Compounds containing a trifluoromethanesulfonyl group

Abstract

The present disclosure is in the field of medicinal chemistry and relates to compounds containing a trifluoromethanesulfonyl group, specifically to the compound of formula I or a pharmaceutically acceptable salt thereof, methods for making same, pharmaceutical compositions containing same, and uses thereof in the treatment of tumor diseases. TIFF2026507476000211.tif64170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of Chinese Patent Application No. 202310134195.8 filed with the State Intellectual Property Office of China on February 17, 2023, and Chinese Patent Application No. 202410136766.6 filed with the State Intellectual Property Office of China on January 31, 2024, the entire contents of which are hereby incorporated by reference in their entirety.

[0002] The present disclosure relates to compounds containing a trifluoromethanesulfonyl group, methods for their preparation, pharmaceutical compositions containing such compounds, and their use in the treatment of tumor diseases. [Background technology]

[0003] The B-cell lymphoma 2 (Bcl-2) protein family, consisting of pro- and anti-apoptotic members, plays a crucial role in determining cell fate by regulating the intrinsic apoptotic pathway. Anti-apoptotic Bcl-2 family proteins (e.g., Bcl-2, Bcl-xL, Bcl-W, and Mcl-1) are upregulated in many cancers and are associated with tumor initiation, progression, and resistance to chemotherapy and targeted therapy. Because the growth of most solid tumors does not depend on BCL-2 protein, inhibitors targeting only BCL-2 have shown no significant efficacy in treating solid tumors. However, BCL-XL protein expression is significantly elevated in many leukemia cells and solid tumors. Studies have shown that BCL-XL expression in tumor tissues is positively correlated with tumor drug resistance, making targeting BCL-XL a potential and ideal antitumor molecular target.

[0004] PROTAC (proteolysis targeting chimera) molecules are a series of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds induce target proteins to be recognized by the cellular proteasome, leading to their degradation and effectively reducing the amount of target proteins in cells. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC molecule-based technology can be used to treat a variety of diseases, and this technology has attracted considerable attention in recent years. Summary of the Invention

[0005] The present disclosure relates to compounds of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R is OH, NH, CN, halogen, or C optionally substituted by one or more of OH, NH, CN, halogen. 1~6 selected from alkyl groups, X is selected from CH2, NH or O; L is a linking functional group; ULM is [ka] and In the formula, R 1 is C optionally substituted by one or more halogens 1~6 selected from alkyl groups, R 2 is optionally substituted by one or more of OH, NH, CN, halogen 1~6 selected from alkyl groups, X 1 , X 2 , X 3 , X 4 and X 5are each independently selected from CH, C, N, NH, O, or S; Individual R 3 are OH, NH2, CN, halogen, and C, respectively. 1~6 Alkyl group or C 1~6 alkoxy groups, wherein the NH, C 1~6 Alkyl group or C 1~6 the alkoxy group is optionally substituted by one or more OH, NH, CN or halogen; m and q are each independently selected from 0, 1, 2, or 3; The condition is that ULM [ka] It is not, Individual R, X, L, R 1 , R 2 , X 1 , X 2 , X 3 , X 4 or X 5 are each independently optionally substituted with one or more substituents.

[0006] The present disclosure relates to compounds of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R is OH, NH, CN, halogen, or C optionally substituted by one or more of OH, NH, CN, halogen. 1~6 selected from alkyl groups, X is selected from CH2, NH or O; L is a linking functional group; ULM is [ka] and In the formula, R 1is C optionally substituted by one or more halogens 1~6 selected from alkyl groups, R 2 is optionally substituted by one or more of OH, NH, CN, halogen 1~6 selected from alkyl groups, X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from CH, C, N, O, or S; Individual R 3 are OH, NH2, CN, halogen, and C, respectively. 1~6 Alkyl group or C 1~6 alkoxy groups, wherein the OH, NH, C 1~6 Alkyl group or C 1~6 the alkoxy group is optionally substituted by one or more OH, NH, CN or halogen; m and q are each independently selected from 0, 1, 2, or 3; The condition is that ULM [ka] It is not, Individual R, X, L, R 1 , R 2 , X 1 , X 2 , X 3 , X 4 or X 5 are each independently optionally substituted with one or more substituents.

[0007] In some embodiments, the R is a halogen or a C optionally substituted by one or more of OH, NH, CN, halogen. 1~6 It is selected from alkyl groups.

[0008] In some embodiments, the R is F, Cl, Br, or C optionally substituted by one or more of OH, NH, CN, halogen. 1~3 It is selected from alkyl groups.

[0009] In some embodiments, the R is F, Cl, Br, or C optionally substituted by one or more F or Cl. 1~3 It is selected from alkyl groups.

[0010] In some embodiments, R is selected from F, Cl, Br, or a trifluoromethyl group.

[0011] In some embodiments, R is selected from Cl.

[0012] In some embodiments, q is selected from 0, 1, or 2; or q is selected from 0 or 1.

[0013] In some embodiments, R is selected from Cl and q is selected from 1.

[0014] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0015] In some embodiments, X is selected from NH or O.

[0016] In some embodiments, X is selected from NH.

[0017] In some embodiments, X is selected from O.

[0018] In some embodiments, L is a bond, -C 1~20 Alkyl-, -C 2~20 Alkenyl- or -C 2~20 alkynyl-, wherein -C 1~20 Alkyl-, -C 2~20 Alkenyl- or -C 2~20 One or more -CH2- in alkynyl- may (each independently) optionally be R x wherein R is replaced by x -O-, -NR a -, -S(O)2-, -S(O)2NR a -, -S(O)-, -S(O)NR a -, -C(O)-, -C(O)O-, -C(O)NR a -, -C(O)N(R a )O-, -OC(O)-, -OC(O)NR a -, -N(R a )C(O)O-, -N(R a )C(O)-, -N(R a )S(O)2-, 5- to 12-membered heteroaryl group, phenyl group, C 3~10 cycloalkyl group, 3- to 10-membered heterocycloalkyl group, or -S-; R a is hydrogen or C 1~6 alkyl groups, and each R x or R a are each independently optionally substituted with one or more substituents.

[0019] -C as described in this disclosure 1~20 Alkyl-, -C 2~20 Alkenyl- or -C 2~20 One or more -CH2- in alkynyl- may optionally be R x and each of said replacements occurs independently, for example, said L is a bond, -C 1~20 Alkyl-, -C 2~20 Alkenyl- or -C 2~20 alkynyl-, wherein -C 1~20 Alkyl-, -C 2~20 Alkenyl- or -C2~20 One or more -CH2- in alkynyl- may optionally each independently be R x wherein R is replaced by x -O-, -NR a -, -S(O)2-, -S(O)2NR a -, -S(O)-, -S(O)NR a -, -C(O)-, -C(O)O-, -C(O)NR a -, -C(O)N(R a )O-, -OC(O)-, -OC(O)NR a -, -N(R a )C(O)O-, -N(R a )C(O)-, -N(R a )S(O)2-, 5- to 12-membered heteroaryl group, phenyl group, C 3~10 cycloalkyl group, 3- to 10-membered heterocycloalkyl group, or -S-; R a is hydrogen or C 1~6 alkyl groups, and each R x or R a are each independently optionally substituted with one or more substituents.

[0020] In some embodiments, R a is hydrogen or C 1~4 alkyl group, or hydrogen or C 1~3 alkyl group, or hydrogen or C 1~2 It is selected from alkyl groups, or from hydrogen or methyl groups.

[0021] In some embodiments, the R x represents -O-, -C(O)-, 5- to 12-membered heteroaryl groups, phenyl groups, C 3~10 Cycloalkyl groups, 3- to 10-membered heterocycloalkyl groups, -NH-, -N(C 1~6 alkyl)- or -S-.

[0022] In some embodiments, the R x is -O-, -C(O)-, 5- to 6-membered heteroaryl group, phenyl group, C3~6 Cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, -NH-, -N(C 1~6 alkyl)- or -S-.

[0023] In some embodiments, the R x -O-, -C(O)-, phenyl group, C 5~6 Cycloalkyl groups, 5- to 6-membered heterocycloalkyl groups, -NH-, -N(C 1~3 alkyl)- or -S-.

[0024] In some embodiments, the R x -O-, -C(O)-, phenyl group, pipet Lysinyl group, piperazinyl group, -NH-, -N(C 1~3 alkyl)- or -S-.

[0025] In some embodiments, the R x is selected from -C(O)- or a piperazinyl group.

[0026] In some embodiments, the R x is -C(O)- or [ka] In some embodiments, the R x is selected from -C(O)-.

[0027] The substitutions in L described in the present disclosure occur independently of one another, for example, L may be a bond, -C 1~12 Alkyl-, -C 2~12 Alkenyl- or -C 2~12 alkynyl-, wherein -C 1~12 Alkyl-, -C 2~12 Alkenyl- or -C 2~12 One or more -CH2- in alkynyl- may optionally each independently be R x wherein R is replaced by xis defined in this disclosure.

[0028] In some embodiments, L is a bond, -C 1~12 Alkyl-, -C 2~12 Alkenyl- or -C 2~12 alkynyl-, wherein -C 1~12 Alkyl-, -C 2~12 Alkenyl- or -C 2~12 One or more -CH2- in alkynyl- may (each independently) optionally be R x wherein R is replaced by x is defined in this disclosure.

[0029] In some embodiments, L is a bond, -C 3~12 Alkyl-, -C 3~12 Alkenyl- or -C 3~12 alkynyl-, wherein -C 3~12 Alkyl-, -C 3~12 Alkenyl- or -C 3~12 One or more -CH2- in alkynyl- may optionally each independently be R x wherein R is replaced by x is defined in this disclosure.

[0030] In some embodiments, L is a bond, -C 6~12 Alkyl-, -C 6~12 Alkenyl- or -C 6~12 alkynyl-, wherein -C 6~12 Alkyl-, -C 6~12 Alkenyl- or -C 6~12 One or more -CH2- in alkynyl- may optionally each independently be R x wherein R is replaced by x is defined in this disclosure.

[0031] In some embodiments, L is a bond, -C 8~9 Alkyl-, -C 8~9 Alkenyl- or -C8~9 alkynyl-, wherein -C 8~9 Alkyl-, -C 8~9 Alkenyl- or -C 8~9 One or more -CH2- in alkynyl- may optionally each independently be R x wherein R is replaced by x is defined in this disclosure.

[0032] In some embodiments, L is a bond, -C 6~12 Alkyl-, -C 6~12 Alkenyl- or -C 6~12 alkynyl-, wherein -C 6~12 Alkyl-, -C 6~12 Alkenyl- or -C 6~12 One or more -CH2- in alkynyl- may optionally each independently be R x wherein R is replaced by x represents -O-, -C(O)-, phenyl group, piperidinyl group, piperazinyl group, -NH-, -N( C 1~3 alkyl)- or -S-.

[0033] In some embodiments, L is a bond, -C 6~12 Alkyl-, -C 6~12 Alkenyl- or -C 6~12 alkynyl-, wherein -C 6~12 Alkyl-, -C 6~12 Alkenyl- or -C 6~12 One or more -CH2- in alkynyl- may (each independently) optionally be R x wherein R is replaced by x represents -O-, -C(O)-, phenyl group, piperidinyl group, piperazinyl group, -NH-, -N(C 1~3 alkyl)- or -S-.

[0034] In some embodiments, L is -C 3~12 alkyl-, wherein the -C 3~12One or more -CH2- in alkyl- may optionally each independently be R x wherein R is replaced by x is selected from -C(O)- or a piperazinyl group.

[0035] In some embodiments, L is -C 6~12 alkyl-, wherein the -C 6~12 One or more -CH2- in alkyl- may optionally each independently be R x wherein R is replaced by x is selected from -C(O)- or a piperazinyl group.

[0036] In some embodiments, L is -C 6~10 alkyl-, wherein the -C 6~10 One or more -CH2- in alkyl- may optionally each independently be R x wherein R is replaced by x is selected from -C(O)- or a piperazinyl group.

[0037] In some embodiments, L is -C 6~10 alkyl-, wherein the -C 6~10 One or more -CH2- in alkyl- may optionally each independently be R x wherein R is replaced by x is -C(O)- or [ka] Selected from.

[0038] In some embodiments, L is -C 8~10 alkyl-, wherein the -C 8~10 One or more -CH2- in alkyl- are optionally each independently replaced by -C(O)-.

[0039] In some embodiments, L is [ka] or [ka] wherein n is selected from 0 to 10, or n is selected from 1 to 9, or n is selected from 1 to 7.

[0040] In some embodiments, L is [ka] or [ka] wherein n is selected from 0 to 10, or n is selected from 1 to 9, or n is selected from 1 to 7.

[0041] In some embodiments, L is [ka] or [ka] Selected from.

[0042] In some embodiments, L is [ka] or [ka] In some embodiments, L is selected from: [ka] or [ka] In some embodiments, L is selected from: [ka] or [ka] In some embodiments, L is selected from: [ka] or [ka] In some embodiments, L is selected from: [ka] or [ka] In some embodiments, L is selected from: [ka] or [ka] In some specific embodiments, L is selected from: [ka] In some specific embodiments, L is selected from: [ka] or [ka] In some specific embodiments, L is selected from: [ka] In some specific embodiments, L is selected from: [ka] In some specific embodiments, L is selected from: [ka] In some other embodiments, L is selected from: [ka] or [ka] In some other embodiments, L is selected from: [ka] or [ka] Selected from.

[0043] In some embodiments, either end of the L is linked to a ULM.

[0044] In some embodiments, the right end of the L is linked to a ULM. For example, [ka] The right end of is connected to ULM.

[0045] In some embodiments, the left end of the L is linked to a ULM.

[0046] In some embodiments, L is [ka] or [ka] where * indicates that the end is linked to a ULM.

[0047] In some embodiments, X 1 , X 2 , X 3 , X 4 and X 5 are CH, Independently selected from C, N, O or S.

[0048] In some embodiments, X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from CH, C, N, NH, O, or S. In some embodiments, X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from CH, C, N, NH, or S. In some embodiments, X 1 , X 2 , X 3 , X4 and X 5 are each independently selected from CH, C, NH, or N.

[0049] In some embodiments, the X 1 and X 2 are each independently selected from N or NH, and X 3 and X 4 are each independently selected from CH, and X 5 is selected from C. In some embodiments, X 1 , X 2 and X 4 is selected from CH, and X 3 and X 5 is selected from N or NH. 1 , X 2 and X 4 is selected from CH, and X 3 is selected from N or NH, and X 5 is selected from N. In some embodiments, the X 1 is selected from S, and X 2 and X 4 is selected from CH, and X 3 is selected from N or NH, and X 5 is selected from C.

[0050] In some embodiments, the X 1 and X 2 is selected from N, and X 3 and X 4 are each independently selected from CH, and X 5 is selected from C, or X 1 , X 2 and X 4 is selected from CH, and X 3 and X 5 is selected from N, or X 1 is selected from S, and X 2 and X 4 is selected from CH, and X 3 is selected from N, and X 5 is selected from C.

[0051] In some embodiments, the structural unit [ka] teeth, [ka] or [ka] In some embodiments, the structural unit is selected from [ka] teeth, [ka] or [ka] In some embodiments, the structural unit is selected from [ka] teeth, [ka] In some embodiments, the structural unit is selected from [ka] teeth, [ka] In some embodiments, the structural unit is selected from [ka] teeth, [ka] Selected from.

[0052] In some embodiments, the R 1 is C optionally substituted by one or more halogens 1~4 It is selected from alkyl groups.

[0053] In some embodiments, the R 1 is C optionally substituted by one or more halogens 3~4 It is selected from alkyl groups.

[0054] In some embodiments, the R 1 is selected from an isopropyl group or a tert-butyl group optionally substituted with one or more halogens.

[0055] In some embodiments, the R 1 is selected from an isopropyl group or a tert-butyl group.

[0056] In some embodiments, the R 2 is optionally substituted by one or more of OH, NH, CN, halogen 1~4 It is selected from alkyl groups.

[0057] In some embodiments, the R 2 is selected from a methyl group optionally substituted by one or more of OH, NH2, CN, halogen.

[0058] In some embodiments, the R 2 is selected from a methyl group optionally substituted by one or more OH.

[0059] In some embodiments, the R 2 is selected from a hydroxymethyl group or a methyl group.

[0060] In some embodiments, the X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from CH, C, N, NH, O, or S, and at least one is N or NH.

[0061] In some embodiments, the X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from CH, C, N, NH, O, or S, and at least two are heteroatoms.

[0062] In some embodiments, the X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from CH, C, N, NH, O, or S, and at least two are selected from N, NH, or S.

[0063] In some embodiments, the X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from CH, C, N, O, or S, and at least one is N.

[0064] In some embodiments, the X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from CH, C, N, O, or S, and at least two are heteroatoms.

[0065] In some embodiments, the X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from CH, C, N, O, or S, and at least two are selected from N or S.

[0066] In some embodiments, X 5 is C.

[0067] In some embodiments, X 5 is N.

[0068] In some embodiments, X 1 , X 2 , X 3 , X 4 and X 5 The ring formed by X has aromatic character. 1 , X 2 , X 3 , X 4 and X 5 The ring formed by is a five-membered heteroaromatic ring.

[0069] In some embodiments, the structural unit [ka] teeth, [ka] or [ka] In some embodiments, the structural unit is selected from [ka] teeth, [ka] In some embodiments, the structural unit is selected from [ka] teeth, [ka] Selected from.

[0070] In some embodiments, the structural unit [ka] teeth, [ka] or [ka] In some embodiments, the structural unit is selected from [ka] teeth, [ka] In some embodiments, the structural unit is selected from [ka] teeth, [ka] Selected from.

[0071] In some embodiments, each R 3are OH, NH2, CN, halogen, and C, respectively. 1~3 Alkyl group or C 1~3 alkoxy groups, wherein the OH, NH, C 1~3 Alkyl group or C 1~3 The alkoxy group is optionally substituted by one or more of OH, NH2, CN or halogen.

[0072] In some embodiments, each R 3 are respectively, C 1~3 Alkyl group or C 1~3 are independently selected from alkoxy groups.

[0073] In some embodiments, each R 3 are each independently selected from OH, NH2, CN, a halogen, a methyl group, or an ethyl group.

[0074] In some embodiments, each R 3 are respectively, C 1~3 In some embodiments, each R 3 are each independently selected from a methyl group or an ethyl group.

[0075] In some embodiments, the structural unit [ka] teeth, [ka] or [ka] In some embodiments, the structural unit is selected from [ka] teeth, [ka] or [ka] Selected from.

[0076] In some embodiments, the ULM is: [ka]

[0077] In some embodiments, the ULM is: [ka] or [ka]

[0078] In some embodiments, m and q are each 1.

[0079] The compound of formula I of the present disclosure, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula II, formula III, formula II-A, formula III-A, formula III-B, formula IV, formula V, formula VI, or formula VII, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; [ka] In the formula, R, q, L, ULM, X, R 1 , R 2 or R 3 The definitions of are provided in this disclosure. That's right.

[0080] In this disclosure, each R, X, L, R 1 , R 2, X 1 , X 2 , X 3 , X 4 , X 5 , R x or R a are each independently optionally substituted with one or more substituents.

[0081] The present disclosure relates to the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or [ka]

[0082] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound described herein, its stereoisomer, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0083] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound described herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0084] In another aspect, the present disclosure relates to the use of a compound described herein, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for preventing or treating a condition treated by degrading a target protein that binds to a targeting ligand (e.g., a small molecule structural moiety related to BCL-XL).

[0085] In another aspect, the present disclosure relates to the use of a compound according to the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for preventing or treating a condition that is treated by binding to a cerebellar protein in the body.

[0086] In another aspect, the present disclosure relates to the use of a compound according to the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for preventing or treating a condition treated by binding to a protein in the cerebellum.

[0087] In another aspect, the present disclosure relates to the use of a compound described in the present disclosure, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for preventing or treating a disease associated with BCL-XL.

[0088] The present disclosure relates to a method for treating or preventing a condition in a mammal that is treated by degrading a target protein that binds to a targeting ligand, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound described in the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0089] The present disclosure relates to a method for treating or preventing a condition treated by binding to a protein in the cerebellum, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound described herein, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0090] The present disclosure provides a method for treating or preventing a condition treated in vivo by binding to a cerebellar protein, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound described herein, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a compound thereof. The present invention relates to a method comprising administering a pharmaceutical composition of the formula:

[0091] In another aspect, the present disclosure relates to a method for treating a disease associated with BCL-XL in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound described in the present disclosure, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0092] In another aspect, the present disclosure relates to a compound according to the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a condition that is treated by degrading a target protein that binds to a targeting ligand.

[0093] In another aspect, the present disclosure relates to a compound according to the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a condition that is treated by binding to a protein in the cerebellum.

[0094] In another aspect, the present disclosure relates to a compound according to the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a condition that is treated by binding to a cerebellar protein in the body.

[0095] In another aspect, the present disclosure relates to a compound described in the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a disease associated with BCL-XL.

[0096] In another aspect, the present disclosure relates to the use of a compound according to the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of a condition that is treated by degrading a target protein that binds to a targeting ligand.

[0097] In another aspect, the present disclosure relates to the use of a compound according to the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of a condition treated by binding to a protein in the cerebellum.

[0098] In another aspect, the present disclosure relates to the use of a compound according to the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of a condition that is treated in the body by binding to a cerebellar protein.

[0099] In another aspect, the present disclosure relates to the use of a compound described herein, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of a disease associated with BCL-XL.

[0100] In some specific embodiments, the BCL-XL associated disease is selected from conditions that are treated by degrading and / or inhibiting proteins that bind to BCL-XL target protein ligands; in some specific embodiments, the BCL-XL associated disease is selected from conditions that are treated by binding to cerebellar proteins; in some specific embodiments, the BCL-XL associated disease is selected from conditions that are treated in vivo by binding to cerebellar proteins; in some embodiments, the disease or condition is selected from tumors or cancers.

[0101] In some specific embodiments, the condition treated by binding to a cerebellar protein in vivo is selected from a BCL-XL associated disease, hi some specific embodiments, the BCL-XL associated disease is selected from tumors or cancer.

[0102] In some embodiments, the present disclosure includes the above-defined variables and embodiments thereof, and any combination thereof. [Effects of the Invention]

[0103] The compounds disclosed herein have growth inhibitory effects on RS4;11 cells and MOLT-4 cells, can degrade BCL-XL protein in MOLT-4 cells, have favorable BCL-XL protein degradation kinetics, are stably metabolized in vivo (e.g., in human, rat, or mouse liver microsomes), have low toxicity to platelets (e.g., canine platelets), and have favorable in vivo efficacy (e.g., favorable tumor-inhibiting effects) and pharmacokinetic properties in vivo (e.g., in mice, rats, or dogs). Furthermore, the compounds disclosed herein have effective tumor growth inhibitory effects in vivo. Furthermore, the compounds disclosed herein have low platelet toxicity, providing favorable safety when used as drugs. DETAILED DESCRIPTION OF THE INVENTION

[0104] (definition) Unless otherwise specified, the following terms used in this disclosure have the following meanings: Certain terms, unless otherwise defined, are not to be considered open-ended or indefinite but are to be understood in their ordinary sense in the art. When trade names appear herein, they refer to the corresponding product or its active ingredient.

[0105] Unless otherwise specified, [ka] teeth, [ka] represents that a hydrogen atom at any position of the functional group within the group may be substituted with a functional group linked to "-", for example, linked to L and substituted.

[0106] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, provided that the valence of the atom is normal and the resulting compound is stable. When the substituent is oxo (=O), this means that two hydrogen atoms are replaced. Oxo does not occur in aryl groups.

[0107] The term "optional" or "optionally" refers to the subsequently described event or circumstance, which may or may not occur, and includes both cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, when an ethyl group is "optionally" substituted with a halogen, the ethyl group may be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). Those skilled in the art will understand that spatially inexistent and / or synthetically incapable substitutions or substitution schemes are not permitted for any functional group containing one or more substituents.

[0108] The "substituents" referred to herein include all substituents mentioned in the context of the present specification, including, but not limited to, terms such as "alkyl group," "alkoxy group," "heteroalkyl group," "alkenyl group," "alkynyl group," "cycloalkenyl group," "cycloalkyl group," "heterocycloalkyl group," "heterocycloalkenyl group," "heterocyclyl group," "heteroaryl group," and the like mentioned below, and corresponding non-limiting or exemplary functional groups, where some non-limiting examples of said "substituents" are deuterium, tritium, -OH, - SH, halogen, -NH2, nitro group, nitroso group, -CN, azide functional group, sulfoxide functional group, sulfone functional group, sulfonamide functional group, carboxy group, acetal functional group, imine functional group, alkyl group, halo-alkyl group, cycloalkyl group, halo-cycloalkyl group, alkenyl group, halo-alkenyl group, cycloalkenyl group, halo-cycloalkenyl group, alkynyl group, halo-alkynyl group, cycloalkynyl group, halo-cycloalkynyl group, heteroalkyl group, halo-heteroalkyl group, alkoxy group, alkylthio group, aryl group, arylthio group oxy group, arylthio group, aralkyl group, arylalkoxy group, arylalkylthio group, heteroaryl group, heteroaryloxy group, heteroarylthio group, heteroaralkyl group, heteroarylalkoxy group, heteroarylalkylthio group, heterocyclyl group, heterocyclyloxy group, heterocyclylthio group, heterocyclylalkyl group, heterocyclylalkoxy group, heterocyclylalkylthio group, acyl group, acyloxy group, carbamate functional group, amide functional group, ureido group, epoxy functional group and ester functional group. The functional group optionally is oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH, -C(O)NH-alkyl, -C(O)N(alkyl), -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)-alkyl, -S(O)NH,It is substituted by one or more substituents selected from -S(O)NH-alkyl group, -S(O)N(alkyl)2, cycloalkyl group, cycloalkylalkyl group, cycloalkyloxy group, heterocyclyl group, heterocyclylalkyl group, heterocyclyloxy group, heterocycloalkyl group, heterocycloalkylalkyl group, heterocycloalkyloxy group, heteroaryl group, heteroarylalkyl group, heteroaryloxy group, aryl group, arylalkyl group, or aryloxy group.

[0109] Herein, C m~n means that the moiety has an integer number of carbon atoms within a given range. For example, "C 1~6 " means that the functional group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. For example, C 1~3 means that the functional group may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0110] In some embodiments herein, the substituent is selected from the group consisting of deuterium, tritium, a hydroxy group, a mercapto group, a halogen, an amino group, a nitro group, a nitroso group, a cyano group, an azide functional group, a sulfoxide functional group, a sulfone functional group, a sulfonamide functional group, a carboxy group, an aldehyde group, an imine functional group, a C 1~12 Alkyl groups, halo-C 1~12 Alkyl groups, 3- to 12-membered cycloalkyl groups, halo-3- to 12-membered cycloalkyl groups, C 2~12 Alkenyl group, halo-C 2~12 Alkenyl group, 3- to 12-membered cycloalkenyl group, halo-3- to 12-membered cycloalkenyl group, C 2~12 Alkynyl group, halo-C 2~12 Alkynyl group, 8- to 12-membered cycloalkynyl group, halo-8- to 12-membered cycloalkynyl group, C 1~12 Heteroalkyl groups, halo-C 1~12 Heteroalkyl groups, C 1~12 Alkoxy group, C 1~12Alkylthio group, 6- to 10-membered aryl group, 6- to 10-membered aryloxy group, 6- to 10-membered arylthio group, 6- to 10-membered arylC 1~12 Alkylene group, 6-10 membered aryl C 1~12 Alkoxy group, 6-10 membered aryl C 1~12 Alkylthio group, 5- to 10-membered heteroaryl group , a 5- to 10-membered heteroaryloxy group, a 5- to 10-membered heteroarylthio group, a 5- to 10-membered heteroarylalkylene group, a 5- to 10-membered heteroarylalkoxy group, a 5- to 10-membered heteroarylalkylthio group, a 3- to 12-membered heterocyclyl group, a 3- to 12-membered heterocyclyloxy group, a 3- to 12-membered heterocyclylthio group, a 3- to 12-membered heterocyclylC 1~12 Alkylene group, 3-12 membered heterocyclyl C 1~12 Alkoxy group, 3- to 12-membered heterocyclyl C 1~12 Alkylthio group, C 1~12 Acyl group, C 1~12 Acyloxy group, carbamate functional group, C 1~12 Amide group, ureido group, epoxy functional group, C 2~12 ester functional groups and oxo, the substituents being optionally selected from oxo, hydroxy groups, amino groups, nitro groups, halogens, cyano groups, C 1~12 Alkyl group, C 2~12 Alkenyl group, C 2~12 Alkynyl group, C 1~12 Alkoxy group, haloC 1~12 Alkoxy group, C 1~12 Alkylamino group, diC 1~12 Alkylamino group, haloC 1~12 Alkylamino group, HalodiC 1~12 Alkylamino group, carboxy group, -C(O)OC 1~12 Alkyl group, -OC(O)-C 1~12 Alkyl group, -C(O)NH2, -C(O)NH-C 1~12 Alkyl group, -C(O)N(C 1~12 alkyl)2, -NHC(O)-C 1~12 Alkyl group, -C(O)-C 1~12 Alkyl group, -S(O)-C 1~12 Alkyl group, -S(O)2-C 1~12Alkyl group, -S(O)2NH2, -S(O)2NH-C 1~12 Alkyl group, -S(O)N(C 1~12 Alkyl) 2, 3- to 12-membered cycloalkyl group, 3- to 12-membered cycloalkyl C 1~12 Alkylene group, 3- to 12-membered cycloalkyloxy, 3- to 12-membered heterocyclyl group, 3- to 12-membered heterocyclylC 1~12 Alkylene group, 3- to 12-membered heterocyclyloxy group, 3- to 12-membered heterocycloalkyl group, 3- to 12-membered heterocycloalkylC 1~12 Alkylene group, 3- to 12-membered heterocycloalkyloxy, 5- to 10-membered heteroaryl group, 5- to 10-membered heteroarylC 1~12 Alkylene group, 5- to 10-membered heteroaryloxy group, 6- to 10-membered aryl group, 6- to 10-membered arylC 1~12 It is substituted with one or more substituents selected from an alkylene group or a 6- to 10-membered aryloxy group.

[0111] As used herein, "one or more" refers to an integer between 1 and 10. For example, "one or more" refers to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or "one or more" refers to 1, 2, 3, 4, 5, or 6, or "one or more" refers to 1, 2, or 3.

[0112] In some embodiments, the "one or more" is selected from 1, 2, 3, 4, 5, 6 or more. In some embodiments, the "one or more" is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the "one or more" is selected from 1, 2, or 3. In some embodiments, the "one or more" is selected from 1 or 2.

[0113] When any variable (e.g., R) occurs more than one time in a compound composition or structure, it is independently defined at each occurrence. For example, if a functional group contains two R, each R has independent options.

[0114] When a bond connects two atoms of a ring (including monocyclic, fused, and spiro rings), such bond can be attached to any atom on the ring (including monocyclic, fused, and spiro rings).

[0115] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0116] The term "hydroxy group" refers to an -OH functional group.

[0117] The term "amino group" refers to an -NH2 functional group.

[0118] The term "cyano" refers to a -CN functionality.

[0119] The term "mercapto" refers to an -SH functionality.

[0120] The term "nitro group" refers to the -NO2 functional group.

[0121] The term "heteroatom" includes atoms of any element except carbon and hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, sulfur, silicon, and phosphorus. In one embodiment, the heteroatom is selected from N, O, and S, where the nitrogen atom is optionally quaternized, and the nitrogen, sulfur, and phosphorus heteroatoms may optionally be oxidized (i.e., NO, S(O)). p , P(O) p and p is 1 or 2).

[0122] The term "alkyl group" refers to a group having the general formula C n H 2n+1 The alkyl group may be a straight chain or a branched chain. For example, "C 1~6The term "alkyl group" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl group) of an alkoxy group, alkylamino group, dialkylamino group, alkylsulfonyl group, and alkylthio group has the same definition as above. Also, for example, "C 1~3 The term "alkyl group" refers to alkyl groups containing 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, and isopropyl groups).

[0123] The term "alkoxy" refers to an --O-alkyl group.

[0124] The term "heteroalkyl group" refers to an alkyl group structure containing a heteroatom. Unless otherwise specified, the heteroalkyl group is generally an alkyl group containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. Generally, when more than one heteroatom is present, the heteroatoms are not adjacent to one another. Exemplary heteroalkyl groups include alkoxy groups, alkoxyalkyl groups, alkylamino groups, alkylaminoalkyl groups, dialkylamino groups, dialkylaminoalkyl groups, and the like.

[0125] The term "alkenyl group" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0126] The term "alkynyl group" refers to a straight or branched unsaturated aliphatic hydrocarbon group composed of carbon and hydrogen atoms and having at least one triple bond. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH), 2-propynyl (-CH-C≡CH), 1,3-butadiynyl (-C≡CC≡CH), and the like.

[0127] The term "cycloalkenyl group" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bicyclic bridged ring, or spiro ring. Unless otherwise specified, the carbocyclic ring is typically a 4- to 20-membered, 4- to 15-membered, 4- to 10-membered, or 4- to 8-membered ring. Non-limiting examples of cycloalkenyl groups include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, and cycloheptadienyl groups. These include, but are not limited to:

[0128] The term "cycloalkyl group" refers to a carbocyclic ring that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, the carbocyclic ring is typically 3-20, 3-15, 3-12, or 3-10 (e.g., 5-8) membered. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantanyl, and the like.

[0129] The term "heterocycloalkyl group" refers to a cyclic functional group that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, the heterocycle generally is a 3-20, 3-15, 3-10, 3-7, 3-6, or 3-5 membered ring containing 1 to 3 (preferably 1 or 2) heteroatoms independently selected from boron, nitrogen, oxygen, sulfur, silicon, and phosphorus (preferably sulfur, oxygen, and / or nitrogen), where the nitrogen atom is optionally quaternized, and the nitrogen, sulfur, and phosphorus heteroatoms are optionally oxidized (i.e., NO, S(O)). p , P(O) p and p is 1 or 2. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thiiranyl, and aziridinyl groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; and examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydrofuryl. Examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups. Examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, and thiepanyl groups. Preferred are monocyclic heterocycloalkyl groups having 5 or 6 ring atoms.

[0130] The term "heterocycloalkenyl group" includes cycloalkenyl groups in which up to three carbon atoms, and in one embodiment up to two carbon atoms, and in another embodiment one carbon atom, are each independently replaced by nitrogen, oxygen, sulfur, silicon, or phosphorus (preferably O, S, or N), provided that at least one cycloalkenyl group carbon-carbon double bond is retained, and wherein the nitrogen atom is optionally quaternized, and the nitrogen, sulfur, and phosphorus heteroatoms are optionally oxidized (i.e., NO, S(O)). p , P(O) p and p is 1 or 2. The cyclic functional group, which may exist as a monocyclic, bridged, or spiro ring, may be a 3- to 20-membered, 3- to 15-membered, 3- to 12-membered, or 3- to 10-membered (e.g., 5- to 8-membered) ring. Examples of heterocycloalkenyl groups include, but are not limited to, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepinyl, or azaspirooctene.

[0131] Unless otherwise specified, the carbocyclic ring is generally a 4- to 20-membered ring, a 4- to 15-membered ring, a 4- to 12-membered ring, or a 4- to 8-membered ring (or a 5- to 6-membered ring). Non-limiting examples of cycloalkenyl groups include, but are not limited to, a cyclopentenyl group, a cyclopentadienyl group, a cyclohexenyl group, a cyclohexadienyl group, a cycloheptenyl group, and a cycloheptadienyl group.

[0132] The term "heterocyclyl group" refers to a group that is fully saturated or partially unsaturated (but not fully unsaturated). Unless otherwise specified, the heterocycle generally is a 3- to 20-, 3- to 15-, 3- to 10-, or 3- to 7- (or 5- to 6-) membered ring containing 1 to 3 (preferably 1 or 2) heteroatoms independently selected from boron, nitrogen, oxygen, sulfur, silicon, and phosphorus (preferably sulfur, oxygen, and / or nitrogen), where the nitrogen atom is optionally quaternized, and the nitrogen, sulfur, and phosphorus heteroatoms may optionally be oxidized (i.e., NO, S(O)). p, P(O) p and p is 1 or 2. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuryl, dihydrofuryl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, and the like.

[0133] The term "aryl group" refers to an aromatic cyclic group having an all-carbon monocyclic or fused polycyclic ring with a conjugated π-electron system. For example, an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms (6 to 10 carbon atoms, or 6 carbon atoms, i.e., a phenyl group). Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthryl groups.

[0134] The term "heteroaryl group" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, or S, with the remaining ring atoms being C, and at least one aromatic ring. Preferably, the heteroaryl group has a 4- to 8-membered ring, particularly a 5- to 8-membered ring (or a 5- to 6-membered ring), or multiple fused rings containing 6 to 20, 6 to 15, or 6 to 14, and particularly 6 to 10, ring atoms. Non-limiting examples of heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, and isoindolyl.

[0135] Functional groups or structural fragments such as -L- and specific options thereof in this disclosure can optionally be read from left to right and correspondingly linked to the functional groups to the left and right of the functional group or fragment in the general formula, e.g., L is [ka] When reading from left to right, the left side of L is the corresponding left side fragment in the general formula [ka] and the right side is ligated to the right fragment ULM, [ka] and optionally, functional groups or structural fragments such as -L- and specific options thereof in the present disclosure can be read from right to left and are correspondingly linked to the functional groups to the left and right of the functional group or fragment in the general formula, for example, L is [ka] When reading from right to left, the right side of L is the corresponding left side fragment in the general formula [ka] and the left side is linked to the corresponding right side fragment ULM in the general formula to form a fragment [ka] The same applies to other functional groups.

[0136] The term "treatment" means administering a compound or formulation described in this disclosure to improve or eliminate a disease or one or more symptoms associated with said disease, and (i) arresting the disease or disease state, i.e., inhibiting its progression; (ii) Alleviating a disease or disease state, i.e., eliminating the disease or disease state.

[0137] The term "prevention" refers to the administration of a compound or formulation described in this disclosure to prevent a disease or one or more symptoms associated with said disease, and includes preventing the appearance of a disease or disease state in a mammal, particularly when the mammal is predisposed to the disease state but has not yet been diagnosed with the disease state.

[0138] The term "therapeutically effective amount" refers to an amount of a compound of the present disclosure used to (i) treat or prevent a particular disease, condition, or disorder, (ii) reduce, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The "therapeutically effective amount" of a compound of the present disclosure will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal being treated, but can be determined by one of ordinary skill in the art based on their knowledge and the present disclosure.

[0139] The term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are medically determined to be suitable for use in contact with the tissues of humans and animals, are not toxic or irritating, and are not likely to cause an allergic reaction or other problem or complication, and for which the benefit-risk ratio is reasonable.

[0140] Pharmaceutically acceptable salts include, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, and the like.

[0141] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof with pharmaceutically acceptable excipients, which facilitates administration of the compounds of the present disclosure to an organism.

[0142] The term "pharmaceutically acceptable additive" refers to an additive that is not obviously irritating to living organisms and does not impair the physiological activity and properties of the active compound. Examples include carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, and the like. Suitable additives such as solvents, water, etc. are well known to those skilled in the art.

[0143] The term "comprise" and similar terms, such as the English expressions "comprises" or "comprising," are to be understood in an open and non-exclusive sense, meaning "including, but not limited to."

[0144] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be interconverted via a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton transfer, such as ketone-enol isomerization and imine-enamine isomerization. A specific example of a proton tautomer is an imidazole moiety, where a proton can be transferred between two ring nitrogen atoms. Valence tautomers include interconversions via recombination of some bonding electrons.

[0145] The present disclosure further includes compounds of the present disclosure that are the same as the compounds described herein, except that one or more atoms have been replaced by an atom whose atomic mass or mass number differs from the normal atomic mass or mass number found in nature, i.e., isotopically labeled. Examples of isotopes that can be attached to compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, each of which is represented by the following: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O.31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 For example, one or more water atoms in the compounds of formula I of the present disclosure may be Compounds in which hydrogen atoms are replaced with deuterium atoms are also included among the compounds of Formula I of the present disclosure. I would like you to understand this.

[0146] Some isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C) can be used for tissue distribution analysis of compounds and / or substrates. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred because they are easy to prepare and detect. Positron-emitting isotopes, e.g., 15 O. 13 N, 11 C and 18 F can be used to measure substrate occupancy in positron emission tomography (PET) studies. Generally, isotopically labeled compounds of the present disclosure can be prepared by the methods disclosed below and / or analogous procedures in the Examples, by using an isotopically labeled reagent to substitute for a non-isotopically labeled reagent.

[0147] Also, isotopes with higher mass numbers (e.g., deuterium, i.e. 2 Substitution with hydrogen (H) can provide greater metabolic stability and therapeutic advantages (e.g., increased in vivo half-life or reduced dose requirements), and is therefore sometimes preferred. However, deuterium substitution can be partial or complete, with partial deuterium substitution meaning that at least one hydrogen is replaced with at least one deuterium.

[0148] The compounds of the present disclosure may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are included. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized using chiral raw materials or chiral reagents.

[0149] Pharmaceutical compositions of the present disclosure can be prepared by combining a compound of the present disclosure with suitable pharmaceutically acceptable excipients.

[0150] The pharmaceutical compositions of the present disclosure can be manufactured by conventional methods well known in the art, for example, by mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, lyophilizing or the like.

[0151] In all methods of administration of the compounds of Formula I described herein, the daily dose is 0.0 The dose is 0.1 to 2000 mg / kg body weight, and can be administered in a single dose or in divided doses.

[0152] All patents, patent applications, and other identified publications are expressly incorporated by reference herein for purposes of description and disclosure. The incorporation of any such publication into this specification does not constitute an admission that such publication becomes common general knowledge in the art.

[0153] The compounds of the present disclosure can be produced by various synthetic methods familiar to those skilled in the art, including the specific embodiments listed below, embodiments in combination with other chemical synthetic methods, and equivalent alternative forms familiar to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0154] The chemical reactions of specific embodiments of the present disclosure are carried out in suitable solvents, which must be compatible with the chemical transformations of the present disclosure and the reagents and raw materials used. In some cases, those skilled in the art will need to modify or select synthetic steps or reaction processes in light of existing embodiments to obtain compounds of the present disclosure.

[0155] In the art, one of the important factors to be considered when planning a synthetic route is the selection of an appropriate protecting group for a reactive functional group (e.g., an amino group in the present disclosure). In this regard, reference can be made, for example, to "Greene's Protective Groups in Organic Synthesis (4th Ed.)". Hoboken, New Jersey: John Wiley & Sons, Inc."

[0156] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can be prepared by employing the synthetic routes described below. [ka] wherein R, q, L, ULM, or X are defined as described in this disclosure.

[0157] The following abbreviations are used in this disclosure: HATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, DCM represents dichloromethane, MeOH represents methanol, DIPEA represents N-ethyldiisopropylamine, and Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]dichloroparaben. palladium(II), PE represents petroleum ether, EA represents ethyl acetate, Tf2O represents trifluoromethanesulfonic anhydride, Pd(PPh3)4 represents tetrakis(triphenylphosphine)palladium(0), LAH represents lithium aluminum hydride, NaOH represents sodium hydroxide, DMSO represents dimethyl sulfoxide, DMAP represents 4-dimethylaminopyridine, EDCI represents carbodiimide hydrochloride, Boc represents tert-butoxycarbonyl group, and Et represents ethyl group.

[0158] The present invention will be further described below using examples to clarify the present invention, but the examples are not intended to limit the scope of the present disclosure. All reagents used in this disclosure are commercially available products and can be used without further purification. [Example]

[0159] Detailed Description The following specific examples are provided to enable those skilled in the art to clearly understand and practice the present disclosure, and should not be considered as limitations on the scope of the present disclosure, but as illustrative and representative examples of the present disclosure.

[0160] Example 1: Preparation of Compound 1 [ka] Preparation of Intermediate 1-2: Intermediate 1-1 (400 mg) was dissolved in dichloromethane, and trifluoroacetic acid (1088 μL, 15.2 mmol) was added in two portions, followed by a reaction at room temperature overnight. The reaction was monitored by TLC, and upon completion, the mixture was concentrated at 45°C to obtain a crude product of intermediate 1-2, which was directly used without further purification. The next step was entered. LCMS(ESI)m / z:428.3[M+H] + .

[0161] Preparation of Intermediate 1-3: Intermediate 1-2 (100 mg) was dissolved in dichloromethane, and monomethyl suberate (53 mg) was added, followed by triethylamine (142 mg) and HATU (133 mg), and the mixture was allowed to react at room temperature for 3 hours. Upon completion of the reaction, the reaction mixture was directly purified and separated using silica gel column chromatography (DCM-MeOH) to obtain 105 mg of intermediate 1-3. LCMS(ESI)m / z:598.3[M+H] + .

[0162] Preparation of Intermediate 1-4: Intermediate 1-3 (0.43 g) was dissolved in methanol, and an aqueous solution of lithium hydroxide (2N, 2.16 mL) was added and stirred at room temperature overnight. The pH of the reaction solution was adjusted to 5-6 with 3N hydrochloric acid, and DCM was added for extraction. The mixture was separated, dried, and concentrated to give 0.27 g of Intermediate 1-4. LCMS(ESI)m / z:584.3[M+H] + .

[0163] Preparation of Intermediate 1-5: Intermediate A-12 (0.25 g) and A-1 (0.21 g) were dissolved in 3 mL of DCM, and EDCI·HCl (0.092 g), DMAP (0.059 g), and triethylamine (199 μL) were added and stirred overnight at room temperature. The reaction mixture was diluted with a DCM-methanol mixture, and the pH was adjusted to 5-6 with 10% acetic acid. The organic phase was extracted and separated. The organic phase was washed with saturated sodium bicarbonate solution until the pH reached 7-8. The organic phase was separated, dried, concentrated, and purified by column chromatography (DCM-MeOH) to obtain 0.25 g of intermediate 1-5. LCMS(ESI)m / z:1073.4[M+H] + .

[0164] Preparation of Intermediate 1-6: Intermediate 1-5 (48 mg) was dissolved in dichloromethane, and trifluoroacetic acid (135 μL) was added in two portions. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the mixture was concentrated at 45° C. to give Intermediate 1-6, which was used directly in the next step without further purification. LCMS(ESI)m / z:487.7[M+2H] 2+ .

[0165] Preparation of Compound 1: Intermediate 1-6 (91 mg) was dissolved in dichloromethane, and intermediate 1-4 (65 mg) was added, followed by triethylamine (130 μL) and HATU (53 mg). The mixture was allowed to react at room temperature for 1.5 hours. The mixture was diluted with DCM, saturated ammonium chloride solution was added, and the mixture was extracted and separated. The organic phase was washed with water and separated. The aqueous phase was back-extracted with DCM. The organic phases were combined, washed with saturated sodium chloride solution, and separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated, and the crude product was subjected to preparative liquid chromatography to obtain 71 mg of compound 1. LCMS(ESI)m / z:770.5[M+2H] 2+ . 1 H NMR(500MHz,CDCl3)δ 8.34(d,J=1.8Hz,1H),8.17(s,1H),8.09(dd,J=9.2,1.7Hz,1H),7.70(d,J=8.8Hz,2H),7 .50(d,J=1.8Hz,1H),7.39(dt,J=11.5,7.7Hz,8H),7.31-7.27(m,4H),7.07(t,J=8.2Hz, 1H),6.98(d,J=8.3Hz,2H),6.76(d,J=8.9Hz,2H),6.61(d,J=9.5Hz,1H),6.44(t,J=11.9 Hz,1H),6.27(d,J=1.8Hz,1H),5.09(dt,J=14.2,7.0Hz,2H),4.72(t,J=8.0Hz,1H),4.61( d,J=8.9Hz,1H),4.51(s,1H),4.11(d,J=11.5Hz,1H),3.87(s,3H),3.67(s,1H),3.60(dd,J=11.2,3. 1Hz,1H),3.45(s,2H),3.34(s,4H),3.10(dd,J=13.8,4.9Hz,1H),3.06-2.96(m,3H),2.62(d,J=13.9 Hz,2H),2.55(s,4H),2.43(ddd,J=24.1,12.8,5.5Hz,6H),2.32-2.15(m,8H),2.01(d,J=9.3Hz,2H), 1.71(dd,J=23.3,17.4Hz,1H),1.46(t,J=7.0Hz,6H),1.38-1.23(m,6H),1.04(s,10H),0.97(s,6H).

[0166] Example 2: Preparation of Compound 2 [ka] Preparation of Intermediate 2-2: Intermediate 2-1 (5.0 g) and (S)-(-)-1-(4-bromobenzene)ethylamine (3.5 g) were dissolved in dichloromethane, HATU (8.3 g) and DIPEA (5.6 g) were added, and the mixture was allowed to react at room temperature overnight. Water was added for extraction, and the layers were separated. The organic phase was washed with saturated sodium chloride, separated, dried, and concentrated. The crude product was purified by column chromatography (DCM-MeOH) to obtain 7.5 g of Intermediate 2-2. LCMS(ESI)m / z:526.2[M+H] + .

[0167] Preparation of intermediate 2-3: Intermediate 2-2 (1.0 g) and 1-ethylpyrazole-5-boronic acid pinacol ester (0.51 g) were dissolved in 20 mL of dioxane and 10 mL of water. Potassium carbonate (1.3 g) and Pd(dppf)Cl (0.14 g) were added, and the mixture was purged with nitrogen. The mixture was then reacted at 105 °C for 5 hours. The mixture was cooled, suction filtered through diatomaceous earth, concentrated to dryness, extracted with water and DCM, and the layers were separated. The organic phase was washed with saturated sodium chloride, separated, dried, and concentrated. The crude product was subjected to column chromatography (DCM-MeOH) to obtain 1.0 g of Intermediate 2-3. LCMS(ESI)m / z:542.3[M+H] + .

[0168] Preparation of intermediate 2-4: Intermediate 2-3 (890 mg) was dissolved in dichloromethane, and trifluoroacetic acid (2448 μL) was added in two portions. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the mixture was concentrated at 45° C. to give Intermediate 2-4, which was used directly in the next step without further purification. LCMS(ESI)m / z:442.3[M+H] + .

[0169] Preparation of Intermediate 2-5: Intermediate 2-4 (720 mg) was dissolved in dichloromethane, and monomethyl suberate (740 mg) was added, followed by triethylamine (2.0 mL) and HATU (930 mg), and the mixture was allowed to react at room temperature overnight. The reaction was monitored by TLC, and upon completion, the reaction mixture was extracted with water and dichloromethane, and the layers were separated. The organic layer was washed with saturated sodium chloride, separated, dried, and concentrated. The crude product was separated by silica gel column chromatography (DCM-MeOH) to obtain 520 mg of Intermediate 2-5. LCMS(ESI)m / z:612.3[M+H] + .

[0170] Preparation of intermediate 2-6: Intermediate 2-5 (0.52 g) was dissolved in methanol, and an aqueous solution of lithium hydroxide (2N, 2.54 mL) was added and stirred at room temperature overnight. The pH of the reaction mixture was adjusted to 5-6 with 3N hydrochloric acid, and DCM was added for extraction. The mixture was separated, dried, and concentrated to give 0.45 g of Intermediate 2-6. LCMS(ESI)m / z:598.3[M+H] + .

[0171] Preparation of Compound 2: Intermediate 1-6 (82 mg) was dissolved in dichloromethane, and intermediate 2-6 (60 mg) was added, followed by triethylamine (117 μL) and HATU (48 mg). The mixture was allowed to react at room temperature for 1.5 hours. The mixture was diluted with DCM, saturated ammonium chloride solution was added, and the mixture was extracted and separated. The organic phase was washed with water and separated. The aqueous phase was back-extracted with DCM. The organic phases were combined, washed with saturated sodium chloride solution, separated, and the organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated, and the crude product was subjected to preparative liquid chromatography to obtain 83 mg of compound 2. LCMS(ESI)m / z:777.0[M+2H] 2+ . 1 H NMR(500MHz,CDCl3)δ 8.34(d,J=1.8Hz,1H),8.17(s,2H),8.12-8.07(m,1H),7.69(t,J=9.1Hz,2H),7.54(d,J=1.8Hz,1H),7.37(dt,J=12. 9,7.9Hz,7H),7.30(t,J=8.0Hz,4H),7.07(t,J=7.8Hz,1H),6.99(d,J=8.3Hz,2H),6.76(d,J=8.9Hz,2H),6.61(d,J=9.5Hz,1H),6.48(d,J=8.7 Hz,1H),6.24(d,J=1.7Hz,1H),5.09(dd,J=14.2,6.9Hz,2H),4.70(dd,J=26.3,18.2Hz,2H),4.62(d,J=8.9Hz,1H),4.51(s,1H),4.14(dt,J=20. 7,10.2Hz,3H),3.89(s,1H),3.75-3.53(m,3H),3.52-3.43(m,3H),3.36 (s,4H),3.14-3.08(m,3H),3.06-2.97(m,1H),2.61(s,4H),2.51-2.39( m,6H),2.35-2.16(m,8H),2.04(s,2H),1.76-1.66(m,1H),1.47(t,J=6. 5Hz, 5H), 1.40 (t, J=7.2Hz, 3H), 1.28 (s, 6H), 1.04 (s, 9H), 0.98 (s, 6H).

[0172] Example 3: Preparation of Compound 3 [ka] Preparation of intermediate 3-2: 300 mL of dimethyltetrahydrofuran was added to a reaction flask, and the mixture was stirred at 0°C under nitrogen protection. When the temperature reached a predetermined level, NaH (25.6 g) was added. Intermediate 3-1 (20 g) was dissolved in 50 mL of dimethyltetrahydrofuran and slowly added dropwise to the suspension. Dimethyl carbonate (25.6 g) was added, and the mixture was refluxed at 75°C for 5 hours, and the reaction was completed. The reaction mixture was monitored by LC-MS until the reaction mixture was dissolved. The reaction mixture was cooled to room temperature and slowly added to 300 mL of ice water to quench the reaction. Once the mixture was added, the mixture spontaneously separated into layers. The organic layer was dried over anhydrous sodium sulfate, filtered under suction, and the filtrate was concentrated to give 25 g of a crude product. The crude product was subjected to column chromatography (PE-EA) to give 10 g of intermediate 3-2.

[0173] Preparation of intermediate 3-3: Intermediate 3-2 (9.0 g) was dissolved in 108 mL of DCM and stirred at -78 °C. When the temperature reached the desired level, DIPEA (21.5 g) was added. TfO (28.2 g) was slowly added dropwise to the reaction mixture. Once the mixture was added, the mixture was stirred for 30 minutes, then allowed to return to room temperature and react overnight. The mixture was extracted with 100 mL of saturated sodium bicarbonate solution in an ice bath, and the layers were separated. The organic layer was washed with saturated sodium chloride solution, separated, dried, and concentrated to obtain 50 g of crude product, which was used directly in the next step without further purification.

[0174] Preparation of intermediate 3-4: Intermediate 3-3 (2.6 g) was dissolved in 40 mL of a toluene-ethanol (2:1) mixed solvent, and p-chlorophenylboronic acid (1.2 g) was added. Pd(PPh3)4 (0.15 g) and aqueous sodium carbonate solution (2N, 6.45 mL) were then added. The atmosphere was purged with nitrogen, and the reaction was carried out at 90°C for 8 hours. The mixture was filtered under suction, the cake was washed with EA, and the filtrates were combined and concentrated. EA and water were added for extraction, and the layers were separated. The EA layer was dried and concentrated. The crude product was subjected to column chromatography to obtain 1.2 g of Intermediate 3-4. ESI-MS: m / z = 365.1 [M+H] + .

[0175] Preparation of intermediate 3-5: Intermediate 3-4 (6.5 g) was dissolved in 90 mL of anhydrous tetrahydrofuran and stirred at 0 ° C. LAH (1.7 g) was added in three portions and reacted for 3 hours at 0 ° C. 1.7 mL of water was added and stirred, and then 1.7 mL of a 15% aqueous NaOH solution was added, 5.1 mL of water was added, and the mixture was returned to room temperature and stirred for 30 minutes. Anhydrous sodium sulfate was added and stirred for 3 hours, and the mixture was suction filtered through diatomaceous earth. The solid on the wall was washed with EA, and the filtrate was combined, dried over anhydrous sodium sulfate, and concentrated to give 4.5 g of a crude product. 45 mL of a 1:9 DCM:n-hexane mixture was added to form a slurry, and the slurry was suction filtered to give 3.6 g of intermediate 3-5. ESI-MS: m / z=289.1 [M+Na] + .

[0176] Preparation of intermediate 3-6: Intermediate 3-5 (1.0 g) was dissolved in 15 mL of DCM and stirred at -30° C. NCS (0.55 g) was dissolved in 3 mL of DCM and added, and dimethyl thioether (300 μL) was added and reacted for 2 hours at -30° C. After the reaction was completed, the mixture was extracted with DCM and water, separated, and the DCM phase was dried and concentrated to obtain 1.2 g of a crude product. This was then subjected to column chromatography (PE-EA) to obtain 0.56 g of intermediate 3-6.

[0177] Preparation of intermediate 3-7: Intermediate 3-6 (3.9 g) was dissolved in 78 mL of acetonitrile, and ethyl (4-piperazin-1-yl)benzoate (4.8 g) and potassium carbonate (5.7 g) were added in that order. The mixture was allowed to react overnight at room temperature. After the reaction was complete, the mixture was extracted with ethyl acetate and water, and the layers were separated. The organic layer was washed with saturated sodium chloride, dried, and concentrated to give 7 g of crude product. 5 g of silica gel was added for dry loading, and the mixture was subjected to column chromatography (PE-EA) to give 4.77 g of intermediate 3-7. ESI-MS: m / z = 483.2 [M+H] + .

[0178] Preparation of intermediate 3-8: Dissolve oxalyl chloride (4.37 mL) in dichloromethane (43.2 mL) and The mixture was purged with nitrogen and cooled to -78°C. A solution of DMSO (5.47 mL) in dichloromethane was added. After stirring for 15 minutes, a solution of intermediate 3-7 (2.4 g) in dichloromethane was added. After stirring for 30 minutes, triethylamine (21.4 mL) was added, and after 10 minutes, the mixture was returned to room temperature and stirred. After 2.5 hours, the pH was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane. The organic phase obtained by extraction was concentrated and subjected to column chromatography (PE-EA) to obtain intermediate 3-8 (200 mg).

[0179] Preparation of intermediate 3-9: Intermediate 3-8 (250 mg) and tert-butyl piperazine-1-carboxylate (145.36 mg) were dissolved in anhydrous dichloromethane (10 mL), triethylamine (722.9 μL) was added, and the mixture was protected by nitrogen purging and stirred at room temperature. After 30 minutes, sodium triacetoxyborohydride (772 mg) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was quenched by adding 50 mL of water. Extraction was performed with 50 mL of dichloromethane. The organic phase obtained by extraction was concentrated and subjected to column chromatography (PE-EA) to obtain intermediate 3-9 (200 mg).

[0180] Preparation of Intermediate 3-10: Intermediate 3-9 (200 mg) was dissolved in a 5:1:1 mixture of methanol, tetrahydrofuran, and water (28 mL), and lithium hydroxide monohydrate (387 mg) was added and stirred at room temperature for 16 hours. 1N hydrochloric acid was added to the mixture to adjust the pH to neutral, and water and ethyl acetate were added for extraction. The organic phase was dried and concentrated to give Intermediate 3-10 (192 mg).

[0181] Preparation of Intermediate 3-11: Intermediate 3-10 (192 mg) and (R)-4-((4-morpholin-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (187 mg) were dissolved in dichloromethane (4 mL), and EDCI (148 mg) and DMAP (94 mg) were added and stirred at room temperature for 16 hours. Saturated sodium bicarbonate solution was added to the system to adjust the pH to neutral, and dichloromethane was added for extraction. The organic phase was concentrated and subjected to column chromatography (DCM-MeOH) to obtain intermediate 3-11 (332 mg).

[0182] Preparation of intermediate 3-12: Intermediate 3-11 (332 mg) was dissolved in dichloromethane (3 mL), and a hydrochloric acid-dioxane solution (0.287 mL) was added thereto, followed by stirring at room temperature for 1 hour. The system was directly concentrated to give a crude product, Intermediate 3-12 (300 mg).

[0183] Preparation of intermediate 3-13: Intermediate 2-1 (3.0 g) and (R)-2-amino-2-(4-bromophenyl)ethanol (1.88 g) were dissolved in dichloromethane, and EDCI (2.34 g) and DIPEA (2.25 g) were added. The mixture was allowed to react at room temperature overnight. 5% aqueous hydrochloric acid (100 mL) was added to the reaction mixture, which was then extracted with dichloromethane. The aqueous phase was back-extracted once. The combined organic phases were washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3.8 g of Intermediate 3-13. ESI-MS: m / z = 543.1 [M+H] + .

[0184] Preparation of intermediate 3-14: Intermediate 3-13 (1.0 g) and 1-ethylpyrazole-5-boronic acid pinacol ester (0.51 g) were dissolved in 20 mL of dioxane and 10 mL of water, and potassium carbonate (1.3 g) and Pd(dppf)Cl (0.14 g) were added. After purging with nitrogen, the mixture was reacted at 105 °C for 5 hours. The mixture was cooled, suction filtered through diatomaceous earth, concentrated to dryness, and then water and DCM were added. The organic phase was extracted, separated, washed with saturated sodium chloride, separated, dried and concentrated, and the crude product was subjected to column chromatography (DCM-MeOH) to give 1.0 g of intermediate 3-14. ESI-MS: m / z = 558.2 [M+H] + .

[0185] Preparation of intermediate 3-15: Intermediate 3-14 (890 mg) was dissolved in dichloromethane, trifluoroacetic acid (2448 μL) was added in two portions, and the mixture was allowed to react at room temperature overnight. After completion of the reaction, the mixture was concentrated at 45° C. to give crude intermediate 3-15, which was directly used in the next step. ESI-MS: m / z = 458.3 [M+H] + .

[0186] Preparation of intermediate 3-16: Intermediate 3-15 (720 mg) was dissolved in dichloromethane, and monomethyl suberate (740 mg) was added, followed by triethylamine (2.0 mL) and HATU (930 mg), and the mixture was allowed to react at room temperature overnight. The reaction was monitored by TLC, and upon completion, the reaction mixture was extracted with water and dichloromethane, and the layers were separated. The organic layer was washed with saturated sodium chloride, separated, dried, and concentrated. The crude product was separated by silica gel column chromatography (DCM-MeOH) to obtain 520 mg of intermediate 3-16. ESI-MS: m / z=628.3 [M+H] + .

[0187] Preparation of intermediate 3-17: Intermediate 3-16 (0.52 g) was dissolved in methanol, and an aqueous solution of lithium hydroxide (2N, 2.54 mL) was added and stirred at room temperature overnight. The pH of the reaction solution was adjusted to 5-6 with 3N hydrochloric acid, and the mixture was extracted three times with DCM. The mixture was separated, dried, and concentrated to give 0.45 g of Intermediate 3-17. ESI-MS: m / z=614.3 [M+H] + .

[0188] Preparation of Compound 3: Intermediate 3-12 (121 mg) was dissolved in DMF, and then Intermediate 3-17 (70 mg), DIPEA (148 mg), and HATU (65 mg) were added, followed by a reaction at room temperature for 3 hours. The crude reaction mixture was purified by preparative liquid chromatography to give target compound 3 (46 mg). ESI-MS: m / z=828.1 [M+2H] 2+ .

[0189] Example 4: Preparation of Compound 4 [ka] Intermediate 3-12 (106 mg) was dissolved in dichloromethane, and Intermediate 1-4 (70 mg) was added, followed by triethylamine (140 μL) and HATU (57 mg). The mixture was allowed to react at room temperature for 1.5 hours. DCM was added for dilution, and saturated ammonium chloride solution was added. The mixture was extracted and separated. The organic phase was washed with water and separated. The aqueous phase was back-extracted with DCM. The organic phases were combined. The organic phase was washed with saturated sodium chloride solution, separated, dried over anhydrous sodium sulfate, suction filtered, concentrated, and the crude product was subjected to preparative liquid chromatography to obtain 64 mg of the target compound 4. LCMS(ESI)m / z:812.5[M+2H] 2+ .

[0190] Example 5: Preparation of Compound 5 [ka] Intermediate 3-12 (100 mg) was dissolved in dichloromethane, and Intermediate 2-6 (68 mg) was added, followed by triethylamine (125 μL) and HATU (53 mg). The mixture was allowed to react at room temperature for 1.5 hours. The mixture was diluted with DCM, saturated ammonium chloride solution was added, and the mixture was extracted and separated. The organic phase was washed with water and separated. The aqueous phase was back-extracted with DCM. The organic phases were combined, washed with saturated sodium chloride solution, and separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated, and the crude product was subjected to preparative liquid chromatography to obtain 21 mg of the target compound 5. ESI-MS: m / z=820.2 [M+2H] 2+

[0191] Example 6: Preparation of Compound 6 [ka] Preparation of intermediate 4-2: Intermediate 4-1 (1.4 g) and 1-ethylpyrazole-5-boronic acid pinacol ester (2.16 g) were dissolved in a 4:1 mixture of 1,4-dioxane and water (50 mL). Potassium carbonate (2.76 g) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (730 mg) were added, and the mixture was protected by purging with nitrogen. The temperature was raised to 90 °C and stirred for 3 hours. After 3 hours, heating was stopped, and the reaction mixture was directly concentrated to dryness. Column chromatography (dichloromethane-methanol) was performed to obtain the product, Intermediate 4-2 (1.52 g). LC-MS: m / z [M+H] + :232.1

[0192] Preparation of intermediate 4-3: Intermediate 4-2 (2.031 g) and 1-(Boc-L-pentyl)-(4R)-4-hydroxy-L-proline (1.421 g) were dissolved in N,N-dimethylformamide (40 mL), N,N-diisopropylethylamine (2.142 mL) was added, and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.675 g) was added to the reaction mixture. The mixture was stirred for 16 hours. The reaction mixture was diluted with 60 mL of ethyl acetate and washed with 60 mL of saturated brine. After washing, the organic phase was concentrated and subjected to column chromatography (dichloromethane-methanol) to obtain the product intermediate 4-3 (2 g). LC-MS: m / z [M+H] + :544.3

[0193] Preparation of intermediate 4-4: Intermediate 4-3 (2 g) was dissolved in a 1:3 trifluoroacetic acid:dichloromethane system (20 mL) and stirred at room temperature for 30 minutes. After that, 7 M ammonia-methanol solution was added to adjust the pH to 7, and the system was concentrated to dryness and subjected to column chromatography (dichloromethane-methanol) to obtain the product intermediate 4-4 (2 g). LC-MS: m / z [M+H] + :444.47

[0194] Preparation of intermediate 4-5: Intermediate 4-4 (100 mg) and monomethyl suberate (44.5 μL) were dissolved in dichloromethane (5 mL), triethylamine (62.5 μL) was added, and the mixture was stirred at room temperature for 30 minutes. HATU (94 mg) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then directly concentrated to dryness. Column chromatography (dichloromethane-methanol) was performed to obtain the product, intermediate 4-5 (85 mg). LC-MS: m / z [M+H] + :614.3

[0195] Preparation of intermediate 4-6: Intermediate 4-5 (85 mg) was dissolved in methanol (1.5 mL), 2N lithium hydroxide solution (208 μL) was added, and the mixture was stirred at room temperature for 16 hours. 2N hydrochloric acid was added to adjust the pH to neutral, and ethyl acetate was added for extraction. The organic phase was directly concentrated to dryness to obtain the product intermediate 4-6 (80 mg). LC-MS: m / z [M+H] + :600.3

[0196] Preparation of Compound 6: Intermediate 4-6 (28 mg) and intermediate 3-12 (50 mg) were dissolved in dichloromethane (1 mL), triethylamine (66 μL) was added, and the mixture was stirred for 30 minutes. HATU (27 mg) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated, and preparative chromatography was performed to obtain the target compound 6 (51 mg, purity 98.85%). ESI-MS: m / z=821.16 [M+2H] 2+ .

[0197] Example 7: Preparation of Compound 7 [ka] 1) Preparation of Intermediate 7-1 7-A (2 g) and (R)-2-amino-2-(4-bromophenyl)ethanol (1.43 g, 6.663 mmol) were dissolved in dichloromethane, EDCI (2.32 g) and HOBT (1.64 g) were added, and the mixture was allowed to react at room temperature overnight. Water was added, the mixture was separated, and the organic phase was purified by silica gel column chromatography (DCM-MeOH) to obtain 2.8 g of intermediate 7-1. ESI-MS: m / z = 550.2 [M + Na] +

[0198] 2) Preparation of Intermediate 7-2 Intermediate 7-1 (500 mg) and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (197 mg) were dissolved in 10 mL of dioxane and 2 mL of water, and potassium carbonate (262 mg) and Pd(dppf)Cl (35 mg) were added. The atmosphere was purged with nitrogen, and the mixture was reacted at 90°C for 3 hours. The mixture was cooled, dried, and concentrated. Column chromatography (DCM-MeOH) afforded 512 mg of intermediate 7-2. ESI-MS: m / z = 552.3 [M+Na] +

[0199] 3) Preparation of Intermediate 7-3 Intermediate 7-2 (512 mg) was dissolved in 4 M hydrochloric acid-dioxane and stirred at room temperature for 3 hours. The mixture was concentrated at 38° C. to give Intermediate 7-3. ESI-MS: m / z=430.4 [M+H] +

[0200] 4) Preparation of Intermediate 7-4 Intermediate 7-3 (100 mg) was dissolved in dichloromethane, and monomethyl pimelate (49 mg) was added. DIPEA (104 mg) and EDCI (67 mg) were added, and the mixture was allowed to react at room temperature overnight. After the reaction was completed, the mixture was concentrated and separated by silica gel column chromatography (DCM-MeOH) to obtain 135 mg of intermediate 7-4. ESI-MS: m / z = 586.3 [M+H] +

[0201] 5) Preparation of Intermediate 7-5 Intermediate 7-4 (135 mg) was dissolved in methanol and added to an aqueous solution of lithium hydroxide (2N, 0 0.5 mL) was added and stirred at room temperature overnight. The pH of the reaction mixture was adjusted to 5-6 with 2N hydrochloric acid, and DCM was added for extraction. The mixture was separated, dried, and concentrated to give 64 mg of intermediate 7-5. ESI-MS: m / z = 572.3 [M+H] +

[0202] 6) Preparation of Compound 7 Intermediate 1-6 (50 mg), Intermediate 7-5 (29 mg), triethylamine (26 mg), and HATU (29 mg) were dissolved in dichloromethane (3 mL), stirred at room temperature for 16 hours, concentrated under reduced pressure, and purified by preparative chromatography to give compound 7 (3 mg). ESI-MS: m / z=763.7 [M+2H] 2+ 1 H NMR(500MHz,CDCl3)δ 8.36(d,1H),8.08(dd,1H),7.71(d,2H),7.49(d,1H),7.39-7.25(m,10H),7.11(t,1H),6. 97(d,2H),6.75(d,2H),6.62(d,1H),6.36(d,1H),6.27(d,1H),5.07(dt,1H),4.72(t,1H), 4.61(d,1H),4.49(s,1H),4.08(d,1H),3.89(s,4H),3.65-3.36(m,13H),3.08(qd,3H),2. 89(s,1H),2.50-2.01(m,19H),1.58(s,5H),1.45(t,6H),1.38-1.23(m,4H),0.98(s,12H).

[0203] Example 8: Preparation of Compound 8 [ka] 1) Preparation of Intermediate 8-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 4-4 to obtain Intermediate 8-1 (138 mg). ESI-MS: m / z=600.3 [M+H] +

[0204] 2) Preparation of Intermediate 8-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 8-1 to give Intermediate 8-2 (70 mg). ESI-MS: m / z=586.3 [M+H] +

[0205] 3) Preparation of Compound 8 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 8-2 to give compound 8 (2 mg). ESI-MS: m / z=770.7 [M+2H] 2+ 1 H NMR(500MHz,CDCl3)δ 8.35(d,1H),8.08(dd,1H),7.71(d,2H),7.50(d,1H),7.39-7.25(m,10H),7.11(t,1H),6.97(d,2H),6.73 (d,2H),6.60(d,1H),6.36(d,1H),6.27(d,1H),5.07(dt,1H),4.71(t,1H),4.61(d,1H),4.48(s,1H),4.08 (d,1H),3.89(s,4H),3.65-3.33(m,13H),3.07(qd,3H),2.88(s,1H),2.50 -2.01(m,19H),1.58(s,5H),1.45(t,6H),1.38-1.23(m,6H),0.98(s,12H).

[0206] Example 9: Preparation of Compound 9 [ka] 1) Preparation of Intermediate 9-1 Intermediate 7-1 (500 mg) and 4-methyl-5-thiazoleboronic acid ester (214 mg) were dissolved in 10 mL of dioxane and 2 mL of water, and potassium carbonate (262 mg) and Pd(dppf)Cl2 (35 mg) were added. The mixture was purged with nitrogen and reacted at 90 °C for 3 hours. The mixture was cooled, dried, and concentrated. Purification was performed by silica gel column chromatography (DCM-MeOH) to obtain 500 mg of intermediate 9-1. ESI-MS: m / z = 569.2 [M + Na] +

[0207] 2) Preparation of Intermediate 9-2 Intermediate 9-1 (500 mg) was dissolved in 4 M hydrochloric acid-dioxane and stirred at room temperature for 3 hours. The mixture was concentrated at 38°C to give Intermediate 9-2. ESI-MS: m / z = 447.3 [M+H] +

[0208] 3) Preparation of Intermediate 9-3 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 9-2 to give Intermediate 9-3 (139 mg). ESI-MS: m / z=603.3 [M+H] +

[0209] 4) Preparation of Intermediate 9-4 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 9-3 to give Intermediate 9-4 (50 mg). ESI-MS: m / z=589.3 [M+H] +

[0210] 5) Preparation of Compound 9 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 9-4 to give compound 9 (3 mg). ESI-MS: m / z=772.3 [M+2H] 2+ 1 H NMR(500MHz,CDCl3)δ 8.35(d,1H),8.07(dd,1H),7.70(d,2H),7.50(d,1H),7.39-7.25(m,10H),7.11(t,1H),6. 98(d,2H),6.73(d,2H),6.61(d,1H),6.36(d,1H),6.27(d,1H),5.07(dt,1H),4.71(t,1H), 4.61(d,1H),4.48(s,1H),4.08(d,1H),3.89(s,4H),3.65-3.35(m,13H),3.07(qd,3H),2. 89(s,1H),2.51-2.03(m,18H),1.58(s,5H),1.45(t,6H),1.38-1.24(m,4H),0.98(s,12H).

[0211] Example 10: Preparation of Compound 10 [ka] 1) Preparation of Intermediate 10-1 Referring to Step 2 of Example 7, 1-methyl-1H-pyrazole-5-boronic acid pinacol ester was replaced with 4-methyl-5-thiazoleboronic acid ester to give Intermediate 10-1 (1g). ESI-MS: m / z=545.3 [M+H] +

[0212] 2) Preparation of Intermediate 10-2 Referring to Step 3 of Example 7, Intermediate 7-2 was replaced with Intermediate 10-1 to obtain Intermediate 10-2 (0.8 g). ESI-MS: m / z=445.2 [M+H] +

[0213] 3) Preparation of Intermediate 10-3 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 10-2, and monomethyl pimelate was replaced with monomethyl suberate to give Intermediate 10-3 (141 mg). ESI-MS: m / z=615.3 [M+H] +

[0214] 4) Preparation of Intermediate 10-4 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 10-3 to give Intermediate 10-4 (80 mg). ESI-MS: m / z=601.3 [M+H] +

[0215] 5) Preparation of Compound 4 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 10-4 to give compound 10 (20 mg). ESI-MS: m / z=778.3 [M+2H] 2+ 1H NMR(500MHz,CDCl3)δ 8.67(s,1H),8.34(d,1H),8.09(dd,1H),7.71(d,2H),7.43-7.23(m,12H),7.07(t,1H),6. 98(d,2H),6.75(d,2H),6.61(d,1H),6.38(d,1H),5.07(dt,1H),4.72(t,1H),4.61(d,1H) ,4.49(s,1H),4.08(d,1H),3.89(s,3H),3.65-3.36(m,11H),3.08(qd,3H),2.89(s,1H),2 .50-2.01(m,19H),1.58(s,5H),1.46(t,6H),1.38-1.23(m,6H),1.04(s,6H),0.97(s,9H).

[0216] Example 11: Preparation of Compound 11 [ka] 1) Preparation of Intermediate 11-1 11-A (600 mg) and (S)-(-)-1-(4-bromobenzene)ethylamine (400 mg) were dissolved in dichloromethane, EDCI (697 mg) and HOBT (491 mg) were added, and the mixture was allowed to react at room temperature overnight. Water was added, and the organic phase was separated. The organic phase was purified by column chromatography (DCM-MeOH) to obtain 750 mg of intermediate 11-1. ESI-MS: m / z = 534.2 [M + Na] +

[0217] 2) Preparation of Intermediate 11-2 Referring to Step 2 of Example 7, Intermediate 7-1 was replaced with Intermediate 11-1 to obtain Intermediate 11-2 (0.5 g). ESI-MS: m / z=514.3 [M+H] +

[0218] 3) Preparation of Intermediate 11-3 Referring to Step 3 of Example 7, intermediate 7-2 was replaced with intermediate 11-2, and intermediate 1 Obtained 1-3 (0.4 g). ESI-MS: m / z = 414.2 [M+H] +

[0219] 4) Preparation of Intermediate 11-4 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 11-3, and monomethyl pimelate was replaced with monomethyl suberate to give Intermediate 11-4 (120 mg). ESI-MS: m / z=584.3 [M+H] +

[0220] 5) Preparation of Intermediate 11-5 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 11-4 to give Intermediate 11-5 (80 mg). ESI-MS: m / z=570.3 [M+H] +

[0221] 6) Preparation of Compound 11 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 11-5 to give compound 11 (5 mg). ESI-MS: m / z=762.7 [M+2H] 2+ 1 H NMR(500MHz,CDCl3)δ 8.35(d,1H),8.07(dd,1H),7.70(d,2H),7.49(d,1H),7.39-7.25(m,10H),7.10(t,1H),6. 98(d,2H),6.75(d,2H),6.62(d,1H),6.36(d,1H),6.27(d,1H),5.07(dt,1H),4.72(t,1H), 4.61(d,1H),4.49(s,1H),4.08(d,1H),3.89(s,4H),3.65-3.36(m,12H),3.08(qd,3H),2. 89(s,3H),2.50-2.01(m,18H),1.58(s,5H),1.45(t,6H),1.38-1.23(m,6H),0.98(s,12H).

[0222] Example 12: Preparation of Compound 12 [ka] 1) Preparation of Intermediate 12-1 Referring to Step 4 of Example 7, monomethyl pimelate was replaced with monomethyl suberate to give Intermediate 12-1 (114 mg). ESI-MS: m / z=600.3 [M+H] +

[0223] 2) Preparation of Intermediate 12-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 12-1 to give Intermediate 12-2 (70 mg). ESI-MS: m / z=586.3 [M+H] +

[0224] 3) Preparation of Compound 12 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 12-2 to give compound 12 (6 mg). ESI-MS: m / z=770.7 [M+2H] 2+ 1 H NMR(500MHz,CDCl3)δ 8.36(d,1H),8.09(dd,1H),7.71(d,2H),7.49(d,1H),7.39-7.25(m,10H),7.11(t,1H),6. 98(d,2H),6.77(d,2H),6.62(d,1H),6.36(d,1H),6.27(d,1H),5.07(dt,1H),4.71(t,1H), 4.63(d,1H),4.49(s,1H),4.08(d,1H),3.89(s,4H),3.66-3.36(m,13H),3.07(qd,3H),2. 89(s,1H),2.50-2.01(m,19H),1.58(s,5H),1.46(t,6H),1.38-1.23(m,6H),0.98(s,12H).

[0225] Example 13: Preparation of Compound 13 [ka] 1) Preparation of Compound 13 Referring to Step 5 of Example 7, intermediate 7-5 was replaced with intermediate 4-6 to give compound 13 (27 mg). ESI-MS: m / z=777.7 [M+2H] 2+ 1 H NMR(500MHz,CDCl3)δ 8.35(d,1H),8.09(dd,1H),7.71(d,2H),7.54(d,1H),7.43-7.24(m,10H),7.07(t,1H),6.98( d,2H),6.75(d,2H),6.64(d,1H),6.38(d,1H),6.21(d,1H),5.29(dt,1H),4.65(t,1H),4.53( d,1H),4.45(s,1H),4.08(d,1H),3.90(s,3H),3.65-3.36(m,14H),3.089(qd,3H),2.88(s,1H) ),2.40-2.01(m,21H),1.58(s,5H),1.46(t,6H),1.39-1.25(m,6H),0.98(s,6H),0.94(s,6H).

[0226] Example 14: Preparation of Compound 14 [ka] 1) Preparation of Intermediate 14-1 Referring to Step 2 of Example 7, 1-methyl-1H-pyrazole-5-boronic acid pinacol ester was replaced with 4-methyl-5-thiazoleboronic acid ester to give intermediate 14-1 (200 mg). ESI-MS: m / z = 553.3 [M+Na] +

[0227] 2) Preparation of Intermediate 14-2 Referring to Step 3 of Example 7, Intermediate 7-2 was replaced with Intermediate 14-1 to give Intermediate 14-2 (162 mg). ESI-MS: m / z=431.3 [M+H] +

[0228] 3) Preparation of intermediate 14-3 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 14-2, and monomethyl pimelate was replaced with monomethyl suberate to give Intermediate 14-3 (141 mg). ESI-MS: m / z=601.3 [M+H] +

[0229] 4) Preparation of intermediate 14-4 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 14-3 to give Intermediate 14-4 (75 mg). ESI-MS: m / z=587.3 [M+H] +

[0230] 5) Preparation of Compound 14 Referring to step 6 of example 7, intermediate 7-5 was replaced with intermediate 14-4 to give compound 14 (4 mg). ESI-MS: m / z=771.3 [M+2H] 2+ 1 H NMR(500MHz,CDCl3)δ 8.36(d,1H),8.08(dd,1H),7.71(d,2H),7.50(d,1H),7.41-7.24(m,10H),7.10(t,1H),6 .97(d,2H),6.73(d,2H),6.60(d,1H),6.34(d,1H),6.28(d,1H),5.03(dt,1H),4.72(t,1 H),4.61(d,1H),4.48(s,1H),4.09(d,1H),3.90(s,4H),3.65-3.34(m,12H),3.07(qd,3H ),2.88(s,1H),2.51-2.01(m,19H),1.58(s,5H),1.45(t,6H),1.38-1.23(m,6H),0.98(s, 12H).

[0231] Example 15: Preparation of Compound 15 [ka] 1) Preparation of Intermediate 15-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 9-2, and monomethyl pimelate was replaced with monomethyl suberate to give Intermediate 15-1 (73 mg). ESI-MS: m / z=617.15 [M+H] +

[0232] 2) Preparation of Intermediate 15-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 15-1 to give Intermediate 15-2 (60 mg). ESI-MS: m / z=603.17 [M+H] +

[0233] 3) Preparation of Compound 15 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 15-2 to give compound 15 (6 mg). ESI-MS: m / z=779.3 [M+2H] 2+ 1 H NMR(500MHz,DMSO-d6+D2O)δ 8.95(s,1H),8.26(s,5H),8.07(s,1H),7.90(s,1H),7.70(m,2H),7.35(m,10H),7.18(m ,1H),7.10(m,2H),6.90(s,1H),6.75(m,2H),4.88(m,1H),4.56-4.43(m,3H),4.30(s,1 H),3.69-3.53(m,9H),3.33(m,4H),3.15(s,4H),2.74(s,3H),2.44(s,3H),2.30(s,7H) ,2.24(s,5H),1.84(s,1H),1.70(s,1H),1.55-1.35(m,7H),1.25(s,9H),0.94(s,12H).

[0234] Example 16: Preparation of Compound 16 [ka] 1) Preparation of Intermediate 16-1 Referring to Step 2 of Example 7, Intermediate 7-1 was replaced with Intermediate 3-13 to obtain Intermediate 16-1 (1g). ESI-MS: m / z=544.3 [M+H] +

[0235] 2) Preparation of Intermediate 16-2 Referring to Step 3 of Example 7, Intermediate 7-2 was replaced with Intermediate 16-1 to give Intermediate 16-2 (200 mg). ESI-MS: m / z=444.2 [M+H] +

[0236] 3) Preparation of intermediate 16-3 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 16-2, and monomethyl pimelate was replaced with monomethyl azelaate to give Intermediate 16-3 (283 mg). ESI-MS: m / z=628.3 [M+H] +

[0237] 4) Preparation of intermediate 16-4 Referring to step 5 of example 7, intermediate 7-4 was replaced with intermediate 16-3 to give intermediate 16-4 (270 mg). ESI-MS: m / z=614.3 [M+H] +

[0238] 5) Preparation of Compound 16 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 16-4 to give compound 16 (30 mg). ESI-MS: m / z=784.7 [M+2H] 2+ 1 H NMR(500MHz,DMSO)δ 8.37(s,1H),8.13(s,2H),7.96(s,1H),7.76(m,3H),7.51-6.82(m,16 H),6.37(s,1H),5.11(s,1H),4.90(s,1H),4.75(s,1H),4.55-4.46(m ,2H),4.29(s,2H),4.09(s,2H),3.84(s,3H),3.63(s,5H),3.27-3.10 (s,7H),2.88(s,2H),2.61-1.73(m,25H),1.34(m,12H),0.95(s,14H).

[0239] Example 17: Preparation of Compound 17 [ka] 1) Preparation of Intermediate 17-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 3-15, and monomethyl pimelate was replaced with monomethyl azelaate to give Intermediate 17-1 (280 mg). ESI-MS: m / z = 642.3 [M+H] +

[0240] 2) Preparation of Intermediate 17-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 17-1 to give Intermediate 17-2 (270 mg). ESI-MS: m / z=628.3 [M+H] +

[0241] 3) Preparation of Compound 17 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 17-2 to give compound 17 (13 mg). ESI-MS: m / z=792.46 [M+2H] 2+ 1 H NMR(500MHz,DMSO)δ 8.40(s,1H),8.14(s,2H),7.93(s,1H),7.75(m,3H),7.50-6.80(m,16 H),6.35(s,1H),5.12(s,1H),4.94(s,1H),4.73(s,1H),4.55-4.45(m ,2H),4.29(s,2H),4.08(s,2H),3.85(s,3H),3.63(s,5H),3.26-3.10 (s,7H),2.89(s,2H),2.62-1.75(m,25H),1.35(m,14H),0.94(s,14H)

[0242] Example 18: Preparation of Compound 18 [ka] 1) Preparation of intermediate 18-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 10-2, and monomethyl pimelate was replaced with monomethyl azelaate to give Intermediate 18-1 (141 mg). ESI-MS: m / z=629.3 [M+H] +

[0243] 2) Preparation of Intermediate 18-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 18-1 to give Intermediate 18-2 (80 mg). ESI-MS: m / z=615.3 [M+H] +

[0244] 3) Preparation of Compound 18 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 18-2 to give compound 18 (5 mg). ESI-MS: m / z=785.6 [M+2H] 2+ 1 H NMR(500MHz,CDCl3)δ 8.66(s,1H),8.34(d,1H),8.09(dd,1H),7.71(d,2H),7.46-7.24(m,12H),7.09(t,1H),6. 98(d,2H),6.77(d,2H),6.61(d,1H),6.38(d,1H),5.07(dt,1H),4.72(t,1H),4.60(d,1H) ,4.49(s,1H),4.07(d,1H),3.89(s,3H),3.65-3.36(m,11H),3.08(qd,3H),2.89(s,1H),2 .50-2.01(m,19H),1.58(s,5H),1.46(t,6H),1.38-1.23(m,8H),1.04(s,6H),0.97(s,9H).

[0245] Example 19: Preparation of Compound 19 [ka] 1) Preparation of intermediate 19-1 Referring to Step 2 of Example 7, Intermediate 7-1 was replaced with Intermediate 3-13, and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester was replaced with (4-methylthiazol-5-yl)boronic acid to give Intermediate 19-1 (1.2 g). ESI-MS: m / z=561.2 [M+H] +

[0246] 2) Preparation of intermediate 19-2 Referring to Step 3 of Example 7, Intermediate 7-2 was replaced with Intermediate 19-1 to obtain Intermediate 19-2 (0.9 g). ESI-MS: m / z=461.3 [M+H] +

[0247] 3) Preparation of intermediate 19-3 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 19-2, and monomethyl pimelate was replaced with monomethyl azelaate to give Intermediate 19-3 (370 mg). ESI-MS: m / z=645.3 [M+H] +

[0248] 4) Preparation of intermediate 19-4 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 19-3 to give Intermediate 19-4 (210 mg). ESI-MS: m / z=631.3 [M+H] +

[0249] 5) Preparation of Compound 19 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 19-4 to give compound 19 (38 mg). ESI-MS: m / z=793.2 [M+2H] 2+ 1 H NMR (500 MHz, DMSO-d + D2O) δ 8.96(s,1H),8.27(s,5H),8.05(s,1H),7.92(s,1H),7.72(m,2H),7.36(m, 10H),7.20(m,1H),7.12(m,2H),6.86(s,1H),6.79(m,2H),4.87(m,1H),4.5 4-4.44(m,3H),4.30(s,1H),3.67-3.57(m,9H),3.32(m,4H),3.13(s,4H),2 .75(s,2H),2.46(s,3H),2.28(s,7H),2.21(s,5H),1.83(s,1H),1.71(s,1H ),1.53-1.39(m,7H),1.24(s,11H),0.95(s,15H)

[0250] Example 20: Preparation of Compound 20 [ka] 1) Preparation of Intermediate 20-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 11-3, and monomethyl pimelate was replaced with monomethyl azelaate to obtain Intermediate 20-1 (0.3 g). ESI-MS: m / z=598.3 [M+H] +

[0251] 2) Preparation of Intermediate 20-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 20-1 to obtain Intermediate 20-2 (140 mg). ESI-MS: m / z=584.2 [M+H] +

[0252] 3) Preparation of Compound 20 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 20-2 to give compound 20 (15 mg). ESI-MS: m / z = 771.0 [M+2H] 2+ 1 H NMR(500MHz,DMSO)δ 8.37(s,1H),8.12(s,2H),7.95(s,1H),7.77(m,3H),7.52-6.81(m,16 H),6.35(s,1H),5.10(s,1H),4.89(s,1H),4.72(s,1H),4.53-4.45(m ,2H),4.28(s,2H),4.10(s,2H),3.86(s,3H),3.65(s,5H),3.25-3.08 (s,7H),2.90(s,2H),2.60-1.70(m,23H),1.36(m,15H),0.95(s,11H).

[0253] Example 21: Preparation of Compound 21 [ka] 1) Preparation of Intermediate 21-1 Referring to Step 4 of Example 7, monomethyl pimelate was replaced with monomethyl azelaate to give Intermediate 21-1 (380 mg). ESI-MS: m / z = 614.3 [M+H] +

[0254] 2) Preparation of Intermediate 21-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 21-1 to give Intermediate 21-2 (200 mg). ESI-MS: m / z=600.2 [M+H] +

[0255] 3) Preparation of Compound 21 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 21-2 to give compound 21 (5 mg). ESI-MS: m / z=777.7 [M+2H] 2+ 1 H NMR(500MHz,DMSO)δ 8.39(s,1H),8.13(s,2H),7.95(s,1H),7.77(m,3H),7.50-6.81(m,16 H),6.36(s,1H),5.09(s,1H),4.92(s,1H),4.74(s,1H),4.57-4.43(m ,2H),4.30(s,2H),4.11(s,2H),3.83(s,3H),3.66(s,5H),3.25-3.06 (s,7H),2.85(s,2H),2.61-1.70(m,26H),1.38(m,12H),0.95(s,11H).

[0256] Example 22: Preparation of Compound 22 [ka] 1) Preparation of Intermediate 22-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 4-4, and monomethyl pimelate was replaced with monomethyl azelaate to give Intermediate 22-1 (280 mg). ESI-MS: m / z=628.29 [M+H] +

[0257] 2) Preparation of Intermediate 22-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 22-1 to give Intermediate 22-2 (153 mg). ESI-MS: m / z=614.3 [M+H] +

[0258] 3) Preparation of Compound 22 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 22-2 to give compound 22 (6 mg). ESI-MS: m / z=784.7 [M+2H] 2+ 1 H NMR(500MHz,DMSO)δ 8.40(s,1H),8.15(s,2H),7.94(s,1H),7.76(m,3H),7.60-6.75(m,16 H),6.38(s,1H),5.10(s,1H),4.90(s,1H),4.75(s,1H),4.58-4.40(m ,2H),4.28(s,2H),4.10(s,2H),3.85(s,3H),3.64(s,5H),3.25-3.09 (s,7H),2.87(s,2H),2.60-1.70(m,26H),1.36(m,14H),0.94(s,11H).

[0259] Example 23: Preparation of Compound 23 [ka] 1) Preparation of Intermediate 23-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 14-2, and monomethyl pimelate was replaced with monomethyl azelaate to give Intermediate 23-1 (231 mg). ESI-MS: m / z=615.2 [M+H] +

[0260] 2) Preparation of Intermediate 23-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 23-1 to give Intermediate 23-2 (180 mg). ESI-MS: m / z=601.2 [M+H] +

[0261] 3) Preparation of Compound 23 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 23-2 to give compound 23 (6 mg). ESI-MS: m / z=778.3 [M+2H] 2+ 1 H NMR(500MHz,DMSO-d6+D2O)δ 8.90(s,1H),8.25(s,5H),8.09(s,1H),7.86(s,1H),7.72(m,2H),7.38(m,10H),7.20(m ,1H),7.07(m,2H),6.89(s,1H),6.73(m,2H),4.90(m,1H),4.55-4.33(m,3H),4.29(s,1H) ),3.66-3.51(m,8H),3.32(m,4H),3.12(s,4H),2.72(s,3H),2.47(s,3H),2.35(s,5H), 2.26(s,5H),1.85(s,1H),1.70(s,1H),1.56-1.32(m,10H),1.26(s,11H),0.94(s,12H).

[0262] Example 24: Preparation of Compound 24 [ka] 1) Preparation of Intermediate 24-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 9-2, and monomethyl pimelate was replaced with monomethyl azelaate to give Intermediate 24-1 (65 mg). ESI-MS: m / z=631.3 [M+H] +

[0263] 2) Preparation of Intermediate 24-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 24-1 to give Intermediate 24-2 (55 mg). ESI-MS: m / z=617.2 [M+H] +

[0264] 3) Preparation of Compound 24 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 24-2 to give compound 24 (4 mg). ESI-MS: m / z=786.3 [M+2H] 2+ 1 H NMR(500MHz,DMSO-d6+D2O)δ 8.96(s,1H),8.26(s,5H),8.08(s,1H),7.89(s,1H),7.68(m,2H),7.36(m,10H),7.19(m ,1H),7.11(m,2H),6.93(s,1H),6.78(m,2H),4.87(m,1H),4.53-4.43(m,3H),4.28(s,1 H),3.66-3.50(m,9H),3.31(m,4H),3.13(s,4H),2.75(s,3H),2.46(s,3H),2.31(s,7H) ,2.22(s,5H),1.86(s,1H),1.72(s,1H),1.54-1.32(m,9H),1.23(s,9H),0.95(s,12H).

[0265] Example 25: Preparation of Compound 25 [ka] 1) Preparation of Intermediate 25-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 14-2 to give Intermediate 25-1 (120 mg). ESI-MS: m / z=587.3 [M+H] +

[0266] 2) Preparation of Intermediate 25-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 25-1 to give Intermediate 25-2 (100 mg). ESI-MS: m / z=573.3 [M+H] +

[0267] 3) Preparation of Compound 25 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 25-2 to give compound 25 (15 mg). ESI-MS: m / z=764.3 [M+2H] 2+ 1 H NMR(500MHz,DMSO)δ 12.18(s,1H),8.99(s,1H),8.35(m,1H),8.19(m,1H),8.00(m,1H),7.90(m,1H),7.78(m,2H),7.47-7 .35(m,6H),7.29(m,2H),7.23(m,2H),7.19-7.12(m,4H),6.97(m,2H),4.91(m,1H),4.44-4.27(m,5H) ,4.13(s,2H),3.60(m,6H),3.37(m,7H),3.19(s,2H),2.83-2.74(m,2H),2.46(s,3H),2.31(m,4H),2. 22-1.88(m,9H),1.79(m,1H),1.48(m,7H),1.37(m,3H),1.26(m,6H),1.00(s,6H),0.91-0.81(s,6H).

[0268] Example 26: Preparation of Compound 26 [ka] 1) Preparation of Intermediate 26-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 19-2 to give Intermediate 26-1 (150 mg). ESI-MS: m / z=617.3 [M+H] +

[0269] 2) Preparation of intermediate 26-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 26-1 to give Intermediate 26-2 (86 mg). ESI-MS: m / z=603.3 [M+H] +

[0270] 3) Preparation of Compound 26 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 26-2 to give compound 26 (12 mg). ESI-MS: m / z=779.2 [M+2H] 2+

[0271] Example 27: Preparation of Compound 27 [ka] 1) Preparation of intermediate 27-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 2-4 to obtain Intermediate 27-1 (500 mg). ESI-MS: m / z=598.3 [M+H] +

[0272] 2) Preparation of intermediate 27-2 Referring to Step 5 of Example 7, intermediate 7-4 is replaced with intermediate 27-1, and intermediate 2 Obtained 7-2 (334 mg). ESI-MS: m / z = 584.3 [M+H] +

[0273] 3) Preparation of Compound 27 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 27-2 to give compound 27 (50 mg). ESI-MS: m / z=769.7 [M+2H] 2+ 1 H NMR(500MHz,CDCl3)δ 8.34(d,1H),8.17(s,2H),8.12-8.07(m,1H),7.69(t,2H),7.54(d,1H),7.37(dt,7H),7.29(dd,6H),7.07(t,1H),6.9 9(d,2H),6.76(d,2H),6.61(d,1H),6.48(d,1H),6.24(d,1H),5.09(dd,2H),4.70(dd,2H),4.62(d,1H),4.51(s,1H), 4.14(dt,3H),3.89(s,1H),3.75-3.53(m,3H),3.52-3.43(m,3H),3.14-3.08(m,3H),3.06-2.97(m,1H),2.61(s,4H), 2.51-2.39(m,6H),2.36-2.07(m,10H),1.76-1.66(m,1H),1.57-1.40(m,9H),1.28(s,6H),1.04(s,9H),0.98(s,6H).

[0274] Example 28: Preparation of Compound 28 [ka] 1) Preparation of Intermediate 28-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 1-2 to obtain Intermediate 28-1 (423 mg). ESI-MS: m / z=584.3 [M+H] +

[0275] 2) Preparation of Intermediate 28-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 28-1 to give Intermediate 28-2 (260 mg). ESI-MS: m / z=570.3 [M+H] +

[0276] 3) Preparation of Compound 28 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 28-2 to give compound 28 (20 mg). ESI-MS: m / z=762.8 [M+2H] 2+ 1 H NMR(500MHz,CDCl3)δ 8.34(d,1H),8.16(s,2H),8.12-8.06(m,1H),7.70(t,2H),7.55(d,1H),7.37(dt,7H),7.30(dd,6H),7.06(t,1H),6.99(d,2H),6. 76(d,2H),6.61(d,1H),6.48(d,1H),6.25(d,1H),5.09(dd,2H),4.70(dd,2H),4.62(d,1H),4.52(s,1H),4.14(dt,3H),3.89(s,1H) ),3.75-3.54(m,3H),3.52-3.42(m,3H),3.14-3.08(m,3H),3.08-2.97(m,1H),2.61(s,4H),2.51- 2.39(m,6H),2.36-2.07(m,10H),1.76-1.66(m,1H),1.57-1.28(m,13H),1.04(s,9H),0.98(s,6H).

[0277] Example 29: Preparation of Compound 29 [ka] 1) Preparation of intermediate 29-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 3-15, and monomethyl pimelate was replaced with monomethyl suberate to give Intermediate 29-1 (113 mg). ESI-MS: m / z=628.3 [M+H] +

[0278] 2) Preparation of intermediate 29-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 29-1 to give Intermediate 29-2 (69 mg). ESI-MS: m / z=614.3 [M+H] +

[0279] 3) Preparation of Compound 29 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 29-2 to give compound 29 (13 mg). ESI-MS: m / z=784.8 [M+2H] 2+ 1 H NMR(500MHz,DMSO)δ 8.40(s,1H),8.14(s,2H),7.93(s,1H),7.75(m,3H),7.50-6.80(m,16 H),6.35(s,1H),5.12(s,1H),4.94(s,1H),4.73(s,1H),4.55-4.45(m ,2H),4.29(s,2H),4.08(s,2H),3.85(s,3H),3.63(s,5H),3.26-3.10 (s,7H),2.89(s,2H),2.62-1.75(m,24H),1.35(m,12H),0.94(s,15H).

[0280] Example 30: Preparation of Compound 30 [ka] 1) Preparation of Intermediate 30-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 19-2, and monomethyl pimelate was replaced with monomethyl suberate to give Intermediate 30-1 (100 mg). ESI-MS: m / z=631.3 [M+H] +

[0281] 2) Preparation of Intermediate 30-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 30-1 to give Intermediate 30-2 (50 mg). ESI-MS: m / z=617.3 [M+H] +

[0282] 3) Preparation of Compound 30 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 30-2 to give compound 30 (4 mg). ESI-MS: m / z=786.3 [M+2H] 2+ 1 H NMR(500MHz,DMSO)δ 8.98(s,1H),8.35(m,1H),8.12(s,1H),7.95(m,1H),7.79(m,1H),7.72(m,2H),7.38(m,8H),7.27(m,2H),7. 18(m,1H),7.12(m,2H),6.98(m,1H),6.85(m,2H),5.10(m,1H),4.88(m,1H),4.75(m,1H),4.54-4.44(m,2H), 4.29(s,1H),4.08(s,1H),3.61(m,5H),3.23(s,5H),2.82(s,2H),2.46(s,3H),2.36(s,6H),2.22(m,8H),2. 15-2.06(m,2H),1.99(s,5H),1.91(s,1H),1.87-1.73(m,2H),1.53-1.38(m,7H),1.24(s,7H),0.95(s,15H).

[0283] Example 31: Preparation of Compound 31 [ka] 1) Preparation of Intermediate 31-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 16-2, and monomethyl pimelate was replaced with monomethyl suberate to give Intermediate 31-1 (117 mg). ESI-MS: m / z=614.3 [M+H] +

[0284] 2) Preparation of Intermediate 31-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 31-1 to give Intermediate 31-2 (50 mg). ESI-MS: m / z=600.3 [M+H] +

[0285] 3) Preparation of Compound 31 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 31-2 to give compound 31 (6 mg). ESI-MS: m / z=777.7 [M+2H] 2+ 1 H NMR(500MHz,CDCl3)δ 8.35(d,1H),8.16(s,2H),8.12-8.06(m,1H),7.71(t,2H),7.56(d,1H),7.37(dt,7H),7.30(dd,6H),7.06(t,1H), 6.98(d,2H),6.76(d,2H),6.61(d,1H),6.48(d,1H),6.23(d,1H),5.09(dd,2H),4.70(dd,2H),4.62(d,1H),4.53(s ,1H),4.15(dt,3H),3.89(s,1H),3.75-3.54(m,3H),3.51-3.42(m,3H),3.14-3.08(m,3H),3.08-2.97(m,1H),2.6 1(s,4H),2.51-2.39(m,6H),2.36-2.08(m,10H),1.77-1.66(m,1H),1.57-1.28(m,15H),1.04(s,9H),0.98(s,6H).

[0286] Example 32: Preparation of Compound 32 [ka] 1) Preparation of Intermediate 32-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 1-2, and monomethyl pimelate was replaced with monomethyl azelaate to give Intermediate 32-1 (117 mg). ESI-MS: m / z=614.3 [M+H] +

[0287] 2) Preparation of Intermediate 32-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 32-1 to give Intermediate 32-2 (50 mg). ESI-MS: m / z=600.3 [M+H] +

[0288] 3) Preparation of Compound 32 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 32-2 to give compound 32 (20 mg). ESI-MS: m / z=776.8 [M+2H] 2+ 1 H NMR(500MHz,CDCl3)δ 8.35(d,1H),8.15(s,2H),8.12-8.06(m,1H),7.71(t,2H),7.56(d,1H),7.38(dt,7H),7.30(dd,6H),7.06(t,1H), 6.99(d,2H),6.76(d,2H),6.60(d,1H),6.48(d,1H),6.23(d,1H),5.09(dd,2H),4.70(dd,2H),4.62(d,1H),4.53(s ,1H),4.15(dt,3H),3.89(s,1H),3.75-3.55(m,3H),3.51-3.42(m,3H),3.14-3.08(m,3H),3.09-2.97(m,1H),2.6 1(s,4H),2.52-2.39(m,6H),2.36-2.08(m,10H),1.77-1.66(m,1H),1.59-1.26(m,17H),1.05(s,9H),0.98(s,6H).

[0289] Example 33: Preparation of Compound 33 [ka] 1) Preparation of intermediate 33-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 2-4, and monomethyl pimelate was replaced with monomethyl azelaate to give Intermediate 33-1 (150 mg). ESI-MS: m / z = 626.3 [M+H] +

[0290] 2) Preparation of intermediate 33-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 33-1 to give Intermediate 33-2 (105 mg). ESI-MS: m / z=612.3 [M+H] +

[0291] 3) Preparation of Compound 33 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 33-2 to give compound 33 (30 mg). ESI-MS: m / z=783.8 [M+2H] 2+ 1 H NMR(500MHz,DMSO)δ 8.41(s,1H),8.15(s,2H),7.92(s,1H),7.74(m,3H),7.50-6.81(m,16 H),6.34(s,1H),5.12(s,1H),4.95(s,1H),4.73(s,1H),4.55-4.45(m ,2H),4.27(s,2H),4.08(s,2H),3.86(s,3H),3.63(s,5H),3.26-3.10 (s,7H),2.88(s,2H),2.62-1.75(m,24H),1.35(m,14H),0.95(s,15H).

[0292] Example 34: Preparation of Compound 34 [ka] 1) Preparation of intermediate 34-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 3-15 to give Intermediate 34-1 (93 mg). ESI-MS: m / z=614.3 [M+H] +

[0293] 2) Preparation of intermediate 34-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 34-1 to give Intermediate 34-2 (45 mg). ESI-MS: m / z=600.3 [M+H] +

[0294] 3) Preparation of Compound 34 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 34-2 to give compound 34 (5 mg). ESI-MS: m / z=777.8 [M+2H] 2+ 1 H NMR(500MHz,DMSO)δ 8.41(s,1H),8.14(s,2H),7.94(s,1H),7.75(m,3H),7.52-6.80(m,16 H),6.34(s,1H),5.12(s,1H),4.94(s,1H),4.73(s,1H),4.54-4.44(m ,2H),4.29(s,2H),4.08(s,2H),3.85(s,3H),3.63(s,5H),3.26-3.10 (s,7H),2.89(s,2H),2.61-1.75(m,23H),1.35(m,11H),0.96(s,15H).

[0295] Example 35: Preparation of Compound 35 [ka] 1) Preparation of intermediate 35-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 16-2 to give Intermediate 35-1 (120 mg). ESI-MS: m / z=600.3 [M+H] +

[0296] 2) Preparation of intermediate 35-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 35-1 to give Intermediate 35-2 (80 mg). ESI-MS: m / z=586.3 [M+H] +

[0297] 3) Preparation of Compound 35 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 35-2 to give compound 35 (15 mg). ESI-MS: m / z=770.7 [M+2H] 2+ 1 H NMR(500MHz,CDCl3)δ 8.34(d,1H),8.16(s,2H),8.12-8.06(m,1H),7.70(t,2H),7.56(d,1H),7.37(dt,7H),7.31(dd,6H),7.06 (t,1H),6.98(d,2H),6.75(d,2H),6.61(d,1H),6.48(d,1H),6.23(d,1H),5.09(dd,2H),4.70(dd,2H),4.6 2(d,1H),4.53(s,1H),4.15(dt,3H),3.89(s,1H),3.75-3.54(m,3H),3.51-3.42(m,3H),3.14-3.08(m,3H),3.08-2.97(m, 1H),2.61(s,4H),2.51-2.38(m,6H),2.36-2.08(m,10H),1.77-1.65(m,1H),1.57-1.28(m,13H),1.05(s,9H),0.97(s,6H).

[0298] Example 36: Preparation of Compound 36 [ka] 1) Preparation of intermediate 36-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 1-2, and monomethyl pimelate was replaced with monomethyl adipate to give Intermediate 36-1 (110 mg). ESI-MS: m / z=570.3 [M+H] +

[0299] 2) Preparation of intermediate 36-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 36-1 to give Intermediate 36-2 (100 mg). ESI-MS: m / z=556.3 [M+H] +

[0300] 3) Preparation of Compound 36 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 36-2 to give compound 36 (25 mg). ESI-MS: m / z=755.8 [M+2H] 2+ 1 H NMR(500MHz,CDCl3)δ 8.35(d,1H),8.15(s,2H),8.12-8.06(m,1H),7.71(t,2H),7.56(d,1H),7.38(dt,7H),7.31(dd,6H),7.07(t, 1H),6.99(d,2H),6.76(d,2H),6.60(d,1H),6.48(d,1H),6.24(d,1H),5.09(dd,2H),4.71(dd,2H),4.62(d,1H) ),4.53(s,1H),4.14(dt,3H),3.89(s,1H),3.75-3.55(m,3H),3.51-3.42(m,3H),3.14-3.08(m,3H),3.09-2. 97(m,1H),2.61(s,4H),2.52-2.39(m,6H),2.36-2.08(m,10H),1.60-1.26(m,12H),1.05(s,9H),0.97(s,6H).

[0301] Example 37: Preparation of Compound 37 [ka] 1) Preparation of intermediate 37-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 11-3, and monomethyl pimelate was replaced with monomethyl adipate to give Intermediate 37-1 (160 mg). ESI-MS: m / z=556.2 [M+H] +

[0302] 2) Preparation of intermediate 37-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 37-1 to give Intermediate 37-2 (120 mg). ESI-MS: m / z=542.3 [M+H] +

[0303] 3) Preparation of Compound 37 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 37-2 to give compound 37 (20 mg). ESI-MS: m / z=748.7 [M+2H] 2+ 1 H NMR(500MHz,DMSO)δ 8.37(s,1H),8.12(s,2H),7.95(s,1H),7.77(m,3H),7.52-6.81(m,16 H),6.35(s,1H),5.10(s,1H),4.89(s,1H),4.72(s,1H),4.53-4.45(m ,2H),4.28(s,2H),4.10(s,2H),3.86(s,3H),3.65(s,5H),3.25-3.08 (s,7H),2.90(s,2H),2.60-1.70(m,21H),1.36(m,10H),0.95(s,12H).

[0304] Example 38: Preparation of Compound 38 [ka] 1) Preparation of intermediate 38-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 2-4, and monomethyl pimelate was replaced with monomethyl adipate to give Intermediate 38-1 (100 mg). ESI-MS: m / z = 584.3 [M+H] +

[0305] 2) Preparation of intermediate 38-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 38-1 to give Intermediate 38-2 (80 mg). ESI-MS: m / z=570.3 [M+H] +

[0306] 3) Preparation of Compound 38 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 38-2 to give compound 38 (20 mg). ESI-MS: m / z=762.7 [M+2H] 2+ 1H NMR(500MHz,DMSO)δ 8.40(s,1H),8.14(s,2H),7.92(s,1H),7.75(m,3H),7.51-6.82(m,16 H),6.34(s,1H),5.12(s,1H),4.94(s,1H),4.74(s,1H),4.54-4.45(m ,2H),4.27(s,2H),4.08(s,2H),3.86(s,3H),3.63(s,5H),3.26-3.10 (s,7H),2.89(s,2H),2.62-1.74(m,22H),1.35(m,10H),0.96(s,15H).

[0307] Example 39: Preparation of Compound 39 [ka] 1) Preparation of intermediate 39-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 3-15, and monomethyl pimelate was replaced with monomethyl adipate to give Intermediate 39-1 (80 mg). ESI-MS: m / z = 600.3 [M+H] +

[0308] 2) Preparation of intermediate 39-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 39-1 to give Intermediate 39-2 (40 mg). ESI-MS: m / z=586.3 [M+H] +

[0309] 3) Preparation of Compound 39 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 39-2 to give compound 39 (3 mg). ESI-MS: m / z=770.8 [M+2H] 2+ 1H NMR(500MHz,DMSO)δ 8.36(m,1H),8.14(m,1H),7.96(m,1H),7.81(m,1H),7.72(m,2H),7.49(m,1H),7.40(m,7H),7.32(m,2H) ,7.26(m,2H),7.17(m,2H),7.12(m,2H),7.03(m,1H),6.93-6.85(m,3H),6.31(m,1H),5.10(m,1H),4.90( m,1H),4.74(m,1H),4.56-4.43(m,2H),4.29(m,1H),4.11(m,4H),3.67-3.55(m,5H),2.36(s,5H),2.30- 2.22(m,8H),2.12(m,2H),2.00(m,6H),1.83(m,2H),1.51-1.41(m,8H),1.34-1.22(m,9H),0.95(s,15H).

[0310] Example 40: Preparation of Compound 40 [ka] 1) Preparation of Intermediate 40-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 10-2, and monomethyl pimelate was replaced with monomethyl adipate to give Intermediate 40-1 (135 mg). ESI-MS: m / z=587.3 [M+H] +

[0311] 2) Preparation of Intermediate 40-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 40-1 to give Intermediate 40-2 (75 mg). ESI-MS: m / z=573.3 [M+H] +

[0312] 3) Preparation of Compound 40 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 40-2 to give compound 40 (20 mg). ESI-MS: m / z=764.3 [M+2H] 2+

[0313] Example 41: Preparation of Compound 41 [ka] 1) Preparation of Intermediate 41-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 19-2, and monomethyl pimelate was replaced with monomethyl adipate to give Intermediate 41-1 (160 mg). ESI-MS: m / z = 603.3 [M+H] +

[0314] 2) Preparation of intermediate 41-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 41-1 to give Intermediate 41-2 (68 mg). ESI-MS: m / z=589.3 [M+H] +

[0315] 3) Preparation of Compound 41 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 41-2 to give compound 41 (15 mg). ESI-MS: m / z=772.3 [M+2H] 2+

[0316] Example 42: Preparation of Compound 42 [ka] 1) Preparation of Intermediate 42-1 Referring to Step 2 of Example 11, 1-methyl-1H-pyrazole-5-boronic acid pinacol ester was replaced with 1-ethylpyrazole-5-boronic acid pinacol ester to give Intermediate 42-1 (1g). ESI-MS: m / z=528.3 [M+H] +

[0317] 2) Preparation of intermediate 42-2 Referring to Step 3 of Example 7, Intermediate 7-2 was replaced with Intermediate 42-1 to obtain Intermediate 42-2 (0.8 g). ESI-MS: m / z=428.2 [M+H] +

[0318] 3) Preparation of intermediate 42-3 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 42-2 to give Intermediate 42-3 (120 mg). ESI-MS: m / z=584.3 [M+H] +

[0319] 4) Preparation of intermediate 42-4 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 42-3 to give Intermediate 42-4 (70 mg). ESI-MS: m / z=570.3 [M+H] +

[0320] 5) Preparation of Compound 42 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 42-4 to give compound 42 (35 mg). ESI-MS: m / z=762.7 [M+2H] 2+ 1 H NMR(500MHz,DMSO)δ 8.35(s,1H),8.13(s,2H),7.95(s,1H),7.77(m,3H),7.51-6.81(m,16 H),6.35(s,1H),5.10(s,1H),4.89(s,1H),4.72(s,1H),4.53-4.44(m,2H),4.29(s,2H),4.10(s,2H),3. 86(s,3H),3.65(s,5H),3.25-3.08(s,7H),2.90(s,2H),2.61-1.70(m,21H),1.35(m,14H),0.95(s,12H).

[0321] Example 43: Preparation of Compound 43 [ka] 1) Preparation of intermediate 43-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 11-3 to give Intermediate 43-1 (150 mg). ESI-MS: m / z=570.3 [M+H] +

[0322] 2) Preparation of intermediate 43-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 43-1 to give Intermediate 43-2 (90 mg). ESI-MS: m / z=556.3 [M+H] +

[0323] 3) Preparation of Compound 43 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 43-2 to give compound 43 (30 mg). ESI-MS: m / z=755.8 [M+2H] 2+ 1 H NMR(500MHz,DMSO)δ 8.36(s,1H),8.14(s,2H),7.95(s,1H),7.77(m,3H),7.51-6.81(m,16 H),6.35(s,1H),5.11(s,1H),4.90(s,1H),4.72(s,1H),4.53-4.44(m ,2H),4.29(s,2H),4.10(s,2H),3.86(s,3H),3.65(s,5H),3.26-3.09 (s,7H),2.91(s,2H),2.61-1.70(m,21H),1.35(m,12H),0.95(s,12H).

[0324] Example 44: Preparation of Compound 44 [ka] 1) Preparation of intermediate 44-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 42-2, and monomethyl pimelate was replaced with monomethyl suberate to give Intermediate 44-1 (131 mg). ESI-MS: m / z=598.3 [M+H] +

[0325] 2) Preparation of intermediate 44-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 44-1 to give Intermediate 44-2 (80 mg). ESI-MS: m / z=584.3 [M+H] +

[0326] 3) Preparation of Compound 44 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 44-2 to give compound 44 (25 mg). ESI-MS: m / z=769.8 [M+2H] 2+ 1 H NMR(500MHz,DMSO)δ 8.35(s,1H),8.13(s,2H),7.95(s,1H),7.77(m,3H),7.51-6.82(m,16 H),6.34(s,1H),5.10(s,1H),4.89(s,1H),4.72(s,1H),4.55-4.44(m ,2H),4.29(s,2H),4.10(s,2H),3.86(s,3H),3.65(s,5H),3.25-3.08 (s,7H),2.88(s,2H),2.61-1.71(m,21H),1.35(m,16H),0.95(s,12H).

[0327] Example 45: Preparation of Compound 45 [ka] 1) Preparation of Intermediate 45-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 42-2, and monomethyl pimelate was replaced with monomethyl azelaate to give Intermediate 45-1 (108 mg). ESI-MS: m / z=612.2 [M+H] +

[0328] 2) Preparation of intermediate 45-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 45-1 to give Intermediate 45-2 (66 mg). ESI-MS: m / z=598.3 [M+H] +

[0329] 3) Preparation of Compound 45 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 45-2 to give compound 45 (8 mg). ESI-MS: m / z=776.8 [M+2H] 2+ 1H NMR(500MHz,DMSO)δ 8.36(s,1H),8.14(s,2H),7.96(s,1H),7.77(m,3H),7.51-6.82(m,16 H),6.34(s,1H),5.10(s,1H),4.87(s,1H),4.72(s,1H),4.55-4.44(m ,2H),4.30(s,2H),4.10(s,2H),3.87(s,3H),3.65(s,5H),3.27-3.08 (s,7H),2.88(s,2H),2.61-1.71(m,23H),1.35(m,16H),0.95(s,12H).

[0330] Example 46: Preparation of Compound 46 [ka] 1) Preparation of intermediate 46-1 Referring to Step 4 of Example 7, Intermediate 7-3 was replaced with Intermediate 42-2, and monomethyl pimelate was replaced with monomethyl sebacate to give Intermediate 46-1 (100 mg). ESI-MS: m / z=626.3 [M+H] +

[0331] 2) Preparation of intermediate 46-2 Referring to Step 5 of Example 7, Intermediate 7-4 was replaced with Intermediate 46-1 to give Intermediate 46-2 (70 mg). ESI-MS: m / z=612.3 [M+H] +

[0332] 3) Preparation of Compound 46 Referring to Step 6 of Example 7, intermediate 7-5 was replaced with intermediate 46-2 to give compound 46 (10 mg). ESI-MS: m / z=783.7 [M+2H] 2+ 1 H NMR(500MHz,DMSO)δ 8.35(s,1H),8.14(s,2H),7.95(s,1H),7.77(m,3H),7.51-6.82(m,16H),6.34(s,1H),5.10(s,1H),4.87(s,1H),4.73 (s,1H),4.55-4.45(m,2H),4.30(s,2H),4.10(s,2H),3.87(s,3H),3.65(s,5H), 3.27-3.08(s,7H),2.88(s,2H),2.61-1.71(m,23H),1.35(m,18H),0.95(s,12H).

[0333] Example 47: Preparation of Compound 47 [ka] 1) Preparation of Compound 47 Intermediate 3-12 (121 mg) was dissolved in DMF, and Intermediate 30-2 (70 mg), DIPEA (148 mg), and HATU (65 mg) were added. The mixture was allowed to react at room temperature for 3 hours. The crude reaction mixture was purified by preparative liquid chromatography to give Compound 47 (46 mg). ESI-MS: m / z = 828.1 [M+2H] 2+ .

[0334] Example 48: Preparation of Compound 48 [ka] 1) Preparation of Compound 48 Referring to Step 1 of Example 47, intermediate 30-2 was replaced with intermediate 14-4 to give compound 48 (8 mg). ESI-MS: m / z=813.8 [M+2H] 2+ 1 H NMR(500MHz,DMSO)δ 11.95(s,1H),8.98(s,1H),8.35(m,1H),8.12(s,1H),7.92(m,2H),7.71(m,2H),7. 43(m,2H),7.39-7.32(m,5H),7.27(m,2H),7.15(m,3H),6.98(s,1H),6.85(m,2H), 5.07(s,1H),4.90(m,1H),4.49-4.21(m,3H),4.07(s,1H),3.61(s,3H),3.53(s,2H),3.22(s,6H),2.45(s,4H),2.25(s,11H) ,1.99(s,6H),1.91(s,6H),1.79(s,3H),1.57(s,1H),1.46(s,9H),1.37(m,2H),1.24(s,8H),0.95(s,4H),0.91-0.81(s,9H).

[0335] Example 49: Production of Compound 49

change

[0336] Example 50: Preparation of Compound 50 [ka] 1) Preparation of Compound 50 Referring to Step 1 of Example 47, intermediate 30-2 was replaced with intermediate 15-2 to give compound 50 (5 mg). ESI-MS: m / z=821.8 [M+2H] 2+

[0337] Test Example 1: In vitro inhibitory effect of RS4;11 on cell proliferation RS4;11 cells in exponential growth phase and in good condition (provided by Nanjing Kebai Biotechnology Co., Ltd.) were obtained. The cells were collected in a centrifuge tube and centrifuged at 1000 rpm for 5 minutes in a low-speed benchtop centrifuge. The supernatant was discarded and resuspended in 3 mL of inoculation medium (RPMI basal medium + 5% fetal bovine serum) using a pipette. The cells were counted using a cell counter and diluted with inoculation medium to a cell density of 1 × 10 5 The cells were adjusted to a concentration of 100 cells / mL and inoculated into a 96-well plate at 100 μL per well using a multichannel pipette. The cells were then cultured in a 37°C, 5% CO2-containing, humidity-saturated cell incubator. After 24 hours of culture, compounds were loaded using a nanopipette to final compound concentrations of 2000 nM to 0.91 nM in two duplicate wells, including a control. After 72 hours of culture in the cell incubator, 10 μL of CCK-8 (Dojindo Laboratories) was added per well. After 4 hours of incubation in the cell incubator, absorbance was measured at 450 nm using an Envision microplate reader. The inhibition rate was calculated using the formula: inhibition rate (%) = (mean value of negative control group - mean value of experimental group) / (mean value of negative control group - mean value of blank group) × 100%. A dose-response curve was fitted using four-parameter logistic regression, with the logarithm of compound concentration on the horizontal axis and the inhibition rate on the vertical axis. The IC 50 was calculated.

[0338] The test results showed that the compounds of the present disclosure have a growth inhibitory effect on RS4;11 cells.

[0339] Test Example 2: In vitro MOLT-4 cell proliferation inhibitory effect MOLT-4 cells in exponential growth phase and in good condition were obtained from one dish, collected in a centrifuge tube, and centrifuged at 1500 rpm for 3 minutes in a low-speed benchtop centrifuge. The supernatant was discarded, and 5 mL of complete medium (RPMI basal medium + 10% FBS) was added using a pipette to resuspend the cells. The cells were counted using a cell counter and diluted with complete medium to a cell density of 1.6 × 10 5 The serum concentration was adjusted to 5% and the cell density to 8 × 10 cells / mL by adding an equal volume of RPMI basal medium. 4 The cells were inoculated at a concentration of 100 cells / mL. Using a multichannel pipette, 100 μL was inoculated into each well of a 96-well plate, and the plate was then placed in a humidity-saturated cell incubator containing 5% CO2 at 37°C. After 24 hours of incubation, compounds were loaded using a nanopipette to a final compound concentration of 1000 nM to 0.46 nM. Two duplicate wells were placed for each concentration, and cells without compound were used as a negative control. After 72 hours of incubation, CCK-8 (Dojindo Laboratories) was added at 10 μL / well, and after 3.5 hours, the absorbance at 450 nm was measured using an Envision microplate reader. The inhibition rate was calculated as follows: Inhibition rate (%) = (mean value of negative control group - experimental group) / (mean value of negative control group - mean value of blank group) × 100%. A dose-response curve was fitted by four-parameter logistic regression with the logarithm of the compound concentration on the horizontal axis and the inhibition rate on the vertical axis, and the IC 50 was calculated, and the results are shown in Table 1. [Table 1]

[0340] The test results showed that the compounds of the present disclosure have a growth inhibitory effect on RS4;11 cells and MOLT-4 cells in vitro.

[0341] Test Example 3: Measurement of BCL-XL protein degradation in MOLT-4 cells in vitro MOLT-4 cells in exponential growth phase and in good condition were obtained from one dish, collected in a centrifuge tube, and centrifuged at 1500 rpm for 3 minutes in a low-speed benchtop centrifuge. The supernatant was discarded, and 5 mL of complete medium (RPMI basal medium + 10% FBS) was added using a pipette to resuspend the cells. The cells were counted using a cell counter and diluted with complete medium to a cell density of 1 x 10 7 The concentration was adjusted to 100 cells / mL and inoculated into a 96-well plate at 100 μL per well using a multichannel pipette. Compounds were loaded using a nanopipette to achieve final compound concentrations ranging from 1000 nM to 1 nM. Each concentration was placed in duplicate wells and cultured in a 37°C, 5% CO2-saturated humidity cell incubator.

[0342] After 24 hours of culture, the cells were harvested and analyzed by flow cytometry. After washing with 2% BSA in PBS, the cells were fixed with 80% methanol, permeabilized with 0.1% Tween 20 in PBS, blocked with 10% BSA in PBS, and finally labeled with antibodies. The primary antibody, BCL-XL (54H6) rabbit mAb (CST, 2764S), was incubated at room temperature for 30 minutes. After washing with 2% BSA in PBS, the cells were incubated with anti-rabbit IgG (H+L), F(ab')2 fragment (Alexa Fluor®). The cells were incubated with 488 conjugate (CST, 4412S) at room temperature for 30 minutes. After the incubation was completed, the cells were resuspended in PBS containing 2% BSA, washed, and loaded onto IQue3 (Sartorius) for measurement.

[0343] The group labeled with only the secondary antibody was used as the background group, and the cells without the compound were used as the negative control group. The expression of BCL-XL protein was evaluated using the mean fluorescence intensity (MFI) index. The inhibition rate was calculated. Degradation rate (%) = (mean MFI of negative control group - mean MFI of compound group) / (mean MFI of negative control group - mean MFI of background group) x 100%. A dose-response curve was fitted by four-parameter logistic regression with the logarithm of compound concentration on the horizontal axis and the degradation rate on the vertical axis, and the DC 50 (50% decomposition concentration) was calculated.

[0344] The test results showed that the compounds of the present disclosure have a BCL-XL protein degradation activity in MOLT-4 cells in vitro.

[0345] Test Example 4: Evaluation of BCL-XL / BAK binding inhibitory activity The Tag1-BCL-XL protein stock solution was diluted to 8 nM using the dilution buffer provided with the kit (cisbio, 63ADK000CB04PEG). At the same time, the Tag2-BAK protein stock solution was diluted to 20 nM. 5 μL of the Tag1-BCL-XL protein dilution was added to a 384-well plate. Compounds were loaded using a nanopipette to achieve final compound concentrations ranging from 1000 nM to 0.24 nM. Two duplicate wells were simultaneously loaded as controls. 5 μL of the Tag2-BAK protein dilution was added to each well. The mixture was centrifuged to mix evenly and incubated at room temperature for 15 minutes. Anti-Tag1-Eu was then detected using the assay buffer provided with the kit (cisbio, 63ADK000CB04PEG). 3+ Antibody and anti-Tag2-XL665 antibody were diluted to 1x concentration, and anti-Tag1-Eu 3+ The diluted solutions of anti-Tag2 and anti-XL665 antibodies were mixed uniformly at a volume ratio of 1:1. 10 μL of the antibody mixture was added to each well, centrifuged to mix uniformly, and incubated at room temperature for 2 hours. Fluorescence values ​​at 665 nm / 620 nm were measured using an Envision microplate reader, and a dose-response curve was fitted using four-parameter logistic regression to determine the IC 50 was calculated.

[0346] The test results showed that the compounds of the present disclosure have BCL-XL / BAK binding inhibitory activity in vitro.

[0347] Test Example 5: In vitro stability in liver microsomes Liver microsome incubation samples (human, rat, mouse, and monkey) were prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.5 mg / mL), test compound, and NADPH + MgCl2 solution and incubated at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.5 mg / mL), and test compound. Acetonitrile solution containing an internal standard was added to the sample to precipitate proteins, and the supernatant was prepared and diluted for LC / MS / MS analysis.

[0348] The test results showed that the compounds of the present disclosure were stably metabolized in liver microsomes in vitro. See Tables 2 and 3 for the results. [Table 2] [Table 3]

[0349] Test Example 6: Pharmacokinetics in mice ICR mice weighing 18-22 g were allowed to adapt for 3-5 days, then randomly assigned to groups of 9 mice each. Test compound solutions were injected intravenously at a dose of 1 mg / kg. Blood samples were collected via the orbit at 5, 15, and 30 minutes, 1, 2, 3, 4, 6, 8, 10, and 24 hours. Test plasma samples were prepared by orbital blood collection. 20 μL of test plasma samples and standard curve samples were withdrawn, and an acetonitrile solution containing an internal standard was added to precipitate proteins. The supernatant was then diluted for LC / MS / MS analysis. Pharmacokinetic parameters were fitted using a noncompartmental model.

[0350] From the test results, it was found that the compounds of the present disclosure have good pharmacokinetic parameters in the body.

[0351] Test Example 7: Pharmacokinetics in rats SD rats weighing 210 to 230 g were allowed to adapt for 3 to 5 days, then randomly divided into groups of 3 rats each, and the example solution was intravenously injected at a dose of 0.5 mg / kg.

[0352] Blood was collected at 0 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 24 hours, and 32 hours after the test, and test plasma samples were prepared by collecting blood from the orbit.

[0353] 50 μL of test plasma samples and standard curve samples were drawn off, and an acetonitrile solution containing an internal standard was added to precipitate proteins, and the supernatant was obtained and diluted in preparation for LC / MS / MS measurement.

[0354] A non-compartmental model was employed for fitting.

[0355] The test results showed that the compounds of the present disclosure have good pharmacokinetic parameters in rats.

[0356] Test Example 8: Pharmacokinetics in dogs Beagles weighing 10 to 12 kg were allowed to adapt for 3 to 5 days, then randomly divided into groups of 3 animals each, and the Example solution was intravenously injected at a dose of 0.2 mg / kg.

[0357] Blood was collected at 0 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 24 hours, 32 hours, and 48 hours from the forelimb vein to prepare test plasma samples.

[0358] 50 μL of test plasma samples and standard curve samples were drawn off, and an acetonitrile solution containing an internal standard was added to precipitate proteins, and the supernatant was obtained and diluted in preparation for LC / MS / MS measurement.

[0359] A non-compartmental model was employed for fitting.

[0360] The test results showed that the compounds of the present disclosure have good pharmacokinetic parameters in dogs.

[0361] Test Example 9: BCL-XL protein degradation kinetics measurement MOLT-4 cells in exponential growth phase and in good condition were obtained from one dish, collected in a centrifuge tube, and centrifuged at 1500 rpm for 3 minutes in a low-speed benchtop centrifuge. The supernatant was discarded, and 5 mL of complete medium (RPMI basal medium + 10% FBS) was added using a pipette to resuspend the cells. The cells were counted using a cell counter and diluted with complete medium to a cell density of 2 × 10 6 The concentration was adjusted to 100 nM / mL and inoculated into a V-bottom 96-well plate at 100 μL per well using a multichannel pipette. Compounds were loaded using a nanopipette to a final compound concentration of 100 nM. Two duplicate wells were placed for each concentration and cultured in a 37°C, 5% CO2-containing, humidity-saturated cell incubator.

[0362] After 4 hours of incubation, the cells were collected by centrifugation at 300 g for 5 minutes and then washed with ice-cold PBS. After washing, 100 μL of lysis solution was added to each well and mixed thoroughly with a pipette to dissolve the cells. If the cells were fully lysed, no obvious cell precipitates should be visible. The cells were then lysed on ice for 30 minutes. After lysis, the cells were stored in a -80°C refrigerator for further testing.

[0363] The cell lysates were placed on ice to dissolve, then centrifuged at 500 g for 10 minutes. Lysis was measured using a BCLXL ELISA kit (R&D, DYC894-5). A high-binding 96-well plate was first coated overnight with a BCL-XL capture antibody, then blocked with 1% BSA in PBS. The samples were then incubated for 2 hours. After incubation, the test antibody was added and incubated for 2 hours. Finally, streptavidin-HRP was added and incubated for 20 minutes. TMB was added and allowed to develop for 15 minutes before measurement. Absorbance was measured at 450 / 570 nm using an Envision microplate reader. The absorbance at 570 nm and the blank background value were subtracted to calculate the degradation rate (%): 100% × (mean value of negative control group - experimental group) / mean value of negative control group. The results are shown in Table 4. [Table 4]

[0364] The test results showed that the compounds of the present disclosure have good BCL-XL proteolysis kinetic properties.

[0365] Test Example 10: Platelet toxicity evaluation in dogs 9 mL of canine whole blood was collected using a 10 mL sodium citrate vacuum anticoagulated blood collection tube, inverted to mix uniformly, centrifuged at 100 g for 10 minutes at room temperature, the supernatant (i.e., plasma) was collected and carefully transferred to a 50 mL centrifuge tube, and then 5 mL of acid citrate buffer working solution was added, carefully mixed to homogenize, 200 μL was removed and counted, and subsequently centrifuged at 1200 g for 10 minutes at room temperature ( (The speeds of the centrifuge were both set at 5.) Carefully discard the supernatant, then add 2 mL of Tyrode's working solution containing 1 μM prostaglandin E1 (PGE1) and 0.2 units / mL apyrase, and wash briefly. Discard the supernatant, then carefully resuspend and mix uniformly in Tyrode's working solution containing 1 μM prostaglandin E1 and 0.2 units / mL apyrase to a final concentration of 1 × 10 8 / mL and then inoculated into a U-bottom 96-well plate at 90 μL / well, and after plating, an additional 10 μL of FBS was added to all wells.

[0366] Compounds were loaded using a nanopipette to final compound concentrations ranging from 2000 nM to 8.2 nM, with two duplicate wells for each concentration. The plate was then sealed with a sealing film and placed on a microplate thermostat shaker at 20 °C and incubated at 300 rpm. After 72 hours, 10 μL of the assay reagent CCK-8 (Beijing Dojindo Laboratories) was added per well. After 1 hour of incubation in a cell incubator, 50 μL was transferred to a flat-bottom 96-well plate using a multichannel pipette. After shaking to mix uniformly, the absorbance at 450 nm was measured using a PerkinElmer Envision microplate reader. A dose-response curve was fitted using four-parameter logistic regression to determine the IC. 50 The values ​​were calculated, and the results are shown in Table 5. [Table 5]

[0367] The test results showed that the compounds of the present disclosure have low toxicity to dog platelets.

[0368] Test Example 11: Pharmacodynamic evaluation of MOLT-4 human acute lymphoblastic leukemia cells in a CB17-SCID mouse subcutaneously transplanted tumor model 1 × 10 MOLT-4 cells were injected into the right axilla of SPF female CB17-SCID mice (provided by Shanghai Lingchang Biotechnology Co., Ltd.). 7 The average tumor volume was approximately 200 mm 3 When the animals reached the age of 18, they were divided into groups.

[0369] The day of group assignment was Day 0. A single dose was administered via tail vein injection on Day 0. Tumor volume was measured two to three times a week, and mice were weighed and recorded. The general behavior of the mice was also observed and recorded daily. After the experiment was completed, tumors were excised, weighed, and photographed.

[0370] The measurement indicators and calculation formulas are as follows: Tumor volume is expressed as TV (mm 3 )=1 / 2×(a×b 2 ) where a is the longest diameter of the tumor and b is the shortest diameter of the tumor.

[0371] Relative tumor volume is RTV = TV t / TV0, where TV0 is the tumor volume on day 0 and TV t is the tumor volume at each measurement.

[0372] The relative tumor growth rate is T / C (%) = T RTV / C RTV × 100%, where T RTV is the RTV of the treatment group, and C RTV is the RTV of the vehicle control group.

[0373] The tumor growth inhibition rate was calculated as follows: TGI (%) = (1-TW / TW0) x 100%, where TW is the tumor weight in the treatment group and TW0 is the tumor weight in the vehicle control group.

[0374] The weight change rate is WCR (%) = (Wt t -Wt0) / Wt0 × 100%, where Wt0 is the body weight of the mouse on day 0 and Wt t is the body weight of the mouse at each measurement.

[0375] The test results showed that the compounds of the present disclosure have good tumor growth inhibitory effects in vivo (for example, on day 14, the tumor volume inhibition rate is more than 50%, and the tumor weight inhibition rate is more than 50%).

Claims

1. A compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula, R stands for OH, NH ２ , CN, halogens, and optionally one or more OH, NH ２ , CN, C substituted with halogen １～６ Selected from the group consisting of alkyl groups, X is CH ２ Selected from the group consisting of NH and O, L is a linking functional group, ULM is 【Chemistry 2】 And, In the formula, R １ C is optionally substituted with one or more halogens. １～６ Selected from alkyl groups, R ２ is optionally selected from one or more OH, NH ２ , CN, C substituted by halogen １～６ alkyl groups, X １ , X ２ , X ３ , X ４ and X ５ Each of these is independently selected from the group consisting of CH, C, N, NH, O, and S. Individual R ３ These are OH and NH, respectively. ２ CN, halogen, C １～６ Alkyl and C １～６ Independently selected from the group consisting of alkoxy groups, the NH ２ , C １～６ Alkyl alkyl group or C １～６ The alkoxy group can be one or more OH, NH groups, optionally. ２ , substituted with CN or halogen, m and q are each independently selected from the groups 0, 1, 2, and 3. The condition is that ULM 【Transformation 3】 It is not that, Individual R, X, L, R １ , R ２ , X １ , X ２ , X ３ , X ４ or X ５ Each of these can be independently and optionally substituted by one or more substituents.

2. The aforementioned R is a halogen, and optionally one or more OH, NH ２ , CN, C substituted with halogen １～６ Selected from the group consisting of alkyl groups, The aforementioned R is F, Cl, Br, and optionally one or more OH, NH ２ , CN, C substituted with halogen １～３ Selected from the group consisting of alkyl groups, The aforementioned R is F, Cl, Br, and C, which is optionally substituted with one or more F or Cl. １～３ Selected from the group consisting of alkyl groups, The aforementioned R is selected from the group consisting of F, Cl, Br, and a trifluoromethyl group, The aforementioned R is selected from Cl, q is selected from the group consisting of 0, 1, and 2, q is selected from the group consisting of 0 and 1, or structural unit 【Chemistry 4】 teeth, 【Transformation 5】 A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from among.

3. The aforementioned X is a compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of NH and O.

4. The above L is a bond, -C １～２０ Alkyl-, -C ２～２０ Alkenyl- and -C ２～２０ Selected from the group consisting of alkynyl, and the above-C １～２０ Alkyl-, -C ２～２０ Alkenyl- or -C ２～２０ Alkynyl - One or more -CH ２ - is an optional and independent choice for R ｘ Replaced by the R ｘ is -O-, -NR ａ -, -S(O) ２ -, -S(O) ２ NR ａ -, -S(O)-, -S(O)NR ａ -, -C(O)-, -C(O)O-, -C(O)NR ａ -, -C(O)N(R ａ )O-, -OC(O)-, -OC(O)NR ａ -, -N(R ａ )C(O)O-,-N(R ａ )C(O)-,-N(R ａ ) S(O) ２ -, 5-12 member heteroaryl group, phenyl group, C ３～１０ Selected from the group consisting of cycloalkyl groups, 3- to 10-membered heterocycloalkyl groups, and -S-, where R ａ is hydrogen and C １～６ Selected from the group consisting of alkyl groups, each R ｘ Or R ａ Each of these can be independently and optionally substituted by one or more substituents, The aforementioned R ａ is hydrogen and C １～４ Selected from the group consisting of alkyl groups, R ａ is hydrogen and C １～３ Selected from the group consisting of alkyl groups, R ａ is hydrogen and C １～２ Selected from the group consisting of alkyl groups, or R ａ It is selected from the group consisting of hydrogen and methyl groups, The aforementioned R ｘ These are -O-, -C(O)-, 5-12 member heteroaryl groups, phenyl groups, and C ３～１０ Cycloalkyl groups, 3-10 member heterocycloalkyl groups, -NH-, -N(C) １～６ Selected from the group consisting of alkyl)- and -S-, The aforementioned R ｘ These are -O-, -C(O)-, 5-6 member heteroaryl group, phenyl group, C ３～６ Cycloalkyl groups, 3-6 member heterocycloalkyl groups, -NH-, -N(C) １～６ Selected from the group consisting of alkyl)- and -S-, The aforementioned R ｘ is -O-, -C(O)-, phenyl group, C ５～６ Cycloalkyl group, 5-6 member heterocycloalkyl group, -NH-, -N(C) １～３ Selected from the group consisting of alkyl)- and -S-, The aforementioned R ｘ -O-, -C(O)-, phenyl group, piperidinyl group, piperazinyl group, -NH-, -N(C １～３ Selected from the group consisting of alkyl)- and -S-, The aforementioned R ｘ is selected from the group consisting of -C(O)- and piperazinyl groups, The aforementioned R ｘ is -C(O)- and 【Transformation 6】 Selected from the group consisting of, The above L is a bond, -C １～１２ Alkyl-, -C ２～１２ Alkenyl- and -C ２～１２ Selected from the group consisting of alkynyl, and the above-C １～１２ Alkyl-, -C ２～１２ Alkenyl- or -C ２～１２ Alkynyl - One or more -CH ２ - is an optional and independent choice for R ｘ Replaced by the R ｘ Does it have the above definition? Said L is selected from the group consisting of a bond, -C ３～１２ alkyl-, -C ３～１２ alkenyl- and -C ３～１２ alkynyl-, and one or more of the -CH ３～１２ in the alkyl-, -C ３～１２ alkenyl- or -C ３～１２ alkynyl- are optionally and independently replaced by R ２ respectively, and said R ｘ ｘ has the definition as described above, or​ Alternatively, L is a bond, -C ６～１２ Alkyl-, -C ６～１２ Alkenyl- and -C ６～１２ Selected from the group consisting of alkynyl, and the above-C ６～１２ Alkyl-, -C ６～１２ Alkenyl- or -C ６～１２ Alkynyl - One or more -CH ２ - is an optional and independent choice for R ｘ Replaced by the R ｘ Does it have the above definition? The above L is a bond, -C ８～９ Alkyl-, -C ８～９ Alkenyl- and -C ８～９ Selected from the group consisting of alkynyl, and the above-C ８～９ Alkyl-, -C ８～９ Alkenyl- or -C ８～９ Alkynyl - One or more -CH ２ - is an optional and independent choice for R ｘ Replaced by the R ｘ Does it have the above definition? The above L is a bond, -C ６～１２ Alkyl-, -C ６～１２ Alkenyl- and -C ６～１２ Selected from the group consisting of alkynyl, and the above-C ６～１２ Alkyl-, -C ６～１２ Alkenyl- or -C ６～１２ Alkynyl - One or more -CH ２ - is an optional and independent choice for R ｘ Replaced by the R ｘ -O-, -C(O)-, phenyl group, piperidinyl group, piperazinyl group, -NH-, -N(C １～３ Selected from the group consisting of alkyl)- and -S-, The aforementioned L is -C ３～１２ Selected from alkyl-, and the aforementioned -C ３～１２ One or more -CH groups in alkyl- ２ - is an optional and independent choice for R ｘ Replaced by the R ｘ is selected from the group consisting of -C(O)- and piperazinyl groups, The aforementioned L is -C ６～１２ Selected from alkyl-, and the aforementioned -C ６～１２ One or more -CH groups in alkyl- ２ - is an optional and independent choice for R ｘ Replaced by the R ｘ is selected from the group consisting of -C(O)- and piperazinyl groups, The aforementioned L is -C ６～１０ Selected from alkyl-, and the aforementioned -C ６～１０ One or more -CH groups in alkyl- ２ - is an optional and independent choice for R ｘ Replaced by the R ｘ is selected from the group consisting of -C(O)- and piperazinyl groups, The aforementioned L is -C ６～１０ Selected from alkyl-, and the aforementioned -C ６～１０ One or more -CH groups in alkyl- ２ - is an optional and independent choice for R ｘ Replaced by the R ｘ is -C(O)- and 【Transformation 7】 Selected from the group consisting of, Alternatively, L is -C ８～１０ Selected from alkyl-, and the aforementioned -C ８～１０ One or more -CH groups in alkyl- ２ - can be optionally and independently replaced by -C(O)-, The aforementioned L is, 【Transformation 8】 and 【Chemistry 9】 The group is selected from the group consisting of 0 to 10, in the formula n is selected from the group consisting of 1 to 9, or n is selected from the group consisting of 1 to 7. The aforementioned L is, 【Chemistry 10】 and 【Chemistry 11】 The group is selected from the group consisting of 0 to 10, in the formula n is selected from the group consisting of 1 to 9, or n is selected from the group consisting of 1 to 7. The aforementioned L is, 【Chemistry 12】 and 【Chemistry 13】 Selected from a group consisting of, The aforementioned L is, 【Chemistry 14】 and 【Chemistry 15】 Selected from a group consisting of, The aforementioned L is, 【Chemistry 16】 and 【Chemistry 17】 Selected from a group consisting of, The aforementioned L is, [Chemistry 18] and 【Chemistry 19】 Selected from a group consisting of, The aforementioned L is, 【Chemistry 20】 and 【Chemistry 21】 Selected from a group consisting of, Alternatively, L is 【Chemistry 22】 and 【Chemistry 23】 A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

5. Either one end of L is connected to the ULM, or the right end of L is connected to the ULM, or the left end of L is connected to the ULM, or L is 【Chemistry 24】 and 【Chemistry 25】 A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following, wherein * indicates that the end is connected to a ULM.

6. The aforementioned X １ , X ２ , X ３ , X ４ and X ５ Each of these is independently selected from the group consisting of CH, C, N, NH, O, and S, The aforementioned X １ , X ２ , X ３ , X ４ and X ５ Each of these is independently selected from the group consisting of CH, C, N, NH, and S, The aforementioned X １ , X ２ , X ３ , X ４ and X ５ These are independently selected from the group consisting of CH, C, NH, and N, The aforementioned X １ , X ２ , X ３ , X ４ and X ５ Each of these is independently selected from the group consisting of CH, C, N, NH, O, and S, and at least one of them is N. The aforementioned X １ , X ２ , X ３ , X ４ and X ５ Each of these is independently selected from the group consisting of CH, C, N, NH, O, and S, and at least two of them are heteroatoms. The aforementioned X １ , X ２ , X ３ , X ４ and X ５ Each of these is independently selected from the group consisting of CH, C, N, NH, O, and S, and at least two are selected from the group consisting of N or S. X １ , X ２ , X ３ , X ４ and X ５ The ring formed by this is aromatic, X １ , X ２ , X ３ , X ４ and X ５ The ring formed by this is a five-membered heteroaromatic ring, The aforementioned X １ and X ２ Each is independently selected from the groups N and NH, and X ３ and X ４ Each is independently chosen from CH, and X ５ Will it be selected from C, The aforementioned X １ , X ２ and X ４ He was selected from CH, X ３ and X ５ It is selected from the group consisting of N and NH, The aforementioned X １ , X ２ and X ４ He was selected from CH, X ３ It is selected from the group consisting of N and NH, and X ５ It is selected from N, The aforementioned X １ Selected from S, X ２ and X ４ He was selected from CH, X ３ X is selected from the group consisting of N and NH. ５ Will it be selected from C, Structural unit 【Chemistry 26】 teeth, 【Chemistry 27】 and 【Chemistry 28】 Selected from a group consisting of, or structural unit 【Chemistry 29】 teeth, 【Transformation 30】 and 【Chemistry 31】 A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

7. The aforementioned R １ C is a C atom that is optionally replaced by one or more halogens. １～４ Selected from alkyl groups, or the R １ C is a C atom that is optionally replaced by one or more halogens. ３～４ Selected from alkyl groups, or the R １ is selected from the group consisting of isopropyl groups and tert-butyl groups optionally substituted with one or more halogens, or the R １ This is selected from the group consisting of isopropyl groups and tert-butyl groups. and / or the R ２ This is one or more OH and NH groups selected at will. ２ , CN, C substituted with halogen １～４ Selected from alkyl groups, or the R ２ This is one or more OH and NH groups selected at will. ２ , selected from CN, halogen-substituted methyl groups, or the R ２ The R is selected from methyl groups substituted with one or more OH groups as optional, or the R ２ The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of a hydroxymethyl group and a methyl group.

8. The aforementioned individual R ３ These are OH and NH, respectively. ２ CN, halogen, C １～３ Alkyl and C １～３ Independently selected from the group consisting of alkoxy groups, the NH ２ , C １～３ Alkyl or C １～３ The alkoxy group can be one or more OH and NH groups, optionally. ２ , substituted with CN or halogen, or the individual R ３ These are, respectively, C １～３ Alkyl and C １～３ Either independently selected from the group consisting of alkoxy groups, or each of the R ３ These are OH and NH, respectively. ２ , independently selected from the group consisting of CN, halogen, methyl group and ethyl group, or the individual R ３ These are independently selected from the group consisting of methyl groups and ethyl groups, Structural unit 【Chemistry 32】 teeth, 【Transformation 33】 and 【Transformation 34】 Selected from a group consisting of, Structural unit 【Chemistry 35】 teeth, 【Transformation 36】 and 【Chemistry 37】 Selected from a group consisting of, Structural unit 【Transformation 38】 teeth, 【Chemistry 39】 and 【Chemistry 40】 Selected from a group consisting of, or structural unit 【Chemistry 41】 teeth, 【Chemistry 42】 and 【Chemistry 43】 A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

9. The aforementioned ULM is 【Chemistry 44】 Alternatively, 【Chemistry 45】 And, Alternatively, the ULM is, 【Chemistry 46】 or 【Chemistry 47】 That is, The compound described in claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof.

10. The aforementioned m and q are each independently selected from 1, and are the compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formula II, formula III, formula II-A, formula III-A, formula III-B, formula IV, formula V, formula VI, and formula VII, their stereoisomers, or pharmaceutically acceptable salts thereof. 【Chemistry 48】 (In the formula, R, q, L, ULM, X, R １ , R ２ or R ３ The definition is as described in claim 1.

12. A compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, selected from the group consisting of the following formulas. 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】

13. A compound according to any one of claims 1 to 12, a stereoisomer thereof, or a pharmaceutically acceptable compound A pharmaceutical composition comprising a salt thereof, and optionally further comprising pharmaceutically acceptable additives.

14. The pharmaceutical composition according to claim 13, for the prevention or treatment of a medical condition that is treated by degrading a target protein bound to a targeted ligand.

15. A pharmaceutical composition according to claim 13 for the prevention or treatment of a disease that is treated by binding to a protein in the cerebellum, Preferably, the pharmaceutical composition is selected from cancer as the disease to be treated by binding to the cerebellar protein.

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