Trifluoromethanesulfonyl group-containing compound

Abstract

The invention belongs to the field of medicinal chemistry, and relates to a compound containing trifluoromethanesulfonyl, in particular to a compound shown as a formula (I) or pharmaceutically acceptable salt thereof, a preparation method of the compound, a pharmaceutical composition containing the compound and application of the compound to treatment of tumor diseases. # imgabs0 #

Description

Compounds containing trifluoromethanesulfonyl groups

[0001] Citation of Related Applications

[0002] This application claims priority and benefits of Chinese Patent Application No. 202310134195.8 filed with the State Intellectual Property Office of the People's Republic of China on February 17, 2023, and Chinese Patent Application No. 202410136766.6 filed with the State Intellectual Property Office of the People's Republic of China on January 31, 2024, the entire contents of which are hereby incorporated by reference into the text in their entirety. Technical Field

[0003] The present disclosure relates to a compound containing a trifluoromethanesulfonyl group, a preparation method thereof, a pharmaceutical composition containing the compound, and use thereof in treating tumor diseases. Background Art

[0004] The B-cell lymphoma 2 (Bcl-2) family of proteins, composed of pro-apoptotic and anti-apoptotic members, plays a key role in determining cell fate by regulating the intrinsic apoptotic pathway. Anti-apoptotic Bcl-2 family proteins (such as 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 therapies. Because the growth of most solid tumors is independent of BCL-2 proteins, simply targeting BCL-2 inhibitors has no significant effect in the treatment of 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. Targeting BCL-XL is a potential ideal anti-tumor molecular target.

[0005] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds can induce the recognition of target proteins by the cell's proteasome, causing their degradation and effectively reducing their levels in cells. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology has become possible for the treatment of various diseases, and this technology has also received widespread attention in recent years.

[0006] Detailed Description of the Invention

[0007] The present disclosure relates to compounds of formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof,

[0008] in,

[0009] R is selected from OH, NH2, CN, halogen, or C optionally substituted with one or more OH, NH2, CN, halogen 1-6 alkyl;

[0010] X is selected from CH2, NH or O;

[0011] L is a linking group;

[0012] ULM is

[0013] where R 1 is selected from C optionally substituted by one or more halogens 1-6 alkyl;

[0014] R 2 Selected from C optionally substituted by one or more OH, NH2, CN, halogen 1-6 alkyl;

[0015] X 1 、X 2 、X 3 、X 4 and X 5 are independently selected from CH, C, N, NH, O or S;

[0016] Every R 3 are independently selected from OH, NH2, CN, halogen, C 1-6 Alkyl or C 1-6 Alkoxy, the NH2, C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more OH, NH2, CN or halogen;

[0017] m and q are each independently selected from 0, 1, 2 or 3;

[0018] The condition is that ULM is not

[0019] Each R, X, L, R 1 、R 2 、X 1 、X 2 、X 3 、X 4 or X 5 Each is independently optionally substituted with one or more substituents.

[0020] The present disclosure relates to compounds of formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof,

[0021] in,

[0022] R is selected from OH, NH2, CN, halogen, or C optionally substituted with one or more OH, NH2, CN, halogen 1-6 alkyl;

[0023] X is selected from CH2, NH or O;

[0024] L is a linking group;

[0025] ULM is

[0026] where R 1 is selected from C optionally substituted by one or more halogens 1-6 alkyl;

[0027] R 2 Selected from C optionally substituted by one or more OH, NH2, CN, halogen 1-6 alkyl;

[0028] X 1 、X 2 、X 3 、X 4 and X 5 are independently selected from CH, C, N, O or S;

[0029] Every R 3 are independently selected from OH, NH2, CN, halogen, C 1-6 Alkyl or C 1-6 Alkoxy, the OH, NH2, C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more OH, NH2, CN or halogen;

[0030] m and q are each independently selected from 0, 1, 2 or 3;

[0031] The condition is that ULM is not

[0032] Each R, X, L, R 1 、R 2 、X 1 、X 2 、X 3 、X 4 or X 5 Each is independently optionally substituted with one or more substituents.

[0033] In some embodiments, R is selected from halogen, or C optionally substituted with one or more OH, NH2, CN, halogen, 1-6 alkyl.

[0034] In some embodiments, R is selected from F, Cl, Br, or C optionally substituted with one or more OH, NH2, CN, halogen, 1-3 alkyl.

[0035] In some embodiments, R is selected from F, Cl, Br, or C optionally substituted with one or more F or Cl. 1-3 alkyl.

[0036] In some embodiments, R is selected from F, Cl, Br, or trifluoromethyl.

[0037] In some embodiments, said R is selected from Cl.

[0038] In some embodiments, q is selected from 0, 1, or 2; alternatively, q is selected from 0 or 1.

[0039] In some embodiments, R is selected from Cl, and q is selected from 1.

[0040] In some embodiments, the structural unit Selected from

[0041] In some embodiments, X is selected from NH or O.

[0042] In some embodiments, said X is selected from NH.

[0043] In some embodiments, X is selected from O.

[0044] In some embodiments, said L is selected from a bond, -C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 One or more -CH2- (each independently) in the alkynyl- is optionally replaced by R x Replace the R x Selected from -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-, 5-12 membered heteroaryl, phenyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl or -S-, R a Selected from hydrogen or C 1-6 Alkyl; each R x or R a Each is independently optionally substituted with one or more substituents.

[0045] The present disclosure 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 One or more -CH2- in the alkynyl- is optionally replaced by R x Replacement, said replacement is each independently occurred, for example, said L is selected from a bond, -C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 One or more -CH2- in the alkynyl- is optionally each independently replaced by R x Replace the R x Selected from -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-, 5-12 membered heteroaryl, phenyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl or -S-, R a Selected from hydrogen or C 1-6 Alkyl; each R x or R a Each is independently optionally substituted with one or more substituents.

[0046] In some embodiments, R a Selected from hydrogen or C 1-4 Alkyl; or, selected from hydrogen or C 1-3 Alkyl; or, selected from hydrogen or C 1-2 Alkyl; or, selected from hydrogen or methyl.

[0047] In some embodiments, the Rx Selected from -O-, -C(O)-, 5-12 membered heteroaryl, phenyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, -NH-, -N(C 1-6 alkyl)- or -S-.

[0048] In some embodiments, the R x Selected from -O-, -C(O)-, 5-6 membered heteroaryl, phenyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -NH-, -N(C 1-6 alkyl)- or -S-.

[0049] In some embodiments, the R x Selected from -O-, -C(O)-, phenyl, C 5-6 Cycloalkyl, 5-6 membered heterocycloalkyl, -NH-, -N(C 1-3 alkyl)- or -S-.

[0050] In some embodiments, the R x Selected from -O-, -C(O)-, phenyl, piperidinyl, piperazinyl, -NH-, -N(C 1-3 alkyl)- or -S-.

[0051] In some embodiments, the R x is selected from -C(O)- or piperazinyl.

[0052] In some embodiments, the R x Selected from -C(O)- or In some embodiments, the R x Selected from -C(O)-.

[0053] The replacements in L described in the present disclosure occur independently, for example, L is selected from a bond, -C 1-12 Alkyl-, -C 2-12 Alkenyl- or -C 2-12 Alkynyl-, the-C 1-12 Alkyl-, -C 2-12 Alkenyl- or -C 2-12 One or more -CH2- in the alkynyl- is optionally each independently replaced by R x Replace the R x As defined in this disclosure.

[0054] In some embodiments, said L is selected from a bond, -C 1-12 Alkyl-, -C 2-12 Alkenyl- or -C 2-12 Alkynyl-, the-C 1-12 Alkyl-, -C 2-12Alkenyl- or -C 2-12 One or more -CH2- (each independently) in the alkynyl- is optionally replaced by R x Replace the R x As defined in this disclosure.

[0055] In some embodiments, said L is selected from a bond, -C 3-12 Alkyl-, -C 3-12 Alkenyl- or -C 3-12 Alkynyl-, the-C 3-12 Alkyl-, -C 3-12 Alkenyl- or -C 3-12 One or more -CH2- in the alkynyl- is optionally each independently replaced by R x Replace the R x As defined in this disclosure.

[0056] In some embodiments, said L is selected from a bond, -C 6-12 Alkyl-, -C 6-12 Alkenyl- or -C 6-12 Alkynyl-, the-C 6-12 Alkyl-, -C 6-12 Alkenyl- or -C 6-12 One or more -CH2- in the alkynyl- is optionally each independently replaced by R x Replace the R x As defined in this disclosure.

[0057] In some embodiments, said L is selected from a bond, -C 8-9 Alkyl-, -C 8-9 Alkenyl- or -C 8-9 Alkynyl-, the-C 8-9 Alkyl-, -C 8-9 Alkenyl- or -C 8-9 One or more -CH2- in the alkynyl- is optionally each independently replaced by R x Replace the R x As defined in this disclosure.

[0058] In some embodiments, said L is selected from a bond, -C 6-12 Alkyl-, -C 6-12 Alkenyl- or -C 6-12 Alkynyl-, the-C 6-12 Alkyl-, -C 6-12 Alkenyl- or -C 6-12 One or more -CH2- in the alkynyl- is optionally each independently replaced by R x Replace the R x Selected from -O-, -C(O)-, phenyl, piperidinyl, piperazinyl, -NH-, -N(C1-3 alkyl)- or -S-.

[0059] In some embodiments, said L is selected from a bond, -C 6-12 Alkyl-, -C 6-12 Alkenyl- or -C 6-12 Alkynyl-, the-C 6-12 Alkyl-, -C 6-12 Alkenyl- or -C 6-12 One or more -CH2- (each independently) in the alkynyl- is optionally replaced by R x Replace the R x Selected from -O-, -C(O)-, phenyl, piperidinyl, piperazinyl, -NH-, -N(C 1-3 alkyl)- or -S-.

[0060] In some embodiments, the L is selected from -C 3-12 Alkyl-, the-C 3-12 One or more -CH2- in the alkyl- are optionally each independently replaced by R x Replace the R x is selected from -C(O)- or piperazinyl.

[0061] In some embodiments, the L is selected from -C 6-12 Alkyl-, the-C 6-12 One or more -CH2- in the alkyl- are optionally each independently replaced by R x Replace the R x is selected from -C(O)- or piperazinyl.

[0062] In some embodiments, the L is selected from -C 6-10 Alkyl-, the-C 6-10 One or more -CH2- in the alkyl- are optionally each independently replaced by R x Replace the R x is selected from -C(O)- or piperazinyl.

[0063] In some embodiments, the L is selected from -C 6-10 Alkyl-, the-C 6-10 One or more -CH2- in the alkyl- are optionally each independently replaced by R x Replace the R x Selected from -C(O)- or

[0064] In some embodiments, the L is selected from -C 8-10 Alkyl-, the-C 8-10 One or more -CH2- groups in the alkyl- group are optionally each independently replaced by -C(O)-.

[0065] In some embodiments, the L is selected from wherein n is selected from 0-10; or n is selected from 1-9; or n is selected from 1-7.

[0066] In some embodiments, the L is selected from

[0067] wherein n is selected from 0-10; or n is selected from 1-9; or n is selected from 1-7.

[0068] In some embodiments, the L is selected from

[0069] In some embodiments, the L is selected from In some embodiments, L is selected from In some embodiments, L is selected from In some embodiments, L is selected from In some embodiments, L is selected from In some embodiments, L is selected from In some embodiments, L is selected from In some embodiments, L is selected from In some embodiments, L is selected from In some embodiments, L is selected from In some embodiments, L is selected from In other embodiments, L is selected from In other embodiments, L is selected from

[0070] In some embodiments, any one end of L is connected to ULM.

[0071] In some embodiments, the right end of the L is connected to ULM. For example, The right end is connected to the ULM.

[0072] In some embodiments, the left end of the L is connected to ULM.

[0073] In some embodiments, the L is selected from Among them, * indicates that the end is connected to the ULM.

[0074] In some embodiments, X 1 、X 2 、X 3 、X 4 and X 5 are independently selected from CH, C, N, O or S.

[0075] In some embodiments, X 1 、X 2 、X 3 、X 4 and X 5 are 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 independently selected from CH, C, N, NH or S. In some embodiments, X 1 、X 2 、X 3 、X 4 and X 5 are independently selected from CH, C, NH, or N.

[0076] In some embodiments, the X 1 and X 2 are independently selected from N or NH, X 3 and X 4 are independently selected from CH; X 5 In some embodiments, the X 1 、X 2 and X 4 Selected from CH, X 3 and X 5 In some embodiments, X 1 、X 2 and X 4 Selected from CH, X 3 selected from N or NH, and X 5 In some embodiments, X 1 Selected from S, X 2 and X 4 Selected from CH, X 3 Selected from N or NH, X 5 Selected from C.

[0077] In some embodiments, the X 1 and X 2 Selected from N, X 3 and X 4 are independently selected from CH; X5 Selected from C; or, X 1 、X 2 and X 4 Selected from CH, X 3 and X 5 Selected from N; or, X 1 Selected from S, X 2 and X 4 Selected from CH, X 3 Selected from N, X 5 Selected from C.

[0078] In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from

[0079] In some embodiments, the R 1 is selected from C optionally substituted by one or more halogens 1-4 alkyl.

[0080] In some embodiments, the R 1 is selected from C optionally substituted by one or more halogens 3-4 alkyl.

[0081] In some embodiments, the R 1 is selected from isopropyl or tert-butyl optionally substituted by one or more halogens.

[0082] In some embodiments, the R 1 is selected from isopropyl or tert-butyl.

[0083] In some embodiments, the R 2 Selected from C optionally substituted by one or more OH, NH2, CN, halogen 1-4 alkyl.

[0084] In some embodiments, the R 2 Selected from methyl optionally substituted by one or more OH, NH2, CN, halogen.

[0085] In some embodiments, the R 2 is selected from methyl optionally substituted with one or more OH.

[0086] In some embodiments, the R 2 Selected from hydroxymethyl or methyl.

[0087] In some embodiments, the X 1 、X 2 、X 3 、X 4 and X 5 are independently selected from CH, C, N, NH, O or S, and at least one is N or NH.

[0088] In some embodiments, the X 1 、X 2 、X 3 、X 4 and X 5 are independently selected from CH, C, N, NH, O or S, and at least two of them are heteroatoms.

[0089] In some embodiments, the X 1 、X 2 、X 3 、X 4 and X 5 are independently selected from CH, C, N, NH, O or S, and at least two are selected from N, NH or S.

[0090] In some embodiments, the X 1 、X 2 、X 3 、X 4 and X 5 are independently selected from CH, C, N, O or S, and at least one of them is N.

[0091] In some embodiments, the X 1 、X 2 、X 3 、X 4 and X 5 are independently selected from CH, C, N, O or S, and at least two of them are heteroatoms.

[0092] In some embodiments, the X 1 、X 2 、X 3 、X 4 and X 5 are independently selected from CH, C, N, O or S, and at least two are selected from N or S.

[0093] In some embodiments, X 5 For C.

[0094] In some embodiments, X 5is N.

[0095] In some embodiments, X 1 、X 2 、X 3 、X 4 and X 5 The ring formed by X is aromatic. 1 、X 2 、X 3 、X 4 and X 5 The ring formed is a five-membered heteroaromatic ring.

[0096] In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from

[0097] In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from

[0098] In some embodiments, each of said R 3 are independently selected from OH, NH2, CN, halogen, C 1-3 Alkyl or C 1-3 Alkoxy, the OH, NH2, C 1-3 Alkyl or C 1-3 The alkoxy group is optionally substituted with one or more OH, NH2, CN or halogen.

[0099] In some embodiments, each of said R 3 are independently selected from C 1-3 Alkyl or C 1-3 Alkoxy.

[0100] In some embodiments, each of said R 3 Each is independently selected from OH, NH2, CN, halogen, methyl or ethyl.

[0101] In some embodiments, each of said R 3 are independently selected from C 1-3 In some embodiments, each of the R 3 are independently selected from methyl or ethyl.

[0102] In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from

[0103] In some embodiments, the ULM is

[0104] In some embodiments, the ULM is

[0105] In some embodiments, m and q are each 1.

[0106] The compound of formula I of the present disclosure or a pharmaceutically acceptable salt thereof is selected from the group consisting of 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,

[0107] Among them R, q, L, ULM, X, R 1 、R 2 or R 3 The definition of is as described in this disclosure.

[0108] Each R, X, L, R 1 、R 2 、X 1 、X 2 、X 3 、X 4 、X 5 、R x or R a Each is independently optionally substituted with one or more substituents.

[0109] The present disclosure relates to the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof,

[0110] In another aspect, the present disclosure relates to a pharmaceutical composition comprising the compound of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0111] On the other hand, the present disclosure relates to a pharmaceutical composition comprising the compound described in the present disclosure, its stereoisomers or pharmaceutically acceptable salts thereof, and the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0112] In another aspect, the present disclosure relates to the use of the compound described herein, its stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of a medicament for preventing or treating a disease that is treated by degrading a target protein bound to a targeting ligand (e.g., a small molecule moiety associated with BCL-XL).

[0113] In another aspect, the present disclosure relates to use of the compound of the present disclosure, its stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in the preparation of a medicament for preventing or treating a disease that is treated by binding to a cerebellar protein in vivo.

[0114] In another aspect, the present disclosure relates to use of the compound of the present disclosure, its stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions thereof in the preparation of a medicament for preventing or treating a disease that is treated by binding to a cerebellar protein.

[0115] In another aspect, the present disclosure relates to use of the compound, stereoisomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating a disease associated with BCL-XL.

[0116] The present disclosure relates to a method for treating or preventing a disease in a mammal by degrading a target protein bound to a targeting ligand, comprising administering a therapeutically effective amount of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0117] The present disclosure relates to a method for treating or preventing a disorder that can be treated by binding to a cerebellar protein, comprising administering a therapeutically effective amount of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0118] The present disclosure relates to a method for treating or preventing a disease that is treated by binding to a cerebellar protein in vivo, comprising administering a therapeutically effective amount of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0119] 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 of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0120] In another aspect, the present disclosure relates to a compound of the present disclosure, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a disease that is treated by degrading a target protein bound to a targeting ligand.

[0121] In another aspect, the present disclosure relates to a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a disease that is treated by binding to a cerebellar protein.

[0122] In another aspect, the present disclosure relates to a compound of the present disclosure, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a disease that is treated by binding to a cerebellar protein in vivo.

[0123] In another aspect, the present disclosure relates to a compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in preventing or treating a disease associated with BCL-XL.

[0124] On the other hand, the present disclosure relates to the use of the compound described in the present disclosure, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in preventing or treating diseases that are treated by degrading a target protein bound to a targeting ligand.

[0125] In another aspect, the present disclosure relates to use of the compound of the present disclosure, its stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions thereof in preventing or treating diseases that are treated by binding to cerebellar proteins.

[0126] In another aspect, the present disclosure relates to the use of the compound of the present disclosure, its stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions thereof in preventing or treating diseases that are treated by binding to cerebellar proteins in vivo.

[0127] In another aspect, the present disclosure relates to use of the compound, stereoisomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof described herein for preventing or treating diseases associated with BCL-XL.

[0128] In some embodiments, the disease associated with BCL-XL is selected from a condition treated by degradation and / or inhibition of proteins that bind to BCL-XL target protein ligands; in some embodiments, the disease associated with BCL-XL is selected from a condition treated by binding to cerebellum protein; in some embodiments, the disease associated with BCL-XL is selected from a condition treated by binding to cerebellum protein in vivo; in some embodiments, the disease or condition is selected from a tumor or cancer.

[0129] In some embodiments, the condition treated by binding to the cerebellum protein in vivo is selected from a disease associated with BCL-XL. In some embodiments, the disease associated with BCL-XL is selected from a tumor or cancer.

[0130] In some embodiments, the present disclosure encompasses the defined variables and embodiments thereof, and any combination thereof.

[0131] Technical Effects

[0132] The disclosed compounds have proliferation inhibitory effects on RS4;11 cells and MOLT-4 cells; can degrade BCL-XL protein in MOLT-4 cells; have good BCL-XL protein degradation kinetics; are metabolically stable in vitro (e.g., in human, rat, or mouse liver microsomes); have low platelet toxicity (e.g., in canine platelets); and have good in vivo efficacy (e.g., good tumor suppression effects) and pharmacokinetic properties in vivo (e.g., in mice, rats, or dogs). Furthermore, the disclosed compounds have effective tumor growth inhibition effects in vivo. Furthermore, the disclosed compounds have low platelet toxicity, providing good safety for use as drugs.

[0133] definition

[0134] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0135] Unless otherwise specified, Used to indicate The hydrogen atom at any position of the group can be replaced by a group connected by "—", for example, by L.

[0136] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0137] The term "optionally" or "optionally" means that the event or circumstance described subsequently may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0138] The "substituent" described herein includes all substituents mentioned herein, including but not limited to the terms "alkyl", "alkoxy", "heteroalkyl", "alkenyl", "alkynyl", "cycloalkenyl", "cycloalkyl", "heterocycloalkyl", "heterocycloalkenyl", "heterocyclyl", "heteroaryl", etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include deuterium, tritium, -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, azide, sulfoxide group, sulfone group, sulfone group, sulfonamide group, carboxyl group, carboxaldehyde group, imine 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, aryloxy 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 alkyl, -C(O)-alkyl, -C(O)-alkyl, -C(O)-alkyl, -C(O)- ... 2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, aryl, arylalkyl or aryloxy.

[0139] In this article, C m-n, means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 " means that the 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 It means that the group may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0140] In some embodiments herein, the substituent is selected from deuterium, tritium, hydroxyl, sulfhydryl, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, halo-C 1-12 Alkyl, 3-12 membered cycloalkyl, halogenated 3-12 membered cycloalkyl, C 2-12 Alkenyl, halo-C 2-12 Alkenyl, 3-12 membered cycloalkenyl, halogenated 3-12 membered cycloalkenyl, C 2-12 Alkynyl, halo-C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated 8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 Alkylene, 6-10 membered aryl C 1-12 Alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclylC 1-12 Alkylene, 3-12 membered heterocyclic group C 1-12 Alkoxy, 3-12 membered heterocyclic group C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acyloxy, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 Ester group and oxo, said substituent being optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, di-C1-12 Alkylamino, halogenated C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl, -C(O)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)2N(C 1-12 alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12 Alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC 1-12 Alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 an alkylene group or a 6- to 10-membered aryloxy group.

[0141] As used herein, "one or more" refers to an integer from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten; or, "one or more" refers to one, two, three, four, five, or six; or, "one or more" refers to one, two, or three.

[0142] In some embodiments, the "one or more" is selected from one, two, three, four, five, or six or more. In some embodiments, the "one or more" is selected from one, two, three, four, five, or six. In some embodiments, the "one or more" is selected from one, two, or three. In some embodiments, the "one or more" is selected from one, or two.

[0143] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. For example, if a group contains two R's, each R has an independent option.

[0144] When a bond crosses two atoms in a ring (including a monocyclic, fused, or spirocyclic ring), the bond may be bonded to any atom in the ring (including a monocyclic, fused, or spirocyclic ring).

[0145] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0146] The term "hydroxy" refers to an -OH group.

[0147] The term "amino" refers to a -NH2 group.

[0148] The term "cyano" refers to a -CN group.

[0149] The term "mercapto" refers to a -SH group.

[0150] The term "nitro" refers to a -NO2 group.

[0151] The term "heteroatom" includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, sulfur, silicon and phosphorus. In one embodiment, the heteroatoms are selected from N, O and S, 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 , p is 1 or 2).

[0152] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6 The term "alkyl" 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) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition. For another example, the term "C 1-3 The term "alkyl" refers to an alkyl group containing 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, and isopropyl).

[0153] The term "alkoxy" refers to an -O-alkyl group.

[0154] The term "heteroalkyl" refers to an alkyl structure containing heteroatoms. Unless otherwise indicated, the heteroalkyl group is typically an alkyl group containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Typically, where there is more than one heteroatom, the heteroatoms are not adjacent to each other. Exemplary heteroalkyl groups include alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, etc.

[0155] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0156] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms 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-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butadiynyl (-C≡C≡CH), and the like.

[0157] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bicyclic bridged ring or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 4 to 20-membered ring, a 4 to 15-membered ring, a 4 to 10-membered ring or a 4 to 8-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc.

[0158] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocycle, a bridged ring, or a spirocycle. Unless otherwise indicated, the carbocyclic ring is typically 3 to 20 rings, 3 to 15 rings, 3 to 12 rings, or 3 to 10 rings (e.g., 5 to 8 rings). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, etc.

[0159] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3-20 membered ring, 3-15 membered ring, 3-10 membered ring, 3-7 membered ring, 3-6 membered ring or 3-5 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from boron, nitrogen, oxygen, sulfur, silicon and / or phosphorus (preferably sulfur, oxygen and / or nitrogen), 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, p is 1 or 2). Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thioethanethiol, and nitrilanyl; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl; 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; examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl. Preferably, the heterocycloalkyl group is a monocyclic group having 5 or 6 ring atoms.

[0160] The term "heterocycloalkenyl" includes cycloalkenyl groups wherein up to 3 carbon atoms, in one embodiment up to 2 carbon atoms, in another embodiment 1 carbon atom are each independently replaced by boron, nitrogen, oxygen, sulfur, silicon or phosphorus (preferably O, S or N), provided that at least one cycloalkenyl carbon-carbon double bond remains, wherein the nitrogen atom is optionally quaternized, and the nitrogen, sulfur and phosphorus heteroatoms may be optionally oxidized (i.e., NO, S(O) p 、P(O) p , p is 1 or 2). The cyclic group may exist as a monocyclic, bridged, or spirocyclic ring, and may be a 3- to 20-membered ring, a 3- to 15-membered ring, a 3- to 12-membered ring, or a 3- to 10-membered ring (e.g., a 5- to 8-membered ring). Examples of heterocycloalkenyl groups include, but are not limited to, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine, or azaspirocyclooctenyl.

[0161] Unless otherwise indicated, the carbocyclic ring is typically 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, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.

[0162] The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocyclic ring is typically a 3-20-membered ring, a 3-15-membered ring, a 3-10-membered ring or a 3-7-membered ring (or a 5-6-membered ring) containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from boron, nitrogen, oxygen, sulfur, silicon and / or phosphorus (preferably sulfur, oxygen and / or nitrogen), 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, p is 1 or 2). Non-limiting examples of heterocyclyl include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, and the like.

[0163] The term "aryl" refers to an aromatic ring group of an all-carbon monocyclic or fused polycyclic ring having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms (6-10 carbon atoms, or 6 carbon atoms, i.e., phenyl). Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

[0164] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C and having at least one aromatic ring. Preferred heteroaryls have single 4 to 8-membered rings, especially 5 to 8-membered rings (or 5 to 6-membered rings), or multiple fused rings containing 6 to 20, 6 to 15 or 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

[0165] The groups or structural fragments in the present disclosure, such as -L- and their specific options, can optionally be read from left to right, and are connected to the left and right groups of the group or fragment in the general formula, respectively. For example, when L is selected from Reading from left to right, the left side of L corresponds to the left side of the general formula Connect, the right side connects with the right side fragment ULM to form Optionally, the groups or structural fragments in the present disclosure, such as -L- and their specific options, can be read from right to left, and are connected to the left and right groups of the group or fragment in the general formula, respectively. For example, when L is selected from According to the reading order from right to left, the right side of L corresponds to the left side of the general formula The fragment formed by connecting the left side with the fragment ULM corresponding to the right side of the general formula is as follows Other groups are the same as described above.

[0166] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0167] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0168] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0169] The term "prevention" means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0170] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0171] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0172] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0173] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0174] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0175] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0176] 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 of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0177] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 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, it should be understood that compounds wherein one or more hydrogen atoms in the compounds of Formula I disclosed herein are replaced by deuterium atoms are still within the scope of the compounds of Formula I disclosed herein.

[0178] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0179] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0180] The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0181] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.

[0182] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0183] In all methods of administration described herein, the compounds of formula I are administered at a dosage of 0.001 to 2000 mg / kg body weight per day in single or divided doses.

[0184] All patents, patent applications and other identified publications are expressly incorporated herein by reference for the purposes of description and disclosure. Any citation of these publications herein does not constitute an admission that the publications become part of the common general knowledge in the art.

[0185] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples disclosed herein.

[0186] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0187] An important consideration in synthetic route planning in this field is the selection of appropriate protecting groups for reactive functional groups (such as the amino groups in the present disclosure). For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0188] The disclosed compounds or pharmaceutically acceptable salts thereof can be prepared using the following preparation routes:

[0189] wherein R, q, L, ULM or X are as defined in the present disclosure.

[0190] This disclosure uses the following abbreviations:

[0191] HATU stands for 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DCM stands for dichloromethane; MeOH stands for methanol; DIPEA stands for N-ethyldiisopropylamine; Pd(dppf)Cl2 stands for (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride; PE stands for petroleum ether; EA stands for ethyl acetate; Tf2O stands for trifluoromethanesulfonic anhydride; Pd(PPh3)4 stands for tetrakis(triphenylphosphine)palladium; LAH stands for lithium aluminum hydride; NaOH stands for sodium hydroxide; DMSO stands for dimethyl sulfoxide; DMAP stands for 4-dimethylaminopyridine; EDCI stands for carbodiimide hydrochloride; Boc stands for tert-butyloxycarbonyl; and Et stands for ethyl.

[0192] For the sake of clarity, the present invention is further illustrated by examples, but the examples are not intended to limit the scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification. DETAILED DESCRIPTION

[0193] The purpose of the following specific embodiments is to enable those skilled in the art to more clearly understand and implement the present disclosure. They should not be considered as limiting the scope of the present disclosure, but are merely exemplary descriptions and typical representatives of the present disclosure.

[0194] Example 1: Preparation of Compound 1

[0195] Preparation of intermediate 1-2

[0196] Intermediate 1-1 (400 mg) was dissolved in dichloromethane, and trifluoroacetic acid (1088 μL, 15.2 mmol) was added in two portions. The mixture was allowed to react overnight at room temperature. The reaction was monitored by TLC and concentrated at 45°C to obtain the crude intermediate 1-2, which was used directly in the next step without purification.

[0197] LCMS (ESI) m / z: 428.3 [M+H] + .

[0198] Preparation of intermediate 1-3

[0199] Intermediate 1-2 (100 mg) was dissolved in dichloromethane, and monomethyl suberate (53 mg) was added, along with triethylamine (142 mg) and HATU (133 mg). The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, the reaction solution was directly purified by silica gel column chromatography (DCM:MeOH) to obtain 105 mg of Intermediate 1-3.

[0200] LCMS (ESI) m / z: 598.3 [M+H] + .

[0201] Preparation of intermediates 1-4

[0202] Intermediate 1-3 (0.43 g) was dissolved in methanol, and a 2N aqueous lithium hydroxide solution (2.16 mL) was added, followed by stirring at room temperature overnight. The reaction mixture was adjusted to pH 5-6 with 3N hydrochloric acid, extracted with DCM, separated, dried, and concentrated to afford 0.27 g of intermediate 1-4.

[0203] LCMS (ESI) m / z: 584.3 [M+H] + .

[0204] Preparation of intermediate 1-5

[0205] Intermediate A-12 (0.25 g) and A-1 (0.21 g) were dissolved in 3 mL of DCM. EDCI·HCl (0.092 g), DMAP (0.059 g), and triethylamine (199 μL) were added and stirred at room temperature overnight. The reaction solution 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 to pH 7-8, separated, dried, concentrated, and purified by column chromatography (DCM:MeOH) to obtain 0.25 g of intermediate 1-5.

[0206] LCMS (ESI) m / z: 1073.4 [M+H] + .

[0207] Preparation of intermediate 1-6

[0208] Intermediate 1-5 (48 mg) was dissolved in dichloromethane, trifluoroacetic acid (135 μL) was added in two portions, and the mixture was allowed to react overnight at room temperature. The reaction was monitored by TLC and concentrated at 45°C to obtain the crude intermediate 1-6, which was used directly in the next step without purification.

[0209] LCMS (ESI) m / z: 487.7 [M+2H] 2+ .

[0210] Preparation of compound 1

[0211] Intermediate 1-6 (91 mg) was dissolved in dichloromethane, and intermediate 1-4 (65 mg) was added. Triethylamine (130 μL) and HATU (53 mg) were added, and the mixture was reacted at room temperature for 1.5 h. DCM was added for dilution, and saturated ammonium chloride was added for extraction. The organic phase was washed with water, separated, and the aqueous phase was back-extracted with DCM. The organic phases were combined, washed with saturated sodium chloride, separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was liquid-phased to obtain 71 mg of compound 1.

[0212] LCMS (ESI) m / z: 770.5 [M+2H] 2+ .

[0213] 1H NMR (500MHz, CDCl3) δ8.34 (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=11.9Hz, 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=13.9Hz,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).

[0214] Example 2: Preparation of Compound 2

[0215] Preparation of intermediate 2-2

[0216] Intermediate 2-1 (5.0 g) and (S)-(-)-1-(4-bromophenyl)ethylamine (3.5 g) were dissolved in dichloromethane, and HATU (8.3 g) and DIPEA (5.6 g) were added. 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 yield 7.5 g of intermediate 2-2.

[0217] LCMS (ESI) m / z: 526.2 [M+H] + .

[0218] Preparation of intermediate 2-3

[0219] 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)Cl2 (0.14 g) were added. After nitrogen displacement, the reaction was carried out at 105°C for 5 h. The mixture was cooled, filtered through celite, concentrated to dryness, and extracted with water and DCM. The organic phase was separated and washed with saturated sodium chloride, separated, dried, and concentrated. The crude product was purified by column chromatography (DCM:MeOH) to yield 1.0 g of Intermediate 2-3.

[0220] LCMS (ESI) m / z: 542.3 [M+H] + .

[0221] Preparation of intermediate 2-4

[0222] Intermediate 2-3 (890 mg) was dissolved in dichloromethane, trifluoroacetic acid (2448 μL) was added in two batches, and the mixture was allowed to react overnight at room temperature. The reaction was monitored by TLC and concentrated at 45°C to obtain the crude intermediate 2-4, which was used directly in the next step without purification.

[0223] LCMS (ESI) m / z: 442.3 [M+H] + .

[0224] Preparation of intermediate 2-5

[0225] Intermediate 2-4 (720 mg) was dissolved in dichloromethane, and monomethyl suberate (740 mg) was added, along with triethylamine (2.0 ml) and HATU (930 mg). The mixture was allowed to react overnight at room temperature. The reaction was monitored by TLC. The reaction solution was extracted with water and dichloromethane, and the layers were separated. The organic phase was washed with saturated sodium chloride, separated, dried, and concentrated. The crude product was isolated by silica gel column chromatography (DCM:MeOH) to afford 520 mg of Intermediate 2-5.

[0226] LCMS (ESI) m / z: 612.3 [M+H] + .

[0227] Preparation of intermediate 2-6

[0228] Intermediate 2-5 (0.52 g) was dissolved in methanol, and a 2N aqueous lithium hydroxide solution (2.54 mL) was added, followed by stirring at room temperature overnight. The reaction mixture was adjusted to pH 5-6 with 3N hydrochloric acid, extracted with DCM, separated, dried, and concentrated to obtain 0.45 g of intermediate 2-6.

[0229] LCMS (ESI) m / z: 598.3 [M+H] + .

[0230] Preparation of compound 2

[0231] 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 reacted at room temperature for 1.5 h. DCM was added for dilution, and saturated ammonium chloride was added for extraction. The organic phase was washed with water, separated, and the aqueous phase was back-extracted with DCM. The organic phases were combined, washed with saturated sodium chloride, separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 83 mg of the crude liquid phase of compound 2.

[0232] LCMS (ESI) m / z: 777.0 [M+2H] 2+ .

[0233] 1 H NMR(500MHz, CDCl3)δ8.34(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=8.7Hz,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),3.06–2.9 7(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).

[0234] Example 3: Preparation of Compound 3

[0235] Preparation of intermediate 3-2

[0236] Add 300mL of dimethyltetrahydrofuran to the reaction flask, stir at 0°C under nitrogen protection, and add NaH (25.6g) after reaching the temperature. Dissolve intermediate 3-1 (20g) in 50mL of dimethyltetrahydrofuran and slowly add it dropwise to the above suspension. Add dimethyl carbonate (25.6g), reflux at 75°C for 5h, and monitor by LC-MS until the reaction is complete. The reaction solution is cooled to room temperature and slowly added to 300mL of ice water to quench. After the addition is completed, the layers are separated naturally. The organic layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain 25g of crude product. The crude product is subjected to column chromatography (PE:EA) to obtain 10g of intermediate 3-2.

[0237] Preparation of intermediate 3-3

[0238] Intermediate 3-2 (9.0 g) was dissolved in 108 mL of DCM and stirred at -78°C. DIPEA (21.5 g) was added after warming. Tf2O (28.2 g) was slowly added dropwise to the reaction solution. After addition, the mixture was stirred for 30 minutes and allowed to react at room temperature overnight. Extraction was performed with 100 mL of saturated sodium bicarbonate under an ice bath. The organic layer was washed with saturated sodium chloride, separated, and dried and concentrated to yield 50 g of crude product, which was used directly in the next step without purification.

[0239] Preparation of intermediate 3-4

[0240] Intermediate 3-3 (2.6 g) was dissolved in 40 mL of a 2:1 toluene-ethanol mixture. p-Chlorophenylboronic acid (1.2 g) and Pd(PPh3)4 (0.15 g) were added, followed by a 2N aqueous sodium carbonate solution (6.45 mL). After nitrogen replacement, the mixture was reacted at 90°C for 8 h. The mixture was filtered, the filter cake washed with EA, and the combined filtrates were concentrated. EA and water were added for extraction, the layers separated, and the EA layer dried and concentrated. The crude product was purified by column chromatography to yield 1.2 g of intermediate 3-4.

[0241] ESI-MS: m / z = 365.1 [M+H] + .

[0242] Preparation of intermediate 3-5

[0243] 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 allowed to react at 0°C for 3 h. 1.7 mL of water was added and stirred, followed by 1.7 mL of a 15% aqueous NaOH solution and 5.1 mL of water. The mixture was brought to room temperature and stirred for 0.5 h. Anhydrous sodium sulfate was added and stirred for 3 h. The mixture was filtered with celite, and the solid on the wall of the flask was washed with EA. The filtrates were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 4.5 g of the crude product. 45 mL of a 1:9 mixture of DCM:n-hexane was added to the mixture, and the mixture was slurried. The mixture was filtered with suction to obtain 3.6 g of Intermediate 3-5.

[0244] ESI-MS: m / z = 289.1 [M + Na] + .

[0245] Preparation of intermediate 3-6

[0246] 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, followed by dimethyl sulfide (300 μL) and allowed to react at -30°C for 2 h. After the reaction, DCM and water were added for extraction. The phases were separated, and the DCM phase was dried and concentrated to yield 1.2 g of crude product. Column chromatography (PE:EA) afforded 0.56 g of intermediate 3-6.

[0247] Preparation of intermediate 3-7

[0248] 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 sequentially. The mixture was allowed to react at room temperature overnight. After completion of the reaction, ethyl acetate and water were added for extraction. The organic phase was separated, and the organic phase was washed with saturated sodium chloride. The organic phase was separated, dried, and concentrated to obtain 7 g of crude product. 5 g of silica gel was added for column chromatography (PE:EA) to obtain 4.77 g of intermediate 3-7.

[0249] ESI-MS: m / z = 483.2 [M+H] + .

[0250] Preparation of intermediate 3-8

[0251] Dissolve oxalyl chloride (4.37 mL) in dichloromethane (43.2 mL), replace nitrogen, and cool to -78°C. Add a dichloromethane solution of DMSO (5.47 mL). After stirring for 15 minutes, add a dichloromethane solution of intermediate 3-7 (2.4 g). After stirring for 30 minutes, add triethylamine (21.4 mL), and after 10 minutes, move to room temperature and stir. After 2.5 hours, add saturated sodium bicarbonate to adjust the pH to neutral, and extract three times with dichloromethane. The organic phase obtained by extraction is concentrated and column chromatography (PE / EA) is obtained to obtain intermediate 3-8 (200 mg).

[0252] Preparation of intermediate 3-9

[0253] Intermediate 3-8 (250 mg) and tert-butyl piperazine-1-carboxylate (145.36 mg) were dissolved in anhydrous dichloromethane (10 mL), triethylamine (722.9 uL) was added, nitrogen was replaced, and the mixture was stirred at room temperature. After half an hour, sodium triacetoxyborohydride (772 mg) was added and stirred at room temperature for 16 hours. 50 mL of water was added to quench the mixture. 50 mL of dichloromethane was added for extraction. The organic phase obtained by the extraction was concentrated by column chromatography (PE / EA) to obtain intermediate 3-9 (200 mg).

[0254] Preparation of intermediate 3-10

[0255] Intermediate 3-9 (200 mg) was dissolved in a 5 / 1 / 1 methanol / tetrahydrofuran / water system (28 mL). Lithium hydroxide monohydrate (387 mg) was added and stirred at room temperature for 16 hours. 1N hydrochloric acid was added to the system to adjust the pH to neutral. Water and ethyl acetate were added for extraction. The organic phase was dried and concentrated to afford Intermediate 3-10 (192 mg).

[0256] Preparation of intermediate 3-11

[0257] 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). EDCI (148 mg) and DMAP (94 mg) were added, and the mixture was 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 column chromatography (DCM / MeOH) was performed to obtain Intermediate 3-11 (332 mg).

[0258] Preparation of intermediate 3-12

[0259] Intermediate 3-11 (332 mg) was dissolved in dichloromethane (3 mL), and a solution of hydrochloric acid in dioxane (0.287 mL) was added, and the mixture was stirred at room temperature for 1 hour. The system was directly concentrated to obtain the crude product Intermediate 3-12 (300 mg).

[0260] Preparation of intermediate 3-13

[0261] 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 solution, extracted with dichloromethane, and back-extracted once with aqueous solution. The organic phases were combined, washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 3.8 g of intermediate 3-13.

[0262] ESI-MS: m / z = 543.1 [M+H] + .

[0263] Preparation of intermediate 3-14

[0264] 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. Potassium carbonate (1.3 g) and Pd(dppf)Cl2 (0.14 g) were added. After nitrogen displacement, the reaction was carried out at 105°C for 5 h. The mixture was cooled, filtered through celite, concentrated to dryness, and extracted with water and DCM. The organic phase was separated, washed with saturated sodium chloride, separated, dried, and concentrated. The crude product was purified by column chromatography (DCM:MeOH) to yield 1.0 g of intermediate 3-14.

[0265] ESI-MS: m / z = 558.2 [M+H] + .

[0266] Preparation of intermediate 3-15

[0267] 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 overnight at room temperature. The reaction was monitored by TLC and concentrated at 45°C to obtain the crude intermediate 3-15, which was directly used in the next step.

[0268] ESI-MS: m / z = 458.3 [M+H] + .

[0269] Preparation of intermediate 3-16

[0270] Intermediate 3-15 (720 mg) was dissolved in dichloromethane, and monomethyl suberate (740 mg) was added, along with triethylamine (2.0 ml) and HATU (930 mg). The mixture was allowed to react at room temperature overnight. The reaction was monitored by TLC. The reaction solution was extracted with water and dichloromethane, separated, and the organic phase was washed with saturated sodium chloride, separated, dried, and concentrated. The crude product was isolated by silica gel column chromatography (DCM:MeOH) to afford 520 mg of Intermediate 3-16.

[0271] ESI-MS: m / z = 628.3 [M+H] + .

[0272] Preparation of intermediate 3-17

[0273] Intermediate 3-16 (0.52 g) was dissolved in methanol, and a 2N aqueous lithium hydroxide solution (2.54 mL) was added. The mixture was 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 obtain 0.45 g of intermediate 3-17.

[0274] ESI-MS: m / z = 614.3 [M+H] + .

[0275] Preparation of compound 3

[0276] Intermediate 3-12 (121 mg) was dissolved in DMF, and intermediate 3-17 (70 mg), DIPEA (148 mg), and HATU (65 mg) were added. The mixture was reacted at room temperature for 3 h. The crude reaction solution was purified by preparative liquid phase to obtain the target compound 3 (46 mg).

[0277] ESI-MS: m / z = 828.1 [M + 2H] 2+ .

[0278] Example 4: Preparation of Compound 4

[0279] Intermediate 3-12 (106 mg) was dissolved in dichloromethane, and Intermediate 1-4 (70 mg) was added, along with triethylamine (140 μL) and HATU (57 mg). The mixture was allowed to react at room temperature for 1.5 h. The mixture was diluted with DCM and extracted with saturated ammonium chloride. The organic phase was washed with water, separated, and the aqueous phase was back-extracted with DCM. The organic phases were combined, washed with saturated sodium chloride, separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 64 mg of the crude liquid phase of target compound 4.

[0280] LCMS (ESI) m / z: 812.5 [M+2H] 2+ .

[0281] Example 5: Preparation of Compound 5

[0282] Intermediate 3-12 (100 mg) was dissolved in dichloromethane, and Intermediate 2-6 (68 mg) was added, along with triethylamine (125 μL) and HATU (53 mg). The mixture was allowed to react at room temperature for 1.5 h. The mixture was diluted with DCM and extracted with saturated ammonium chloride. The organic phase was washed with water, separated, and the aqueous phase was back-extracted with DCM. The organic phases were combined, washed with saturated sodium chloride, separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 21 mg of the crude liquid phase of target compound 5.

[0283] ESI-MS: m / z = 820.2 [M + 2H] 2+

[0284] Example 6: Preparation of Compound 6

[0285] Preparation of intermediate 4-2

[0286] Intermediate 4-1 (1.4 g) and 1-ethylpyrazole-5-boronic acid pinacol ester (2.16 g) were dissolved in 1,4-dioxane / water = 4 / 1 (50 ml). Potassium carbonate (2.76 g) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (730 mg) were added. The atmosphere was replaced with nitrogen, and the temperature was raised to 90°C and stirred for three hours. After three hours, heating was stopped and the reaction solution was concentrated to dryness. Column chromatography (dichloromethane / methanol) afforded the product, Intermediate 4-2 (1.52 g).

[0287] LC-MS: m / z[M+H] + :232.1

[0288] Preparation of intermediate 4-3

[0289] 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 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 system. Stirring was continued 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 column chromatography (dichloromethane / methanol) was performed to obtain the product, Intermediate 4-3 (2 g).

[0290] LC-MS: m / z[M+H] + :544.3

[0291] Preparation of intermediate 4-4

[0292] Intermediate 4-3 (2 g) was dissolved in trifluoroacetic acid / dichloromethane = 1 / 3 system (20 mL) and stirred at room temperature for 30 minutes. Then, 7 M ammonia methanol solution was added to adjust the pH to 7. The system was concentrated to dryness and column chromatography (dichloromethane / methanol) was performed to obtain the product intermediate 4-4 (2 g).

[0293] LC-MS: m / z[M+H] + :444.47

[0294] Preparation of intermediate 4-5

[0295] Intermediate 4-4 (100 mg) and monomethyl suberate (44.5 μL) were dissolved in dichloromethane (5 ml). Triethylamine (62.5 μL) was added and stirred at room temperature for half an hour. HATU (94 mg) was added and stirred at room temperature for 16 hours. The reaction solution was then concentrated to dryness. Column chromatography (dichloromethane / methanol) afforded the product, Intermediate 4-5 (85 mg).

[0296] LC-MS: m / z[M+H] + :614.3

[0297] Preparation of intermediate 4-6

[0298] Intermediate 4-5 (85 mg) was dissolved in methanol (1.5 ml), 2N lithium hydroxide solution (208 uL) 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).

[0299] LC-MS: m / z[M+H] + :600.3

[0300] Preparation of compound 6

[0301] Intermediate 4-6 (28 mg) and Intermediate 3-12 (50 mg) were dissolved in dichloromethane (1 mL), triethylamine (66 uL) was added, and the mixture was stirred for half an hour. HATU (27 mg) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated to yield the target compound 6 (51 mg, 98.85% purity).

[0302] ESI-MS: m / z = 821.16 [M+2H] 2+ .

[0303] Example 7: Preparation of Compound 7

[0304] 1) Preparation of Intermediate 7-1

[0305] 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 allowed to react at room temperature overnight. Water was added, the layers separated, and the organic phase was purified by silica gel column chromatography (DCM:MeOH) to yield 2.8 g of intermediate 7-1. ESI-MS: m / z = 550.2 [M+Na] +

[0306] 2) Preparation of Intermediate 7-2

[0307] 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. Potassium carbonate (262 mg) and Pd(dppf)Cl2 (35 mg) were added. After nitrogen substitution, the mixture was reacted at 90°C for 3 h. 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]+

[0308] 3) Preparation of Intermediate 7-3

[0309] Intermediate 7-2 (512 mg) was dissolved in hydrochloric acid / dioxane (4 M) and stirred at room temperature for 3 h. The mixture was concentrated at 38°C to obtain intermediate 7-3. ESI-MS: m / z = 430.4 [M+H] +

[0310] 4) Preparation of Intermediate 7-4

[0311] Intermediate 7-3 (100 mg) was dissolved in dichloromethane, and monomethyl pimelate (49 mg) was added, along with DIPEA (104 mg) and EDCI (67 mg). The mixture was allowed to react overnight at room temperature. After completion of the reaction, the mixture was concentrated and separated by silica gel column chromatography (DCM:MeOH) to afford 135 mg of intermediate 7-4. ESI-MS: m / z = 586.3 [M+H] +

[0312] 5) Preparation of Intermediate 7-5

[0313] Intermediate 7-4 (135 mg) was dissolved in methanol, and a 2N aqueous lithium hydroxide solution (0.5 mL) was added. The mixture was stirred at room temperature overnight. The pH of the reaction solution was adjusted to 5-6 with 2N hydrochloric acid, and DCM was added for extraction. The mixture was separated, dried, and concentrated to obtain 64 mg of intermediate 7-5. ESI-MS: m / z = 572.3 [M+H] +

[0314] 6) Preparation of Compound 7

[0315] 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 h, and concentrated under reduced pressure to obtain compound 7 (3 mg) after purification.

[0316] ESI-MS: m / z = 763.7 [M+2H] 2+

[0317] 1H NMR(500MHz, CDCl3)δ8.36(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).

[0318] Example 8: Preparation of Compound 8

[0319] 1) Preparation of Intermediate 8-1

[0320] 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] +

[0321] 2) Preparation of Intermediate 8-2

[0322] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 8-1 to obtain intermediate 8-2 (70 mg). ESI-MS: m / z=586.3 [M+H] +

[0323] 3) Preparation of Compound 8

[0324] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 8-2 to obtain compound 8 (2 mg). ESI-MS: m / z=770.7 [M+2H] 2+

[0325] 1H NMR(500MHz, CDCl3)δ8.35(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).

[0326] Example 9: Preparation of Compound 9

[0327] 1) Preparation of Intermediate 9-1

[0328] Intermediate 7-1 (500 mg) and 4-methyl-5-thiazole borate (214 mg) were dissolved in 10 mL of dioxane and 2 mL of water. Potassium carbonate (262 mg) and Pd(dppf)Cl2 (35 mg) were added. After nitrogen substitution, the mixture was reacted at 90°C for 3 h. The mixture was cooled, dried, and concentrated. Purification by silica gel column chromatography (DCM:MeOH) afforded 500 mg of intermediate 9-1. ESI-MS: m / z = 569.2 [M+Na] +

[0329] 2) Preparation of Intermediate 9-2

[0330] Intermediate 9-1 (500 mg) was dissolved in hydrochloric acid / dioxane (4 M) and stirred at room temperature for 3 h. The mixture was concentrated at 38°C to obtain intermediate 9-2. ESI-MS: m / z = 447.3 [M+H] +

[0331] 3) Preparation of Intermediate 9-3

[0332] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 9-2 to obtain intermediate 9-3 (139 mg). ESI-MS: m / z=603.3 [M+H] +

[0333] 4) Preparation of Intermediate 9-4

[0334] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 9-3 to obtain intermediate 9-4 (50 mg). ESI-MS: m / z=589.3 [M+H] +

[0335] 5) Preparation of Compound 9

[0336] With reference to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 9-4 to obtain compound 9 (3 mg).

[0337] ESI-MS: m / z = 772.3 [M + 2H] 2+

[0338] 1 H NMR(500MHz, CDCl3)δ8.35(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).

[0339] Example 10: Preparation of Compound 10

[0340] 1) Preparation of Intermediate 10-1

[0341] Referring to step 2 of Example 7, 1-methyl-1H-pyrazole-5-boronic acid pinacol ester was replaced with 4-methyl-5-thiazole borate to obtain intermediate 10-1 (1 g). ESI-MS: m / z=545.3 [M+H] +

[0342] 2) Preparation of Intermediate 10-2

[0343] 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] +

[0344] 3) Preparation of Intermediate 10-3

[0345] 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 obtain intermediate 10-3 (141 mg). ESI-MS: m / z=615.3 [M+H] +

[0346] 4) Preparation of Intermediate 10-4

[0347] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 10-3 to obtain intermediate 10-4 (80 mg). ESI-MS: m / z=601.3 [M+H] +

[0348] 5) Preparation of Compound 4

[0349] With reference to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 10-4 to obtain compound 10 (20 mg).

[0350] ESI-MS: m / z = 778.3 [M + 2H] 2+

[0351] 1 H NMR(500MHz, CDCl3)δ8.67(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,1 H),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).

[0352] Example 11: Preparation of Compound 11

[0353] 1) Preparation of Intermediate 11-1

[0354] 11-A (600 mg) and (S)-(-)-1-(4-bromophenyl)ethylamine (400 mg) were dissolved in dichloromethane, and EDCI (697 mg) and HOBT (491 mg) were added. The mixture was allowed to react at room temperature overnight. Water was added, and the organic phase was separated and purified by column chromatography (DCM:MeOH) to obtain 750 mg of intermediate 11-1. ESI-MS: m / z = 534.2 [M+Na] +

[0355] 2) Preparation of Intermediate 11-2

[0356] 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] +

[0357] 3) Preparation of Intermediate 11-3

[0358] Referring to step 3 of Example 7, intermediate 7-2 was replaced with intermediate 11-2 to obtain intermediate 11-3 (0.4 g). ESI-MS: m / z = 414.2 [M+H] +

[0359] 4) Preparation of Intermediate 11-4

[0360] 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 obtain intermediate 11-4 (120 mg). ESI-MS: m / z=584.3 [M+H] +

[0361] 5) Preparation of Intermediate 11-5

[0362] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 11-4 to obtain intermediate 11-5 (80 mg). ESI-MS: m / z=570.3 [M+H] +

[0363] 6) Preparation of Compound 11

[0364] With reference to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 11-5 to obtain compound 11 (5 mg).

[0365] ESI-MS: m / z = 762.7 [M + 2H] 2+

[0366] 1H NMR(500MHz, CDCl3)δ8.35(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).

[0367] Example 12: Preparation of Compound 12

[0368] 1) Preparation of Intermediate 12-1

[0369] Referring to step 4 of Example 7, monomethyl pimelate was replaced with monomethyl suberate to obtain intermediate 12-1 (114 mg). ESI-MS: m / z=600.3 [M+H] +

[0370] 2) Preparation of Intermediate 12-2

[0371] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 12-1 to obtain intermediate 12-2 (70 mg). ESI-MS: m / z=586.3 [M+H] +

[0372] 3) Preparation of Compound 12

[0373] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 12-2 to obtain compound 12 (6 mg). ESI-MS: m / z=770.7 [M+2H] 2+

[0374] 1H NMR(500MHz, CDCl3)δ8.36(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).

[0375] Example 13: Preparation of Compound 13

[0376] 1) Preparation of Compound 13

[0377] With reference to step 5 of Example 7, intermediate 7-5 was replaced with intermediate 4-6 to obtain compound 13 (27 mg).

[0378] ESI-MS: m / z = 777.7 [M + 2H] 2+

[0379] 1 H NMR(500MHz, CDCl3)δ8.35(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).

[0380] Example 14: Preparation of Compound 14

[0381] 1) Preparation of Intermediate 14-1

[0382] Referring to step 2 of Example 7, 1-methyl-1H-pyrazole-5-boronic acid pinacol ester was replaced with 4-methyl-5-thiazole borate to obtain intermediate 14-1 (200 mg). ESI-MS: m / z=553.3 [M+Na] +

[0383] 2) Preparation of Intermediate 14-2

[0384] Referring to step 3 of Example 7, intermediate 7-2 was replaced with intermediate 14-1 to obtain intermediate 14-2 (162 mg). ESI-MS: m / z=431.3 [M+H] +

[0385] 3) Preparation of Intermediate 14-3

[0386] 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 obtain intermediate 14-3 (141 mg). ESI-MS: m / z=601.3 [M+H] +

[0387] 4) Preparation of Intermediate 14-4

[0388] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 14-3 to obtain intermediate 14-4 (75 mg). ESI-MS: m / z=587.3 [M+H] +

[0389] 5) Preparation of Compound 14

[0390] With reference to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 14-4 to obtain compound 14 (4 mg).

[0391] ESI-MS: m / z = 771.3 [M + 2H] 2+

[0392] 1H NMR(500MHz, CDCl3)δ8.36(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,1H),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).

[0393] Example 15: Preparation of Compound 15

[0394] 1) Preparation of Intermediate 15-1

[0395] 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 obtain intermediate 15-1 (73 mg). ESI-MS: m / z=617.15 [M+H] +

[0396] 2) Preparation of Intermediate 15-2

[0397] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 15-1 to obtain intermediate 15-2 (60 mg). ESI-MS: m / z=603.17 [M+H] +

[0398] 3) Preparation of Compound 15

[0399] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 15-2 to obtain compound 15 (6 mg). ESI-MS: m / z=779.3 [M+2H] 2+

[0400] 1H NMR(500MHz,DMSO-d6+D2O)δ8.95(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,1H),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).

[0401] Example 16: Preparation of Compound 16

[0402] 1) Preparation of Intermediate 16-1

[0403] Referring to step 2 of Example 7, intermediate 7-1 was replaced with intermediate 3-13 to obtain intermediate 16-1 (1 g). ESI-MS: m / z=544.3 [M+H] +

[0404] 2) Preparation of Intermediate 16-2

[0405] Referring to step 3 of Example 7, intermediate 7-2 was replaced with intermediate 16-1 to obtain intermediate 16-2 (200 mg). ESI-MS: m / z=444.2 [M+H] +

[0406] 3) Preparation of Intermediate 16-3

[0407] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 16-2, and monomethyl pimelate was replaced with monomethyl azelaic acid to obtain intermediate 16-3 (283 mg). ESI-MS: m / z=628.3 [M+H] +

[0408] 4) Preparation of Intermediate 16-4

[0409] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 16-3 to obtain intermediate 16-4 (270 mg).

[0410] ESI-MS: m / z = 614.3 [M+H] +

[0411] 5) Preparation of Compound 16

[0412] With reference to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 16-4 to obtain compound 16 (30 mg).

[0413] ESI-MS: m / z = 784.7 [M + 2H] 2+

[0414] 1 H NMR(500MHz,DMSO)δ8.37(s,1H),8.13(s,2H),7.96(s,1H),7.76(m,3H),7 .51–6.82(m,16H),6.37(s,1H),5.11(s,1H),4.90(s,1H),4.75(s,1H),4.5 5–4.46(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).

[0415] Example 17: Preparation of Compound 17

[0416] 1) Preparation of Intermediate 17-1

[0417] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 3-15, and monomethyl pimelate was replaced with monomethyl azelaic acid to obtain intermediate 17-1 (280 mg). ESI-MS: m / z=642.3 [M+H] +

[0418] 2) Preparation of Intermediate 17-2

[0419] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 17-1 to obtain intermediate 17-2 (270 mg). ESI-MS: m / z=628.3 [M+H] +

[0420] 3) Preparation of Compound 17

[0421] With reference to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 17-2 to obtain compound 17 (13 mg).

[0422] ESI-MS: m / z = 792.46 [M+2H] 2+

[0423] 1H NMR(500MHz,DMSO)δ8.40(s,1H),8.14(s,2H),7.93(s,1H),7.75(m,3H),7 .50–6.80(m,16H),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)

[0424] Example 18: Preparation of Compound 18

[0425] 1) Preparation of Intermediate 18-1

[0426] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 10-2, and monomethyl pimelate was replaced with monomethyl azelaic acid to obtain intermediate 18-1 (141 mg). ESI-MS: m / z=629.3 [M+H] +

[0427] 2) Preparation of Intermediate 18-2

[0428] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 18-1 to obtain intermediate 18-2 (80 mg). ESI-MS: m / z=615.3 [M+H] +

[0429] 3) Preparation of Compound 18

[0430] With reference to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 18-2 to obtain compound 18 (5 mg).

[0431] ESI-MS: m / z = 785.6 [M + 2H] 2+

[0432] 1H NMR(500MHz, CDCl3)δ8.66(s,1H),8.34(d,1H),8.09(dd,1H),7.71(d,2H),7.46–7.24(m,12H),7.09(t,1 H),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).

[0433] Example 19: Preparation of Compound 19

[0434] 1) Preparation of Intermediate 19-1

[0435] 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 obtain intermediate 19-1 (1.2 g). ESI-MS: m / z=561.2 [M+H] +

[0436] 2) Preparation of Intermediate 19-2

[0437] 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] +

[0438] 3) Preparation of Intermediate 19-3

[0439] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 19-2, and monomethyl pimelate was replaced with monomethyl azelaic acid to obtain intermediate 19-3 (370 mg). ESI-MS: m / z=645.3 [M+H] +

[0440] 4) Preparation of Intermediate 19-4

[0441] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 19-3 to obtain intermediate 19-4 (210 mg). ESI-MS: m / z=631.3 [M+H] +

[0442] 5) Preparation of Compound 19

[0443] With reference to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 19-4 to obtain compound 19 (38 mg).

[0444] ESI-MS: m / z = 793.2 [M + 2H] 2+

[0445] 1 H NMR(500MHz,DMSO-d6+D2O)δ8.96(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),4.54–4.44(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)

[0446] Example 20: Preparation of Compound 20

[0447] 1) Preparation of Intermediate 20-1

[0448] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 11-3, and monomethyl pimelate was replaced with monomethyl azelaic acid to obtain intermediate 20-1 (0.3 g). ESI-MS: m / z=598.3 [M+H] +

[0449] 2) Preparation of Intermediate 20-2

[0450] 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] +

[0451] 3) Preparation of Compound 20

[0452] With reference to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 20-2 to obtain compound 20 (15 mg).

[0453] ESI-MS: m / z = 771.0 [M+2H] 2+

[0454] 1 H NMR(500MHz,DMSO)δ8.37(s,1H),8.12(s,2H),7.95(s,1H),7.77(m,3H),7 .52–6.81(m,16H),6.35(s,1H),5.10(s,1H),4.89(s,1H),4.72(s,1H),4.5 3–4.45(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).

[0455] Example 21: Preparation of Compound 21

[0456] 1) Preparation of Intermediate 21-1

[0457] Referring to step 4 of Example 7, monomethyl pimelate was replaced with monomethyl azelaic acid to obtain intermediate 21-1 (380 mg). ESI-MS: m / z=614.3 [M+H] +

[0458] 2) Preparation of Intermediate 21-2

[0459] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 21-1 to obtain intermediate 21-2 (200 mg). ESI-MS: m / z=600.2 [M+H] +

[0460] 3) Preparation of Compound 21

[0461] With reference to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 21-2 to obtain compound 21 (5 mg).

[0462] ESI-MS: m / z = 777.7 [M + 2H] 2+

[0463] 1H NMR(500MHz,DMSO)δ8.39(s,1H),8.13(s,2H),7.95(s,1H),7.77(m,3H),7 .50–6.81(m,16H),6.36(s,1H),5.09(s,1H),4.92(s,1H),4.74(s,1H),4.5 7–4.43(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).

[0464] Example 22: Preparation of Compound 22

[0465] 1) Preparation of Intermediate 22-1

[0466] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 4-4, and monomethyl pimelate was replaced with monomethyl azelaic acid to obtain intermediate 22-1 (280 mg). ESI-MS: m / z=628.29 [M+H] +

[0467] 2) Preparation of Intermediate 22-2

[0468] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 22-1 to obtain intermediate 22-2 (153 mg). ESI-MS: m / z=614.3 [M+H] +

[0469] 3) Preparation of Compound 22

[0470] With reference to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 22-2 to obtain compound 22 (6 mg).

[0471] ESI-MS: m / z = 784.7 [M + 2H] 2+

[0472] 1H NMR(500MHz,DMSO)δ8.40(s,1H),8.15(s,2H),7.94(s,1H),7.76(m,3H),7 .60–6.75(m,16H),6.38(s,1H),5.10(s,1H),4.90(s,1H),4.75(s,1H),4.5 8–4.40(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).

[0473] Example 23: Preparation of Compound 23

[0474] 1) Preparation of Intermediate 23-1

[0475] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 14-2, and monomethyl pimelate was replaced with monomethyl azelaic acid to obtain intermediate 23-1 (231 mg). ESI-MS: m / z=615.2 [M+H] +

[0476] 2) Preparation of Intermediate 23-2

[0477] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 23-1 to obtain intermediate 23-2 (180 mg). ESI-MS: m / z=601.2 [M+H] +

[0478] 3) Preparation of Compound 23

[0479] With reference to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 23-2 to obtain compound 23 (6 mg).

[0480] ESI-MS: m / z = 778.3 [M + 2H] 2+

[0481] 1H NMR(500MHz,DMSO-d6+D2O)δ8.90(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,3 H),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).

[0482] Example 24: Preparation of Compound 24

[0483] 1) Preparation of Intermediate 24-1

[0484] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 9-2, and monomethyl pimelate was replaced with monomethyl azelaic acid to obtain intermediate 24-1 (65 mg). ESI-MS: m / z=631.3 [M+H] +

[0485] 2) Preparation of Intermediate 24-2

[0486] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 24-1 to obtain intermediate 24-2 (55 mg). ESI-MS: m / z=617.2 [M+H] +

[0487] 3) Preparation of Compound 24

[0488] With reference to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 24-2 to obtain compound 24 (4 mg).

[0489] ESI-MS: m / z = 786.3 [M + 2H] 2+

[0490] 1H NMR(500MHz,DMSO-d6+D2O)δ8.96(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,1H),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).

[0491] Example 25: Preparation of Compound 25

[0492] 1) Preparation of Intermediate 25-1

[0493] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 14-2 to obtain intermediate 25-1 (120 mg). ESI-MS: m / z=587.3 [M+H] +

[0494] 2) Preparation of Intermediate 25-2

[0495] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 25-1 to obtain intermediate 25-2 (100 mg). ESI-MS: m / z=573.3 [M+H] +

[0496] 3) Preparation of Compound 25

[0497] With reference to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 25-2 to obtain compound 25 (15 mg).

[0498] ESI-MS: m / z = 764.3 [M + 2H] 2+

[0499] 1H NMR(500MHz,DMSO)δ12.18(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).

[0500] Example 26: Preparation of Compound 26

[0501] 1) Preparation of Intermediate 26-1

[0502] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 19-2 to obtain intermediate 26-1 (150 mg). ESI-MS: m / z=617.3 [M+H] +

[0503] 2) Preparation of Intermediate 26-2

[0504] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 26-1 to obtain intermediate 26-2 (86 mg). ESI-MS: m / z=603.3 [M+H] +

[0505] 3) Preparation of Compound 26

[0506] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 26-2 to obtain compound 26 (12 mg). ESI-MS: m / z=779.2 [M+2H] 2+

[0507] Example 27: Preparation of Compound 27

[0508] 1) Preparation of Intermediate 27-1

[0509] 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] +

[0510] 2) Preparation of Intermediate 27-2

[0511] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 27-1 to obtain intermediate 27-2 (334 mg). ESI-MS: m / z=584.3 [M+H] +

[0512] 3) Preparation of Compound 27

[0513] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 27-2 to obtain compound 27 (50 mg). ESI-MS: m / z=769.7 [M+2H] 2+

[0514] 1 H NMR(500MHz, CDCl3)δ8.34(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),6.99(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).

[0515] Example 28: Preparation of Compound 28

[0516] 1) Preparation of Intermediate 28-1

[0517] 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]+

[0518] 2) Preparation of Intermediate 28-2

[0519] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 28-1 to obtain intermediate 28-2 (260 mg). ESI-MS: m / z=570.3 [M+H] +

[0520] 3) Preparation of Compound 28

[0521] With reference to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 28-2 to obtain compound 28 (20 mg).

[0522] ESI-MS: m / z = 762.8 [M + 2H] 2+

[0523] 1 H NMR(500MHz, CDCl3)δ8.34(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,1 H),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).

[0524] Example 29: Preparation of Compound 29

[0525] 1) Preparation of Intermediate 29-1

[0526] 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 obtain intermediate 29-1 (113 mg). ESI-MS: m / z=628.3 [M+H] +

[0527] 2) Preparation of Intermediate 29-2

[0528] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 29-1 to obtain intermediate 29-2 (69 mg). ESI-MS: m / z=614.3 [M+H] +

[0529] 3) Preparation of Compound 29

[0530] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 29-2 to obtain compound 29 (13 mg). ESI-MS: m / z=784.8 [M+2H] 2+

[0531] 1 H NMR(500MHz,DMSO)δ8.40(s,1H),8.14(s,2H),7.93(s,1H),7.75(m,3H),7 .50–6.80(m,16H),6.35(s,1H),5.12(s,1H),4.94(s,1H),4.73(s,1H),4.5 5–4.45(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).

[0532] Example 30: Preparation of Compound 30

[0533] 1) Preparation of Intermediate 30-1

[0534] 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 obtain intermediate 30-1 (100 mg). ESI-MS: m / z=631.3 [M+H] +

[0535] 2) Preparation of Intermediate 30-2

[0536] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 30-1 to obtain intermediate 30-2 (50 mg). ESI-MS: m / z=617.3 [M+H] +

[0537] 3) Preparation of Compound 30

[0538] With reference to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 30-2 to obtain compound 30 (4 mg).

[0539] ESI-MS: m / z = 786.3 [M + 2H] 2+

[0540] 1 H NMR(500MHz,DMSO)δ8.98(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).

[0541] Example 31: Preparation of Compound 31

[0542] 1) Preparation of Intermediate 31-1

[0543] 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 obtain intermediate 31-1 (117 mg). ESI-MS: m / z=614.3 [M+H] +

[0544] 2) Preparation of Intermediate 31-2

[0545] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 31-1 to obtain intermediate 31-2 (50 mg). ESI-MS: m / z=600.3 [M+H] +

[0546] 3) Preparation of Compound 31

[0547] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 31-2 to obtain compound 31 (6 mg). ESI-MS: m / z=777.7 [M+2H] 2+

[0548] 1 H NMR(500MHz, CDCl3)δ8.35(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,1 H),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),2.51–2.39(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).

[0549] Example 32: Preparation of Compound 32

[0550] 1) Preparation of Intermediate 32-1

[0551] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 1-2, and monomethyl pimelate was replaced with monomethyl azelaic acid to obtain intermediate 32-1 (117 mg). ESI-MS: m / z=614.3 [M+H] +

[0552] 2) Preparation of Intermediate 32-2

[0553] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 32-1 to obtain intermediate 32-2 (50 mg). ESI-MS: m / z=600.3 [M+H] +

[0554] 3) Preparation of Compound 32

[0555] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 32-2 to obtain compound 32 (20 mg). ESI-MS: m / z=776.8 [M+2H]2+

[0556] 1 H NMR(500MHz, CDCl3)δ8.35(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,1 H),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) ,2.61(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).

[0557] Example 33: Preparation of Compound 33

[0558] 1) Preparation of Intermediate 33-1

[0559] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 2-4, and monomethyl pimelate was replaced with monomethyl azelaic acid to obtain intermediate 33-1 (150 mg). ESI-MS: m / z=626.3 [M+H] +

[0560] 2) Preparation of Intermediate 33-2

[0561] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 33-1 to obtain intermediate 33-2 (105 mg). ESI-MS: m / z=612.3 [M+H] +

[0562] 3) Preparation of Compound 33

[0563] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 33-2 to obtain compound 33 (30 mg). ESI-MS: m / z=783.8 [M+2H] 2+

[0564] 1H NMR(500MHz,DMSO)δ8.41(s,1H),8.15(s,2H),7.92(s,1H),7.74(m,3H),7 .50–6.81(m,16H),6.34(s,1H),5.12(s,1H),4.95(s,1H),4.73(s,1H),4.5 5–4.45(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).

[0565] Example 34: Preparation of Compound 34

[0566] 1) Preparation of Intermediate 34-1

[0567] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 3-15 to obtain intermediate 34-1 (93 mg). ESI-MS: m / z=614.3 [M+H] +

[0568] 2) Preparation of Intermediate 34-2

[0569] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 34-1 to obtain intermediate 34-2 (45 mg). ESI-MS: m / z=600.3 [M+H] +

[0570] 3) Preparation of Compound 34

[0571] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 34-2 to obtain compound 34 (5 mg). ESI-MS: m / z=777.8 [M+2H] 2+

[0572] 1H NMR(500MHz,DMSO)δ8.41(s,1H),8.14(s,2H),7.94(s,1H),7.75(m,3H),7 .52–6.80(m,16H),6.34(s,1H),5.12(s,1H),4.94(s,1H),4.73(s,1H),4.5 4–4.44(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).

[0573] Example 35: Preparation of Compound 35

[0574] 1) Preparation of Intermediate 35-1

[0575] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 16-2 to obtain intermediate 35-1 (120 mg). ESI-MS: m / z=600.3 [M+H] +

[0576] 2) Preparation of Intermediate 35-2

[0577] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 35-1 to obtain intermediate 35-2 (80 mg). ESI-MS: m / z=586.3 [M+H] +

[0578] 3) Preparation of Compound 35

[0579] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 35-2 to obtain compound 35 (15 mg). ESI-MS: m / z=770.7 [M+2H] 2+

[0580] 1H NMR(500MHz, CDCl3)δ8.34(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),4.62(d,1 H),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).

[0581] Example 36: Preparation of Compound 36

[0582] 1) Preparation of Intermediate 36-1

[0583] 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 obtain intermediate 36-1 (110 mg). ESI-MS: m / z=570.3 [M+H] +

[0584] 2) Preparation of Intermediate 36-2

[0585] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 36-1 to obtain intermediate 36-2 (100 mg). ESI-MS: m / z=556.3 [M+H] +

[0586] 3) Preparation of Compound 36

[0587] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 36-2 to obtain compound 36 (25 mg). ESI-MS: m / z=755.8 [M+2H] 2+

[0588] 1H NMR(500MHz, CDCl3)δ8.35(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(d d,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),3.0 9–2.97(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).

[0589] Example 37: Preparation of Compound 37

[0590] 1) Preparation of Intermediate 37-1

[0591] 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 obtain intermediate 37-1 (160 mg). ESI-MS: m / z=556.2 [M+H] +

[0592] 2) Preparation of Intermediate 37-2

[0593] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 37-1 to obtain intermediate 37-2 (120 mg). ESI-MS: m / z=542.3 [M+H] +

[0594] 3) Preparation of Compound 37

[0595] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 37-2 to obtain compound 37 (20 mg). ESI-MS: m / z=748.7 [M+2H] 2+

[0596] 1H NMR(500MHz,DMSO)δ8.37(s,1H),8.12(s,2H),7.95(s,1H),7.77(m,3H),7 .52–6.81(m,16H),6.35(s,1H),5.10(s,1H),4.89(s,1H),4.72(s,1H),4.5 3–4.45(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).

[0597] Example 38: Preparation of Compound 38

[0598] 1) Preparation of Intermediate 38-1

[0599] 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 obtain intermediate 38-1 (100 mg). ESI-MS: m / z=584.3 [M+H] +

[0600] 2) Preparation of Intermediate 38-2

[0601] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 38-1 to obtain intermediate 38-2 (80 mg). ESI-MS: m / z=570.3 [M+H] +

[0602] 3) Preparation of Compound 38

[0603] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 38-2 to obtain compound 38 (20 mg). ESI-MS: m / z=762.7 [M+2H] 2+

[0604] 1H NMR(500MHz,DMSO)δ8.40(s,1H),8.14(s,2H),7.92(s,1H),7.75(m,3H),7 .51–6.82(m,16H),6.34(s,1H),5.12(s,1H),4.94(s,1H),4.74(s,1H),4.5 4–4.45(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).

[0605] Example 39: Preparation of Compound 39

[0606] 1) Preparation of Intermediate 39-1

[0607] 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 obtain intermediate 39-1 (80 mg). ESI-MS: m / z=600.3 [M+H] +

[0608] 2) Preparation of Intermediate 39-2

[0609] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 39-1 to obtain intermediate 39-2 (40 mg). ESI-MS: m / z=586.3 [M+H] +

[0610] 3) Preparation of Compound 39

[0611] With reference to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 39-2 to obtain compound 39 (3 mg).

[0612] ESI-MS: m / z = 770.8 [M + 2H] 2+

[0613] 1H NMR(500MHz,DMSO)δ8.36(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,7 H),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).

[0614] Example 40: Preparation of Compound 40

[0615] 1) Preparation of Intermediate 40-1

[0616] 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 obtain intermediate 40-1 (135 mg). ESI-MS: m / z=587.3 [M+H] +

[0617] 2) Preparation of Intermediate 40-2

[0618] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 40-1 to obtain intermediate 40-2 (75 mg). ESI-MS: m / z=573.3 [M+H] +

[0619] 3) Preparation of Compound 40

[0620] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 40-2 to obtain compound 40 (20 mg). ESI-MS: m / z=764.3 [M+2H] 2+

[0621] Example 41: Preparation of Compound 41

[0622] 1) Preparation of Intermediate 41-1

[0623] 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 obtain intermediate 41-1 (160 mg). ESI-MS: m / z=603.3 [M+H] +

[0624] 2) Preparation of Intermediate 41-2

[0625] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 41-1 to obtain intermediate 41-2 (68 mg). ESI-MS: m / z=589.3 [M+H] +

[0626] 3) Preparation of Compound 41

[0627] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 41-2 to obtain compound 41 (15 mg). ESI-MS: m / z=772.3 [M+2H] 2+

[0628] Example 42: Preparation of Compound 42

[0629] 1) Preparation of Intermediate 42-1

[0630] 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 obtain intermediate 42-1 (1 g). ESI-MS: m / z=528.3 [M+H] +

[0631] 2) Preparation of Intermediate 42-2

[0632] 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] +

[0633] 3) Preparation of Intermediate 42-3

[0634] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 42-2 to obtain intermediate 42-3 (120 mg). ESI-MS: m / z=584.3 [M+H] +

[0635] 4) Preparation of Intermediate 42-4

[0636] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 42-3 to obtain intermediate 42-4 (70 mg). ESI-MS: m / z=570.3 [M+H] +

[0637] 5) Preparation of Compound 42

[0638] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 42-4 to obtain compound 42 (35 mg). ESI-MS: m / z=762.7 [M+2H] 2+

[0639] 1 H NMR(500MHz,DMSO)δ8.35(s,1H),8.13(s,2H),7.95(s,1H),7.77(m,3H),7 .51–6.81(m,16H),6.35(s,1H),5.10(s,1H),4.89(s,1H),4.72(s,1H),4.5 3–4.44(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).

[0640] Example 43: Preparation of Compound 43

[0641] 1) Preparation of Intermediate 43-1

[0642] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 11-3 to obtain intermediate 43-1 (150 mg). ESI-MS: m / z=570.3 [M+H] +

[0643] 2) Preparation of Intermediate 43-2

[0644] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 43-1 to obtain intermediate 43-2 (90 mg). ESI-MS: m / z=556.3 [M+H] +

[0645] 3) Preparation of Compound 43

[0646] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 43-2 to obtain compound 43 (30 mg). ESI-MS: m / z=755.8 [M+2H] 2+

[0647] 1 H NMR(500MHz,DMSO)δ8.36(s,1H),8.14(s,2H),7.95(s,1H),7.77(m,3H),7 .51–6.81(m,16H),6.35(s,1H),5.11(s,1H),4.90(s,1H),4.72(s,1H),4.5 3–4.44(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).

[0648] Example 44: Preparation of Compound 44

[0649] 1) Preparation of Intermediate 44-1

[0650] 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 obtain intermediate 44-1 (131 mg). ESI-MS: m / z=598.3 [M+H] +

[0651] 2) Preparation of Intermediate 44-2

[0652] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 44-1 to obtain intermediate 44-2 (80 mg). ESI-MS: m / z=584.3 [M+H] +

[0653] 3) Preparation of Compound 44

[0654] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 44-2 to obtain compound 44 (25 mg). ESI-MS: m / z=769.8 [M+2H] 2+

[0655] 1H NMR(500MHz,DMSO)δ8.35(s,1H),8.13(s,2H),7.95(s,1H),7.77(m,3H),7 .51–6.82(m,16H),6.34(s,1H),5.10(s,1H),4.89(s,1H),4.72(s,1H),4.5 5–4.44(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).

[0656] Example 45: Preparation of Compound 45

[0657] 1) Preparation of Intermediate 45-1

[0658] Referring to step 4 of Example 7, intermediate 7-3 was replaced with intermediate 42-2, and monomethyl pimelate was replaced with monomethyl azelaic acid to obtain intermediate 45-1 (108 mg). ESI-MS: m / z=612.2 [M+H] +

[0659] 2) Preparation of Intermediate 45-2

[0660] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 45-1 to obtain intermediate 45-2 (66 mg). ESI-MS: m / z=598.3 [M+H] +

[0661] 3) Preparation of Compound 45

[0662] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 45-2 to obtain compound 45 (8 mg). ESI-MS: m / z=776.8 [M+2H] 2+

[0663] 1H NMR(500MHz,DMSO)δ8.36(s,1H),8.14(s,2H),7.96(s,1H),7.77(m,3H),7 .51–6.82(m,16H),6.34(s,1H),5.10(s,1H),4.87(s,1H),4.72(s,1H),4.5 5–4.44(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).

[0664] Example 46: Preparation of Compound 46

[0665] 1) Preparation of Intermediate 46-1

[0666] 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 obtain intermediate 46-1 (100 mg). ESI-MS: m / z=626.3 [M+H] +

[0667] 2) Preparation of Intermediate 46-2

[0668] Referring to step 5 of Example 7, intermediate 7-4 was replaced with intermediate 46-1 to obtain intermediate 46-2 (70 mg). ESI-MS: m / z=612.3 [M+H] +

[0669] 3) Preparation of Compound 46

[0670] Referring to step 6 of Example 7, intermediate 7-5 was replaced with intermediate 46-2 to obtain compound 46 (10 mg). ESI-MS: m / z=783.7 [M+2H] 2+

[0671] 1H NMR(500MHz,DMSO)δ8.35(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),4.5 5–4.45(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).

[0672] Example 47: Preparation of Compound 47

[0673] 1) Preparation of Compound 47

[0674] Intermediate 3-12 (121 mg) was dissolved in DMF, and intermediate 30-2 (70 mg) was added, along with DIPEA (148 mg) and HATU (65 mg). The mixture was allowed to react at room temperature for 3 h. The crude product was purified by preparative liquid phase to afford compound 47 (46 mg). ESI-MS: m / z = 828.1 [M+2H] 2+ .

[0675] Example 48: Preparation of Compound 48

[0676] 1) Preparation of Compound 48

[0677] Referring to step 1 of Example 47, intermediate 30-2 was replaced with intermediate 14-4 to obtain compound 48 (8 mg).

[0678] ESI-MS: m / z = 813.8 [M + 2H] 2+

[0679] 1H NMR(500MHz,DMSO)δ11.95(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).

[0680] Example 49: Preparation of Compound 49

[0681] 1) Preparation of Compound 49

[0682] Referring to step 1 of Example 47, intermediate 30-2 was replaced with intermediate 44-2 to obtain compound 49 (10 mg).

[0683] ESI-MS: m / z = 812.2 [M + 2H] 2+

[0684] 1H NMR(500MHz,DMSO)δ11.92(s,1H),8.36(m,1H),8.12(m,1H),7.97–7.88(m,2H),7.72(m,2H),7.48(m,1H),7.39(m,4H),7.33(m,2H),7. 27(m,2H),7.18(m,1H),7.12(m,2H),6.97(m,1H),6.85(m,2H),6.31(m,1H),5.08(m,1H),4.93(m,1H),4.42(m,1H),4.38–4.26(m,2H),4 .11(m,3H),3.61(m,2H),3.53(s,4H),3.43(s,4H),3.21(s,4H),2.47(s,3H),2.35(m,4H),2.25(m,5H),2.20–2.06(m,5H),2.04–1.93( m,5H),1.91(s,6H),1.79(m,2H),1.61–1.53(m,1H),1.47(m,7H),1.38(m,3H),1.30(m,4H),1.27–1.20(m,7H),0.95(s,3H),0.86(s,6H)

[0685] Example 50: Preparation of Compound 50

[0686] 1) Preparation of Compound 50

[0687] Referring to step 1 of Example 47, intermediate 30-2 was replaced with intermediate 15-2 to obtain compound 50 (5 mg). ESI-MS: m / z=821.8 [M+2H] 2+

[0688] Test Example 1: In vitro RS4;11 cell proliferation inhibition

[0689] RS4;11 cells (from Nanjing Kebai) in good exponential growth phase were collected into a centrifuge tube and centrifuged at 1000 rpm for 5 min. The supernatant was discarded and 3 mL of seed culture medium (RPMI basal medium + 5% fetal bovine serum) was added with a pipette to resuspend. The cells were counted using a cell counter and diluted with seed culture medium to adjust the cell density to 1×10 5 / mL, inoculated on a 96-well plate using a spray gun, 100μL / well, and cultured in a cell culture incubator at 37°C and 5% CO2 saturated humidity. After culturing for 24 hours, the compound was added using a nanoliter pipette to a final concentration of 2000nM-0.91nM, with 2 replicates, and a control was set up at the same time. After continuing to culture in the cell culture incubator for 72 hours, the detection reagent CCK-8 (manufacturer: Japan Dojin Chemical) was added at 10μL / well. After incubation in the cell culture incubator for 4 hours, the absorbance was detected at 450nm by an Envision microplate reader, and the inhibition rate was calculated. The inhibition rate (%) = (average value of the negative control group - average value of the experimental group) / (average value of the negative control group - average value of the blank group) * 100%, with the logarithm of the compound concentration as the horizontal axis and the inhibition rate as the vertical axis. Four-parameter analysis was performed, and the dose-effect curve was fitted to calculate the IC 50 .

[0690] The experimental results show that the disclosed compound has a proliferation inhibitory effect on RS4;11 cells.

[0691] Test Example 2: In vitro MOLT-4 cell proliferation inhibition

[0692] Take a MOLT-4 cell dish in good exponential growth phase, collect the cells into a centrifuge tube, centrifuge at a low speed of 1500 rpm for 3 minutes, discard the supernatant, and use a pipette to add 5 mL of complete medium (RPMI basal medium + 10% FBS) to resuspend the cells. Count the cells using a cell counter and dilute with complete medium to adjust the cell density to 1.6*10 5 / mL, and then add an equal amount of RPMI basal medium to adjust the serum concentration to 5% and the cell density to 8*10 4 / mL seed plate. Use a spray gun to inoculate on a 96-well plate, 100μL / well, and culture in a cell culture incubator at 37℃ and 5% CO2 saturated humidity. After culturing for 24h, use a nanoliter sampler to add the compound to a final concentration of 1000nM-0.46nM. Set up 2 replicates for each concentration, and use cells without compound as a negative control. After 72 hours, add CCK-8 (Japan Dojin Chemical) at 10μL / well. After 3.5 hours, use Envision enzyme reader to detect its absorbance at 450nm, and calculate the inhibition rate. Inhibition rate (%) = (average value of negative control group - experimental group) / (average value of negative control group - average value of blank group) × 100%. The logarithm of compound concentration is used as the horizontal axis and the inhibition rate is used as the vertical axis. Four-parameter analysis is performed, and the dose-effect curve is fitted to calculate IC 50 The results are shown in Table 1.

[0693] Table 1. Compound inhibitory activity test results (IC 50 , nM)

[0694] The experimental results show that the disclosed compound has an inhibitory effect on the proliferation of RS4;11 cells and MOLT-4 cells in vitro.

[0695] Experimental Example 3: Degradation of BCL-XL protein in MOLT-4 cells in vitro

[0696] Take a MOLT-4 cell dish in good exponential growth phase, collect the cells into a centrifuge tube, centrifuge at a low speed of 1500 rpm for 3 minutes, discard the supernatant, and use a pipette to add 5 mL of complete medium (RPMI basal medium + 10% FBS) to resuspend the cells. Count the cells using a cell counter and dilute with complete medium to adjust the cell density to 1*10 7 100 μL / well was inoculated onto a 96-well plate using a dispenser. Compounds were added using a nanoliter pipette to a final concentration of 1000 nM to 1 nM. Two replicate wells were set for each concentration. Cells were cultured at 37°C in a humidified, 5% CO2 incubator.

[0697] After culturing for 24 hours, cells were collected for flow cytometry. After washing with PBS containing 2% BSA, the cells were first fixed with 80% methanol, then permeabilized with PBS containing 0.1% Tween20, and then blocked with PBS containing 10% BSA, and finally labeled with antibodies. The cells were incubated with BCL-XL (54H6) Rabbit mAb (CST, 2764S) primary antibody at room temperature for 0.5 hours, and then washed with PBS containing 2% BSA, and then labeled with Anti-rabbit IgG (H+L), F(ab')2 Fragment (Alexa 488 Conjugate) (CST, 4412S) were incubated at room temperature for 0.5 h. After incubation, the cells were washed and resuspended with PBS containing 2% BSA and detected using IQue3 (Sartorius).

[0698] The group labeled with only the secondary antibody was used as the background group, and the cells without compound addition were used as the negative control group. The mean fluorescence intensity (MFI) was used to measure BCL-XL protein expression and calculate the inhibition rate. Degradation rate (%) = (mean MFI of negative control group - MFI of compound group) / (mean MFI of negative control group - mean MFI of background group) × 100%. The logarithm of compound concentration was used as the horizontal axis and the degradation rate was used as the vertical axis. Four-parameter analysis was performed, and the dose-effect curve was fitted to calculate DC. 50 (half-maximal degradation concentration).

[0699] The experimental results show that the disclosed compounds have the effect of degrading BCL-XL protein in MOLT-4 cells in vitro.

[0700] Experimental Example 4: Evaluation of BCL-XL / BAK Binding Inhibitory Activity

[0701] The Tag1-BCL-XL protein stock solution was diluted to 8 nM using the dilution buffer in the kit (cisbio, 63ADK000CB04PEG), and the Tag2-BAK protein stock solution was diluted to 20 nM. 5 μL / well of the Tag1-BCL-XL protein dilution solution was added to a 384-well plate. The compound was added using a nanoliter pipette to make the final concentration of the compound 1000 nM-0.24 nM. Two replicate wells were used, and a control was set up at the same time. 5 μL / well of the Tag2-BAK protein dilution solution was added, centrifuged and mixed, and incubated at room temperature for 15 minutes. Anti-Tag1-Eu was diluted with the detection buffer in the kit (cisbio, 63ADK000CB04PEG). 3+ Antibodies and Anti-Tag2-XL665 antibodies were diluted to 1X concentration, and Anti-Tag1-Eu 3+ Mix the Anti-Tag2-XL665 antibody dilution at a 1:1 volume ratio, add 10 μL / well of the antibody mixture, centrifuge to mix, and incubate at room temperature for 2 hours. Detect the fluorescence value at 665nm / 620nm using an Envision microplate reader, perform a four-parameter analysis, fit the dose-effect curve, and calculate the IC 50 .

[0702] The experimental results show that the disclosed compounds have BCL-XL / BAK binding inhibitory activity in vitro.

[0703] Test Example 5: In vitro liver microsome stability

[0704] Liver microsomal incubation samples (species: human, rat, mouse, and monkey) were prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), test compound, and NADPH + MgCl₂ solution at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), and test compound. The sample was added to acetonitrile containing an internal standard for protein precipitation, and the supernatant was prepared. The supernatant was diluted and used for LC / MS / MS analysis.

[0705] The experimental results show that the disclosed compounds are metabolically stable in liver microsomes in vitro. The results are shown in Tables 2 and 3.

[0706] Table 2

[0707] Table 3

[0708] Test Example 6: Pharmacokinetics in mice

[0709] ICR mice weighing 18-22 g were randomly divided into groups of 9 after acclimation for 3-5 days and injected intravenously with the test compound solution at a dose of 1 mg / kg. Blood was collected from the eye socket at 5, 15, 30, 1, 2, 3, 4, 6, 8, 10, and 24 hours. Twenty μL of the test plasma sample and the standard curve were aspirated and protein precipitated with acetonitrile containing an internal standard. The supernatant was diluted and used for LC / MS / MS analysis. Pharmacokinetic parameters were fitted using a non-compartmental model.

[0710] The test results show that the compounds disclosed herein have good pharmacokinetic parameters in vivo.

[0711] Test Example 7: Pharmacokinetics in rats

[0712] SD rats weighing 210-230 g were randomly divided into groups after acclimation for 3-5 days, with 3 rats in each group, and were intravenously injected with the example solution at a dose of 0.5 mg / kg.

[0713] Blood was collected from the eye sockets at the time points of 0 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, and 32 h to prepare the plasma samples to be tested.

[0714] 50 μL of plasma sample to be tested and standard curve sample were taken, and acetonitrile solution containing internal standard was added to obtain protein precipitation to obtain supernatant, which was diluted and used for LC / MS / MS determination.

[0715] A non-compartmental model was used for fitting.

[0716] The experimental results show that the disclosed compound has good pharmacokinetic parameters in rats.

[0717] Test Example 8: Pharmacokinetics in Dogs

[0718] Beagle dogs weighing 10-12 kg were randomly divided into groups of 3 after acclimation for 3-5 days and were intravenously injected with the example solution at a dose of 0.2 mg / kg.

[0719] Blood was collected from the forelimb vein at the time points of 0 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, 32 h, and 48 h to prepare the plasma samples to be tested.

[0720] 50 μL of plasma sample to be tested and standard curve sample were taken, and acetonitrile solution containing internal standard was added to obtain protein precipitation to obtain supernatant, which was diluted and used for LC / MS / MS determination.

[0721] A non-compartmental model was used for fitting.

[0722] The test results show that the disclosed compound has good pharmacokinetic parameters in dogs.

[0723] Experimental Example 9: Determination of BCL-XL protein degradation kinetics

[0724] Take a dish of MOLT-4 cells in good exponential growth phase, collect the cells into a centrifuge tube, centrifuge at a low speed of 1500 rpm for 3 minutes, discard the supernatant, and use a pipette to add 5 mL of complete medium (RPMI basal medium + 10% FBS) to resuspend the cells. Count the cells using a cell counter and dilute with complete medium to adjust the cell density to 2*10 6 100 μL / well was inoculated into a 96-well V-bottom plate using a dispenser. Compounds were added using a nanoliter pipette to a final concentration of 100 nM. Two replicate wells were plated at this concentration and the cells were cultured in a 37°C, 5% CO2, saturated humidity incubator.

[0725] After 4 hours of incubation, cells were harvested by centrifugation at 300g for 5 minutes and then washed with ice-cold PBS. 100 μL of lysis buffer was added to each well and the cells were thoroughly mixed with a pipette to lyse the cells. After complete lysis, no obvious cell pellet should be present. Lyse the cells on ice for 30 minutes. After lysis, store the cells in a -80°C refrigerator until further testing.

[0726] The cell lysate was thawed on ice, then centrifuged at 500g for 10 minutes, and the lysate was detected using a BCLXL ELISA kit (R&D, DYC894-5). The high-adsorption 96-well plate was first coated with BCLXL capture antibody overnight, then blocked with PBS containing 1% BSA, and then the sample was incubated for 2 hours. After incubation, the detection antibody was added and incubated for 2 hours, and finally streptavidin-HRP was added and incubated for 20 minutes. TMB was added for color development for 15 minutes before detection. The absorbance value was detected at 450 / 570nm using an Envision enzyme reader, and the absorbance value at 570nm and the blank background value were deducted to calculate the degradation rate. The degradation rate (%) = 100% * (average value of the negative control group - experimental group) / average value of the negative control group. The results are shown in Table 4.

[0727] Table 4

[0728] The experimental results show that the disclosed compounds have good BCL-XL protein degradation kinetics.

[0729] Test Example 10: Evaluation of Canine Platelet Toxicity

[0730] Draw 9 mL of canine whole blood into a 10 mL sodium citrate vacuum anticoagulant tube, mix thoroughly by inversion, and centrifuge at 100 g for 10 minutes at room temperature. Collect the supernatant (i.e., plasma) and gently transfer it to a 50 mL centrifuge tube. Add 5 mL of acid citrate buffer and gently mix. Remove 200 μL of the supernatant, count the blood, and continue centrifugation at 1200 g for 10 minutes at room temperature. (Note: Set the centrifuge speed to 5 for both acceleration and deceleration.) Gently discard the supernatant and gently wash the tube with 2 mL of Tyrode's solution containing 1 μM prostaglandin E1 (PGE1) and 0.2 units / mL apyrase. Discard the supernatant and gently resuspend and mix with Tyrode's Solution containing 1μM prostaglandin E1 (PGE1) and 0.2 units / ml apyrase to a final density of 1*10^8 / mL. Then, inoculate 90μL per well in a 96-well U-bottom plate. After plating, add an additional 10μL FBS to all wells.

[0731] Compounds were added using a nanoliter pipette to a final concentration of 2000 nM to 8.2 nM, with two replicate wells set for each concentration. The plate was then sealed with a sealing film and incubated on a microplate shaker at 20°C, shaking at 300 rpm. After 72 hours, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added and incubated in a cell culture incubator for 1 hour. Then, 50 μL was transferred to a 96-well flat-bottom plate using a dispenser and mixed by shaking. The absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 The results are shown in Table 5.

[0732] Table 5

[0733] The test results show that the compounds disclosed herein have low canine platelet toxicity.

[0734] Experimental Example 11: Pharmacodynamic Evaluation of MOLT-4 Human Acute Lymphoblastic Leukemia Cells in a Subcutaneous Transplanted Tumor Model in CB17-SCID Mice

[0735] MOLT-4 cells were subcutaneously inoculated in the right axilla of SPF female CB17-SCID mice (source: Shanghai Lingchang Biotechnology Co., Ltd.) at a rate of 1 × 10 7 When the average tumor volume reaches 200mm 3 When about 30 seconds, divide the animals into groups.

[0736] The day of grouping was designated Day 0. Dosing was performed once per tail vein injection on Day 0. Tumor volume was measured 2-3 times per week, and mice were weighed and recorded. General performance of the mice was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.

[0737] The detection indicators and calculation formulas are as follows:

[0738] Tumor volume, TV (mm 3 )=1 / 2×(a×b 2 ), where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0739] Relative tumor volume, RTV = TV t / TV0; TV0 is the tumor volume on day 0, TV t is the tumor volume at each measurement.

[0740] Relative tumor growth rate, T / C (%) = T RTV / C RTV ×100%; where T RTV RTV for the treatment group; C RTV The vehicle control group was RTV.

[0741] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) × 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[0742] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0×100%; where Wt0 is the weight of mice on day 0, Wt t is the weight of the mice at each measurement.

[0743] The test results show that the disclosed compounds have a good tumor growth inhibition effect in vivo (for example, on day 14, the tumor volume inhibition rate is >50% and the tumor weight inhibition rate is >50%).

Claims

1. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, R is selected from OH, NH2, CN, halogen, or C optionally substituted with one or more OH, NH2, CN, halogen 1-6 alkyl; X is selected from CH2, NH or O; L is a linking group; ULM is Where R 1 is selected from C optionally substituted by one or more halogens 1-6 alkyl; R 2 is selected from C optionally substituted by one or more OH, NH2, CN, halogen 1-6 alkyl; X 1 , X 2 , X 3 , X 4 and X 5 are independently selected from CH, C, N, NH, O or S; Every R 3 are independently selected from OH, NH2, CN, halogen, C 1-6 Alkyl or C 1-6 Alkoxy, the NH2, C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more OH, NH2, CN or halogen; m and q are independently selected from 0, 1, 2 or 3; The condition is that ULM is not Each R, X, L, R 1 , R 2 , X 1 , X 2 , X 3 , X 4 or X 5 Each is independently optionally substituted with one or more substituents.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R is selected from halogen, or C optionally substituted by one or more OH, NH2, CN, halogen 1-6 alkyl; Alternatively, R is selected from F, Cl, Br, or C optionally substituted with one or more OH, NH2, CN, halogen 1-3 alkyl; Alternatively, R is selected from F, Cl, Br, or C optionally substituted with one or more F or Cl. 1-3 alkyl; Alternatively, R is selected from F, Cl, Br, or trifluoromethyl; Alternatively, said R is selected from Cl; Alternatively, q is selected from 0, 1 or 2; Alternatively, q is selected from 0 or 1; Alternatively, the structural unit Selected from 3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The X is selected from NH or O.

4. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The L is selected from a bond, -C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 Alkynyl-, the-C 1-20 Alkyl-, -C 2-20 Alkenyl- or -C 2-20 One or more -CH2- in the alkynyl- is optionally each independently replaced by R x Replace the R x Selected from -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-, 5-12 membered heteroaryl, phenyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl or -S-, wherein R a Selected from hydrogen or C 1-6 Alkyl; each R x or R a each independently optionally substituted with one or more substituents; Alternatively, the R a Selected from hydrogen or C 1-4 Alkyl; or, R a Selected from hydrogen or C 1-3 Alkyl; or, R a Selected from hydrogen or C 1-2 Alkyl; or, R a is selected from hydrogen or methyl; Alternatively, the R x is selected from -O-, -C(O)-, 5-12 membered heteroaryl, phenyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, -NH-, -N(C 1-6 alkyl)- or -S-; Alternatively, the R x is selected from -O-, -C(O)-, 5-6 membered heteroaryl, phenyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -NH-, -N(C 1-6 Alkyl)- or -S-; Alternatively, the R x Selected from -O-, -C(O)-, phenyl, C 5-6 Cycloalkyl, 5-6 membered heterocycloalkyl, -NH-, -N(C 1-3 alkyl)- or -S-; Alternatively, the R x Selected from -O-, -C(O)-, phenyl, piperidinyl, piperazinyl, -NH-, -N(C 1-3 Alkyl)- or -S-; Alternatively, the R x is selected from -C(O)- or piperazinyl; Alternatively, the R x Selected from -C(O)- or Alternatively, said L is selected from a bond, -C 1-12 Alkyl-, -C 2-12 Alkenyl- or -C 2-12 Alkynyl-, the-C 1-12 Alkyl-, -C 2-12 Alkenyl- or -C 2-12 One or more -CH2- in the alkynyl- is optionally each independently replaced by R x Replace the R x As defined above; Alternatively, said L is selected from a bond, -C 3-12 Alkyl-, -C 3-12 Alkenyl- or -C 3-12 Alkynyl-, the-C 3-12 Alkyl-, -C 3-12 Alkenyl- or -C 3-12 One or more -CH2- in the alkynyl- is optionally each independently replaced by R x Replace the R x As defined above; Alternatively, said L is selected from a bond, -C 6-12 Alkyl-, -C 6-12 Alkenyl- or -C 6-12 Alkynyl-, the-C 6-12 Alkyl-, -C 6-12 Alkenyl- or -C 6-12 One or more -CH2- in the alkynyl- is optionally each independently replaced by R x Replace the R x As defined above; Alternatively, said L is selected from a bond, -C 8-9 Alkyl-, -C 8-9 Alkenyl- or -C 8-9 Alkynyl-, the-C 8-9 Alkyl-, -C 8-9 Alkenyl- or -C 8-9 One or more -CH2- in the alkynyl- is optionally each independently replaced by R x Replace the R x As defined above; Alternatively, said L is selected from a bond, -C 6-12 Alkyl-, -C 6-12 Alkenyl- or -C 6-12 Alkynyl-, the-C 6-12 Alkyl-, -C 6-12 Alkenyl- or -C 6-12 One or more -CH2- in the alkynyl- is optionally each independently replaced by R x Replace the R x Selected from -O-, -C(O)-, phenyl, piperidinyl, piperazinyl, -NH-, -N(C 1-3 Alkyl)- or -S-; Alternatively, the L is selected from -C 3-12 Alkyl-, the-C 3-12 One or more -CH2- in the alkyl- are optionally each independently replaced by R x Replace the R x is selected from -C(O)- or piperazinyl; Alternatively, the L is selected from -C 6-12 Alkyl-, the-C 6-12 One or more -CH2- in the alkyl- are optionally each independently replaced by R x Replace the R x is selected from -C(O)- or piperazinyl; Alternatively, the L is selected from -C 6-10 Alkyl-, the-C 6-10 One or more -CH2- in the alkyl- are optionally each independently replaced by R x Replace the R x is selected from -C(O)- or piperazinyl; Alternatively, the L is selected from -C 6-10 Alkyl-, the-C 6-10 One or more -CH2- in the alkyl- are optionally each independently replaced by R x Replace the R x Selected from -C(O)- or Alternatively, the L is selected from -C 8-10 Alkyl-, the-C 8-10 One or more -CH2- in alkyl- are optionally each independently replaced by -C(O)-; Alternatively, L is selected from wherein n is selected from 0-10; or n is selected from 1-9; or n is selected from 1-7; Alternatively, L is selected from wherein n is selected from 0-10; or n is selected from 1-9; or n is selected from 1-7; Alternatively, L is selected from Alternatively, L is selected from Alternatively, L is selected from Alternatively, L is selected from Alternatively, L is selected from Alternatively, L is selected from 5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Any one end of L is connected to ULM; or, the right end of L is connected to ULM; or, the left end of L is connected to ULM; or, L is selected from Among them, * indicates that the end is connected to the ULM.

6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The X 1 , X 2 , X 3 , X 4 and X 5 are independently selected from CH, C, N, NH, O or S; Alternatively, the X 1 , X 2 , X 3 , X 4 and X 5 are independently selected from CH, C, N, NH or S; Alternatively, the X 1 , X 2 , X 3 , X 4 and X 5 are independently selected from CH, C, NH, or N; Alternatively, the X 1 , X 2 , X 3 , X 4 and X 5 are independently selected from CH, C, N, NH, O or S, and at least one of them is N; Alternatively, the X 1 , X 2 , X 3 , X 4 and X 5 are independently selected from CH, C, N, NH, O or S, and at least two of them are heteroatoms; Alternatively, the X 1 , X 2 , X 3 , X 4 and X 5 are independently selected from CH, C, N, NH, O or S, and at least two are selected from N or S; Or, by X 1 , X 2 , X 3 , X 4 and X 5 The ring formed is aromatic; Or, by X 1 , X 2 , X 3 , X 4 and X 5 The ring formed is a five-membered heteroaromatic ring; Alternatively, the X 1 and X 2 are independently selected from N or NH, X 3 and X 4 are independently selected from CH; X 5 Selected from C; Alternatively, the X 1 , X 2 and X 4 Selected from CH, X 3 and X 5 Selected from N or NH; Alternatively, the X 1 , X 2 and X 4 Selected from CH, X 3 is selected from N or NH, and X 5 Selected from N; Alternatively, the X 1 Select from S, X 2 and X 4 Selected from CH, X 3 Selected from N or NH, X 5 Selected from C; Alternatively, the structural unit Selected from Alternatively, the structural unit Selected from 7. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The R 1 is selected from C optionally substituted by one or more halogens 1-4 Alkyl; or, the R 1 is selected from C optionally substituted by one or more halogens 3-4 Alkyl; or, the R 1 is selected from isopropyl or tert-butyl optionally substituted by one or more halogens; or, said R 1 isopropyl or tert-butyl; and / or, the R 2 is selected from C optionally substituted by one or more OH, NH2, CN, halogen 1-4 Alkyl; or, the R 2 is selected from methyl optionally substituted by one or more OH, NH2, CN, halogen; or, said R 2 is selected from methyl optionally substituted by one or more OH; or, said R 2 Selected from hydroxymethyl or methyl.

8. The compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Each of the R 3 are independently selected from OH, NH2, CN, halogen, C 1-3 Alkyl or C 1-3 Alkoxy, the NH2, C 1-3 Alkyl or C 1-3 The alkoxy group is optionally substituted with one or more OH, NH2, CN or halogen; or, each of said R 3 are independently selected from C 1-3 Alkyl or C 1-3 Alkoxy; or, each of said R 3 are independently selected from OH, NH2, CN, halogen, methyl or ethyl; or, each of the R 3 Each independently selected from methyl or ethyl; Alternatively, the structural unit Selected from Alternatively, the structural unit Selected from Alternatively, the structural unit Selected from Or; structural unit Selected from 9. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The ULM is Alternatively, the ULM is 10. The compound according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The m and q are each independently selected from 1.

11. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from Formula II, Formula III, Formula II-A, Formula III-A, Formula III-B, Formula IV, Formula V, Formula VI or Formula VII, its stereoisomer or a pharmaceutically acceptable salt thereof, Among them, R, q, L, ULM, X, R 1 , R 2 or R 3 The definition as described in any one of claims 1-10.

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

14. Use of the compound according to any one of claims 1 to 12, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13 in preventing or treating a disease that is treated by degrading a target protein bound to a targeting ligand.

15. Use of the compound according to any one of claims 1 to 12, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13 in preventing or treating a disease that is treated by binding to a cerebellar protein; Preferably, the disorder treated by binding to cerebellar protein is selected from cancer.

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