (5 mL) at room temperature. Tert-butyl methyl (3-oxopropyl)carbamate (15 mg, 0.08 mmol) and acetic acid (15 mg, 0.24 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. Then, sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added, and the mixture was stirred at room temperature for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a crude product (methanol:dichloromethane = 0-12%), yielding compound 34a (18 mg, 40% yield).

[0736] LCMS(ESI)m / z:[M+H] + =564.3.

[0737] Step 2

[0738] Crude compound 34a (18 mg, 0.032 mmol) was dissolved in methanol (3 mL) at room temperature, and dioxane hydrochloride solution (1 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was evaporated to dryness to obtain crude compound 34b (15 mg).

[0739] LCMS(ESI)m / z:[M+H] + =464.3.

[0740] Step 3

[0741] Reactant 34b (15 mg, 0.03 mmol) was dissolved in DMSO (3 mL), and 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (7 mg, 0.025 mmol), DIPEA (20 mg, 0.15 mmol), and HBTU (12 mg, 0.031 mmol) were added at room temperature. LCMS showed complete conversion of the reactants and detection of the product. The reaction solution was poured into water (50 mL), and then extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC purification (compound HPLC purification preparation method 1) yielded compound C034 (5.23 mg, yield 23%).

[0742] LCMS(ESI)m / z:[M+H] + =714.3.

[0743] 1H NMR(500MHz,DMSO-d6)δ13.16(s,1H),10.50(s,1H),8.85(d,J=12.6Hz,1H),8.31(s,2H),7.84(s,1H) ,7.59(dd,J=23.9,12.7Hz,2H),7.40(s,1H),7.31(t,J=7.7Hz,1H),7.00(dd,J=13.1,7.6Hz,2H),4.25 (d,J=42.2Hz,2H),3.74(s,2H),3.59(s,2H),3.0-3.20(m,4H),2.94(d,J=24.7Hz,3H),2.69(s,5H),2. 21–2.04(m,3H),2.01(s,1H),1.87(s,1H),1.78(s,2H),1.63(d,J=32.3Hz,2H),0.95(d,J=6.5Hz,5H).

[0744] Example 35: Preparation of compound C035

[0745]

[0746] Step 1

[0747] Intermediate 3 (100 mg, 0.26 mmol) was dissolved in dichloromethane (2.5 mL) and methanol (2.5 mL) at room temperature. Methyl (2-oxyethyl) tert-butyl carbamate (67.5 mg, 0.39 mmol) and one drop of glacial acetic acid were added. The reaction mixture was stirred at 25 °C for 12 hours. Sodium triacetoxyborohydride (110 mg, 0.52 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. At the end of the reaction, saturated ammonium chloride aqueous solution and dichloromethane (2 x 10 mL) were added. The organic phases were combined and washed with saturated brine (2 x 20 mL). The organic layer was collected, dried over anhydrous Na₂SO₄, filtered, and rotary evaporated. The crude product was purified by Pre-TLC (dichloromethane / methanol = 10:1) to give compound 35a (98 mg, yield: 62.9%). LCMS (ESI) m / z: [M+H]+=550.7.

[0748] Step 2

[0749] Compound 35a (98 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature. HCl / dioxane (0.5 mL) was added, and the reaction mixture was stirred at 25 °C for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give compound 35b (75 mg, yield: 88.9%). LCMS (ESI) m / z: [M+H]+ = 450.59.

[0750] Step 3

[0751] Compound 35b (30 mg, 0.067 mmol) was dissolved in DMSO (3 mL) at room temperature. Compound DIPEA (43.3 mg, 0.34 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Then, compound 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (18.5 mg, 0.067 mmol) was added to the reaction mixture, and the mixture was stirred at 80 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was extracted with water (15 mL) and ethyl acetate (15 mL x 3), washed with saturated brine (20 mL x 2), and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under vacuum to obtain the crude product. The crude product was prepared by Pre-HPLC (compound HPLC purification preparation method 1) to obtain compound C035 (4.38 mg, yield: 8.8%).

[0752] LCMS (ESI) m / z: [M+H]+=706.3.

[0753] Example 36: Preparation of compound C036

[0754]

[0755] Step 1

[0756] Compound 35b (30 mg, 0.067 mmol) was dissolved in DMSO (3 mL) at room temperature. Compound DIPEA (43.3 mg, 0.34 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Then, compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (18.5 mg, 0.067 mmol) was added to the reaction mixture, and the mixture was stirred at 80 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was extracted with water (15 mL) and ethyl acetate (15 mL x 3), washed with saturated brine (20 mL x 2), and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under vacuum to obtain the crude product. The crude product was prepared by Pre-HPLC (compound HPLC purification preparation method 1) to obtain compound C036 (10.56 mg, yield: 21.2%).

[0757] LCMS(ESI)m / z:[M+H] + =706.3.

[0758] Example 37: Preparation of compound C037

[0759]

[0760] Step 1

[0761] Compound 35b (30 mg, 0.067 mmol) was dissolved in DMSO (3 mL) at room temperature. Compound DIPEA (34.6 mg, 0.27 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (19.8 mg, 0.074 mmol) and HATU (32.3 mg, 0.10 mmol) were added to the reaction mixture, and the reaction was carried out at 25 °C for 1 hour. The reaction was completed by LCMS. The reaction mixture was added to water (20 mL), and extracted with ethyl acetate (3 x 20 mL). The organic layers were combined and washed with saturated saline solution (3 x 20 mL). The combined organic layers were dried with Na2SO4, filtered, and rotary evaporated. The crude product was prepared by Pre-HTLC (compound HPLC purification preparation method 1) to obtain compound C037 (15.26 mg, yield: 31.4%).

[0762] LCMS(ESI)m / z:[M+H] + =701.2.

[0763] Example 38: Preparation of compound C038

[0764]

[0765] Step 1

[0766] Intermediate 1 (150 mg, 0.42 mmol) was dissolved in DCM / DMSO at room temperature in a 1:1 ratio (20 mL). Methyl (2-oxybutyl) tert-butyl carbamate (143 mg, 0.84 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Sodium triacetoxyborohydride (350 mg, 1.65 mmol) was then added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether: ethyl acetate = 0-70%) to give compound 38a (150 mg, yield: 75%).

[0767] Step 2

[0768] Compound 38a (150 mg, 0.31 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 38b (160 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =412.5.

[0769] Step 3

[0770] Compound 38b (160 mg, 0.30 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (123.2 mg, 0.46 mmol), HATU (172 mg, 0.33 mmol), and DIPEA (215 mg, 0.9 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture, and extracted with DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Preparation: HPLC preparation (Compound HPLC purification preparation method 1). Freeze-drying yielded compound C038 (18 mg, yield: 6.4%). LCMS (ESI) m / z: [M+H] + =663.2.

[0771] 1H NMR(500MHz,DMSO-d6)δ9.21(s,1H),7.95–7.72(m,2H),7.66–7.37(m,3H),7.36–6.89(m,3H),5.6 5(d,J=25.3Hz,2H),4.39–3.95(m,3H),3.36–2.87(m,7H),2.85–2.33(m,10H),2.02–1.44(m,8H).

[0772] Example 39: Preparation of compound C039

[0773]

[0774] Step 1

[0775] Intermediate 1 (150 mg, 0.42 mmol) was dissolved in DCM / DMSO at room temperature in a 1:1 ratio (20 mL). Tert-butyl carbamate (2-oxopentyl) ester (143 mg, 0.84 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Sodium triacetoxyborohydride (350 mg, 1.65 mmol) was added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether: ethyl acetate = 0-70%) to give compound 39a (150 mg, yield: 75%).

[0776] Step 2

[0777] Compound 39a (150 mg, 0.31 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 39b (160 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =412.5.

[0778] Step 3

[0779] Compound 39b (160 mg, 0.30 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (123.2 mg, 0.46 mmol), HATU (172 mg, 0.33 mmol), and DIPEA (215 mg, 0.9 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture, and extracted with DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC preparation (compound HPLC purification preparation method 1) was then performed. Freeze-drying yielded compound C039 (18 mg, yield: 6.4%). LCMS (ESI) m / z: [M+H] + =663.2.

[0780] Example 40: Preparation of compound CO40

[0781]

[0782] Step 1

[0783] Intermediate 1 (73 mg, 0.22 mmol) was dissolved in methanol (10 mL) at room temperature. Then, tert-butyl methyl (3-oxopropyl)carbamate (36 mg, 0.22 mmol) and AcOH (6.6 mg, 0.11 mmol) were added. The reaction mixture was stirred at room temperature for 30 min, followed by the addition of sodium borohydride acetate (140 mg, 0.66 mmol) and stirring for 12 h. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a crude product (methanol:dichloromethane = 0.8%). Purification yielded compound 40a (32 mg, yield: 31%).

[0784] LCMS(ESI)m / z:[M+H] + =484.3.

[0785] Step 2

[0786] Compound 40a (32 mg, 0.067 mmol) was dissolved in methanol (10 mL) at room temperature, and dioxane hydrochloride solution (2 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 0.5 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was then evaporated to dryness for later use. No purification was required for this step, yielding crude compound 40b (25 mg).

[0787] LCMS(ESI)m / z:[M+H]+ =384.2.

[0788] Step 3

[0789] Reactant 40b (25 mg, 0.067 mmol) was dissolved in DMSO (3 mL), and 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (12 mg, 0.045 mmol), DIPEA (20 mg, 0.15 mmol), and HBTU (21 mg, 0.055 mmol) were added at room temperature and stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction solution was poured into water (50 mL), and then extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC purification (compound HPLC purification preparation method 1) yielded compound C040 (9.19 mg, yield 22.4%).

[0790] LCMS(ESI)m / z:[M+H] + =634.2.

[0791] 1 H NMR (500MHz, DMSO-d6) δ13.14(s,1H),10.54(s,1H),8.63(t,J=5.5Hz,1H),8.01–7.89(m,2H),7.84(dd, J=8.4,2.1Hz,1H),7.68(d,J=8.3Hz,1H),7.50(s,2H),7.27(t,J=7.7Hz,1H),6.93(t,J=7.0Hz,2H),4.3 6(d,J=4.1Hz,1H),3.79–3.72(m,1H),3.63(dt,J=12.5,6.3Hz,2H),3.30(d,J=6.6Hz,4H),2.76(q,J=6. 7,6.3Hz,2H),2.70(s,1H),2.37(d,J=7.9Hz,5H),2.23(s,2H),1.97(s,2H),1.69(q,J=6.9,6.5Hz,3H).

[0792] Example 41: Preparation of compound C041

[0793]

[0794] Step 1

[0795] Intermediate 3 (30 mg, 0.08 mmol) was dissolved in DCM (5 mL) at room temperature, and 1-Boc-4-piperidinic acid (15 mg, 0.08 mmol) and acetic acid (15 mg, 0.24 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of sodium triacetoxyborohydride (51 mg, 0.24 mmol) and stirring at room temperature for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into 250 mL of water and extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by column chromatography (methanol:dichloromethane = 0.8%) to give compound 41a (18 mg, 40% yield).

[0796] LCMS(ESI)m / z:[M+H] + =604.2.

[0797] Step 2

[0798] Crude compound 41a (18 mg, 0.032 mmol) was dissolved in methanol (3 mL) at room temperature, and dioxane hydrochloride solution (1 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was evaporated to dryness to obtain crude compound 41b (15 mg).

[0799] LCMS(ESI)m / z:[M+H] + =504.3.

[0800] Step 3

[0801] Reactant 41b (15 mg, 0.03 mmol) was dissolved in DMSO (3 mL), and 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (7 mg, 0.025 mmol), DIPEA (20 mg, 0.15 mmol), and HBTU (12 mg, 0.031 mmol) were added at room temperature and stirred for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was poured into water (50 mL), and then extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC purification (compound HPLC purification preparation method 1) yielded compound C041 (6.79 mg, yield: 30%).

[0802] LCMS(ESI)m / z:[M+H] + =754.3.

[0803] Example 42: Preparation of compound CO42

[0804]

[0805] Step 1

[0806] Intermediate 1 (50 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL) at room temperature. Triethylamine (61 mg, 0.61 mmol) was added, and the reaction mixture was stirred at 25 °C for 1 hour. Compound 1-N-BOC-4-acetylpiperidine (51.1 mg, 0.22 mmol) and tetraisopropyl titanate (85 mg, 0.30 mmol) were added to the reaction mixture, and the reaction was carried out at room temperature for 1 hour. Sodium triacetoxyborohydride (79 mg, 0.38 mmol) was added, and the mixture was stirred at 25 °C for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. After the reaction was completed, saturated ammonium chloride aqueous solution (10 mL) and dichloromethane (10 mL) were added. The mixture was filtered, and the filter cake was washed with dichloromethane. The organic phases were combined and washed with saturated brine (2*20 mL). The organic layer was taken, dried with anhydrous Na2SO4, filtered, and rotary evaporated. The crude product was purified by Pre-TLC (dichloromethane / methanol = 10:1) to obtain compound 42a (26 mg, yield: 30.3%).

[0807] LCMS(ESI)m / z:[M+H] + =538.3.

[0808] Step 2

[0809] Compound 42a (26 mg, 0.048 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, and HCl / dioxane (0.5 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give compound 42b (15.1 mg).

[0810] LCMS (ESI) m / z: [M+H]+=438.3.

[0811] Step 3

[0812] Compound 42b (15.1 mg, 0.036 mmol) was dissolved in DMSO (3 mL) at room temperature. Compound DIPEA (14 mg, 0.11 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (11.6 mg, 0.043 mmol) and HATU (17.3 mg, 0.054 mmol) were added to the reaction mixture, and the reaction was carried out at 25 °C for 1 hour. The reaction was completed by LCMS. The reaction mixture was added to water (20 mL), and extracted with ethyl acetate (3 x 20 mL). The organic layers were combined and washed with saturated saline solution (3 x 20 mL). The combined organic layers were dried with Na2SO4, filtered, and rotary evaporated. The crude product was purified by Pre-HTLC (compound HPLC purification preparation method 1) to obtain compound CO42 (2.5 mg, yield: 10.45%).

[0813] LCMS(ESI)m / z:[M+H] + =675.2.

[0814] Example 43: Preparation of compound C043

[0815]

[0816] Step 1

[0817] N-Boc-4-piperidinemethanol (2 g, 9.29 mmol) was dissolved in tetrahydrofuran (100 mL) under ice bath conditions. N-hydroxyphthalimide (1.67 g, 10.22 mmol), triphenylphosphine (2.92 g, 11.15 mmol), and DIAD (2.25 g, 11.15 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain a crude product. Purification was performed by silica gel chromatography (petroleum ether:ethyl acetate = 0-22%) to give compound 43a (3.2 g, yield: 95.58%).

[0818] LCMS(ESI)m / z:[M+Na] + =383.2.

[0819] Step 2

[0820] Compound 43a (500 mg, 1.39 mmol) was dissolved in dioxane hydrochloride (4 mL) at room temperature and stirred at room temperature for 2 hours. The reaction solution was concentrated under vacuum to obtain crude compound 43b (411 mg), which was used directly in the next step without purification.

[0821] Step 3

[0822] Compound 43b (411 mg, 1.39 mmol) was dissolved in methanol (5 mL) and dichloromethane (10 mL) at room temperature. DIPEA (179.64 mg, 1.39 mmol) and 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (592.89 mg, 2.78 mmol) were added, and the reaction mixture was stirred at 35 °C for 16 hours. Then, sodium triacetylborohydride (1.47 g, 6.95 mmol) was added to the reaction mixture, and stirring was continued at 35 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification by silica gel chromatography (methanol:dichloromethane = 0-4%) yielded compound 43c (450 mg, yield: 71.01%).

[0823] LCMS (ESI) m / z: [M+H]+=458.3.

[0824] Step 4

[0825] Compound 43c (450 mg, 0.98 mmol) was dissolved in ethanol (5 mL) at room temperature, and hydrazine hydrate (306.62 mg, 4.9 mmol) was added. The reaction mixture was stirred at 80 °C for 0.5 h. LCMS showed complete conversion of the reactants and detection of the product. The reaction mixture was rotary evaporated, then dissolved in methyl tert-butyl ether (20 mL) and stirred for 10 min. The mixture was filtered to obtain the filtrate, which was then rotary evaporated to give crude compound 43d (322 mg).

[0826] LCMS (ESI) m / z: [M+H]+=328.2.

[0827] Step 5

[0828] Compound 43d (60 mg, 0.26 mmol) was dissolved in methanol (5 mL) at room temperature. Compound 43e (170 mg, 0.52 mmol) and acetic acid (16 mg, 0.27 mmol) were added, and the reaction mixture was stirred at 70 °C for 16 hours under nitrogen atmosphere. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain a crude product. Purification by Pre-TLC (methanol:dichloromethane = 0-10%) yielded compound 43f (80 mg, yield: 56.74%).

[0829] LCMS (ESI) m / z: [M+H]+=539.4.

[0830] Step 6

[0831] Compound 43f (80 mg, 0.15 mmol) was dissolved in dioxane hydrochloride (4 mL, 4 M) at room temperature and stirred for 1 hour at room temperature. LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was concentrated under vacuum to give crude compound 43 g (60 mg).

[0832] LCMS (ESI) m / z: [M+H]+=439.4.

[0833] Step 7

[0834] 43 g (60 mg, 0.14 mmol) of the compound was dissolved in DMSO (5 mL) at room temperature. 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (38 mg, 0.14 mmol), DIPEA (90 mg, 0.70 mmol), and HATU (59 mg, 0.16 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC purification (compound HPLC purification preparation method 1) yielded compound C043 (24.87 mg, yield: 26.38%).

[0835] LCMS (ESI) m / z: [M+H]+=689.3.

[0836] 1 H NMR (500MHz, DMSO-d6) δ13.10(br,s,1H),10.51(s,1H),8.18(s,2H),7.97(dd,J=8.3,1.5Hz,1H),7.63(d,J=8.2H z,1H),7.54(d,J=2.0Hz,1H),7.51(s,1H),7.38(dd,J=8.2,2.0Hz,1H),7.27(td,J=7.6,1.5Hz,1H),6.98–6.86(m, 2H),4.51–4.39(m,1H),4.15(d,J=6.3Hz,2H),3.78–3.71(m,1H),3.65–3.55(m,2H),2.85(d,J=11.0Hz,2H),2.74( q,J=7.1,6.5Hz,2H),2.36(s,3H),2.14(d,J=6.8Hz,2H),1.92–1.55(m,8H),1.32–1.21(m,2H),1.11-1.02(m,2H).

[0837] Example 44: Preparation of compound C044

[0838]

[0839] Step 1

[0840] Intermediate 1 (30 mg, 0.08 mmol) was dissolved in MeOH (5 mL) at room temperature. 1-Boc-4-piperidinecarboxaldehyde (15 mg, 0.08 mmol) and acetic acid (15 mg, 0.24 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. Then, sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added, and the mixture was stirred at room temperature for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound 44a (23 mg, 54% yield) was obtained by silica gel chromatography (methanol:dichloromethane = 0-14%).

[0841] LCMS(ESI)m / z:[M+H] + =524.3.

[0842] Step 2

[0843] The crude compound 44a (23 mg, 0.044 mmol) was dissolved in methanol (3 mL) at room temperature, and dioxane hydrochloride solution (1 mL, 4 M) was added. After reacting at room temperature for 1 h, LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was evaporated to dryness for later use to obtain crude compound 44b (15 mg).

[0844] LCMS(ESI)m / z:[M+H] + =424.2.

[0845] Step 3

[0846] Reactant 44b (15 mg, 0.035 mmol) was dissolved in DMSO (5 mL) at room temperature. 4-Chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (10 mg, 0.026 mmol), DIPEA (20 mg, 0.15 mmol), and HBTU (12 mg, 0.031 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC purification (compound HPLC purification preparation method 1) yielded compound C044 (18.03 mg, yield 89%).

[0847] LCMS(ESI)m / z:[M+H] + =674.3.

[0848] Example 45: Preparation of compound C045

[0849]

[0850] Step 1

[0851] Intermediate 1 (30 mg, 0.08 mmol) was dissolved in MeOH (5 mL) at room temperature, followed by the addition of 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (15 mg, 0.08 mmol) and acetic acid (15 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of sodium triacetoxyborohydride (51 mg, 0.24 mmol) and stirring at room temperature for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound 45a (23 mg, yield: 48%) was obtained by silica gel chromatography (methanol:dichloromethane = 0-11%).

[0852] LCMS(ESI)m / z:[M+H] + =524.3.

[0853] Step 2

[0854] The crude compound 45a (23 mg, 0.038 mmol) was dissolved in MeOH (3 mL) at room temperature, and dioxane hydrochloride solution (1 mL, 4 M) was added. After reacting at room temperature for 1 h, LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was evaporated to dryness for later use to obtain the crude compound (15 mg).

[0855] LCMS(ESI)m / z:[M+H] + =424.2.

[0856] Step 3

[0857] Reactant 45b (15 mg, 0.03 mmol) was dissolved in DMSO (3 mL) at room temperature, and 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (25 mg, 0.06 mmol) and DIPEA (20 mg, 0.15 mmol) were added. The reaction mixture was stirred at 80 °C for 2 hours. The reaction was confirmed to be complete by LCMS. The reaction mixture was poured into water (50 mL) and then extracted with dichloromethane (20 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by pre-HPLC (compound HPLC purification preparation method 1) to obtain compound C045 (4.83 mg, yield: 23%).

[0858] LCMS(ESI)m / z:[M+H] + =680.3.

[0859] 1 H NMR(500MHz,DMSO-d6)δ13.14(s,1H),11.08(s,1H),8.19(s,1H),7.98(dd,J=8.3,1.7Hz,1H),7 .65(d,J=8.5Hz,1H),7.51(s,2H),7.33–7.20(m,3H),6.97–6.91(m,2H),5.06(dd,J=12.8,5.4Hz ,1H),4.42–4.32(m,1H),4.05(d,J=12.9Hz,2H),3.04–2.76(m,4H),2.68(s,2H),2.39(s,3H),2. 24–2.14(m,4H),2.05–1.93(m,3H),1.80(d,J=12.7Hz,3H),1.70(s,3H),1.16(t,J=12.1Hz,2H).

[0860] Example 46: Preparation of compound C046

[0861]

[0862] Step 1

[0863] Intermediate 2 (66 mg, 0.19 mmol) was dissolved in DMSO (10 mL) at room temperature. 1-Boc-4-piperidinic acid (44 mg, 0.19 mmol), DIPEA (123 mg, 0.95 mmol), and HATU (80 mg, 0.21 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification by silica gel chromatography (methanol:dichloromethane = 0-11%) yielded compound 46a (55 mg, yield: 51.48%).

[0864] LCMS(ESI)m / z:[M+H] + =553.4.

[0865] Step 2

[0866] Compound 46a (55 mg, 0.10 mmol) was dissolved in dioxane hydrochloride (4 mL, 4 M) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain crude compound 46b (45 mg), which was used directly in the next step without purification.

[0867] LCMS(ESI)m / z:[M+H] + =453.4.

[0868] Step 3

[0869] Compound 46b (45 mg, 0.099 mmol) was dissolved in DMSO (10 mL) at room temperature. 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (28 mg, 0.10 mmol), DIPEA (64 mg, 0.50 mmol), and HATU (42 mg, 0.11 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC purification (compound HPLC purification preparation method 1) yielded compound C046 (66.2 mg, yield: 92.73%).

[0870] LCMS(ESI)m / z:[M+H] + =703.4.

[0871] 1H NMR (500MHz, DMSO-d6) δ13.14(s,1H),10.50(s,1H),8.19(s,1H),7.97(dd,J=8.3,1.4Hz,1H),7.64(d,J=8.2Hz,1H),7.57(d ,J=1.9Hz,1H),7.51(s,2H),7.40(dd,J=8.2,2.0Hz,1H),7.27(td,J=7.6,1.5Hz,1H),6.98–6.89(m,2H),4.42(d,J=13.0Hz, 2H),4.18(d,J=6.2Hz,2H),4.04(d,J=12.8Hz,1H),3.81–3.72(m,1H),3.66–3.55(m,2H),3.09–3.01(m,1H),2.99–2.93(m,1 H),2.78–2.70(m,2H),2.54(s,2H),2.37(s,3H),2.08–1.97(m,1H),1.82–1.67(m,3H),1.62–1.44(m,3H),1.25–0.97(m,3H).

[0872] Example 47: Preparation of compound C047

[0873]

[0874] Step 1

[0875] Intermediate 1 (300 mg, 0.84 mmol) was dissolved in DCM / DMSO at a ratio of 1:1 (20 mL) at room temperature. Compound 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (280 mg, 1.68 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Sodium triacetoxyborohydride (700 mg, 3.30 mmol) was then added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether:ethyl acetate = 0-70%) to give compound 47a (250 mg, yield: 82%).

[0876] Step 2

[0877] Compound 47a (110 mg, 0.22 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 47b (100 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =424.3.

[0878] Step 3

[0879] Compound 47b (100 mg, 0.24 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 3-(4-fluoro-1-oxoisoindol-2-yl)piperidin-2,6-dione (66.6 mg, 0.24 mmol) and DIPEA (113.4 mg, 0.88 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Preparation was carried out by HPLC (compound purification method 1). Freeze-drying yielded compound C047 (10.1 mg, yield: 6.8%). LCMS (ESI) m / z: [M+H] + =666.8.

[0880] Example 48: Preparation of compound C048

[0881]

[0882] Step 1

[0883] Intermediate 2 (50 mg, 0.15 mmol) was dissolved in DMSO (3 mL) at room temperature. Compound DIPEA (77.5 mg, 0.60 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Then, compound N-Boc-bromoethylamine (67.2 mg, 0.30 mmol) was added to the reaction mixture, and the mixture was heated to 80 °C and stirred for 4 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was extracted with water (15 mL) and ethyl acetate (15 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was subjected to silica gel chromatography (dichloromethane / methanol = 0-10%) to obtain compound 48a (20.1 mg, yield: 27.1%).

[0884] LCMS(ESI)m / z:[M+H] + =484.6.

[0885] Step 2

[0886] Compound 48a (20.1 mg, 0.041 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, and dioxane hydrochloride (0.5 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give compound 48b (12.1 mg, yield: 72.6%).

[0887] LCMS(ESI)m / z:[M+H] + =384.4.

[0888] Step 3

[0889] Compound 48b (10.1 mg, 0.026 mmol) was dissolved in DMSO (1 mL) at room temperature. Compound DIPEA (13.5 mg, 0.10 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (7.0 mg, 0.026 mmol) and HATU (12.5 mg, 0.039 mmol) were added to the reaction mixture, and the reaction was carried out at 25 °C for 1 hour. The reaction was completed as indicated by LCMS. The reaction mixture was added to water (15 mL), and EA (3 x 20 mL) was added. The organic layers were combined and washed with saturated saline solution (3 x 20 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and rotary evaporated. The crude product was purified by Pre-HTLC (compound HPLC purification preparation method 1) to obtain compound C048 (1.01 mg, yield: 6.00%).

[0890] LCMS(ESI)m / z:[M+H] + =635.1.

[0891] Example 49: Preparation of compound C049

[0892]

[0893] Step 1

[0894] Intermediate 3 (50 mg, 0.13 mmol) was dissolved in dichloromethane (5 mL) at room temperature. Compound TEA (33 mg, 0.33 mmol) was added, and the reaction mixture was stirred at 25 °C for 1 hour. Tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (34.2 mg, 0.14 mmol) and tetraisopropyl titanate (73.9 mg, 0.26 mmol) were added to the reaction mixture, and the reaction was carried out at room temperature for 1 hour. Sodium triacetoxyborohydride (55 mg, 0.26 mmol) was then added, and the mixture was stirred at 25 °C for 12 hours. LC-MS showed complete conversion of the reactants and detection of the product. After the reaction was completed, saturated ammonium chloride aqueous solution (5 mL) and dichloromethane (5 mL) were added. The mixture was filtered, and the filter cake was washed with dichloromethane. The organic phases were combined and washed with saturated brine (2*20 mL). The organic layer was taken, dried with anhydrous Na2SO4, filtered, and rotary evaporated. The crude product was purified by Pre-TLC (dichloromethane / methanol = 10:1) to obtain compound 49a (56 mg, yield: 68.1%).

[0895] LCMS(ESI)m / z:[M+H] + =616.3.

[0896] Step 2

[0897] Compound 49a (50 mg, 0.081 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature. HCl / dioxane (0.5 mL) was added, and the reaction mixture was stirred at 25 °C for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give compound 49b (41.1 mg, yield: 94%). LCMS (ESI) m / z: [M+H]+ = 516.69.

[0898] Step 3

[0899] Compound 49b (35.0 mg, 0.068 mmol) was dissolved in DMSO (2 mL) at room temperature. Compound DIPEA (35.2 mg, 0.27 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (18.3 mg, 0.068 mmol) and HATU (32.8 mg, 0.10 mmol) were added to the reaction mixture, and the reaction was carried out at 25 °C for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was extracted with water (15 mL) and ethyl acetate (15 mL * 3). The mixture was washed with saturated brine (20 mL * 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was then prepared by Pre-HTLC (compound HPLC purification preparation method 1) to obtain compound C049 (6.56 mg, yield: 12.4%).

[0900] LCMS(ESI)m / z:[M+H] + =767.3.

[0901] Example 50: Preparation of compound C050

[0902]

[0903] Step 1

[0904] Intermediate 2 (60 mg, 0.18 mmol) was dissolved in DMSO (10 mL) at room temperature. 1-Boc-4-piperidinic acid (44 mg, 0.19 mmol), DIPEA (117 mg, 0.91 mmol), and HATU (76 mg, 0.20 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification by silica gel chromatography (methanol:dichloromethane = 0-12%) yielded compound 50a (93 mg, yield: 95.75%).

[0905] LCMS(ESI)m / z:[M+H] + =553.4.

[0906] Step 2

[0907] Compound 50a (90 mg, 0.16 mmol) was dissolved in dioxane hydrochloride (4 mL, 4 M) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give crude compound 50b (73 mg).

[0908] LCMS(ESI)m / z:[M+H] + =453.3.

[0909] Step 3

[0910] Compound 50b (73 mg, 0.16 mmol) was dissolved in DMSO (10 mL) at room temperature. 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (43 mg, 0.16 mmol), DIPEA (104 mg, 0.80 mmol), and HATU (67 mg, 0.18 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with dichloromethane (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC purification (compound HPLC purification preparation method 1) yielded compound C050 (37.76 mg, yield 33.18%).

[0911] LCMS (ESI) m / z: [M+H]+=703.3.

[0912] 1 H NMR (500MHz, DMSO-d6) δ13.13(s,1H),10.52(s,1H),8.19(s,1H),7.97(dd,J=8.3,1.5Hz,1H),7.64(d,J=8.2Hz,1H),7.57(d,J=1.9Hz, 1H),7.51(s,2H),7.40(dd,J=8.2,2.0Hz,1H),7.27(td,J=7.6,1.5Hz,1H),6.99–6.87(m,2H),4.42(d,J=12.7Hz,2H),4.18(d,J=6.1Hz, 2H),4.03(d,J=14.0Hz,1H),3.76(ddd,J=13.7,8.1,6.0Hz,1H),3.61(dt,J=12.1,6.1Hz,2H),3.09–3.01(m,1H),2.95(d,J=10.2Hz,1H ),2.79–2.68(m,2H),2.54(s,2H),2.37(s,3H),2.08–1.95(m,1H),1.77(dd,J=23.9,12.3Hz,3H),1.62–1.43(m,3H),1.28–1.00(m,3H).

[0913] Example 51: Preparation of compound C051

[0914]

[0915] Step 1

[0916] Intermediate 3 (250 mg, 0.61 mmol) was dissolved in DMSO (10 mL) at room temperature. Compound 1-tert-butoxycarbonyl-4-piperidineacetic acid (163.5 mg, 0.67 mmol), HATU (278.8 mg, 0.74 mmol), and DIPEA (450 mg, 1.8 mmol) were added, and the reaction mixture was stirred for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether: ethyl acetate = 0-70%) to obtain compound 51a (300 mg, yield: 87.9%).

[0917] Step 2

[0918] Compound 51a (125 mg, 0.18 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 51b (130 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =518.7.

[0919] Step 3

[0920] Compound 51b (130 mg, 0.18 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (69 mg, 0.23 mmol), HATU (103 mg, 0.20 mmol), and DIPA (130 mg, 0.54 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Preparation was carried out by HPLC (compound purification method 1). Freeze-drying yielded compound C051 (18 mg, yield: 6.4%). LCMS (ESI) m / z: [M+H] + =769.3.

[0921] Example 52: Preparation of compound C052

[0922]

[0923] Step 1

[0924] Intermediate 2 (30 mg, 0.08 mmol) was dissolved in methanol (5 mL) at room temperature, followed by the addition of N-tert-butoxycarbonyl-4-piperidinone (15 mg, 0.08 mmol) and acetic acid (15 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of sodium triacetoxyborohydride (50 mg, 0.24 mmol) and stirring at room temperature for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL) and extracted with DCM (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. Compound 52a (16 mg, 39% yield) was obtained by silica gel chromatography (methanol:dichloromethane = 10%).

[0925] LCMS(ESI)m / z:[M+H] + =524.3.

[0926] Step 2

[0927] Crude compound 52a (16 mg, 0.031 mmol) was dissolved in MeOH (3 mL) at room temperature, and dioxane hydrochloride solution (1 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was evaporated to dryness to give crude compound 52b (13 mg).

[0928] LCMS(ESI)m / z:[M+H] + =424.2.

[0929] Step 3

[0930] Reactant 52b (13 mg, 0.03 mmol) was dissolved in DMSO (3 mL) at room temperature, and 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (10 mg, 0.026 mmol), DIPEA (20 mg, 0.15 mmol), and HBTU (12 mg, 0.031 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with DCM (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC purification (compound HPLC purification preparation method 1) yielded compound C052 (3.03 mg, yield 13%).

[0931] LCMS(ESI)m / z:[M+H] + =674.2.

[0932] 1 H NMR (500MHz, DMSO-d6) δ13.13(s,1H),10.51(s,1H),8.18(s,1H),7.97(dd,J=8.3,1.7Hz,1H),7.63(d,J=8.2H z,1H),7.56(d,J=2.0Hz,1H),7.51(s,2H),7.40(dd,J=8.2,2.0Hz,1H),7.29–7.23(m,1H),6.96–6.90(m,2H),4 .47(s,1H),4.15(d,J=6.1Hz,2H),3.75(d,J=7.0Hz,1H),3.65–3.57(m,2H),2.88(s,2H),2.74(q,J=7.1,6.4Hz ,3H),2.37(s,3H),2.15(s,3H),1.82(s,1H),1.71(d,J=11.7Hz,4H),1.46–1.37(m,2H),1.24(d,J=7.6Hz,3H).

[0933] Example 53: Preparation of compound C053

[0934]

[0935] Step 1

[0936] Intermediate 3 (180 mg, 0.42 mmol) was dissolved in DCM / DMSO at a ratio of 1:1 (20 mL) at room temperature. N-tert-butyloxycarbonyl-4-piperidinone (140 mg, 0.84 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Sodium triacetoxyborohydride (350 mg, 1.65 mmol) was added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water, and extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether:ethyl acetate = 0-70%) to give compound 53a (110 mg, yield: 75%).

[0937] Step 2

[0938] Compound 53a (110 mg, 0.22 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 53b (90 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H]+ =476.6.

[0939] Step 3

[0940] Compound 53b (90 mg, 0.22 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (66.6 mg, 0.23 mmol), HATU (172 mg, 0.33 mmol), and DIPEA (215 mg, 0.9 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture, and extracted with DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Preparation: HPLC preparation (Compound HPLC purification preparation method 1). Freeze-drying yielded compound C018 (20 mg, yield: 13.8%). LCMS (ESI) m / z: [M+H] + =727.3.

[0941] Example 54: Preparation of compound C054

[0942]

[0943] Step 1

[0944] Intermediate 3 (175 mg, 0.42 mmol) was dissolved in DCM / DMSO at a ratio of 1:1 (20 mL) at room temperature. N-tert-butoxycarbonyl-4-piperidinone (140 mg, 0.84 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Sodium triacetoxyborohydride (350 mg, 1.65 mmol) was then added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water, and the mixture was extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-70%) yielded compound 54a (110 mg, yield: 75%).

[0945] Step 2

[0946] Compound 54a (110 mg, 0.22 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 54b (90 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] +=476.6.

[0947] Step 3

[0948] Compound 54b (90 mg, 0.22 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (66.6 mg, 0.24 mmol) and DIPEA (113.4 mg, 0.88 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Preparation was carried out by HPLC (compound purification method 1). Freeze-drying yielded compound C054 (9.3 mg, yield: 6.4%). LCMS (ESI) m / z: [M+H] + =732.8.

[0949] Example 55: Preparation of compound C055

[0950]

[0951] Step 1

[0952] Intermediate 1 (20 mg, 0.061 mmol) was dissolved in methanol (5 mL) at room temperature. Compound AcOH (7.5 mg, 0.12 mmol) and compound 1-BOC-4-fluoro-4-piperidinecarboxaldehyde (21.2 mg, 0.091 mmol) were added. The reaction mixture was stirred at 25 °C for 12 hours. Sodium triacetoxyborohydride (25.9 mg, 0.12 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. At the end of the reaction, saturated ammonium chloride aqueous solution (10 mL) and dichloromethane (3 x 20 mL) were added. The organic phases were combined and washed with saturated brine (2 x 20 mL). The organic layer was collected, dried over anhydrous Na₂SO₄, filtered, and rotary evaporated. The crude product was purified by Pre-TLC (dichloromethane / methanol = 10:1) to give compound 55a (13 mg, yield: 37.6%).

[0953] LCMS(ESI)m / z:[M+H] + =542.3.

[0954] Step 2

[0955] Compound 55a (13 mg, 0.022 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, and HCl / dioxane (0.5 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give compound 55b (7 mg, yield: 68.6%).

[0956] LCMS(ESI)m / z:[M+H] + =442.5.

[0957] Step 3

[0958] Compound 55b (7 mg, 0.016 mmol) was dissolved in DMSO (1 mL) at room temperature. Compound DIPEA (8.5 mg, 0.064 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (4.3 mg, 0.016 mmol) and HATU (7.7 mg, 0.024 mmol) were added to the reaction mixture, and the reaction was carried out at 25 °C for 1 hour. The reaction was completed by LCMS. The reaction mixture was extracted with water (15 mL) and ethyl acetate (15 mL * 3). The mixture was washed with saturated brine (20 mL * 2). The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was then prepared by HPLC (compound HPLC purification preparation method 1) to obtain compound C055 (1.52 mg, yield: 13.6%).

[0959] LCMS(ESI)m / z:[M+H] + =693.2.

[0960] Example 56: Preparation of compound C056

[0961]

[0962] Step 1

[0963] Compound 62d (50 mg, 0.14 mmol) was dissolved in DMSO (2 mL) at room temperature. Compound DIPEA (90.5 mg, 0.70 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. Then, 1-Boc-4-piperidinic acid (32.2 mg, 0.14 mmol) and HATU (54 mg, 0.17 mmol) were added, and the reaction mixture was stirred at 25 °C for 1 hour. LCMS showed the reaction was complete. The reaction mixture was added to water (20 mL), followed by EA (3 x 20 mL). The organic layers were combined and washed with saturated saline solution (3 x 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and rotary evaporated. The crude product was purified by Pre-TLC (petroleum ether / ethyl acetate = 1:1) to give compound 56a (42.52 mg, yield: 53.6%). LCMS (ESI) m / z: [M+H]⁺ = 578.7.

[0964] Step 2

[0965] Compound 56a (42 mg, 0.022 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature. HCl / dioxane (0.5 mL) was added, and the reaction mixture was stirred at 25 °C for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give compound 56b (25.2 mg, yield: 72%). LCMS (ESI) m / z: [M+H]+ = 478.60.

[0966] Step 3

[0967] Compound 56b (25 mg, 0.052 mmol) was dissolved in DMSO (2 mL) at room temperature. Compound DIPEA (26.9 mg, 0.21 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (14.1 mg, 0.052 mmol) and HATU (25.1 mg, 0.078 mmol) were added to the reaction mixture, and the reaction was carried out at 25 °C for 1 hour. The reaction was completed by LCMS. The reaction mixture was extracted with water (15 mL) and ethyl acetate (15 mL * 3). The mixture was washed with saturated brine (20 mL * 2). The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by preparative HPLC (compound HPLC purification preparation method 1) to obtain compound C056 (12.6 mg, yield: 31.8%). LCMS (ESI) m / z: [M+H]+=729.2.

[0968] Example 57: Preparation of compound C057

[0969]

[0970] Step 1

[0971] Compound 6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (500 mg, 2.34 mmol) was dissolved in tetrahydrofuran (10 mL) under ice bath conditions. N-hydroxyphthalimide (420 mg, 2.57 mmol), triphenylphosphine (740 mg, 2.81 mmol), and DIAD (570 mg, 2.81 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain a crude product. Purification was performed by silica gel chromatography (petroleum ether: ethyl acetate = 0-22%) to give compound 57a (430 mg, yield: 51.18%).

[0972] LCMS(ESI)m / z:[M+Na] + =381.2.

[0973] Step 2

[0974] Compound 57a (430 mg, 1.20 mmol) was dissolved in ethanol (10 mL) at room temperature, and hydrazine hydrate (75 mg, 1.2 mmol, 80% purity) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, concentrated under vacuum to obtain a crude product, which was then slurried with methyl tert-butyl ether (30 mL), filtered, and concentrated under vacuum to obtain crude compound 57b (270 mg).

[0975] Step 3

[0976] Intermediate 1c (200 mg, 0.87 mmol) was dissolved in methanol (5 mL) at room temperature. Compound 57b (270 mg, 1.18 mmol) and acetic acid (104 mg, 1.74 mmol) were added, and the reaction mixture was stirred at 80 °C for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain the crude product. Purification was performed by silica gel chromatography (petroleum ether: ethyl acetate = 0-32%) to obtain compound 57c (383 mg).

[0977] LCMS(ESI)m / z:[M+H] + =440.3.

[0978] Step 4

[0979] Compound 57c (383 mg, 0.87 mmol) was dissolved in dioxane hydrochloride (4 mL, 4 M) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum, then dissolved in saturated sodium carbonate solution (30 mL), and extracted with dichloromethane (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give crude compound 57d (208 mg, yield 70.33%).

[0980] LCMS(ESI)m / z:[M+H] + =340.2.

[0981] Step 5

[0982] Compound 57d (60 mg, 0.18 mmol) was dissolved in methanol (2 mL) and dichloromethane (4 mL) at room temperature. 1-BOC-4-formyl-4-methylpiperidine (82 mg, 0.36 mmol) and acetic acid (22 mg, 0.36 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. Then, sodium triacetoxyborohydride (190 mg, 0.90 mmol) was added, and the mixture was stirred for 1 hour. LC-MS showed approximately 40% conversion of the reactants, and the product was detected. The reaction mixture was concentrated under vacuum to give a crude product. Purification by silica gel chromatography (methanol:dichloromethane = 0-3%) gave compound 57e (17 mg, yield: 17.46%).

[0983] LCMS (ESI) m / z: [M+H]+=551.4.

[0984] Step 6

[0985] Compound 57e (17 mg, 0.031 mmol) was dissolved in dioxane hydrochloride (2 mL, 4 M) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give crude compound 57f (13.9 mg).

[0986] LCMS(ESI)m / z:[M+H] + =451.3.

[0987] Step 7

[0988] Compound 57f (13.9 mg, 0.031 mmol) was dissolved in DMSO (10 mL) at room temperature, and 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (7.9 mg, 0.029 mmol), HATU (13 mg, 0.034 mmol), and DIPEA (20 mg, 0.15 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. LCMS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound C57 (5.93 mg, yield: 26.89%) was obtained by preparative HPLC (compound HPLC purification preparation method 1).

[0989] LCMS(ESI)m / z:[M+H] + =701.4.

[0990] Example 58: Preparation of compound C058

[0991]

[0992] Step 1

[0993] Intermediate 3 (400 mg, 0.84 mmol) was dissolved in DCM / DMSO at a ratio of 1:1 (20 mL) at room temperature. Compound 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (280 mg, 1.68 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Sodium triacetoxyborohydride (700 mg, 3.30 mmol) was then added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water, and the mixture was extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether:ethyl acetate = 0-70%) to give compound 58a (250 mg, yield: 82%).

[0994] Step 2

[0995] Compound 58a (110 mg, 0.22 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was obtained by vacuum concentration. Compound 58b (100 mg) was purified by silica gel chromatography (MeOH:DCM = 10%).

[0996] LCMS(ESI)m / z:[M+H] + =490.7.

[0997] Step 3

[0998] Compound 58b (100 mg, 0.24 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (73.2 mg, 0.27 mmol), HATU (172 mg, 0.33 mmol), and DIPEA (215 mg, 0.9 mmol) were added, and the reaction mixture was stirred for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Preparation was carried out by HPLC (compound purification method 1). Freeze-drying yielded compound C058 (20 mg, yield: 13.7%).

[0999] LCMS(ESI)m / z:[M+H] + =741.3.

[1000] Example 59: Preparation of compound C059

[1001]

[1002] Step 1

[1003] Compound 57d (320 mg, 0.84 mmol) was dissolved in DCM / DMSO (1:1, 20 mL) at room temperature. Compound 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (280 mg, 1.68 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Sodium triacetoxyborohydride (700 mg, 3.30 mmol) was added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water, and extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification by silica gel chromatography (petroleum ether:ethyl acetate = 0-70%) yielded compound 59a (250 mg, yield: 79%).

[1004] Step 2

[1005] Compound 59a (110 mg, 0.22 mmol) was dissolved in dioxane hydrochloride solution (10 mL, 4 M) at room temperature and stirred for 12 hours. LC-MS showed complete conversion of the reactants and detection of the product. The crude product was obtained by vacuum concentration. Compound 59b (100 mg) was purified by silica gel chromatography (MeOH:DCM = 10%).

[1006] LCMS(ESI)m / z:[M+H] + =436.6.

[1007] Step 3

[1008] Compound 59b (100 mg, 0.24 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (66.6 mg, 0.24 mmol) and DIPEA (113.4 mg, 0.88 mmol) were added, and the reaction mixture was stirred for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Preparation was carried out by HPLC (compound purification method 1). Freeze-drying yielded compound C059 (12.1 mg, yield: 9.2%).

[1009] LCMS(ESI)m / z:[M+H] + =692.8.

[1010] Example 60: Preparation of compound C060

[1011]

[1012] Step 1

[1013] Compound 60a (50 mg, 0.093 mmol) was dissolved in dioxane hydrochloride (4 mL, 4 M) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give crude compound 60b (40.6 mg).

[1014] LCMS(ESI)m / z:[M+H] + =437.3.

[1015] Step 2

[1016] Compound 60b (40.6 mg, 0.093 mmol) was dissolved in DMSO (10 mL) at room temperature. 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (24 mg, 0.089 mmol), DIPEA (60 mg, 0.46 mmol), and HATU (39 mg, 0.10 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with DCM (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound C060 (29.12 mg, yield: 45.52%) was obtained by preparative HPLC (compound purification preparation method 1).

[1017] LCMS(ESI)m / z:[M+H] + =687.3.

[1018] 1 H NMR (500MHz, DMSO-d6) δ13.15(s,1H),10.52(s,1H),8.19(s,1H),7.97(dd,J=8.3,1.5Hz,1H),7.62(d,J=8.2Hz ,1H),7.58–7.45(m,3H),7.37(dd,J=8.2,2.0Hz,1H),7.27(td,J=7.6,1.5Hz,1H),6.99–6.87(m,2H),4.48–4.3 5(m,1H),4.09(d,J=7.1Hz,2H),3.79–3.72(m,1H),3.67–3.50(m,3H),2.97(d,J=8.7Hz,2H),2.76–2.70(m,2H) ,2.37(s,3H),2.25(d,J=7.3Hz,4H),1.85–1.55(m,4H),1.51–1.38(m,3H),1.02(qd,J=12.9,12.3,4.2Hz,2H).

[1019] Example 61: Preparation of compound C061

[1020]

[1021] Step 1

[1022] N-hydroxyphthalimide (150 mg, 0.92 mmol) was dissolved in THF (10 mL) at room temperature. Triphenylphosphine (310 mg, 1.2 mmol) and 6-(BOC-amino)-1-hexanol (200 mg, 0.92 mmol) were added under ice bath conditions. After three nitrogen purgings, DIAD (242 mg, 1.2 mmol) was slowly added under ice bath conditions. The temperature was slowly raised from the ice bath to room temperature and stirred for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was poured into water (50 mL) and extracted with DCM (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound 61a (105 mg, yield: 30%) was purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-50%).

[1023] LCMS(ESI)m / z:[M+H] + =362.1.

[1024] Step 2

[1025] Compound 61a (105 mg, 0.3 mmol) was dissolved in EtOH (5 mL) at room temperature, and hydrazine hydrate (0.5 mL, 80%) was added. After stirring at room temperature for 30 min, a white solid was formed. The white solid was filtered, the filtrate was evaporated to dryness, and methyl tert-butyl ether was added and stirred. The filtrate was collected and evaporated to dryness for later use. No purification was required in this step to obtain crude compound 61b (67 mg).

[1026] LCMS(ESI)m / z:[M+H] + =232.2.

[1027] Step 3

[1028] Compound 61b (67 mg, 0.3 mmol) was dissolved in methanol (5 mL) at room temperature, and intermediate 1c (69 mg, 0.3 mmol) and AcOH (10 mg, 0.1 mmol) were added. The reaction mixture was stirred at 60 °C for 16 h. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL) and extracted with DCM (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound 61c (66 mg, yield: 47%) was obtained by silica gel chromatography (methanol: dichloromethane = 0-10%).

[1029] LCMS(ESI)m / z:[M+H] + =443.2.

[1030] Step 4

[1031] Reactant 61c (66 mg, 0.14 mmol) was dissolved in methanol (1 mL) at room temperature, followed by the addition of dioxane hydrochloride solution (1 mL, 4 M) at room temperature and stirring for 1 h. LC-MS showed complete conversion of the reactant and detection of the product. The reaction solution was then directly evaporated to dryness to give crude compound 61d (51 mg).

[1032] LCMS(ESI)m / z:[M+H] + =343.2.

[1033] Step 5

[1034] Compound 61d (51 mg, 0.14 mmol) was dissolved in DMSO (3 mL) at room temperature, and 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (26 mg, 0.11 mmol), DIPEA (40 mg, 0.3 mmol), and HBTU (40 mg, 0.11 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with DCM (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound C061 (7.8 mg, yield: 10%) was obtained by preparative HPLC (compound purification preparation method 1).

[1035] LCMS(ESI)m / z:[M+H] + =593.2.

[1036] Example 62: Preparation of compound C062

[1037]

[1038] Step 1

[1039] N-hydroxyphthalimide (2.0 g, 12.26 mmol) was dissolved in THF (20 mL) at 0 °C. 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (3.55 g, 14.71 mmol) and triphenylphosphine (4.82 g, 18.39 mmol) were added. DIAD (3.72 mg, 18.39 mmol) was added to the reaction solution at 0 °C. The mixture was stirred at 25 °C for 12 hours under nitrogen protection. LC-MS showed complete conversion of the reactants and detection of the product. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (2 x 50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and rotary evaporated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 0%-35%) to give compound 62a (1.83 g, yield: 37.3%).

[1040] LCMS(ESI)m / z:[M+H] + =386.4.

[1041] Step 2

[1042] Compound 62a (1.83 g, 4.66 mmol) was dissolved in ethanol (20 mL) at room temperature, and 80% hydrazine hydrate (0.5 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants. The mixture was filtered, and the filter cake was washed with methyl tert-butyl ether (20 mL). The filtrate was concentrated under vacuum to obtain a crude product. The crude product was then slurried with methyl tert-butyl ether (20 mL) to obtain compound 62b (1.2 g).

[1043] Step 3

[1044] Intermediate 3c (500 mg, 2.18 mmol) was dissolved in methanol (10 mL) at room temperature. Compound AcOH (0.1 mL) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Compound 62b (838 mg, 3.27 mmol) was then added, and the mixture was heated to 75 °C and reacted for 12 hours. LCMS showed that the reaction was complete. After cooling to room temperature, a large amount of solid precipitated. The solid was filtered, and the filter cake was washed with methanol to obtain compound 62c (560 mg).

[1045] LCMS(ESI)m / z:[M+H] + =467.3.

[1046] Step 4

[1047] Compound 62c (560 mg, 1.2 mmol) was dissolved in dichloromethane (6 mL) and methanol (6 mL) at room temperature, and dioxane hydrochloride (2 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give compound 62d (350 mg).

[1048] LCMS(ESI)m / z:[M+H] + =367.4.

[1049] Step 5

[1050] Compound 62d (70 mg, 0.19 mmol) was dissolved in methanol (5 mL) at room temperature. Compound AcOH (11.5 mg, 0.19 mmol) and 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (81 mg, 0.38 mmol) were added, and the reaction mixture was stirred at 25 °C for 12 hours. Sodium triacetoxyborohydride (161 mg, 0.76 mmol) was then added, and the mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. After the reaction was complete, saturated ammonium chloride solution (10 mL) and dichloromethane (2 x 10 mL) were added. The mixture was filtered, and the filter cake was washed with dichloromethane. The organic phases were combined and washed with saturated brine (2 x 20 mL). The organic layer was collected, dried over anhydrous Na₂SO₄, filtered, and rotary evaporated. The crude product was purified by Pre-TLC (dichloromethane / methanol = 10:1) to obtain compound 62e (55 mg, yield: 49.6%).

[1051] LCMS(ESI)m / z:[M+H] + =564.3.

[1052] Step 6

[1053] Compound 62e (35 mg, 0.062 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, and dioxane hydrochloride (0.5 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give compound 62f (26 mg).

[1054] LCMS(ESI)m / z:[M+H] + =464.1.

[1055] Step 7

[1056] Compound 62f (26.0 mg, 0.056 mmol) was dissolved in DMSO (2 mL) at room temperature. Compound DIPEA (30.1 mg, 0.22 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (15 mg, 0.056 mmol) and HATU (30.1 mg, 0.084 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. LCMS showed complete conversion of the reactants and detection of the product. The reaction mixture was added to water (20 mL) and ethyl acetate (3 x 20 mL). The organic layers were combined and washed with saturated saline solution (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and rotary evaporated. The crude product was purified by preparative HPLC (compound HPLC purification preparation method 1) to obtain compound C062 (11.52 mg, yield: 27.8%).

[1057] LCMS(ESI)m / z:[M+H] + =715.2.

[1058] Example 63: Preparation of compound C063

[1059]

[1060] Step 1

[1061] Intermediate 2 (30 mg, 0.08 mmol) was dissolved in MeOH (5 mL) at room temperature. 4-N-Boc-aminocyclohexanone (15 mg, 0.08 mmol) and acetic acid (15 mg, 0.24 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Then, sodium triacetoxyborohydride (50 mg, 0.24 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound 63a (33 mg, 76% yield) was obtained by silica gel chromatography (methanol:dichloromethane = 10%).

[1062] LCMS(ESI)m / z:[M+H] + =538.3.

[1063] Step 2

[1064] Crude compound 63a (33 mg, 0.061 mmol) was dissolved in MeOH (3 mL) at room temperature, and dioxane hydrochloride solution (1 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was evaporated to dryness to obtain crude compound 63b (26.8 mg).

[1065] LCMS(ESI)m / z:[M+H] + =438.2.

[1066] Step 3

[1067] Reactant 63b (26.8 mg, 0.061 mmol) was dissolved in DMSO (3 mL) at room temperature, and 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (15 mg, 0.055 mmol), DIPEA (25 mg, 0.18 mmol), and HBTU (25 mg, 0.067 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. LCMS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with DCM (20 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound C063 (14.3 mg, yield: 34%) was obtained by preparative HPLC (compound purification preparation method 1).

[1068] LCMS(ESI)m / z:[M+H] + =688.2.

[1069] Example 64: Preparation of compound C064

[1070]

[1071] Step 1

[1072] Compound 6-chloronicotinaldehyde (50 mg, 0.35 mmol) was dissolved in THF (5 mL) and water (1 mL) at room temperature. N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (108 mg, 0.35 mmol), Pd(dppf)Cl2·DCM (23 mg, 0.035 mmol), and potassium carbonate (145 mg, 1.05 mmol) were added. The reaction mixture was stirred at ℃ for 2 hours under nitrogen atmosphere. TLC showed complete conversion of the reactants and detection of new spots. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether:ethyl acetate = 0-20%) to give compound 64a (63 mg, yield: 61.86%).

[1073] Step 2

[1074] Compound 64a (63 mg, 0.22 mmol) was dissolved in methanol (3 mL) at room temperature, and dry palladium on carbon (0.23 g, 0.22 mmol) (10%) was added. The reaction mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was filtered and concentrated under vacuum to give crude compound 64b (63 mg).

[1075] LCMS(ESI)m / z:[M+H] +=293.2.

[1076] Step 3

[1077] Compound 64b (63 mg, 0.22 mmol) was dissolved in DCM (3 mL) at room temperature, and activated manganese dioxide (39 mg, 0.45 mmol) was added. The reaction mixture was stirred at 40 °C for 2 hours under nitrogen atmosphere. LCMS showed complete conversion of the reactants and detection of the product. The reaction solution was filtered and concentrated under vacuum to obtain crude compound 64c (62 mg).

[1078] LCMS(ESI)m / z:[M+H] + =235.0.

[1079] Step 4

[1080] Intermediate 1 (45 mg, 0.14 mmol) was dissolved in DMSO (3 mL) and DCM (6 mL) at room temperature. 64c (62 mg, 0.21 mmol), tetraisopropyl titanate (80 mg, 0.28 mmol), and acetic acid (9 mg, 0.15 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. Then, sodium triacetylborohydride (150 mg, 0.70 mmol) was added, and the mixture was stirred at room temperature for 1 hour. LC-MS showed partial conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification by silica gel chromatography (methanol:dichloromethane = 0-9%) yielded compound 64d (47 mg, yield: 28.41%).

[1081] LCMS(ESI)m / z:[M+H] + =602.5.

[1082] Step 5

[1083] Compound 64d (47 mg, 0.039 mmol) was dissolved in dioxane hydrochloride (2 mL, 4 M) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain crude compound 64e (19 mg), which was used directly in the next step without purification.

[1084] LCMS(ESI)m / z:[M+H] + =502.3.

[1085] Step 5

[1086] Compound 64e (19 mg, 0.038 mmol) was dissolved in DMSO (10 mL) at room temperature. 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (10 mg, 0.037 mmol), HATU (16 mg, 0.042 mmol), and DIPEA (25 mg, 0.19 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with DCM (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound C064 (6.88 mg, yield: 23.81%) was obtained by preparative HPLC (compound purification preparation method 1).

[1087] LCMS(ESI)m / z:[M+H] + =752.4.

[1088] Example 65: Preparation of compound C065

[1089]

[1090] Step 1

[1091] Intermediate 1 (200 mg, 0.61 mmol) was dissolved in DMSO (10 mL) at room temperature. Tert-butoxycarbonyl sarcosine (123.5 mg, 0.67 mmol), HATU (278.8 mg, 0.74 mmol), and DIPA (450 mg, 1.8 mmol) were added, and the reaction mixture was stirred for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether: ethyl acetate = 0-70%) to give compound 65a (300 mg, yield: 94.5%).

[1092] Step 2

[1093] Compound 65a (100 mg, 0.18 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 65b (110 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =398.5.

[1094] Step 3

[1095] Compound 65b (100 mg, 0.24 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (66.6 mg, 0.24 mmol) and DIPEA (113.4 mg, 0.88 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Preparation was carried out by HPLC (compound purification method 1). Freeze-drying yielded compound C065 (10.1 mg, yield: 6.8%). LCMS (ESI) m / z: [M+H] + =654.7.

[1096] Example 66: Preparation of compound C066

[1097]

[1098] Step 1

[1099] Intermediate 1 (300 mg, 0.84 mmol) was dissolved in DCM / DMSO (1:1, 20 mL) at room temperature. Compound 1-Boc-3-pyrrolidinecarboxaldehyde (280 mg, 1.68 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Sodium triacetoxyborohydride (700 mg, 3.30 mmol) was added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water, and extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether: ethyl acetate = 0-70%) to give compound 66a (250 mg, yield: 82%).

[1100] Step 2

[1101] Compound 66a (110 mg, 0.22 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 66b (100 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =410.5

[1102] Step 3

[1103] Compound 66b (100 mg, 0.24 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (73.2 mg, 0.27 mmol), HATU (172 mg, 0.33 mmol), and DIPEA (215 mg, 0.9 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture, and extracted with DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Preparation: HPLC preparation (Compound HPLC purification preparation method 1). Freeze-drying yielded compound C066 (20 mg, yield: 13.7%). LCMS (ESI) m / z: [M+H] + =661.2.

[1104] Example 67: Preparation of compound C067

[1105]

[1106] Step 1

[1107] 300 mg (1.24 mmol) of tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate was dissolved in 10 mL of THF at room temperature. N-hydroxyphthalimide (223 mg, 1.37 mmol), triphenylphosphine (423 mg, 1.61 mmol), and DIAD (326 mg, 1.61 mmol) were added, and the mixture was stirred at room temperature under nitrogen for 16 hours. TLC showed complete conversion of the reactants and detection of a new spot. The reaction solution was concentrated under vacuum to obtain a crude product. Purification was performed by silica gel chromatography (petroleum ether: ethyl acetate = 0-22%) to give compound 67a (451 mg, yield: 93.88%).

[1108] Step 2

[1109] Compound 67a (451 mg, 1.17 mmol) was dissolved in ethanol (5 mL) at room temperature, and hydrazine hydrate (1290 mg, 20.58 mmol, 80%) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. Then, it was dissolved in methyl tert-butyl ether (20 mL) and stirred for half an hour. After filtration, the mixture was concentrated under vacuum to obtain the crude compound 67b (299 mg).

[1110] Step 3

[1111] Compound 67b (230 mg, 1.00 mmol) was dissolved in methanol (20 mL) at room temperature. Intermediate 1c (299 mg, 1.17 mmol) and acetic acid (60 mg, 1.0 mmol) were added, and the mixture was stirred at 80 °C for 16 hours under nitrogen atmosphere. LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was concentrated under vacuum to obtain a crude product. Purification was performed by silica gel chromatography (petroleum ether: ethyl acetate = 0-32%) to give compound 67c (193 mg).

[1112] LCMS(ESI)m / z:[M+H] + =468.3.

[1113] Step 4

[1114] Compound 67c (87 mg, 0.19 mmol) was dissolved in dioxane hydrochloride (3 mL, 4 M) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain crude compound 67d (68 mg), which was used directly in the next step without purification.

[1115] LCMS(ESI)m / z:[M+H] + =368.2.

[1116] Step 5

[1117] Compound 67d (34 mg, 0.093 mmol) was dissolved in DMSO (3 mL) and DCM (6 mL) at room temperature. DIPEA (36 mg, 0.28 mmol) and 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (40 mg, 0.19 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. Then, sodium triacetylborohydride (99 mg, 0.46 mmol) was added, and the mixture was stirred for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and extracted with DCM (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (methanol:dichloromethane = 0-7%) to give compound 67e (36 mg, yield: 68.89%).

[1118] LCMS(ESI)m / z:[M+H] + =565.4.

[1119] Step 6

[1120] Compound 67e (36 mg, 0.064 mmol) was dissolved in dioxane hydrochloride (2 mL, 4 M) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain crude compound 67f (29.6 mg), which was used directly in the next step without purification.

[1121] LCMS(ESI)m / z:[M+H] + =465.4.

[1122] Step 7

[1123] Compound 67f (29.6 mg, 0.064 mmol) was dissolved in DMSO (10 mL) at room temperature. 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (16 mg, 0.060 mmol), HATU (26.77 mg, 0.070 mmol), and DIPEA (41.36 mg, 0.32 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound C067 (20.82 mg) was obtained by preparative HPLC (compound purification method 1).

[1124] LCMS(ESI)m / z:[M+H] + =715.4.

[1125] 1 H NMR (500MHz, DMSO-d6) δ13.13(s,1H),10.51(s,1H),8.19(d,J=9.1Hz,2H),7.97(dd,J=8.3,1.4Hz,1H),7.63(d,J =8.2Hz,1H),7.54(d,J=1.9Hz,1H),7.51(s,1H),7.38(dd,J=8.2,2.0Hz,1H),7.30–7.21(m,1H),7.00–6.83(m,2H ),4.51–4.37(m,1H),4.31(dd,J=7.3,3.8Hz,1H),3.76(dt,J=12.5,6.8Hz,1H),3.67–3.47(m,4H),3.04–2.93(m, 4H), 2.74(q,J=7.0,6.5Hz,2H),2.36(s,5H),1.96–1.69(m,5H),1.67–1.35(m,6H),1.08(qd,J=12.5,3.9Hz,2H).

[1126] Example 68: Preparation of compound C068

[1127]

[1128] Step 1

[1129] Compound 68a (34 mg, 0.093 mmol) was dissolved in DCM (6 mL) and DMSO (3 mL) at room temperature. Trans-4-(BOC-amino)cyclohexylcarbaldehyde (43 mg, 0.19 mmol) and acetic acid (5.6 mg, 0.093 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. Then, sodium triacetylborohydride (99 mg, 0.46 mmol) was added, and the mixture was stirred for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification by silica gel chromatography (methanol:dichloromethane = 0-7%) yielded compound 68b (50 mg, yield: 93.37%).

[1130] LCMS(ESI)m / z:[M+H] + =579.3.

[1131] Step 2

[1132] Compound 68b (50 mg, 0.086 mmol) was dissolved in dioxane hydrochloride (2 mL, 4 M) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain crude compound 68c (41 mg), which was used directly in the next step without purification.

[1133] LCMS(ESI)m / z:[M+H] + =479.3

[1134] Step 3

[1135] Compound 68c (41 mg, 0.086 mmol) was dissolved in DMSO (10 mL) at room temperature. 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (23 mg, 0.086 mmol), HATU (36 mg, 0.095 mmol), and DIPEA (56 mg, 0.43 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with DCM (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Pre-HPLC purification (compound HPLC purification preparation method 1) yielded compound C068 (2.26 mg, yield: 3.29%).

[1136] LCMS (ESI) m / z: [M+H]+=729.4.

[1137] Example 69: Preparation of compound C069

[1138]

[1139] Step 1

[1140] Intermediate 2 (30 mg, 0.08 mmol) was dissolved in MeOH (5 mL) at room temperature. N-tert-butoxycarbonyl-4-piperidinone (15 mg, 0.08 mmol) and acetic acid (15 mg, 0.24 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Then, sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound 69a (23 mg, 48% yield) was obtained by silica gel chromatography (methanol:dichloromethane = 0-7%).

[1141] LCMS(ESI)m / z:[M+H] + =524.3.

[1142] Step 2

[1143] Compound 69a (23 mg, 0.038 mmol) was dissolved in MeOH (3 mL) at room temperature, and dioxane hydrochloride solution (1 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was evaporated to dryness to obtain crude product 69b (17 mg).

[1144] LCMS(ESI)m / z:[M+H]+ =424.2.

[1145] Step 3

[1146] Reactant 69b (17 mg, 0.038 mmol) was dissolved in DMSO (3 mL) at room temperature. 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (10 mg, 0.026 mmol), DIPEA (20 mg, 0.15 mmol), and HBTU (12 mg, 0.031 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (30 mL), and then extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound C069 (8.08 mg, 40% yield) was obtained by preparative HPLC (compound purification preparation method 1).

[1147] LCMS(ESI)m / z:[M+H] + =674.2.

[1148] Example 70: Preparation of compound C070

[1149]

[1150] Step 1

[1151] Intermediate 1 (50 mg, 0.15 mmol) was dissolved in methanol (5 mL) at room temperature. AcOH (10.0 mg, 0.15 mmol) and tert-butyl-4-formylacheptan-1-carboxylic acid ester (41.2 mg, 0.18 mmol) were added, and the reaction mixture was stirred at 25 °C for 12 hours. Sodium triacetoxyborohydride (78.1 mg, 0.36 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with dichloromethane (2 x 10 mL). The organic phases were combined and washed with saturated brine (2 x 20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and rotary evaporated. The crude product was purified by Pre-TLC (dichloromethane / methanol = 10:1) to give compound 70a (35 mg, yield: 43.4%).

[1152] LCMS(ESI)m / z:[M+H] + =538.3.

[1153] Step 2

[1154] Compound 70a (35 mg, 0.065 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, and HCl / dioxane (0.5 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give compound 70b (25 mg, yield: 87.8%).

[1155] LCMS(ESI)m / z:[M+H] + =438.5.

[1156] Step 3

[1157] Compound 70b (25 mg, 0.057 mmol) was dissolved in DMSO (2 mL) at room temperature. Compound DIPEA (29.5 mg, 0.23 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (15.3 mg, 0.057 mmol) and HATU (22.0 mg, 0.068 mmol) were added to the reaction mixture, and the reaction was carried out at 25 °C for 1 hour. The reaction was completed as indicated by LCMS. The reaction mixture was extracted with water (15 mL) and ethyl acetate (15 mL * 3). The mixture was washed with saturated brine (20 mL * 2). The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was then purified by preparative HPLC (compound HPLC purification preparation method 1) to obtain compound C070 (8.66 mg, yield: 21.6%).

[1158] LCMS(ESI)m / z:[M+H] + =689.2.

[1159] Example 71: Preparation of compound C071

[1160]

[1161] Step 1

[1162] Intermediate 1 (50 mg, 0.15 mmol) was dissolved in methanol (5 mL) at room temperature. AcOH (10.0 mg, 0.15 mmol) and trans-4-(BOC-amino)cyclohexylcarbaldehyde (41.7 mg, 0.18 mmol) were added, and the reaction mixture was stirred at 25 °C for 12 hours. Sodium triacetoxyborohydride (78.1 mg, 0.36 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. After the reaction was complete, saturated ammonium chloride solution (10 mL) was added, and the mixture was extracted with dichloromethane (2 x 20 mL). The organic phases were combined and washed with saturated brine (2 x 20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and rotary evaporated. The crude product was purified by Pre-TLC (dichloromethane / methanol = 10:1) to give compound 71a (35 mg, yield: 43.4%).

[1163] LCMS(ESI)m / z:[M+H] + =538.2.

[1164] Step 2

[1165] Compound 71a (35 mg, 0.065 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, and dioxane hydrochloride (0.5 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give compound 71b (25 mg, yield: 87.8%).

[1166] LCMS(ESI)m / z:[M+H] + =438.5.

[1167] Step 3

[1168] Compound 71b (25 mg, 0.057 mmol) was dissolved in DMSO (2 mL) at room temperature. DIPEA (29.5 mg, 0.23 mmol), 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (15.3 mg, 0.057 mmol) and HATU (22.0 mg, 0.068 mmol) were added to the reaction solution. The reaction was carried out at 25 °C for 1 hour. LCMS showed that the reaction was complete. The reaction solution was added to water (20 mL) and dichloromethane (3 x 20 mL). The organic layers were combined and washed with saturated sodium chloride solution (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and rotary evaporated. The crude product was prepared by preparative HPLC (compound HPLC purification preparation method 1) to obtain compound C071 (2.05 mg, yield: 5.2%).

[1169] LCMS(ESI)m / z:[M+H] + =689.2.

[1170] Example 72: Preparation of compound C072

[1171]

[1172] Step 1

[1173] Intermediate 2 (30 mg, 0.08 mmol) was dissolved in MeOH (5 mL) at room temperature. Trans-4-(BOC-amino)cyclohexylcarbaldehyde (15 mg, 0.08 mmol) and acetic acid (15 mg, 0.24 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Then, sodium triacetoxyborohydride (50 mg, 0.24 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. After the reaction was complete, saturated ammonium chloride solution (10 mL) was added, and the mixture was extracted with dichloromethane (2 x 20 mL). The organic phases were combined and washed with saturated brine (2 x 20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and rotary evaporated to obtain the crude product. Pre-TLC (methanol:dichloromethane = 10%) yielded compound 72a (12 mg, yield: 25%).

[1174] LCMS(ESI)m / z:[M+H] + =552.3.

[1175] Step 2

[1176] Compound 72a (12 mg, 0.02 mmol) was dissolved in MeOH (3 mL) at room temperature, and dioxane hydrochloride solution (1 mL, 4 M) was added. The reaction mixture was stirred at room temperature for half an hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was evaporated to dryness to obtain crude compound 72b (9.8 mg).

[1177] LCMS(ESI)m / z:[M+H] + =452.3.

[1178] Step 3

[1179] Reactant 72b (9.8 mg, 0.02 mmol) was dissolved in DMSO (3 mL) at room temperature, and 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (6 mg, 0.018 mmol), DIPEA (10 mg, 0.06 mmol), and HBTU (10 mg, 0.02 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. LCMS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with DCM (20 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound C072 (4.31 mg, 0.006 mmol) was obtained by preparative HPLC (compound purification preparation method 1) with a purity of 95.88% and a yield of 30%.

[1180] LCMS(ESI)m / z:[M+H] + =702.3.

[1181] Example 73: Preparation of compound C073

[1182]

[1183] Step 1

[1184] Intermediate 1 (300 mg, 0.84 mmol) was dissolved in DCM / DMSO (1:1, 20 mL) at room temperature. 3-Formylazetane-1-carboxylic acid tert-butyl ester (280 mg, 1.68 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Sodium triacetoxyborohydride (700 mg, 3.30 mmol) was then added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water, and the mixture was extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether: ethyl acetate = 0-70%) to give compound 73a (250 mg, yield: 89%).

[1185] Step 2

[1186] Compound 73a (110 mg, 0.22 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 73b (100 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =396.5.

[1187] Step 3

[1188] Compound 73b (100 mg, 0.24 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (73.2 mg, 0.27 mmol), HATU (172 mg, 0.33 mmol), and DIPEA (215 mg, 0.9 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture, and extracted with DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Preparation: HPLC preparation (Compound HPLC purification preparation method 1). Freeze-drying yielded compound C073 (20 mg, yield: 15.7%). LCMS (ESI) m / z: [M+H] + =647.1.

[1189] Example 74: Preparation of compound C074

[1190]

[1191] Step 1

[1192] Intermediate 1 (100 mg, 0.31 mmol) was dissolved in THF (20 mL) at room temperature, and then added to methyl bromoacetate (51.4 mg, 0.36 mmol) and potassium carbonate (63.3 mg, 0.46 mmol). The reaction mixture was stirred at 80 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification by silica gel chromatography (methanol:dichloromethane = 0-8%) yielded compound 074a (85 mg, yield: 69.7%).

[1193] LCMS(ESI)m / z:[M+H] + =400.5.

[1194] Step 2

[1195] Compound 074a (85 mg, 0.21 mmol) was dissolved in a THF:H₂O mixture of 4:1 (10 mL) at room temperature, followed by the addition of lithium hydroxide (43.4 mg, 1.81 mmol). The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The pH was adjusted to 4 with 3 M hydrochloric acid solution, and the reaction mixture was poured into water (50 mL). Extraction was then performed with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain crude 074b (80 mg).

[1196] LCMS(ESI)m / z:[M+H] + =386.4.

[1197] Step 3

[1198] Compound 074b (80 mg, 0.21 mmol) was dissolved in DMSO (10 mL) at room temperature. 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (81.3 mg, 0.25 mmol), DIPEA (100 mg, 0.8 mmol), and HATU (101 mg, 0.27 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound C074 (10 mg, yield: 6.94%) was obtained by preparative HPLC (compound purification method 1).

[1199] LCMS(ESI)m / z:[M+H] + =694.8.

[1200] Example 75: Preparation of compound C075

[1201]

[1202] Step 1

[1203] 1 g (4.69 mmol) of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate was dissolved in 10 mL of THF at room temperature. N-hydroxyphthalimide (0.84 g, 5.16 mmol), triphenylphosphine (1.60 g, 6.10 mmol), and DIAD (1.23 g, 6.10 mmol) were added, and the mixture was stirred at room temperature under nitrogen for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was concentrated under vacuum to obtain a crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-27%) yielded compound 075a (1.6 g, yield: 95.21%).

[1204] LCMS(ESI)m / z:[M+Na] + =381.1.

[1205] Step 2

[1206] Compound 075a (1.6 g, 4.46 mmol, 100% purity) was dissolved in ethanol (50 mL) at room temperature, and hydrazine hydrate (0.28 g, 4.46 mmol) was added. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered and concentrated under vacuum to obtain the crude product. Then, it was slurried with methyl tert-butyl ether (30 mL) for 1 hour, filtered, and concentrated under vacuum to obtain the crude compound 075b (1 g).

[1207] Step 3

[1208] Compound 075b (300 mg, 1.31 mmol) was dissolved in methanol (5 mL) at room temperature. Compound 075c (600 mg, 2.63 mmol) and acetic acid (78.67 mg, 1.31 mmol) were added, and the reaction mixture was stirred at 80 °C for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-30%) yielded compound 075d (243 mg, yield: 42.25%).

[1209] LCMS(ESI)m / z:[M+H] + =440.3.

[1210] Step 4

[1211] Compound 075d (246 mg, 0.56 mmol) was dissolved in dioxane hydrochloride (3 mL, 4 M) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain crude compound 075e (190 mg), which was used directly in the next step without purification.

[1212] LCMS(ESI)m / z:[M+H] + =340.2.

[1213] Step 5

[1214] Compound 075e (190 mg, 0.56 mmol) was dissolved in DMSO (5 mL) and DCM (10 mL) at room temperature. Trans-4-(Boc-amino)cyclohexylcarbaldehyde (0.19 g, 0.84 mmol) and acetic acid (67 mg, 1.12 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. Then, sodium triacetylborohydride (0.59 g, 2.80 mmol) was added, and the mixture was stirred for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and extracted with DCM (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (methanol:dichloromethane = 0-5) to give compound 075f (144 mg, yield: 46.71%).

[1215] LCMS (ESI) m / z: [M+H]+=551.4.

[1216] Step 6

[1217] Compound 075f (144 mg, 0.26 mmol) was dissolved in dioxane hydrochloride (3 mL, 4 M) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain 75 g (117.8 mg) of crude compound, which was used directly in the next step without purification.

[1218] LCMS(ESI)m / z:[M+H]+=451.3

[1219] Step 7

[1220] 75 g (58 mg, 0.13 mmol) of the compound was dissolved in DMSO (5 mL) at room temperature. 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (33 mg, 0.12 mmol), HATU (54 mg, 0.14 mmol), and DIPEA (84 mg, 0.65 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with DCM (20 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound C075 (28.10 mg, yield: 30.63%) was obtained by preparative HPLC (HPLC purification preparation method 1).

[1221] LCMS(ESI)m / z:[M+H] + =701.4.

[1222] 1H NMR (500MHz, DMSO-d6) δ13.12(s,1H),10.55(s,1H),8.20(d,J=6.2Hz,2H),7.97(dd,J=8.4,1.5Hz,1H),7.94(dd,J=5.3,2.1Hz,1H),7. 84(dd,J=8.4,2.1Hz,1H),7.67(d,J=8.4Hz,1H),7.49(s,2H),7.29-7.25(m,1H),6.99–6.87(m,2H),4.85–4.77(m,1H),3.80–3.68(m,2H ),3.66–3.58(m,2H),3.27–3.24(m,2H),3.22-3.19(m,2H),2.78–2.72(m,2H),2.54–2.52(m,1H),2.43–2.38(m,1H),2.36(s,3H),2.30– 2.20(m,3H),1.84(d,J=9.9Hz,1H),1.76(d,J=14.3Hz,1H),1.58–1.52(m,1H),1.51–1.45(m,1H),1.36–1.17(m,3H),1.04–0.86(m,2H).

[1223] Example 76: Preparation of compound C076

[1224]

[1225] Step 1

[1226] Compound 76a (100 mg, 0.34 mmol) was dissolved in methanol (5 mL) at room temperature, and compound AcOH (0.1 mL) was added. The reaction mixture was stirred at 25 °C for 10 minutes, and then compound 62b (130 mg, 0.51 mmol) was added. The mixture was heated to 75 °C and reacted for 12 hours. LCMS showed that the reaction was complete. After cooling to room temperature, a large amount of solid precipitated. The solid was filtered, and the filter cake was washed with methanol to give compound 76b (60 mg, yield: 33.1%).

[1227] LCMS(ESI)m / z:[M+H] + =533.2.

[1228] Step 2

[1229] Compound 76b (60 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, and HCl / dioxane (0.3 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give compound 76c (45 mg, yield: 92.4%).

[1230] LCMS(ESI)m / z:[M+H] + =433.5.

[1231] Step 3

[1232] Compound 76c (45 mg, 0.1 mmol) was dissolved in methanol (2 mL) at room temperature. Compound AcOH (6.5 mg, 0.11 mmol) and compound 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (32.1 mg, 0.15 mmol) were added, and the reaction mixture was stirred at 25 °C for 12 hours. Sodium triacetoxyborohydride (81 mg, 0.38 mmol) was then added, and the mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. After the reaction was complete, saturated ammonium chloride solution (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined and washed with saturated brine (2 x 20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and rotary evaporated. The crude product was purified by Pre-TLC (dichloromethane / methanol = 10:1) to obtain compound 76d (19.1 mg, yield: 31.1%).

[1233] LCMS(ESI)m / z:[M+H] + =630.3.

[1234] Step 4

[1235] Compound 76d (19.1 mg, 0.031 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, and HCl / dioxane (0.5 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give compound 76e (15.1 mg, yield: 94%).

[1236] LCMS(ESI)m / z:[M+H] + =530.2.

[1237] Step 5

[1238] Compound 76e (15.1 mg, 0.028 mmol) was dissolved in DMSO (2 mL) at room temperature. Compound DIPEA (15.1 mg, 0.11 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (7.64 mg, 0.028 mmol) and HATU (15.0 mg, 0.042 mmol) were added to the reaction mixture, and the reaction was carried out at 25 °C for 1 hour. The reaction was completed by LCMS. The reaction mixture was extracted with water (15 mL) and ethyl acetate (15 mL * 3). The mixture was washed with saturated brine (20 mL * 2). The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was then prepared by HPLC (compound HPLC purification preparation method 1) to obtain compound C076 (1.52 mg, yield: 6.9%).

[1239] LCMS(ESI)m / z:[M+H] + =782.3.

[1240] Example 77: Preparation of compound C077

[1241]

[1242] Step 1

[1243] Intermediate 1 (50 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL) at room temperature. Triethylamine (63.5 mg, 0.61 mmol) was added, and the reaction mixture was stirred at 25 °C for 1 hour. 4-N-Boc-aminocyclohexanone (38.3 mg, 0.18 mmol) and tetraisopropyl titanate (87 mg, 0.30 mmol) were added to the reaction mixture, and the reaction was carried out at room temperature for 1 hour. Sodium triacetoxyborohydride (79.5 mg, 0.38 mmol) was added, and the mixture was stirred at 25 °C for 12 hours. LC-MS showed complete conversion of the reactants and detection of the product. After the reaction was completed, saturated ammonium chloride aqueous solution (10 mL) was added, followed by extraction with dichloromethane (2*10 mL). The organic phases were combined and washed with saturated brine (2*20 mL). The organic layer was collected, dried with anhydrous Na2SO4, filtered, and rotary evaporated. The crude product was purified by Pre-TLC (dichloromethane / methanol = 10:1) to obtain compound 77a (35.1 mg, yield: 44.5%).

[1244] LCMS(ESI)m / z:[M+H] + =524.2.

[1245] Step 2

[1246] Compound 77a (35 mg, 0.067 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, and HCl / dioxane (0.5 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give compound 77b (25 mg).

[1247] LCMS(ESI)m / z:[M+H] + =424.5.

[1248] Step 3

[1249] Compound 77b (25 mg, 0.059 mmol) was dissolved in DMSO (1 mL) at room temperature. DIPEA (34 mg, 0.26 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (15.8 mg, 0.059 mmol) and HATU (22 mg, 0.75 mmol) were added to the reaction mixture, and the reaction was carried out at 25 °C for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was extracted with water (15 mL) and ethyl acetate (15 mL * 3). The mixture was washed with saturated brine (20 mL * 2). The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was then purified by preparative HPLC (compound HPLC purification preparation method 1) to obtain compound C077 (2.56 mg, yield: 6.4%).

[1250] LCMS(ESI)m / z:[M+H] + =675.2.

[1251] Example 78: Preparation of compound C078

[1252]

[1253] Step 1

[1254] Intermediate 1 (50 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL) at room temperature. Triethylamine (63.5 mg, 0.61 mmol) was added, and the reaction mixture was stirred at 25 °C for 1 hour. Tert-butyl 3-oxocyclobutylcarbamate (33.3 mg, 0.18 mmol) and tetraisopropyl titanate were added to the reaction mixture, and the reaction was carried out at room temperature for 1 hour. Sodium triacetoxyborohydride (79.5 mg, 0.38 mmol) was added, and the mixture was stirred at 25 °C for 12 hours. LC-MS showed complete conversion of the reactants and detection of the product. After the reaction was completed, saturated ammonium chloride aqueous solution (10 mL) was added, and dichloromethane (2*10 mL) was used for extraction. The organic phases were combined and washed with saturated brine (2*20 mL). The organic layer was taken, dried with anhydrous Na2SO4, filtered and rotary evaporated. The crude product was purified by Pre-TLC (dichloromethane / methanol = 10:1) to obtain compound 78a (45.1 mg, yield: 60.8%).

[1255] LCMS(ESI)m / z:[M+H] + =524.3.

[1256] Step 2

[1257] Compound 78a (45 mg, 0.091 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, and dioxane hydrochloride (0.5 mL, 4 M) was added. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to give compound 78b (32 mg, yield: 89.1%).

[1258] LCMS(ESI)m / z:[M+H] + =396.3.

[1259] Step 3

[1260] Compound 78b (32 mg, 0.081 mmol) was dissolved in DMSO (1 mL) at room temperature. DIPEA (52 mg, 0.41 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (21.7 mg, 0.081 mmol) and HATU (28.5 mg, 0.97 mmol) were added to the reaction mixture, and the reaction was carried out at 25 °C for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was added to water (15 mL), extracted with ethyl acetate (15 mL * 3), washed with saturated brine (20 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was then purified by preparative HPLC (compound HPLC purification preparation method 1) to obtain compound C078 (12.8 mg, yield: 24.4%).

[1261] LCMS(ESI)m / z:[M+H] + =647.1.

[1262] Example 79: Preparation of compound C079

[1263]

[1264] Step 1

[1265] Intermediate 1 (150 mg, 0.42 mmol) was dissolved in DCM / DMSO at room temperature in a 1:1 ratio (20 mL). 7-oxo-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (160 mg, 0.84 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Sodium triacetoxyborohydride (350 mg, 1.65 mmol) was then added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. TLC showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was achieved by silica gel chromatography (petroleum ether: ethyl acetate = 0-70%) to obtain compound 79a (110 mg, yield: 75%).

[1266] Step 2

[1267] Compound 79a (110 mg, 0.22 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 79b (90 mg) was purified by silica gel chromatography (methanol:dichloromethane = 0-10%). LCMS (ESI) m / z: [M+H] + =450.6.

[1268] Step 3

[1269] Compound 79b (90 mg, 0.22 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (66.6 mg, 0.23 mmol), HATU (172 mg, 0.33 mmol), and DIPEA (215 mg, 0.9 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture, and extracted with DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Preparation: HPLC preparation (Compound HPLC purification preparation method 1). Freeze-drying yielded compound C079 (20 mg, yield: 11.4%). LCMS (ESI) m / z: [M+H] + =701.2.

[1270] Example 80: Preparation of compound C080

[1271]

[1272] Step 1

[1273] tert-butyl 9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid (300 mg, 1.11 mmol) was dissolved in THF (5 mL) at room temperature. N-hydroxyphthalimide (199 mg, 1.22 mmol), triphenylphosphine (378 mg, 1.44 mmol), and DIAD (292 mg, 1.44 mmol) were added. The reaction mixture was stirred at room temperature under nitrogen for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain a crude product. Purification was performed by silica gel chromatography (petroleum ether: ethyl acetate = 0-27%) to give compound 80a (410 mg, yield: 88.82%).

[1274] LCMS(ESI)m / z:[M+Na] + =437.2.

[1275] Step 2

[1276] Compound 80a (410 mg, 0.99 mmol) was dissolved in ethanol (5 mL) at room temperature, and hydrazine hydrate (0.31 g, 4.95 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to obtain a crude product. Then, it was slurried with methyl tert-butyl ether (10 mL) for 1 hour. After filtration and vacuum concentration, crude compound 80b (280 mg) was obtained.

[1277] Step 3

[1278] Compound 80b (300 mg, 1.31 mmol) was dissolved in methanol (5 mL) at room temperature. Intermediate 1c (600 mg, 2.63 mmol) and acetic acid (79 mg, 1.31 mmol) were added, and the reaction mixture was stirred at 80 °C for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-30%) yielded compound 80c (243 mg, yield: 42.25%).

[1279] LCMS(ESI)m / z:[M+H] + =440.3.

[1280] Step 4

[1281] Compound 80c (400 mg, 0.81 mmol) was dissolved in dioxane hydrochloride (4 mL, 4 M) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain crude compound 80d (319 mg), which was used directly in the next step without purification.

[1282] LCMS(ESI)m / z:[M+H] + =396.3.

[1283] Step 5

[1284] Compound 80d (73 mg, 0.18 mmol) was dissolved in DCM (4 mL) and DMSO (4 mL) at room temperature. 1-tert-Butoxycarbonylpiperidine-4-carboxaldehyde (58 mg, 0.27 mmol) and acetic acid (22 mg, 0.36 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. Then, sodium triacetylborohydride (191 mg, 0.90 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. LC-MS showed that most of the reactants were converted and the product was detected. The reaction mixture was poured into water (50 mL), and then extracted with DCM (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification was performed by silica gel chromatography (methanol:dichloromethane = 0-7%) to give compound 80e (41 mg, yield: 37.47%).

[1285] LCMS(ESI)m / z:[M+H] + =593.4.

[1286] Step 6

[1287] Compound 80e (41 mg, 0.069 mmol) was dissolved in dioxane hydrochloride (2 mL, 4 M) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was concentrated under vacuum to obtain crude compound 80f (34 mg), which was used directly in the next step without purification.

[1288] LCMS(ESI)m / z:[M+H] + =493.3.

[1289] Step 7

[1290] Compound 80f (34 mg, 0.069 mmol) was dissolved in DMSO (5 mL) at room temperature. 4-chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (18 mg, 0.067 mmol), HATU (29 mg, 0.076 mmol), and DIPEA (45 mg, 0.35 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with DCM (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound C080 (30.9 mg, yield: 59.38%) was obtained by preparative HPLC (HPLC purification preparation method 1).

[1291] LCMS(ESI)m / z:[M+H] + =743.4.

[1292] 1H NMR (500MHz, DMSO-d6) δ13.16(s,1H),10.53(s,1H),8.19(s,2H),7.98(dd,J=8.3,1.5Hz,1H),7.64(d,J=8.2Hz,1H) ,7.56–7.52(m,2H),7.38(dd,J=8.2,2.0Hz,1H),7.30–7.22(m,1H),6.99–6.86(m,2H),4.50–4.40(m,1H),4.36–4.2 9(m,1H),3.82–3.67(m,2H),3.65–3.54(m,3H),3.11–2.99(m,2H),2.80–2.71(m,2H),2.37(s,3H),2.36–2.30(m,3H ),2.21–2.11(m,2H),1.90–1.71(m,4H),1.67–1.54(m,4H),1.52–1.35(m,4H),1.31–1.19(m,2H),1.14–1.01(m,2H).

[1293] Example 81: Preparation of compound C081

[1294]

[1295] Step 1

[1296] Intermediate 2 (30 mg, 0.08 mmol) was dissolved in MeOH (5 mL) at room temperature. 1-tert-Butoxycarbonylpiperidine-4-carboxaldehyde (15 mg, 0.08 mmol) and acetic acid (15 mg, 0.24 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Then, sodium triacetoxyborohydride (50 mg, 0.24 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding water (30 mL), and extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound 81a (31 mg, 75% yield) was obtained by silica gel chromatography (methanol:dichloromethane = 10%).

[1297] LCMS(ESI)m / z:[M+H] + =538.3.

[1298] Step 2

[1299] Crude compound 81a (31 mg, 0.06 mmol) was dissolved in MeOH (3 mL) at room temperature, and dioxane hydrochloride solution (1 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 30 min. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was evaporated to dryness to obtain crude compound 81b (25 mg).

[1300] LCMS(ESI)m / z:[M+H] + =438.2.

[1301] Step 3

[1302] Reactant 81b (32 mg, 0.06 mmol) was dissolved in DMSO (3 mL) at room temperature. 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (15 mg, 0.054 mmol) and DIPEA (25 mg, 0.18 mmol) were added, and the reaction mixture was stirred at 80 °C for 2 h. LC-MS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding water (30 mL), and the mixture was extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Compound C081 (9.17 mg, yield: 22%) was obtained by preparative HPLC (compound purification preparation method 1).

[1303] LCMS(ESI)m / z:[M+H] + =694.3.

[1304] Example 82: Preparation of compound C082

[1305]

[1306] Step 1

[1307] Intermediate 2 (30 mg, 0.08 mmol) was dissolved in MeOH (5 mL) at room temperature. 1-tert-Butoxycarbonylpiperidine-4-carboxaldehyde (15 mg, 0.08 mmol) and acetic acid (15 mg, 0.24 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Then, sodium triacetoxyborohydride (50 mg, 0.24 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding water (30 mL), and extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification by silica gel chromatography (methanol:dichloromethane = 10%) yielded compound 82a (14 mg, yield: 32%).

[1308] LCMS(ESI)m / z:[M+H]+ =538.3.

[1309] Step 2

[1310] Crude compound 82a (14 mg, 0.026 mmol) was dissolved in MeOH (3 mL) at room temperature, and dioxane hydrochloride solution (1 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 30 min. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was evaporated to dryness to obtain crude compound 82a (11 mg).

[1311] LCMS(ESI)m / z:[M+H] + =438.2.

[1312] Step 3

[1313] Reactant 82a (11 mg, 0.026 mmol) was dissolved in DMSO (3 mL) at room temperature, and 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoic acid (10 mg, 0.023 mmol), DIPEA (15 mg, 0.078 mmol), and HBTU (13 mg, 0.03 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. LCMS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with DCM (20 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was then prepared by HPLC (compound purification method 1) to obtain compound C082 (3.12 mg, yield 15.4%).

[1314] LCMS(ESI)m / z:[M+H] + =672.3.

[1315] 1H NMR(500MHz,DMSO-d6)δ13.13(s,1H),10.51(d,J=11.3Hz,1H),8.23(s,1H),8.00–7.94(m,1H),7.52–7.47(m,2H), 7.37(d,J=7.8Hz,2H),7.27(t,J=8.0Hz,1H),7.16–7.09(m,1H),6.93(dd,J=7.8,6.3Hz,2H),4.15(d,J=6.2Hz,2H) ,3.75(t,J=6.7Hz,2H),2.85(d,J=11.1Hz,2H),2.73(t,J=6.7Hz,2H),2.51-2.56(m,3H),2.36(s,3H),2.13(d,J=7 .0Hz,2H),1.86(t,J=11.5Hz,2H),1.80(s,2H),1.69(d,J=13.2Hz,3H),1.30–1.20(m,3H),1.06(q,J=11.1Hz,3H).

[1316] Example 83: Preparation of compound C083

[1317]

[1318] Step 1

[1319] Intermediate 3 (30 mg, 0.08 mmol) was dissolved in MeOH (5 mL) at room temperature, followed by the addition of N-tert-butoxycarbonyl-4-piperidinone (15 mg, 0.08 mmol) and acetic acid (15 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 2 hours. Subsequently, sodium triacetoxyborohydride (50 mg, 0.24 mmol) was added and the mixture was stirred overnight at room temperature. LC-MS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding water (30 mL), and the mixture was extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. Compound 83a (18 mg, 39% yield) was obtained by silica gel chromatography (methanol:dichloromethane = 0-10%).

[1320] LCMS(ESI)m / z:[M+H] + =576.3.

[1321] Step 2

[1322] Crude compound 83a (18 mg, 0.031 mmol) was dissolved in 3 mL of MeOH at room temperature, and 1 mL of dioxane hydrochloride solution (4 M) was added. The reaction was carried out at room temperature for 30 min. LC-MS showed complete conversion of the reactants and detection of the product. The reaction solution was evaporated to dryness to obtain crude compound 83b (14 mg). LC-MS (ESI) m / z: [M+H] + =476.3.

[1323] Step 3

[1324] The reactant 83b (14 mg, 0.026 mmol) was dissolved in DMSO (3 mL) at room temperature. Then, 3b (10 mg, 0.023 mmol), DIPEA (15 mg, 0.078 mmol), and HBTU (15 mg, 0.028 mmol) were added, and the mixture was stirred at room temperature for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction mixture was poured into water (50 mL), and then extracted with DCM (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was then prepared by HPLC (compound purification method 1) to obtain compound C083 (7.11 mg, yield 38.5%).

[1325] LCMS(ESI)m / z:[M+H] + =726.3.

[1326] 1H NMR (500MHz, DMSO-d6) δ13.13(s,1H),12.89(s,1H),10.52(s,1H),8.86(s,1H),8.43(s,1H),7.84(dd,J=8.0,1.6Hz,1H),7.64(d,J=8.2H z,1H),7.57(d,J=2.0Hz,1H),7.41(dd,J=8.2,2.0Hz,1H),7.35–7.28(m,1H),7.00(td,J=8.2,2.4Hz,2H),4.49(s,1H),4.27(dt,J=8.2,4. 1Hz,1H),3.80–3.72(m,1H),3.66–3.57(m,2H),3.06(s,1H),2.83–2.71(m,5H),2.69(d,J=7.4Hz,2H),2.58(d,J=11.3Hz,1H),2.54(s,1H) ,2.10(m,J=6.7Hz,1H),2.00(s,2H),1.86(s,1H),1.77(d,J=9.5Hz,2H),1.71(s,1H),1.45(td,J=12.5,8.6Hz,2H),0.96(d,J=6.6Hz,5H).

[1327] Example 84: Preparation of compound C084

[1328]

[1329] Step 1

[1330] Intermediate 2 (200 mg, 0.60 mmol) was dissolved in DMF (10 mL) at room temperature. Tert-butyl-4-(2-chloro-2-acetoxy)piperazine-1-carboxylate (163.5 mg, 0.66 mmol) and DIPEA (450 mg, 1.8 mmol) were added, and the reaction mixture was stirred for 2 hours. LC-MS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding water (30 mL), and extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purification by silica gel chromatography (petroleum ether:ethyl acetate = 0-70%) yielded compound 84a (300 mg, yield: 91.2%).

[1331] Step 2

[1332] Compound 84a (100 mg, 0.18 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed complete conversion of the reactants and detection of the product. The crude product was concentrated under vacuum. Compound 84b (110 mg) was purified by silica gel chromatography (MeOH:DCM = 10%). LCMS (ESI) m / z: [M+H] + =467.6.

[1333] Step 3

[1334] Compound 84b (100 mg, 0.24 mmol) was dissolved in DMSO (5 mL) at room temperature. Compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (66.6 mg, 0.24 mmol) and DIPA (113.4 mg, 0.88 mmol) were added, and the reaction mixture was stirred for 2 hours. LCMS showed complete conversion of the reactants and detection of the product. The reaction was quenched by adding 30 mL of water to the reaction mixture. Extraction was performed using DCM (30 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Preparation was carried out by HPLC (compound purification method 1). Freeze-drying yielded compound C084 (10.1 mg, yield: 6.8%). LCMS (ESI) m / z: [M+H] + =723.8.

[1335] Example 85: Preparation of compound C085

[1336]

[1337] Step 1

[1338] Intermediate 3 (30 mg, 0.08 mmol) was dissolved in DCM (5 mL) at room temperature. Tert-butyl methyl (3-oxopropyl)carbamate (15 mg, 0.08 mmol) and acetic acid (15 mg, 0.24 mmol) were added, and the reaction mixture was stirred at 25 °C for 2 hours. Then, sodium triacetoxyborohydride (51 mg, ...

Claims

1. A compound or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, characterized in that, The compound has the structure of formula (I): wherein the dotted line indicates the presence or absence of a bond; denotes cis or trans, said comprising or mixtures thereof; X 1 is selected from CH2, NH, O or S; R 1 selected from -C 1～8 alkyl, -C 0～4 alkylene-NHC 0～4 alkyl, -C 0～4 alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3-12 membered heterocyclyl; the alkyl, heterocyclyl, cycloalkyl in R 1 may be optionally substituted 1-3 times with R x ; R 1 is substituted with A1, A1 is a bond between the linker and L; R 2 is selected from the group consisting of hydrogen, -C 1～6 alkyl, -C 0～3 alkylene-C 3～6 cycloalkyl, -C 0～3 alkylene-3- to 6-membered heterocyclyl, aryl, and 5- to 6-membered heteroaryl; the alkyl, heterocyclyl, cycloalkyl, aryl, and heteroaryl groups in R 2 may be optionally substituted 1 to 3 times with R x ; R 3 independently selected from halogen, cyano, oxo, hydroxy, C 1～3 alkyl, C 1～3 alkoxy and C 1～3 haloalkyl; R 4 independently selected from hydrogen, C 1～6 alkyl, C 1～6 haloalkyl, C 3～6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, and 5- to 6-membered heteroaryl; the alkyl, heterocyclyl, cycloalkyl, aryl, and heteroaryl groups in R 4 are optionally substituted 1 to 3 times with R x ; n is 0, 1, 2, or 3; m is 0, 1, 2, or 3; R x independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amine, C 1～3 alkyl, C 1～3 alkoxy and C 3～6 cycloalkyl; the alkyl, alkoxy, cycloalkyl in said R x may be optionally substituted 1 to 3 times with halogen; L is A1-L 1 -L 2 -L 3 -L 4 -A2; A1 is a bond between the linker and the toxin; A2 is a bond between the degrading moiety and the linker; L 1 is selected from -0-, -S-, -C(O)-, -NR 1a -, C 1-6 alkylene, C 1-6 alkylene-3-10 membered heteroarylene, C 3-6 cycloalkylene and 3-10 membered heterocyclylene, each of said alkylene, cycloalkylene, heterocyclylene and heteroarylene is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; L 2 is a covalent bond, or is selected from -C(O)-, C 1-6 alkylene; L 3 is a covalent bond, or is selected from -O-, -NR 3a -, C 1-6 alkylene, -O-C 1-6 alkylene, C 1-6 alkylene-O-, C 3-6 cycloalkylene, and 3-10 membered heterocyclylene, each of which alkylene, cycloalkylene, and heterocyclylene is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, and C 1-6 haloalkyl; L 4 is a covalent bond, or is selected from -O-, -S-, -NR 4a -, C 1-6 alkylene, -O-C 1-6 alkylene-, C 1-6 alkylene-O-, C 3-6 cycloalkylene, -C(O)-, -C(O)-N(R 4a )-, -C(O)-C 1-6 alkylene-, and 3-10 membered heterocyclyl, each of which alkylene, cycloalkylene and heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; each of which alkylene, cycloalkylene and heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; R 1a , R 3a , and R 4a are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; M is M1, M2, or M3 as shown in the following formula: In M1, Y 1 selected from C(O) or CR Y1-1 R Y1-2 ; R Y1-1 , R Y1-2 is selected from H or optionally substituted C 1-6 alkyl; M 1-1 , M 1-2 , M 1-3 and M 1-4 are each independently H, A2, halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, optionally substituted C2-C9heterocyclyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9heteroaryl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6heteroalkenyl, optionally substituted -O-C3-C6cycloalkyl, hydroxyl, thiol, taken together and are optionally substituted C6-C10aryl, optionally substituted C3-C10cycloalkyl, optionally substituted C2-C9heteroaryl, or C2-C9heterocyclyl, any of which is optionally substituted with A2, or optionally substituted amino; or M 1-1 and M 1-2 , M 1-2 and M 1-3 , and / or M 1-3 and M 1-4 , taken together with the carbon atoms to which each is attached, are and is optionally substituted C6-C 10 aryl, optionally substituted C3-C 10 cycloalkyl, optionally substituted C2-C9heteroaryl, or C2-C9heterocyclyl, any of which is optionally substituted with A2, wherein M 1-1 , M 1-2 , M 1-3 , and M 1-4 is A2, or is substituted with A2; and A2 is a bond between the degrading moiety and the linker; M 1-5 H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; in M2, M 2-1 selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl and 3-12 membered heterocyclyl; M 2-1 substituted by A2, A2is a bond between the degradation moiety and L; M 2-2 each independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, optionally substituted C2-C9heterocyclyl, optionally substituted C6-C10aryl, optionally substituted C2-C9heteroaryl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; M 2-3 selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 12-membered heterocyclyl, each of which alkyl, cycloalkyl and heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; M 2-4 H, or optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, optionally substituted C6-C10aryl, optionally substituted C1-C6alkyl-C3-C10cycloalkyl, or optionally substituted C1-C6alkyl-C6-C10aryl; and each Rbis independently H, or optionally substituted C1-C6alkyl. 10 H, or optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, optionally substituted C6-C 10 H, or optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, optionally substituted C6-C 10 H, or optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, optionally substituted C6 v2 is 0, 1, 2, 3, or 4; A2 is a bond between the degrading moiety and the linker; In M3, ring M3-A is a C3-C10 cycloalkyl group, a 3-9 membered heterocyclic group, or a C6-C cycloalkyl group. 12 Aryl or 5-12 heteroaryl groups; M3-1 is halogen, cyano, hydroxyl, amine, C1-C3 alkyl, or C1-C3 haloalkyl; P is 0, 1, 2, or 3; A2 is a bond between the degrading moiety and the linker.

2. The compound of claim 1, wherein The compound of formula (I) is a compound of formula (I-1): wherein represents a single or double bond; X1 is selected from CH2, NH, or S; R 1 selected from -C 0～4 alkylene-NHC 0～4 alkyl, -C 0～4 alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3 to 12 membered heterocyclyl; the heterocyclyl, cycloalkyl and amine groups in R 1 may be optionally substituted 1 to 3 times with R x ; R2is selected from the group consisting of hydrogen, -C 1～6 alkyl; said alkyl, heterocyclyl and cycloalkyl in R2may be optionally substituted 1 to 3 times with R x substituted 1 to 3 times with R R3is independently selected from halogen, cyano, oxo, C 1～3 alkyl and C 1～3 haloalkyl; R4is independently selected from hydrogen, C 1～3 alkyl, C 1～3 haloalkyl and cyclopropyl; R x independently selected from halogen, cyano, hydroxy, amine, C 1～3 alkyl, C 1～3 alkoxy and C 3～6 cycloalkyl; the alkyl, alkoxy, cycloalkyl in said R x may be optionally substituted 1 to 3 times with halogen.

3. The compound of claim 1, wherein The compound of formula (I) is a compound of formula (I-2): The compound of formula (I) is a compound of formula (I-2): wherein X1 is selected from CH2, NH, or S; R 1 selected from -C 0～4 alkylene-NHC 0～4 alkyl, -C 0～4 alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3 to 12 membered heterocyclyl; the alkyl, heterocyclyl, cycloalkyl and amine groups in R 1 may be optionally substituted 1 to 3 times with R x ; R2is selected from hydrogen, -C 1～6 alkyl; the alkyl in R2may be optionally substituted 1 to 3 times with R x substituted 1 to 3 times with R R3is independently selected from halo, cyano, oxo, C 1～3 alkyl and C 1～3 haloalkyl; R4is independently selected from hydrogen, C 1～3 alkyl, C 1～3 haloalkyl and cyclopropyl; R x independently selected from halogen, cyano, hydroxy, amine, C 1～3 alkyl, C 1～3 alkoxy and C 3～6 cycloalkyl; the alkyl, alkoxy, cycloalkyl in said R x may be optionally substituted 1 to 3 times with halogen.

4. The compound of claim 1 or 2, wherein In formula I-1, the compound of formula (I) is a compound of formula (I-1-1), (I-1-2), or (I-1-3):

5. The compound of claim 1 or 3, wherein In formula (I-2), the compound of formula (I) is a compound of formula (I-2-1) or (I-2-2):

6. The compound of any one of claims 1-5, wherein, The compound of formula I is selected from the group consisting of: (1) R1is independently selected from the group consisting of -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH2NHCH3, -CH2CH2NH2, -CH2NHCH3, -CH2CH2NHCH2CH3, -CH2NHCH2CH3, -CH2CH2CH2NH2, -CH2CH2CH2NHCH3; the alkyl, heterocyclyl, cycloalkyl and amine groups in said R1may be optionally substituted 1 to 3 times with R x substituted 1 to 3 times with R (2) R2is independently selected from the group consisting of -H, -CH3, -CH2CH3, -CH2CH(CH3)2, -CH(CH3)2, said alkyl and heterocyclyl groups in R2may be optionally substituted 1 to 3 times with halogen; (3) R3 is independently selected from -F, -Cl, -Br, =O, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2Cl, CCl3, -CHCl2, -CH2CH2Cl, -CH2CCl3, -CH2F, -CF3, -CHF2, -CH2CH2F, -CH2CF3; (4) R4 is independently selected from -H, -F, -Cl, -Br, -CH3, -CH2CH3, -CH(CH3)2, -CH2F, -CF3, -CHF2, -CH2CF3; (5) X1 is selected from NH or S.

7. The compound of claim 6, wherein The compound of formula I is selected from the group consisting of: (1) R1is independently selected from -CH2CH2NHCH3, (2) R2is independently selected from -H, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, (3) R3 is independently selected from -F, -Cl, -CH3; (4) R4 is independently selected from -H, -CH3.

8. The compound of any one of claims 1, 2, 4, 6-7, wherein In formula I-1, the compound of formula (I) is 9. The compound of any one of claims 1, 3, 5-7, wherein In formula I-2, the compound of formula (I) is 10. The compound of claim 1, wherein In formula I, the M has the structure of formula M1: wherein M is H or methyl, preferably H; 1-5 is H or methyl, preferably H; and / or, each M 1-1 , M 1-2 , M 1-3 and M 1-4 is independently H or A2; and / or Y1-1 is H; and / or Y1-2 is H.

11. The compound of claim 10, wherein The M is selected from any one of the following structures: (1) the M comprises a structure of formula M 1-1 preferably ​ (2) the M comprises a structure of formula M1-2: Preferably (3) the M comprises a structure of formula M1-3: Preferably (4) the M comprises a structure of formula M1-4: Preferably (5) the M comprises a structure of formula M1-5: Preferably (6) the M comprises a structure of formula M1-6: Preferably 12. The compound of claim 1, wherein In formula I, the degrading moiety M has the structure of formula M2: wherein M 2-1 for R B3 Optionally substituted C1-C6 alkyl, Optionally substituted C1-C6 heteroalkyl, Optionally substituted C3-C10 cycloalkyl, Optionally substituted C6-C 10 Aryl, optionally substituted C1-C6 alkyl-C3-C 10 Cycloalkyl or optionally substituted C1-C6 alkyl-C6-C 10 Aryl; M 2-2 selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl or C 1-6 haloalkyl; M 2-3 H or optionally substituted C1-C6alkyl; and M 2-4 selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl and 3-12 membered heterocyclyl.

13. The method of claim 12, wherein, Said M has the structure of formula M2-1: Preferably, said M is Further preferably 14. The compound of claim 1, M3, wherein The ring M3-A is C3-6 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; Alternatively, the ring M3-A is pyridyl, quinolyl, phenothiazinyl, benzodiazepinyl, furanyl, pyrazolonyl, pyrimidinyl, preferably pyridyl, quinolyl, or phenothiazinyl; Alternatively, ring M3-A is C6-C. 10 Aryl, preferably phenyl or naphthyl; Alternatively, the ring M3-A is a 3-9 membered heteroaryl, preferably a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring; for example 15. The compound of claim 14, wherein In formula I, the M has the structure of formula M3: wherein M3-A is selected from phenyl, naphthyl, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring; for example M 3-1 selected from halogen, C 1-3 alkyl and C 1-3 haloalkyl.

16. The compound of claim 14 or 15, wherein The M3 is 17. The compound of claim 1, wherein The L is selected from the group consisting of: (1)L 1 Selected from -C(O)-, C 1-6 Alkylene, C 1-6 alkylene-3-10-membered heteroaryl, C 3-6 Cycloalkylene and 3-10 heterocyclic groups, wherein each of the alkylene, heterocyclic, and heteroaryl groups is optionally composed of one or more elements selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; preferably L 1 It is a covalent bond, or selected from -C(O)-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH(CH3)-, -CH(pyridylene); (2)L 2 It is a covalent bond, or selected from -C(O)- or C 1-6 Alkylene; preferably L 2 It is a covalent bond, or selected from -C(O)-, -CH2-; (3) L 3 is a covalent bond, or is selected from C 3-6 cycloalkylene and 3-10 membered heterocyclylene, each optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; preferably L 3 is a covalent bond, or is selected from (4)L 4 It is a covalent bond, or selected from -O-, -NR 4a -、C 1-6 Alkylene, -C(O)-, -C(O)-N(R) 4a )-、-C(O)-C 1-6 Alkylene; preferably L 4 It is a covalent bond, or selected from -O-, -N(CH3)-, -C(O)-, -C(O)-NH-, C(O)-N(CH3)-, methylene, -C(O)-CH3-.

18. The compound of claim 17, wherein said linker L is -C(O)-C 1-6 alkylene-O-, -C(O)-C 1-6 alkylene-NR 4a -, C 1-6 alkylene-NR 4a -, C 1-6 alkylene-NR 4a C(O)-, -C 1-6 alkylene-3-10 membered heterocyclyl-C(O)-, C 1-6 alkylene-3-10 membered heterocyclyl-, -3-10 membered heterocyclyl-, -C(O)-C 1-6 alkylene-3-10 membered heterocyclyl-, -C(O)-10 membered heterocyclyl-C 1-6 alkylene-, -C 1-6 alkylene-3-10 membered cyclyl-NR 4a C(O)-, C 1-6 alkylene-3-10 membered heterocyclyl-3-10 membered heterocyclyl-C(O)-, preferably said L has the following structure: -CH2-, 19. The compound of any one of claims 1-18, wherein, The compound of formula I has the structure of formula I-i: wherein R 1 is selected from -C 1～8 alkyl, -C 0～4 alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3- to 12-membered heterocyclyl; the alkyl, heterocyclyl, cycloalkyl in R 1 may optionally be substituted 1 to 3 times by R x ; preferably R 1 is selected from -C 0～4 alkylene-3- to 12-membered heterocyclyl; R2is selected from hydrogen, -C 1～6 alkyl; R x independently selected from halogen, cyano, hydroxyl, amine, C 1～3 alkyl, C 1～3 alkoxy; CycloM3-A is C3-C10cycloalkyl, 3-9 membered heterocyclyl, C6-C10aryl, or 3-9 membered heteroaryl; 10 aryl or 3-9 membered heteroaryl; M3-1 is halogen, cyano, hydroxyl, amine, C1-C3 alkyl, or C1-C3 haloalkyl; L is A1-L 1 -L 2 -L 3 -L 4 -A2; L 1 is selected from -0-, -S-, -C(O)-, -NR 1a -, C 1-6 alkylene, C 1-6 alkylene-3-10 membered arycenylene, C 3-6 cycloalkylene, and 3-10 membered heterocyclylene, each of said alkylene, cycloalkylene, heterocyclylene, and heteroarylene being optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, and C 1-6 haloalkyl; L 2 is a covalent bond, or is selected from -C(O)- or C 1-6 alkylene; L 3 is a covalent bond, or is selected from -O-, -NR 3a -, C 1-6 alkylene, -O-C 1-6 alkylene, C 1-6 alkylene-O-, C 3-6 cycloalkylene, and 3-10 membered heterocyclylene, each of which alkylene, cycloalkylene, and heterocyclylene is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, and C 1-6 haloalkyl; L 4 is a covalent bond, or is selected from -O-, -S-, -NR 4a -, C 1-6 alkylene, -O-C 1-6 alkylene-, C 1-6 alkylene-O-, C 3-6 cycloalkylene, -C(O)-, -C(O)-N(R 4a )-, -C(O)-C 1-6 alkylene-, and 3-10 membered heterocyclyl, each of which alkylene, cycloalkylene and heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; each of which alkylene, cycloalkylene and heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; R 1a , R 3a , and R 4a are each independently selected from the group consisting of hydrogen and C 1-6 alkyl.

20. The compound of claim 19, wherein The formula I-i is selected from the group consisting of: (1) R1is independently selected from Preferably, Further preferably (2) ring M3-A is phenyl, preferably phenyl; (3) the linker L has the following structure: -CH2-, Preferably, the linker L has the following structure: Further preferably, the linker L has the following structure:

21. The compound of any one of claims 1-20, wherein, In formula I-i, the compound of formula I is formula I-i-1 22. The compound of any one of claims 1-21, wherein, The compound of Formula I has a structure according to Formula I-ii: wherein R 1 is selected from -C 1～8 alkyl, -C 0～4 alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3 to 12 membered heterocyclyl; the alkyl, heterocyclyl, cycloalkyl and amine groups in R 1 may optionally be substituted 1 to 3 times with R x ; preferably R 1 is selected from -C 0～4 alkylene-C 3～8 cycloalkyl; R2is selected from hydrogen, -C 1～6 alkyl; R x independently selected from halogen, cyano, hydroxyl, amine, C 1～3 alkyl, C 1～3 alkoxy; Y 1 for or CR Y1-1 R Y1-2 ; M 1-5 H, optionally substituted C1-C6alkyl; M 1-1 , M 1-2 , M 1-3 and M 1-4 are each independently H, A2, halogen, L is A1-L 1 -L 2 -L 3 -L 4 -A2; L 1 is selected from -0-, -S-, -C(O)-, -NR 1a -, C 1-6 alkylene, C 1-6 alkylene-3-10 membered heteroarylene, C 3-6 cycloalkylene, and 3-10 membered heterocycloalkylene, each of said alkylene, cycloalkylene, heterocycloalkylene, and heteroarylene is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, and C 1-6 haloalkyl; L 2 is a covalent bond, or is selected from -C(O)- or C 1-6 alkylene; L 3 is a covalent bond, or is selected from -O-, -NR 3a -, C 1-6 alkylene, -O-C 1-6 alkylene, C 1-6 alkylene-O-, C 3-6 cycloalkylene, and 3-10 membered heterocyclylene, each of which alkylene, cycloalkylene, and heterocyclylene is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, and C 1-6 haloalkyl; L 4 is a covalent bond, or is selected from -0-, -S-, -NR 4a -, C 1-6 alkylene, -0-C 1-6 alkylene-, C 1-6 alkylene-0-, C 3-6 cycloalkylene, -C(O)-, -C(0)-N(R 4a )-, -C(0)-C 1-6 alkylene-, and 3-10 membered heterocyclyl, each of which alkylene, cycloalkylene and heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; each of which alkylene, cycloalkylene and heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; R 1a , R 3a , and R 4a are each independently selected from hydrogen and C 1-6 alkyl.

23. The compound of claim 22, wherein The compound of Formula I-ii is selected from the group consisting of: (1) R1is independently selected from Further preferred (2) the L has the following structure: Preferably, the L linker has the following structure 24. The compound of any one of claims 1-18, wherein The compound of Formula I has a structure according to Formula I-iii The structure shown: wherein R 1 is selected from -C 1～8 alkyl, -C 0～4 alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3-12 membered heterocyclyl; the alkyl, heterocyclyl, cycloalkyl in R 1 may be optionally substituted 1-3 times with R x ; preferably R 1 is selected from -C 0～4 alkylene-C 3～8 cycloalkyl; R2is selected from hydrogen, -C 1～6 alkyl; R x independently selected from halogen, cyano, hydroxyl, amine, C 1～3 alkyl, C 1～3 alkoxy; M2-3 is H or optionally substituted C1-C6 alkyl; and L is A1-L 1 -L 2 -L 3 -L 4 -A2; L 1 is selected from -0-, -S-, -C(O)-, -NR 1a -, C 1-6 alkylene, C 1-6 alkylene-3-10 membered heteroarylene, C 3-6 cycloalkylene, and 3-10 membered heterocyclylene, each of said alkylene, cycloalkylene, heterocyclylene, and heteroarylene is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, and C 1-6 haloalkyl; L 2 is a covalent bond, or is selected from -C(O)- or C 1-6 alkylene; L 3 is a covalent bond, or is selected from -O-, -NR 3a -, C 1-6 alkylene, -O-C 1-6 alkylene, C 1-6 alkylene-O-, C 3-6 cycloalkylene, and 3-10 membered heterocyclylene, each of which alkylene, cycloalkylene, and heterocyclylene is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, and C 1-6 haloalkyl; L 4 is a covalent bond, or is selected from -O-, -S-, -NR 4a -, C 1-6 alkylene, -O-C 1-6 alkylene-, C 1-6 alkylene-O-, C 3-6 cycloalkylene, -C(O)-, -C(O)-N(R 4a )-, -C(O)-C 1-6 alkylene-, and 3-10 membered heterocyclyl, each of which alkylene, cycloalkylene and heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; each of which alkylene, cycloalkylene and heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; R 1a , R 3a , and R 4a are each independently selected from hydrogen and C 1-6 alkyl.

25. The compound of claim 24, wherein The compound of Formula I-iii is selected from the group consisting of: (1) R1is independently selected from Further preferred (2) the L has the following structure: -CH2-, Preferably said linker L has the structure: -CH2- or 26. The compound of any one of claims 1-18, wherein The compound of Formula I has a structure according to Formula I-IV wherein R 1 is selected from -C 1～8 alkyl, -C 0～4 alkylene-C 3～8 cycloalkyl; and 0～4 alkylene-3 to 12 membered heterocyclyl; the alkyl, heterocyclyl, cycloalkyl in R 1 may optionally be substituted 1 to 3 times with R x ; preferably R 1 is selected from -C 0～4 alkylene-C 3～8 cycloalkyl; and R2is selected from hydrogen, -C 1～6 alkyl; R x independently selected from the group consisting of halogen, cyano, hydroxy, amine, C 1～3 alkyl, C 1～3 alkoxy and C 3～6 cycloalkyl; the alkyl, alkoxy, cycloalkyl in said R x may optionally be substituted 1 to 3 times with halogen; CycloM3-A is C3-C10cycloalkyl, 3-9 membered heterocyclyl, C6-C10aryl, or 3-9 membered heteroaryl; 10 aryl or 3-9 membered heteroaryl; M3-1 is halogen, cyano, hydroxyl, amine, C1-C3 alkyl, or C1-C3 haloalkyl; L is A1-L 1 -L 2 -L 3 -L 4 -A2; L 1 is selected from -0-, -S-, -C(O)-, -NR 1a -, C 1-6 alkylene, C 1-6 alkylene-3-10 membered heteroarylene, C 3-6 cycloalkylene, and 3-10 membered heterocyclylene, each of said alkylene, cycloalkylene, heterocyclylene, and heteroarylene is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, and C 1-6 haloalkyl; L 2 is a covalent bond, or is selected from -C(O)- or C 1-6 alkylene; L 3 is a covalent bond, or is selected from -O-, -NR 3a -, C 1-6 alkylene, -O-C 1-6 alkylene, C 1-6 alkylene-O-, C 3-6 cycloalkylene, and 3-10 membered heterocyclyl ene, each of which alkylene, cycloalkylene, and heterocyclyl ene is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, and C 1-6 haloalkyl; L 4 is a covalent bond, or is selected from -0-, -S-, -NR 4a -, C 1-6 alkylene, -0-C 1-6 alkylene-, C 1-6 alkylene-0-, C 3-6 cycloalkylene, -C(O)-, -C(0)-N(R 4a )-, -C(0)-C 1-6 alkylene-, and 3-10 membered heterocyclyl, each of which alkylene, cycloalkylene and heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; each of which alkylene, cycloalkylene and heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; R 1a , R 3a , and R 4a are each independently selected from the group consisting of hydrogen and C 1-6 alkyl.

27. The compound of claim 26, wherein The compound of Formula I-iii is selected from the group consisting of: (1) ring M3-A is a phenyl ring, preferably phenyl; (2) R1is independently selected from the group consisting of said alkyl, heterocyclyl, cycloalkyl and amine groups in R1may optionally be substituted with halogen; preferably R1is independently selected from the group consisting of -CH2CH2CH3, more preferably preferably R1is independently selected from the group consisting of -CH2CH2CH3, further preferably (3) said L has the following structure: -CH2-, Preferably said linker L has the following structure: further preferred even further preferred 28. The compound of any one of claims 1-18, wherein The compound of Formula I has a structure according to Formula I-V wherein R 1 is selected from -C 1～8 alkyl, -C 0～4 alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3 to 12 membered heterocyclyl; the alkyl, heterocyclyl, cycloalkyl in R 1 may be optionally substituted 1 to 3 times with R x ; preferably R 1 is selected from -C 0～4 alkylene-3 to 12 membered heterocyclyl; R2is selected from hydrogen, -C 1～6 alkyl; R x independently selected from the group consisting of halogen, cyano, hydroxy, amine, C 1～3 alkyl, C 1～3 alkoxy and C 3～6 cycloalkyl; the alkyl, alkoxy, cycloalkyl in said R x may optionally be substituted 1 to 3 times with halogen; Y 1 For or CR Y1-1 R Y1-2 ; M 1-5 H, optionally substituted C1-C6alkyl; M 1-1 , M 1-2 , M 1-3 and M 1-4 are each independently H, A2, halogen, L is A1-L 1 -L 2 -L 3 -L 4 -A2; wherein, A1 is a bond between the linker and the ring system A; A2 is a bond between the degradation moiety and the linker; L 1 selected from -0-, -S-, -C(O)-, -NR 1a -, C 1-6 alkylene, C 1-6 alkylene-3-10 membered heterocyclyl, C 3-6 cycloalkylene, and 3-10 membered heterocyclylene, each of said alkylene, cycloalkylene, heterocyclylene, and heteroarylene being optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, and C 1-6 haloalkyl; L 2 is a covalent bond, or is selected from -C(O)- or C 1-6 alkylene; L 3 is a covalent bond, or is selected from -O-, -NR 3a -, C 1-6 alkylene, -O-C 1-6 alkylene, C 1-6 alkylene-O-, C 3-6 cycloalkylene, and 3-10 membered heterocyclyl ene, each of which alkylene, cycloalkylene, and heterocyclyl ene is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, and C 1-6 haloalkyl; L 4 is a covalent bond, or is selected from -O-, -S-, -NR 4a -, C 1-6 alkylene, -O-C 1-6 alkylene-, C 1-6 alkylene-O-, C 3-6 cycloalkylene, -C(O)-, -C(O)-N(R 4a )-, -C(O)-C 1-6 alkylene-, and 3-10 membered heterocyclyl, each of which alkylene, cycloalkylene and heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; each of which alkylene, cycloalkylene and heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; R 1a , R 3a , and R 4a are each independently selected from the group consisting of hydrogen and C 1-6 alkyl.

29. The compound of claim 28, wherein The compound of Formula I-V is selected from the group consisting of: (1) R1is independently selected from the group consisting of said alkyl, heterocyclyl, cycloalkyl and amine groups in R1may optionally be substituted 1 to 3 times; preferably R1is independently selected from the group consisting of x -CH2CH2CH3, more preferably R1is independently selected from the group consisting of -CH2CH2CH3, further preferably ​ (2) the L has the following structure: -CH2-, -CH2-, Preferably said linker L has the following structure: more preferably Further preferred 30. The compound of any one of claims 1-18, wherein The compound of Formula I has a structure according to Formula I-VI wherein R 1 is selected from -C 1～8 alkyl, -C 0～4 alkylene-C 3～8 cycloalkyl, -C 0～4 alkylene-3 to 12 membered heterocyclyl; the alkyl, heterocyclyl, cycloalkyl in R 1 may be optionally substituted 1 to 3 times with R x ; preferably R 1 is selected from -C 0～4 alkylene-C 3～8 cycloalkyl; R2is selected from hydrogen, -C 1～6 alkyl; R x independently selected from the group consisting of halogen, cyano, hydroxy, amine, C 1～3 alkyl, C 1～3 alkoxy and C 3～6 cycloalkyl; the alkyl, alkoxy, cycloalkyl in said R x may optionally be substituted 1 to 3 times with halogen; M2-3 is H or optionally substituted C1-C6 alkyl; L is A1-L 1 -L 2 -L 3 -L 4 -A2; L 1 selected from -0-, -S-, -C(O)-, -NR 1a -, C 1-6 alkylene, C 1-6 alkylene-3-10 membered heterocyclyl, C 3-6 cycloalkylene, and 3-10 membered heterocyclylene, each of said alkylene, cycloalkylene, heterocyclylene, and heteroarylene being optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, and C 1-6 haloalkyl; L 2 is a covalent bond, or is selected from -C(O)- or C 1-6 alkylene; L 3 is a covalent bond, or is selected from -O-, -NR 3a -, C 1-6 alkylene, -O-C 1-6 alkylene, C 1-6 alkylene-O-, C 3-6 cycloalkylene, and 3-10 membered heterocyclylene, each of which alkylene, cycloalkylene, and heterocyclylene is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, and C 1-6 haloalkyl; L 4 is a covalent bond, or is selected from -O-, -S-, -NR 4a -, C 1-6 alkylene, -O-C 1-6 alkylene-, C 1-6 alkylene-O-, C 3-6 cycloalkylene, -C(O)-, -C(O)-N(R 4a )-, -C(O)-C 1-6 alkylene-, and 3-10 membered heterocyclyl, each of which alkylene, cycloalkylene and heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; each of which alkylene, cycloalkylene and heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; R 1a , R 3a , and R 4a are each independently selected from hydrogen and C 1-6 alkyl.

31. The compound of claim 30, wherein The compound of Formula I-VI is selected from the group consisting of: (1) R1is independently selected from the group consisting of said alkyl, heterocyclyl, cycloalkyl and amine groups in R1may optionally be substituted 1 to 3 times with R x ; preferably R1is independently selected from the group consisting of -CH2CH2CH, Further preferred (2) the L has the following structure: -CH2-, -CH2-, -CH2- is further preferred.

32. The method of any one of claims 1-31, wherein, The compound of Formula I is any one of the following compounds:

33. A pharmaceutical composition comprising a prophylactically and / or therapeutically effective amount of a compound of any one of claims 1-32, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

34. A kit comprising a compound of any one of claims 1-32, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of claim 33.

35. A compound of any one of claims 1-32, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of claim 33, which targets the SMARCA2 protein and is used to inhibit or degrade the SMARCA2 protein.

36. A compound of any one of claims 1-32, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of claim 33, for use in the prevention and / or treatment of a SMARCA2-mediated related disease.

37. Use of a compound of any one of claims 1-32, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of claim 33, in the manufacture of a medicament for the prevention and / or treatment of a SMARCA2-mediated related disease.

38. A method of preventing and / or treating a disease associated with SMARCA2, comprising administering to a subject in need thereof a prophylactically and / or therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug of any one of claims 1-32, or a pharmaceutical composition of claim 33.

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