A phenylpyrazole compound, and a preparation method and application thereof

Abstract

The application discloses a phenyl pyrazole compound, a preparation method and application thereof. The application provides a phenyl pyrazole compound as shown in formula I, a stereoisomer or a pharmaceutically acceptable salt thereof. The compound can effectively and selectively inhibit a key protein MCL-1 in an apoptosis process at a molecular level, or the compound has obvious killing effect and high selectivity on cancer cells, especially human plasma cell leukemia cells H929 and human myelomonocytic leukemia cells MV-4-11, has potential to be prepared into a novel anti-acute myeloid leukemia drug, and has a good market prospect.

Description

Technical Field

[0001] This invention discloses a phenylpyrazole compound, its preparation method, and its application. Background Technology

[0002] Apoptosis and cell proliferation are fundamental phenomena of life. Modern research suggests that tumorigenesis is actually caused by an imbalance between cell proliferation and apoptosis. Therefore, restoring the inherent apoptosis mechanism in tumor cells is a recognized and scientifically effective anti-tumor strategy. As key regulators in the mitochondrial apoptosis pathway, the development of small molecule drugs targeting BCL-2 family proteins has become a hot topic in anti-tumor research. The successful launch of venetoclax validates this target and its enormous market potential.

[0003] However, as a selective inhibitor of the BCL-2 protein, venetoclax releases pro-apoptotic factors upon binding to BCL-2, which can still be captured by another member of the BCL-2 family, MCL-1 protein. This inhibits the activation of pro-apoptotic factors, leading to drug resistance in tumor cells overexpressing MCL-1 protein (such as leukemia and multiple myeloma). Furthermore, numerous studies have shown that MCL-1 is one of the major driving carcinogenic factors in the development of acute myeloid leukemia (AML) and is a potential target for treating AML, possessing significant market demand and development potential. Therefore, developing selective small-molecule inhibitors targeting MCL-1 protein can not only effectively address the drug resistance problem of existing BCL-2-targeting drugs and expand their anti-tumor applications, but also provide new therapeutic strategies for malignant tumors primarily driven by MCL-1 protein. Summary of the Invention

[0004] The technical problem this invention aims to solve is the lack of highly selective and highly active small-molecule inhibitors or protease degraders for MCL-1. This invention provides a phenylpyrazole compound, a pharmaceutical composition, its preparation method, and its applications. These compounds can effectively and selectively inhibit the key protein MCL-1 in the apoptosis process at the molecular level. Alternatively, they exhibit significant killing effects and high selectivity against cancer cells, especially human plasma cell leukemia cells H929 and human myeloid monocytic leukemia cells MV-4-11, showing potential as novel anti-acute myeloid leukemia drugs and possessing good market prospects.

[0005] This invention provides a phenylpyrazole compound as shown in Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0006]

[0007] in,

[0008] R aFor R 1 -(CH2) m -;

[0009] The value of m is 0, 1, 2, 3, 4, 5, or 6;

[0010] The R mentioned 1 It is a phenyl group or is composed of one or more R groups. 1-1 Substituted phenyl groups; when multiple substituents are present, the substituents may be the same or different;

[0011] The R mentioned 1-1 Independently, it is -NH2, -OH, -SH, C1-C4 alkoxy, 3-8 membered cycloalkyl, or 3-8 membered heterocycloalkyl; the number of heteroatoms in the 3-8 membered heterocycloalkyl is 1, 2, 3, or 4, and the heteroatoms are independently N, O, and S;

[0012] R b1 R b2 and R b3 Independently, it is H, halogen, or C1–C6 alkyl;

[0013] R c It is H or C1-C4 alkyl;

[0014] R d It is a phenyl, 3-10 heteroaryl group, with one or more R groups 2 Substituted phenyl or substituted with one or more R 2 Substituted 3-10 heteroaryl; the “3-10 heteroaryl” and “substituted by one or more R” 2 In the 3-10 membered heteroaryl group of the substituted 3-10 membered heteroaryl group, the number of heteroatoms is independently 1, 2, 3 or 4, and the heteroatoms are independently N, O and S; when multiple substituents are present, the substituents may be the same or different;

[0015] The R 2 It is independently a hydroxyl group or a C1-C6 alkyl group;

[0016] Indicates z configuration E configuration or a mixture thereof;

[0017] Chiral carbons marked with "*" are in the S configuration, R configuration, or a mixture thereof.

[0018] In one scheme, the R... 1 For R 1-1 Substituted phenyl groups.

[0019] In one scheme, the R... 1-1Independently, it is -NH2, -OH, C1-C4 alkoxy, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; the number of heteroatoms in the 3-8 membered heterocycloalkyl is 1, 2, 3 or 4, and the heteroatoms are independently N, O and S.

[0020] In one scheme, the R... 1-1 It can be independently -NH2, -OH, -SH or 3-8 membered cycloalkyl.

[0021] In one scheme, the R... 1-1 It can be independently -NH2, -OH, or a 3-8 membered cycloalkyl group.

[0022] In one scheme, the R... 1-1 It is independently a C1-C4 alkoxy or a 3-8 membered heterocyclic alkyl; the number of heteroatoms in the 3-8 membered heterocyclic alkyl is 1, 2, 3 or 4, and the heteroatoms are independently N, O and S.

[0023] In one scheme, the R... b1 R b2 and R b3 One of them is a halogen or a C1-C6 alkyl group, and the remainder is H; preferably, R b2 It is a halogen or a C1-C6 alkyl group, R b1 and R b3 For H; more preferably, R b2 For halogens, R b1 and R b3 For H.

[0024] In one scheme, the R... d It is a 3-10 member heteroaryl group, surrounded by one or more R groups. 2 Substituted phenyl or substituted with one or more R 2 Substituted 3-10 heteroaryl; the “3-10 heteroaryl” and “substituted by one or more R” 2 In the substituted 3-10 heteroaryl group, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are independently N, O and S.

[0025] In one scheme, the R... d It is a 3-10 membered heteroaryl group; the number of heteroatoms in the 3-10 membered heteroaryl group is 1, 2, 3 or 4, and the heteroatoms are independently N, O and S.

[0026] In one scheme, the R... 2 It is a C1 to C6 alkyl group.

[0027] In one particular scheme, where

[0028] R a For R1 -(CH2) m -;

[0029] The value of m is 0;

[0030] The R mentioned 1 For R 1-1 Substituted phenyl;

[0031] The R mentioned 1-1 Independently -NH2, -OH, or 3-8 membered cycloalkyl;

[0032] R b1 R b2 and R b3 Independently, it is H, halogen, or C1–C6 alkyl;

[0033] R c It is H or C1-C4 alkyl;

[0034] R d It is a 3-10 member heteroaryl group or "with one or more R 2 "Substituted 3-10 heteroaryl"; the "3-10 heteroaryl" and "substituted by one or more R 2 In the substituted 3-10 heteroaryl group, the number of heteroatoms is 1 or 2, and the heteroatoms are N;

[0035] The R 2 It is a C1 to C6 alkyl group.

[0036] In one particular scheme, where

[0037] R a For R 1 -(CH2) m -;

[0038] The value of m is 0;

[0039] The R mentioned 1 For R 1-1 Substituted phenyl;

[0040] The R mentioned 1-1 It is independently a C1-C4 alkoxy or a 3-8 membered heterocyclic alkyl; the number of heteroatoms in the 3-8 membered heterocyclic alkyl is 1, 2, 3 or 4, and the heteroatoms are independently N, O and S;

[0041] R b1 R b2 and R b3 Independently, it is H, halogen, or C1–C6 alkyl;

[0042] R c It is H or C1-C4 alkyl;

[0043] R d It is a 3-10 member heteroaryl group or "with one or more R 2 "Substituted 3-10 heteroaryl"; the "3-10 heteroaryl" and "substituted by one or more R 2 In the substituted 3-10 heteroaryl group, the number of heteroatoms is 1 or 2, and the heteroatoms are N;

[0044] The R 2 It is a C1 to C6 alkyl group.

[0045] In one scheme, m is 0, 1, 2, 3 or 4.

[0046] In one particular scheme, m is 0.

[0047] In one scheme, the R... 1-1 The number of substitutions can be one or more, such as 2, 3, 4, or 5, when there are multiple R... 1-1 At that time, R 1-1 Same or different.

[0048] In one scheme, the R... 1-1 It can be independently located at the ortho, meta, or para position of the "phenyl-pyrazole linkage site", preferably at the para position.

[0049] In a certain scheme, when R 1-1 When the alkoxy group is C1-C4, the C1-C4 alkoxy group is methoxy, ethoxy, propoxy, or butoxy, preferably methoxy.

[0050] In a certain scheme, when R 1-1 When the alkyl group is a 3-8 membered cycloalkyl group, the 3-8 membered cycloalkyl group is cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclohexyl.

[0051] In a certain scheme, when R 1-1 When the heterocyclic alkyl group is 3-8 membered, the heterocyclic alkyl group is a 5-6 membered heterocyclic alkyl group with heteroatoms selected from N and / or O and having 1 to 2 heteroatoms, such as morpholino.

[0052] In a certain scheme, when R b1 R b2 and R b3 When the halogen is used independently, the halogen is fluorine, chlorine, bromine or iodine, preferably chlorine.

[0053] In a certain scheme, when R b1 R b2 and R b3When independently a C1 to C6 alkyl group, the C1 to C6 alkyl group is preferably a C1 to C4 alkyl group, such as methyl, ethyl, propyl or butyl.

[0054] In a certain scheme, when R c When the alkyl group is C1 to C4, the C1 to C4 alkyl group is methyl, ethyl, propyl or butyl.

[0055] In a certain scheme, when R d "3-10 aryl" or "containing one or more R 2 When "substituted 3-10 heteroaryl" is used, the 3-10 heteroaryl is a 5-10 heteroaryl with heteroatoms selected from N and having 1 to 2 heteroatoms, such as indole.

[0056] In a certain scheme, when R d For one or more R 2 When substituted 3-10 heteroaryl groups are present, multiple R 2 At that time, R 2 Same or different.

[0057] In a certain scheme, when R d For one or more R 2 When 3-10 heteroaryl groups are substituted, R 2 It is independently located at the ortho, meta, or para position of the site where it connects with other groups;

[0058] In a certain scheme, when R 2 When the alkyl group is C1 to C6, the C1 to C6 alkyl group is C1 to C4 alkyl, such as methyl, ethyl, propyl or butyl.

[0059] In one scheme, the R a for

[0060] In one scheme, the R a for

[0061] In one scheme, the R a for

[0062] In one scheme, the R a for

[0063] In one scheme, the R d for

[0064] In one scheme, the R... 1-1Independently, it is -NH2, -OH, C1-C4 alkoxy, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; the 3-8 membered heterocycloalkyl is a 5-6 membered heterocycloalkyl with heteroatoms selected from N and / or O and having 1 to 2 heteroatoms.

[0065] In one scheme, the R... 1-1 It can be independently -NH2, -OH, C1-C4 alkoxy, 3-8 membered cycloalkyl or morpholino.

[0066] In one scheme, the R... d It is a phenyl, 3-10 heteroaryl group, with one or more R groups 2 Substituted phenyl or substituted with one or more R 2 Substituted 3-10 heteroaryl; the “3-10 heteroaryl” and “substituted by one or more R” 2 In the substituted 3-10 heteroaryl group, the number of heteroatoms is 1 or 2, and the heteroatoms are N.

[0067] In one scheme, the R... d It is a 3-10 member heteroaryl group or is surrounded by one or more R groups. 2 Substituted 3-10 heteroaryl; the “3-10 heteroaryl” and “substituted by one or more R” 2 In the substituted 3-10 heteroaryl group, the number of heteroatoms is 1 or 2, and the heteroatoms are N.

[0068] In one scheme, the R... d It is phenyl, indole, or contains one or more R groups. 2 Substituted indole group.

[0069] In one scheme, the R... d It is an indole group or is surrounded by one or more R groups. 2 Substituted indole group.

[0070] In one scheme, the R... 2 It can be independently a hydroxyl group or a C1-C4 alkyl group.

[0071] In one embodiment, the phenylpyrazole compound I can be any of the following compounds:

[0072]

[0073]

[0074] This invention provides a compound as shown in Formula II, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0075]

[0076] in,

[0077] X is the ligand (conjugate, binder) of E3 (ubiquitin) ligase, which is

[0078] L stands for connector (linker), for example

[0079] End a is connected to Y, and end b is connected to X;

[0080] n1 and n2 are independently 0, 1, 2, 3, 4 or 5;

[0081] L 1 and L 2 Independently -O-, -S-, or -NH-;

[0082] Y is (target protein binder);

[0083] R b1 R b2 R b3 R c and R d The definition is as described in any of the above schemes;

[0084] L 3 For R 3 -(CH2) m -;

[0085] The value of m is 0, 1, 2, 3, 4, 5, or 6;

[0086] The R mentioned 3 It is a phenyl or R 3-1 Substituted phenyl;

[0087] The L is connected to L 3 The adjacent, meta, or para position of the pyrazole linkage site;

[0088] The R 3-1 Independently, it is -NH2, -OH, -SH, C1-C4 alkoxy, 3-8 membered cycloalkyl, or 3-8 membered heterocycloalkyl; the number of heteroatoms in the 3-8 membered heterocycloalkyl is 1, 2, 3, or 4, and the heteroatoms are independently N, O, and S;

[0089] Indicates Z configuration, E configuration, or a mixture thereof;

[0090] Chiral carbons marked with "*" are in the S configuration, R configuration, or a mixture thereof.

[0091] In one embodiment of the present invention, L is...

[0092] In one aspect of the present invention, the L 1 It is -O-.

[0093] In one aspect of the present invention, the L 2 It is -O-.

[0094] In one embodiment of the present invention, L is connected to L 3 Parallel to the pyrazole linker site.

[0095] In one aspect of the present invention, the R 3 It is a phenyl group.

[0096] In one aspect of the present invention, the R 3-1 Independently, it is -NH2, -OH, C1-C4 alkoxy, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; the number of heteroatoms in the 3-8 membered heterocycloalkyl is 1, 2, 3 or 4, and the heteroatoms are independently N, O and S.

[0097] In one scheme, the R... 3-1 It can be independently -NH2, -OH, -SH or 3-8 membered cycloalkyl.

[0098] In one scheme, the R... 3-1 It can be independently -NH2, -OH, or a 3-8 membered cycloalkyl group.

[0099] In one scheme, the R... 3-1 It is independently a C1-C4 alkoxy or a 3-8 membered heterocyclic alkyl group.

[0100] In one scheme, n1 is 0, 1, 2 or 3.

[0101] In one scheme, n2 is 0, 1, 2 or 3.

[0102] In one scheme, m is 0, 1, 2, 3 or 4.

[0103] In one particular scheme, m is 0.

[0104] In one scheme, the R... 3-1 The number of substitutions can be one or more, such as 2, 3, 4, or 5, when there are multiple R... 3-1 At that time, R 3-1 Same or different.

[0105] In a certain scheme, when R 3-1 When the alkoxy group is C1-C4, the C1-C4 alkoxy group is methoxy, ethoxy, propoxy, or butoxy, preferably methoxy.

[0106] In a certain scheme, when R 3-1 When the alkyl group is a 3-8 membered cycloalkyl group, the 3-8 membered cycloalkyl group is cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclohexyl.

[0107] In a certain scheme, when R 3-1 When the heterocyclic alkyl group is 3-8 membered, the heterocyclic alkyl group is a 5-6 membered heterocyclic alkyl group with heteroatoms selected from N and / or O and having 1 to 2 heteroatoms, such as morpholino.

[0108] In one scheme, the R... 3-1 Independently, it is .NH2, -OH, C1-C4 alkoxy, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; the 3-8 membered heterocycloalkyl is a 5-6 membered heterocycloalkyl with heteroatoms selected from N and / or O and having 1 to 2 heteroatoms.

[0109] In one scheme, the R... 3-1 It can be independently -NH2, -OH, C1-C4 alkoxy, 3-8 membered cycloalkyl or morpholino.

[0110] In one particular scheme, X is...

[0111] In one particular scheme, L is...

[0112] In one particular scheme, Y is...

[0113] In one aspect of the present invention, the compound represented by Formula II, its stereoisomers, or its pharmaceutically acceptable salts may be of Formula II-a.

[0114]

[0115] Among them, R c R b1 R b2 R b3 and R d The definition is as described above;

[0116] n can be 1, 2, 3, 4 or 5.

[0117] In one aspect of the present invention, the compound represented by Formula II, its stereoisomer, or a pharmaceutically acceptable salt thereof may be any of the following compounds:

[0118]

[0119] The present invention also provides a method for preparing the compound of formula I, which includes method 1 or method 2;

[0120] Method 1 includes the following steps: in an organic solvent, in the presence of a catalyst, the compound III and compound IV are subjected to an amidation reaction as shown below to obtain the compound I;

[0121]

[0122] Among them, R a R b1 R b2 R b3 and R d The definition is as described above.

[0123] Method 2 includes the following steps: in an organic solvent, "R" c Compound I, which is a C1-C4 alkyl group, undergoes the hydrolysis reaction shown below to give "R". c Compound I, which is "-OH", is acceptable;

[0124]

[0125] Among them, R a R b1 R b2 R b3 and R d The definition is as described above.

[0126] In Method 1, the conditions for the amidation reaction can be those conventional to this reaction in the art, such as the following conditions:

[0127] The organic solvent may be an amide solvent (e.g., N,N-dimethylformamide). The amount of organic solvent used may be the conventional amount used in the art, as long as it does not affect the reaction.

[0128] The catalyst may be one or more of N,N′-diisopropylethylamine (DIPEA), 2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI).

[0129] The molar ratio of compound III to compound IV is preferably 1:1 to 1:2 (e.g., 1:2).

[0130] The progress of the amidation reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), and the reaction endpoint is generally defined as when compound III no longer reacts, with a reaction time of 6 hours.

[0131] In Method 2, the conditions for the hydrolysis reaction can be those conventional to this reaction in the art, such as the following conditions:

[0132] The organic solvent may be an ether solvent (e.g., tetrahydrofuran). The amount of organic solvent used may be the amount conventional in the art, as long as it does not affect the reaction.

[0133] The hydrolysis is preferably carried out in the presence of an alkali, which may be an alkali metal hydroxide (e.g., NaOH).

[0134] The preparation method of compound I may further include the following steps: in an organic solvent, in the presence of a base, compound IV and compound V undergo an addition-elimination reaction as shown below to obtain compound III;

[0135]

[0136] Among them, R a R b1 R b2 and R b3 As mentioned above;

[0137] The R e It is a C1 to C4 alkyl group (e.g., ethyl).

[0138] The conditions for the addition-elimination reaction can be the conventional conditions for this reaction in the art, such as the following conditions:

[0139] The organic solvent may be an ether solvent (e.g., tetrahydrofuran). The amount of organic solvent used may be the amount conventional in the art, as long as it does not affect the reaction.

[0140] The molar ratio of compound V to compound VI is preferably 1:2 to 1:3 (e.g., 1:2.2).

[0141] The preparation method of compound I may further include the following steps: in an organic solvent, in the presence of a catalyst, compound VII is subjected to a Vilsmeier-Haack formylation reaction with a disubstituted formamide as shown below to obtain compound V;

[0142]

[0143] Among them, R a R b1 R b2 and R b3 As stated above.

[0144] The conditions for the Vilsmeier-Haack formylation reaction can be those conventional to this reaction in the art, such as the following:

[0145] The organic solvent may be a formamide solvent (e.g., N,N-dimethylformamide). The amount of organic solvent used may be the conventional amount used in the art, as long as it does not affect the reaction.

[0146] The disubstituted formamide may be N,N-dimethylformamide.

[0147] The catalyst is POCl3.

[0148] The molar ratio of compound VII to the catalyst is preferably 1:2 to 1:5 (e.g., 1:4).

[0149] The preparation method of compound I may further include the following steps: in an organic solvent, in the presence of a catalyst, compound VIII and compound IX undergo a condensation reaction as shown below to obtain compound VII;

[0150]

[0151] Among them, R a R b1 R b2 and R b3 As stated above.

[0152] The conditions for the condensation reaction can be those conventional to this reaction in the art, such as the following conditions:

[0153] The organic solvent may be an alcohol solvent (e.g., ethanol). The amount of organic solvent used may be the amount conventional in the art, as long as it does not affect the reaction.

[0154] The catalyst may be acetic acid.

[0155] The molar ratio of compound VIII to compound IX described in this invention is preferably 1:1 to 1:1.5 (e.g., 1:1.2).

[0156] The present invention also provides a method for preparing compound II-a, comprising the following steps: in a solvent, under the action of a catalyst, compound II-b reacts with compound II-c to obtain a compound as shown in formula II-a;

[0157]

[0158] Among them, R b1 R b2 R b3 R c and Rd The definition is as described above;

[0159] n can be 1, 2, 3, 4 or 5.

[0160] The reaction conditions can be those conventional to this reaction in the art, such as the following conditions:

[0161] The solvent may be a formamide solvent (e.g., N,N-dimethylformamide). The amount of solvent used may be the conventional amount used in the art, as long as it does not affect the reaction.

[0162] The catalyst may be N,N′-diisopropylethylamine (DIPEA).

[0163] The molar ratio of compound II-b to compound II-c is preferably 1:1 to 1:1.5.

[0164] In one embodiment, the preparation method of compound II-a may further include the following steps: in a solvent, compound II-d is deprotected to obtain a compound as shown in formula II-b;

[0165]

[0166] Among them, R b1 R b2 R b3 R c and R d The definition is as described above;

[0167] n can be 1, 2, 3, 4 or 5.

[0168] The reaction conditions can be those conventional to this reaction in the art, such as the following conditions:

[0169] The solvent may be a haloalkane solvent (e.g., dichloromethane). The amount of solvent used may be the conventional amount used in the art, as long as it does not affect the reaction.

[0170] The deprotecting agent can be an acid, such as trifluoroacetic acid.

[0171] In one embodiment, the preparation method of compound II-a may further include the following steps: in a solvent, in the presence of a base and a condensing agent, compound II-e reacts with compound II-f to obtain a compound as shown in formula II-d;

[0172]

[0173] Among them, R b1 R b2 R b3 Rc and R d The definition is as described above;

[0174] n can be 1, 2, 3, 4 or 5.

[0175] The reaction conditions can be those conventional to this reaction in the art, such as the following conditions:

[0176] The solvent may be a formamide solvent (e.g., N,N-dimethylformamide). The amount of solvent used may be the conventional amount used in the art, as long as it does not affect the reaction.

[0177] The catalyst may be N,N′-diisopropylethylamine (DIPEA) or 2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU).

[0178] The molar ratio of the compound of formula II-e to the compound of formula II-f is preferably 1:1 to 1:1.5, more preferably 1:1.1 to 1:1.2.

[0179] The present invention provides a pharmaceutical composition comprising substance A, its stereoisomer or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients; wherein substance A is a compound as shown in Formula I or II; and wherein substance A, its stereoisomer or a pharmaceutically acceptable salt thereof may be in a therapeutically effective amount.

[0180] The present invention also provides the use of substance A, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of Bcl antiapoptotic protein inhibitors or in the preparation of medicaments for the treatment and / or prevention of diseases associated with Bcl antiapoptotic protein;

[0181] The substance A is either compound I or compound II mentioned above;

[0182] The “Bcl anti-apoptotic protein” is one or more of Bc1-XL, Bc1-2 and Mcl-1 proteins, preferably Mcl-1;

[0183] The “diseases associated with Bcl anti-apoptotic protein” may be cancer; the cancer is preferably leukemia; the leukemia may be, for example, human acute lymphoblastic leukemia or human plasma cell leukemia.

[0184] The present invention also provides the use of substance B, its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of protease degrading agents; said substance B is compound II.

[0185] The present invention also provides a method for treating diseases related to Bcl anti-apoptotic protein, comprising administering to a patient a therapeutically effective amount of substance A, its stereoisomer, its pharmaceutically acceptable salt, or the above-described pharmaceutical composition.

[0186] The “Bcl anti-apoptotic protein” is one or more of Bcl-XL, Bcl-2 and Mcl-1 proteins, preferably Mcl-1;

[0187] The “Bcl anti-apoptotic protein-related diseases” mentioned above can be cancer; the cancer mentioned above can be leukemia; the leukemia mentioned above can be human acute lymphoblastic leukemia or human plasma cell leukemia.

[0188] In the aforementioned applications, the Bc1 anti-apoptotic protein inhibitor can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of the Bcl anti-apoptotic protein inhibitory effect.

[0189] The pharmaceutical excipients described herein may be those widely used in the pharmaceutical manufacturing field. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods for enabling the active ingredient to dissolve at a desired rate after administration to a subject, or to promote the effective absorption of the active ingredient after administration to a subject. The pharmaceutical excipients may be inert fillers, or provide a function such as stabilizing the overall pH of the composition or preventing the degradation of the active ingredient. The pharmaceutical excipients may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0190] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0191] The pharmaceutical compositions of this invention can be administered in any form, including by injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical, or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical compositions of this invention can also be controlled-release or delayed-release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, tablets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of parenteral formulations include, but are not limited to, solutions for injection, dry formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and tablets.

[0192] Unless otherwise specified, all technical and scientific terms used herein have the standard meaning in the field to which the claimed subject matter pertains. Where multiple definitions exist for a term, the definition herein shall prevail.

[0193] It should be understood that the above general description and the following detailed description are merely illustrative and are not intended to limit the invention. The singular forms used in this invention, such as "a" or "an," include plural references unless otherwise specified. Furthermore, the term "comprising" is an open-ended limitation, not a closed one.

[0194] Unless otherwise stated, the present invention employs conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, or pharmacological detection. The steps and conditions can be referred to conventional operating procedures and conditions in the art.

[0195] Unless otherwise specified, this invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry. In certain cases, standard techniques are used in chemical synthesis, chemical analysis, drug preparation, formulation and drug delivery, and patient treatment.

[0196] The term "pharmaceutical acceptable" as used in this invention refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0197] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in the present invention, having specific substituents. When the compounds of the present invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, an acid addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, and certain specific compounds of the present invention contain both basic and acidic functional groups, thus allowing them to be converted into either a base or an acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, followed by separation of the parent compound, thereby regenerating the neutral form of the compound. The parent form of the compound differs from the forms of its various salts in certain physical properties, such as different solubilities in polar solvents.

[0198] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both. Non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred.

[0199] The small molecule Bcl anti-apoptotic protein inhibitor described in this invention can be used as a single agent or in combination with other therapeutic agents to enhance the efficacy of these therapeutic agents.

[0200] The terms “active ingredient,” “therapeutic agent,” or “active substance” refer to a chemical entity that can effectively treat a target disorder, disease, or symptom.

[0201] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0202] In this invention, the term "C1-C6 alkyl" preferably refers to methyl, ethyl, propyl, butyl, pentyl, or hexyl, each independently; wherein propyl is a C3 alkyl (including isomers, such as n-propyl or isopropyl); butyl is a C4 alkyl (including isomers, such as n-butyl, sec-butyl, isobutyl, or tert-butyl); and pentyl is a C5 alkyl (including isomers, such as n-pentyl < for example...). >, isopentyl < for example > or neopentyl < for example >); Hexyl is a C6 alkyl group (including isomers, such as n-hexyl);

[0203] In this invention, the term "C1-C4 alkyl" preferably refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, each independently.

[0204] In this invention, the term "C1-C4 alkoxy" is preferably independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy.

[0205] In this invention, the number of terms “substitution” can be one or more <e.g., 2, 3, 4 or 5>, and when there are multiple “substitutions”, the “substitutions” may be the same or different.

[0206] In this invention, the position of the term "replace" can be arbitrary unless otherwise specified.

[0207] The term "stereoisomer" in this document refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified, and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin-layer chromatography, rotational chromatography, column chromatography, gas chromatography, high-performance liquid chromatography, etc.). They can also be obtained through chiral resolution by bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound is not less than 95% relative to all stereoisomers of the compound.

[0208] The term "aryl" in this article refers to an aryl group having a specified number of carbon atoms (e.g., C6–C7). 10 Aryl groups are cyclic, unsaturated, monovalent hydrocarbon groups, which can be monocyclic or polycyclic (e.g., two or three). In polycyclic cases, the monocyclic rings share two atoms and one bond, and each ring is aromatic. The aryl group is linked to the rest of the aromatic ring molecule. Aryl groups include, but are not limited to, phenyl and naphthyl groups.

[0209] The term "heteroaryl" in this document refers to a cyclic, unsaturated monovalent group having a specified number of ring atoms (e.g., 3 to 10), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic; polycyclic forms are monocyclic rings that share two atoms and one bond (fusion), and each ring is aromatic. Heteroaryl groups are attached to the rest of the molecule via carbon atoms or heteroatoms; they are attached to the rest of the molecule via rings with or without heteroatoms. Heteroaryl groups include, but are not limited to: wait.

[0210] The term "heterocyclic alkyl" in this document refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 3 to 8), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which can be monocyclic, bicyclic, or polycyclic (preferably monocyclic). Heterocyclic alkyl groups are attached to the remainder of the molecule via carbon atoms or heteroatoms. (Monocyclic) heterocyclic alkyl groups include, but are not limited to: wait.

[0211] The term "cycloalkyl" in this document refers to a cyclic, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C3 to C8), which can be monocyclic, bicyclic, or polycyclic (preferably monocyclic). Cycloalkyl groups include, but are not limited to: wait.

[0212] The term "ligand" in this article is a biological concept, referring to a molecule or group that can bind to a target protein.

[0213] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0214] The reagents and raw materials used in this invention are all commercially available.

[0215] The significant advantages of this invention are that the phenylpyrazole compounds provided can effectively and selectively inhibit the key protein MCL-1 in the apoptosis process at the molecular level. Alternatively, they exhibit significant killing effects and high selectivity against cancer cells, especially human plasma cell leukemia cells H929 and human myeloid monocytic leukemia cells MV-4-11. They have the potential to be developed into novel anti-acute myeloid leukemia drugs and possess promising market prospects. Detailed Implementation

[0216] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0217] Example 1: Preparation of (E)-1-(1-(2-naphthyl)ethylene)-2-(m-tolyl)hydrazine (1)

[0218]

[0219] Add 3.54 g (20.8 mmol) of 2-naphthyl ethyl ketone, 50 mL of ethanol, 0.5 mL of acetic acid, and 4 g (25 mmol) of m-tolylhydrazine hydrochloride to a 100 mL round-bottom flask, and heat under reflux for 2 h with stirring. Extract three times with water (150 mL) and dichloromethane (30 mL), dry, filter, concentrate, and proceed directly to the next step.

[0220] Example 2 Preparation of 3-(2-ylnaphthalene)-1-(m-tolyl)-1H-pyrazole-4-carboxaldehyde (2)

[0221]

[0222] Add (E)-1-(1-(2-naphthyl)ethylene)-2-(m-tolyl)hydrazine (4.93 g, 18 mmol) and DMF (50 mL) to a 100 mL pear-shaped flask. Add phosphorus oxychloride (5.6 mL, 61.9 mmol) dropwise at 0 °C and stir at room temperature for 6 h. Extract three times with sodium bicarbonate aqueous solution (150 mL) and dichloromethane (50 mL), dry, filter, and concentrate. Column chromatography with petroleum ether:ethyl acetate (5:1) yields the solid product 3-(2-ylnaphthalene)-1-(m-tolyl)-1H-pyrazole-4-carboxaldehyde (2.8 g, 50%). 1 H NMR (400MHz, CDCl3) δ10.14 (s, 1H), 8.57 (s, 1H), 8.33 (s, 1H), 8.02-7.84 (m, 4H), 7.68(s, 1H), 7.64-7.49(m, 3H), 7.40(s, 1H), 7.23(s, 1H), 2.47(s, 3H).

[0223] Example 3 Preparation of 2-(diphenoxyphosphoryl)ethyl acetate (3)

[0224]

[0225] Diphenyl phosphate (8.23 g, 43 mmol), anhydrous dichloromethane (20 mL), and ethyl bromoacetate (6.2 mL, 55.9 mmol) were added to a 100 mL round-bottom flask. Triethylamine (7.77 mL, 55.9 mmol) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 6 h. The mixture was then extracted three times with 100 mL of aqueous solution and 40 mL of dichloromethane. The extract was dried, filtered, and concentrated. Column chromatography with petroleum ether:ethyl acetate (4:1) yielded a clear oil (7 g, 51%). 1 H NMR (400MHz, CDCl3) δ7.39-7.30(m, 4H), 7.26-7.12(m, 6H), 4.25-4.20(m, 2H), 3.35-3.12(m, 2H), 1.30-1.26(m, 3H).

[0226] Example 4: Preparation of (Z / E)-3-(3-(2-ylnaphthalene)-1-(m-tolyl)-1H-pyrazole-4-yl)ethyl acrylate (4)

[0227]

[0228] Add 2.8 g (8.8 mmol) of 2-(diphenoxyphosphoryl)ethyl acetate and 20 mL of anhydrous tetrahydrofuran to a 100 mL round-bottom flask. While stirring, add dropwise a tetrahydrofuran solution of 1.25 g (4 mmol) of 3-(2-ylnaphthalene)-1-(m-tolyl)-1H-pyrazole-4-carboxaldehyde. Stir at room temperature for 3 h. Extract three times with 100 mL of aqueous solution and 30 mL of dichloromethane. Dry, filter, concentrate, and proceed directly to the next step.

[0229] Example 5: Preparation of (Z / E)-3-(3-(2-naphthyl)-1-(m-tolyl)-1H-pyrazole-4-yl)acrylic acid (5)

[0230]

[0231] A mixture of (Z)-3-(3-(2-ylnaphthalene)-1-(m-tolyl)-1H-pyrazole-4-yl)acrylate and (E)-3-(3-(2-ylnaphthalene)-1-(m-tolyl)-1H-pyrazole-4-yl)acrylate, and tetrahydrofuran (20 mL) were added to a 100 mL pouch. A sodium hydroxide aqueous solution (960 mg, 24 mmol) was added dropwise with stirring, and the mixture was heated and stirred for 6 h. The pH was adjusted to acidic with dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate (20 mL). The extract was dried, filtered, and concentrated. Column chromatography with petroleum ether:ethyl acetate = 10:1 yielded yellow solids cis-5 (0.7 g, 49%) and trans-5 (0.5 g, 35%). cis-5: 1 H NMR (600MHz, DMSO-d6) δ12.36 (s, 1H), 9.24 (d, J = 0.6Hz, 1H), 8.15 (dd, J = 1.6, 0.8Hz, 1H), 8.07-8.05 (m, 2H), 8.01-7.99 (m, 1H), 7.82 (dd, J=8.4, 1.7Hz, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.70-7.67 (m, 1H), 7.60-7.57 (m, 2H), 7.45 (t, J=7.8Hz, 1H), 7.22 (ddt, J=7. 5, 1.7, 0.9Hz, 1H), 6.97 (dd, J=12.5, 0.7Hz, 1H), 5.94 (d, J=12.5Hz, 1H), 2.43 (s, 3H); 13C NMR(151 MHz,DMSO-d6)δ167.74,153.74,139.92,139.60,133.46,133.29,133.13,131.43,130.06,129.92,128.79,128.73,128.29,128.24,128.10,127.14,127.06,126.89,119.93,118.39,116.57,116.20,21.50;ESI-MS:m / z 355.1[M+H]+,ESI-HRMS:calcd for C 23 H 19 O2N2[M+H] + 355.1441,found 355.1439.

[0232] trans-5: 1 H NMR(600MHz,DMSO-d6)δ12.26(s,1H),9.26(s,1H),8.18(d,J=1.7Hz,1H),8.11-8.04(m,2H),8.01(dd,J=6.1,3.4Hz,1H),7.82(d,J=2.0Hz,1H),7.80(dd,J=8.4,1.7Hz,1H),7.76(dd,J=8.0,2.2Hz,1H),7.64-7.58(m,3H),7.45(t,J=7.8Hz,1H),7.22(dd,J=7.6,1.6Hz,1H),6.48(d,J=15.8Hz,1H),2.43(s,3H); 13 C NMR(151MHz,DMSO-d6)δ168.18,152.45,139.80,139.46,134.65,133.35,133.16,130.04,129.97,129.06,128.89,128.72,128.19,128.17,127.91,127.20,127.18,126.65,119.63,119.12,117.71,116.28,21.53;ESI-MS:m / z 355.1[M+H] + ,ESI-HRMS:calcd for C 23 H 19 O2N2[M+H] + 355.1441,found 355.1440.

[0233] Example 6: Preparation of (Z / E)-(3-(3-(2-naphthyl)-1-(m-tolyl)-1H-4-pyrazolyl)acryloyl)tryptophan (I-1, I-2)

[0234]

[0235] Add 5 (70 mg, 0.2 mmol), anhydrous DMF (10 mL), HATU (114 mg, 0.3 mmol), DIPEA (100 μL, 0.6 mmol), and L-tryptophan methyl ester hydrochloride (102 mg, 0.4 mmol) to a 50 mL round-bottom flask, and stir at room temperature for 6 h. Add water (60 mL), extract three times with ethyl acetate (15 mL), dry, filter, concentrate, and add to the next step. Add the previous raw material, tetrahydrofuran (10 mL), and potassium hydroxide aqueous solution (60 mg) to a 50 mL round-bottom flask, and heat and stir for 2 h. Adjust the pH to acidic by adding dilute hydrochloric acid, extract three times with ethyl acetate (15 mL), dry, filter, and concentrate. Column chromatography with petroleum ether:ethyl acetate = 1:1 yielded a yellow solid I-1 (83 mg, 77%), and I-2 was obtained in the same manner.

[0236] (Z)-(3-(3-(2-naphthyl)-1-(m-tolyl)-1H-4-pyrazolyl)acryloyl)-L-tryptophan (I-1)

[0237]

[0238] 1H NMR (600MHz, DMSO-d6) δ12.64 (s, 1H), 10.85 (d, J = 2.5Hz, 1H), 9.32 (s, 1H), 8.54 (d, J = 7.8Hz, 1H), 8.13 (d, J = 1.7Hz, 1H), 8.07-8.03 (m, 2H ), 7.99 (dt, J=6.9, 3.5Hz, 1H), 7.79 (dd, J=8.4, 1.7Hz, 1H), 7.68 (d, J=2.0Hz, 1H), 7.62 (dd, J=8.1, 2.3Hz, 1H), 7.60-7.56 (m, 3H), 7.42 (t, J=7.8Hz, 1H), 7.35-7.31 (m, 1H), 7.22-7.17 (m, 2H), 7.07 (ddd, J=8.1, 7.0, 1.2Hz, 1H), 6.99 (ddd, J=7.9, 6.9, 1.0Hz, 1H), 6.70 (d, J=12.5H z, 1H), 6.04 (d, J=12.6Hz, 1H), 4.63 (ddd, J=9.2, 7.8, 4.8Hz, 1H), 3.26 (dd, J=14.7, 4.8Hz, 1H), 3.08 (dd, J=14.7, 9.2Hz, 1H), 2.42 (s, 3H); 13 C NMR (151MHz, DMSO-d6) δ174.09, 166.12, 153.66, 139.86, 139.65, 136.57, 133. 28, 133.07, 131.58, 130.10, 130.03, 128.79, 128.77, 128.65, 128.33, 128.10, 128.06, 127.62, 127.08, 127.06, 127.02, 124.10, 121.42, 120.93, 119.74, 118 .87, 118.65, 116.53, 116.47, 111.88, 110.49, 53.57, 27.58, 21.51; ESI-MS: m / z 541.2[M+H] + ESI-HRMS: calcd for C 34 H 29 O3N4[M+H] + 541.2234, found 541.2234.

[0239] (E)-(3-(3-(2-naphthyl)-1-(m-tolyl)-1H-4-pyrazolyl)acryloyl)-L-tryptophan (I-2)

[0240]

[0241] 1 H NMR(600MHz,DMSO-d6)δ12.48(s,1H),10.85(d,J=2.4Hz,1H),8.98(s,1H),8.39(d,J=7.9Hz,1H),8.16(d,J=1.7Hz,1H),8.09-7.97(m,3H),7.84-7.74(m,3H),7.61-7.54(m,3H),7.48-7.42(m,2H),7.34(d,J=8.1Hz,1H),7.20(d,J=7.5Hz,1H),7.16(d,J=2.4Hz,1H),7.06(ddd,J=8.2,6.9,1.2Hz,1H),6.97(ddd,J=8.0,6.9,1.0Hz,1H),6.58(d,J=15.7Hz,1H),4.60(ddd,J=9.2,7.8,4.8Hz,1H),3.23(dd,J=14.6,4.8Hz,1H),3.08(dd,J=14.7,9.2Hz,1H),2.42(s,3H); 13 C NMR(151 MHz,DMSO-d6)δ174.04,172.48,165.62,152.08,139.75,139.56,136.58,133.37,133.12,130.27,129.93,129.87,128.80,128.73,128.23,128.14,128.05,127.71,127.62,127.10,126.63,124.05,122.13,121.41,119.70,118.86,118.63,118.16,116.32,111.86,110.51,53.64,27.53,21.54;ESI-MS:m / z541.2[M+H] + ,ESI-HRMS:calcd for C 34 H 29 O3N4[M+H] + 541.2234,found 541.2235.

[0242] In Example 7, 2-naphthyl ethyl ketone was replaced with p-methoxyacetophenone, and m-methylphenylhydrazine hydrochloride was replaced with m-chlorophenylhydrazine hydrochloride. The other required raw materials, reagents and preparation methods were the same as in Example 6. The esterification product (Z)-(3-(1-(3-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester was retained and further hydrolyzed to obtain the product (Z)-(3-(1-(3-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan). The same procedure yields (E)-(3-(1-(3-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester and (E)-(3-(1-(3-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan.

[0243] (Z)-(3-(1-(3-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan methyl ester (I-31)

[0244]

[0245] 1 H NMR (600MHz, DMSO-d6) δ10.87 (d, J=2.4Hz, 1H), 9.21 (s, 1H), 8.66 (d, J=7.5Hz, 1H), 7.89 (t, J=2.1Hz, 1H), 7.76 (ddd, J=8. 2, 2.2, 0.9Hz, 1H), 7.54 (td, J=7.9, 5.7Hz, 4H), 7.41 (ddd, J=8.0, 2.0, 0.9Hz, 1H), 7.33 (dt, J=8.1, 0.9Hz, 1H), 7.18 (d, J= 2.2Hz, 1H), 7.07 (dd, J=8.8, 2.2Hz, 3H), 6.99 (ddd, J=7.9, 7.0, 1.0Hz, 1H), 6.58 (d, J=12.6Hz, 1H), 6.01 (d, J=12.6Hz, 1H) , 4.66 (ddt, J=7.4, 5.4, 3.7Hz, 1H), 3.82 (s, 3H), 3.63 (s, 3H), 3.22 (dd, J=14.6, 5.4Hz, 1H), 3.10 (dd, J=14.6, 8.8Hz, 1H); 13C NMR (151MHz, DMSO-d6) δ173.13, 166.13, 160.04, 154.00, 140.77, 136.57, 134.53, 131.92, 131.46, 130.52 (2C), 128.81, 127.49, 126.90, 124 .61, 124.22, 121.47, 120.97, 118.92, 118.87, 118.48, 117.62, 116.50 , 114.63(2C), 111.94, 109.99, 55.71, 53.68, 52.40, 27.55; ESI-MS: m / z 555.2[M+H] + ESI-HRMS: calcd for C 31 H 28 O4N4Cl[M+H] + 555.1794, found 555.1792.

[0246] (Z)-(3-(1-(3-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan (I-32)

[0247]

[0248] 1 H NMR (600MHz, DMSO-d6) δ12.71 (s, 1H), 10.84 (d, J = 2.4Hz, 1H), 9.26 (s, 1H), 8.51 (d, J = 7.8Hz, 1H), 7.88 (t, J = 2.1Hz, 1H), 7.75 (ddd, J=8.2, 2.2, 0.9Hz, 1H), 7.58-7.51 (m, 4H), 7.41 (ddd, J=8.0, 2.1, 0.9Hz, 1H), 7.32 (d, J=8.0Hz, 1H), 7.17 (d, J=2.1Hz, 1H), 7.09-7.04 (m, 3H), 6.99 (ddd, J=8.0, 7.0, 1.0Hz, 1H), 6.56 (d, J=12.6Hz, 1H), 6.01 (d, J=12.6 Hz, 1H), 4.61 (ddt, J=9.2, 4.9, 3.1Hz, 1H), 3.82 (s, 3H), 3.25 (dd, J=14.7, 4.8Hz, 1H), 3.07 (dd, J=14.7, 9.1Hz, 1H); 13C NMR (151MHz, DMSO-d6) δ174.05, 166.01, 160.03, 154.05, 140.78, 136.56, 134.54, 131.92, 131.57, 130.54 (2C), 128.59, 127.62, 126.88, 124.62, 124.10, 121.41, 121.17, 118.90, 118.86, 118.65, 117.58, 116.54, 114.62(2C), 111.86, 110.46, 60.23, 55.70, 27.57; ESI-MS: m / z 541.2[M+H] + ESI-HRMS: calcdfor C 30 H 26 O4N4Cl[M+H] + 541.1637, found 541.1637.

[0249] (E)-(3-(1-(3-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan methyl ester (I-33)

[0250]

[0251] 1 H NMR (600MHz, DMSO-d6) δ10.88 (d, J=2.5Hz, 1H), 9.04 (d, J=0.7Hz, 1H), 8.58 (d, J=7.6Hz, 1H), 8.05 (t, J=2.1Hz, 1H), 7.92 (ddd, J=8.3, 2.2, 0.9Hz, 1H), 7.58-7.51 (m, 4H), 7.42 (ddd, J=8.0, 2.0, 0.9Hz, 1H), 7.38-7.33 (m, 2H) , 7.17 (d, J = 2.2Hz, 1H), 7.11-7.05 (m, 3H), 6.99 (ddd, J = 8.0, 7.0, 1.1Hz, 1H), 6.52 (d, J = 15.7Hz, 1H), 4.62 (ddt , J=7.3, 5.5, 3.7Hz, 1H), 3.82 (s, 3H), 3.62 (s, 3H), 3.21 (dd, J=14.8, 5.2Hz, 1H), 3.11 (dd, J=14.7, 8.9Hz, 1H); 13C NMR (151MHz, DMSO-d6) δ173.06, 165.63, 162.78, 160.11, 152.59, 140.71, 136.59, 134.53, 131.81, 130.07 (2C), 128.39, 127.49, 126.89, 124 .71, 124.16, 121.75, 121.47, 118.92, 118.73, 118.46, 118.11, 117.52 , 114.76(2C), 111.93, 110.07, 55.71, 53.81, 52.35, 27.48; ESI-MS: m / z 555.2[M+H] + ESI-HRMS: calcd for C 31 H 28 O4N4Cl[M+H] + 555.1794, found 555.1788.

[0252] (E)-(3-(1-(3-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan (I-34)

[0253]

[0254] 1 H NMR (600MHz, DMSO-d6) δ12.69 (s, 1H), 10.85 (d, J = 2.4Hz, 1H), 9.02 (s, 1H), 8.42 (d, J = 7.9Hz, 1H), 8.04 (t, J = 2.1Hz, 1H), 7.92 (ddd, J=8.2, 2.2, 0.9Hz, 1H), 7.58-7.53 (m, 4H), 7.41 (ddd, J=8.0, 2.1, 0.9Hz, 1H), 7.37-7. 32 (m, 2H), 7.16 (d, J=2.1Hz, 1H), 7.10-7.05 (m, 3H), 6.98 (ddd, J=7.9, 7.0, 1.0Hz, 1H), 6.53 (d, J=15.7Hz, 1H ), 4.59 (ddt, J=9.4, 4.9, 3.1Hz, 1H), 3.82 (s, 3H), 3.24 (dd, J=14.7, 4.8Hz, 1H), 3.09 (dd, J=14.7, 9.3Hz, 1H); 13C NMR(151 MHz, DMSO-d6) δ174.02, 165.54, 160.09, 152.55, 140.72, 136.57, 134.53, 131.80, 130.06 (2C), 129.79, 128.31, 127.62, 126.86, 124. 74, 124.05, 122.14, 121.41, 118.86, 118.72, 118.63, 118.18, 117.51, 114.75(2C), 111.86, 110.53, 60.23, 55.71, 27.51; ESI-MS: m / z 541.2[M+H] + ESI-HRMS: calcd for C 30 H 26 O4N4Cl[M+H] + 541.1637, found 541.1629.

[0255] In Example 8, 2-naphthyl ethyl ketone was replaced with 3-methoxyphenylacetone, and m-methylphenylhydrazine hydrochloride was replaced with m-chlorophenylhydrazine hydrochloride. The other required raw materials, reagents and preparation methods were the same as in Example 6. The esterification product (Z)-(3-(1-(3-chlorophenyl)-3-(3-methoxyphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester was retained, and (E)-(3-(1-(3-chlorophenyl)-3-(3-methoxyphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester was obtained by the same operation.

[0256] (Z)-(3-(1-(3-chlorophenyl)-3-(3-methoxyphenyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan methyl ester (I-35)

[0257]

[0258] 1H NMR (600MHz, DMSO-d6) δ10.87 (s, 1H), 9.21 (s, 1H), 8.67 (d, J = 7.5Hz, 1H), 7.91 (q, J = 1.9Hz, 1H), 7.78 (d , J=8.2Hz, 1H), 7.59-7.51(m, 2H), 7.47-7.41(m, 2H), 7.33(d, J=8.1Hz, 1H), 7.20-7.15(m, 2H), 7.14(s, 1H), 7.10-7.03 (m, 2H), 7.00 (t, J=7.5Hz, 1H), 6.62 (d, J=12.6Hz, 1H), 6.04 (d, J=12.6Hz, 1H), 4.69-4.6 2 (m, 1H), 3.83 (d, J = 1.7Hz, 3H), 3.63 (s, 3H), 3.23 (dd, J = 14.7, 5.4Hz, 1H), 3.10 (dd, J = 14.7, 8.8Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ172.47, 165.47, 159.19, 153.27, 140.09, 135.94, 133.92, 132.97, 131.30, 130.93, 129.65, 127.95, 126.86, 126.44, 123 .58, 120.92, 120.84, 120.68, 118.38, 118.29, 117.84, 117.15, 116.12, 1 14.10, 113.88, 111.30, 109.36, 55.03, 53.06, 51.76, 26.90.ESI-MS: m / z 555.2[M+H] + ,

[0259] (E)-(3-(1-(3-chlorophenyl)-3-(3-methoxyphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester (I-36)

[0260]

[0261] 1H NMR (600MHz, DMSO-d6) δ10.87 (d, J=2.3Hz, 1H), 9.06 (s, 1H), 8.59 (d, J=7.5Hz, 1H), 8.06 (t, J=2.0Hz, 1 H), 7.94 (dd, J=8.2, 2.2Hz, 1H), 7.58 (td, J=8.1, 1.3Hz, 1H), 7.52 (d, J=7.9Hz, 1H), 7.48-7.33 (m, 4H), 7.20-7.16 (m, 3H), 7.10-7.04 (m, 2H), 6.99 (t, J=7.4Hz, 1H), 6.54 (dd, J=15.8, 1.3Hz, 1H), 4.64 (td, J= 8.4, 6.3Hz, 1H), 3.82 (s, 3H), 3.62 (s, 3H), 3.22 (dd, J=14.6, 5.5Hz, 1H), 3.11 (dd, J=14.6, 8.9Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ172.39, 164.96, 159.28, 151.86, 140.02, 135.96, 133.92, 133.04, 131.20, 129.81, 129.29, 127.95, 126.86, 126.44, 123 .50, 121.41, 120.84, 120.47, 118.29, 118.25, 117.82, 117.75, 117.05, 1 14.13, 113.50, 111.30, 109.42, 55.03, 53.17, 51.71, 26.84.ESI-MS: m / z 555.2[M+H] + ,

[0262] In Example 9, 2-naphthyl ethyl ketone was replaced with 2-methoxyphenylacetone, and m-methylphenylhydrazine hydrochloride was replaced with m-chlorophenylhydrazine hydrochloride. The other required raw materials, reagents and preparation methods were the same as in Example 6. The esterification product (Z)-(3-(1-(3-chlorophenyl)-3-(2-methoxyphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester was retained, and (E)-(3-(1-(3-chlorophenyl)-3-(2-methoxyphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester was obtained by the same operation.

[0263] (Z)-(3-(1-(3-chlorophenyl)-3-(2-methoxyphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester (I-37)

[0264]

[0265] 1H NMR (600MHz, DMSO-d6) δ10.87 (s, 1H), 9.34 (d, J = 3.0Hz, 1H), 8.63-8.59 (m, 1H), 7.85 (s, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.55 (tt, J=8.3, 3.0Hz, 2H), 7.52-7.46 (m, 1H), 7.44-7.39 (m, 1H), 7.367.32 (m, 2H), 7.19-7.15 (m, 2H), 7.10-7.04 (m, 2H), 7.03-6.98 (m, 1H), 6.21 (dd, J=12.9, 3.0Hz, 1H), 5.88 (dd, J=12.8, 3.0Hz, 1H), 4.67 (dd, J=9.2, 5.3Hz, 1H), 3.75 (d, J=3.0Hz, 3H), 3.64 (d, J=3.0Hz, 3H), 3.25-3.20 (m, 1H), 3.13-3.06 (m, 1H). 13 C NMR (151MHz, DMSO-d6) δ172.51, 165.63, 156.88, 152.58, 140.18, 135.95, 133.90, 131.33 (2C), 130.48, 130.23, 128.76, 126.86, 126.23, 123.5 5, 120.84, 120.48, 120.32, 118.90, 118.29, 118.20, 117.84, 117.72, 11 6.95, 111.49, 111.30, 109.39, 55.23, 53.03, 51.77, 26.91.ESI-MS: m / z 555.2[M+H] + ,

[0266] (E)-(3-(1-(3-chlorophenyl)-3-(2-methoxyphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester (I-38)

[0267]

[0268] 1H NMR (600MHz, DMSO-d6) δ10.86 (s, 1H), 9.00 (d, J = 2.7Hz, 1H), 8.48 (d, J = 7.6Hz, 1H), 8.01 (s, 1H), 7.89 (d , J=8.4Hz, 1H), 7.56 (td, J=8.2, 2.6Hz, 1H), 7.50 (t, J=8.2Hz, 2H), 7.41 (d, J=8.1Hz, 1H), 7.39-7.32 (m, 2H), 7.20-7.16 (m, 1H), 7.15 (s, 1H), 7.11-7.05 (m, 3H), 7.01-6.96 (m, 1H), 6.32 (dd, J=15.8, 2.8Hz, 1H) , 4.59 (d, J = 7.6Hz, 1H), 3.71 (d, J = 2.7Hz, 3H), 3.60 (d, J = 2.7Hz, 3H), 3.223.17 (m, 1H), 3.123.05 (m, 1H). 13 CNMR (151MHz, DMSO-d6) δ172.44, 165.14, 156.77, 150.52, 140.13, 135.9 3, 133.89, 131.18, 130.99, 130.46, 130.18, 127.08, 126.84, 126.16, 123 .46, 120.82, 120.76, 120.36, 119.85, 119.32, 118.28, 118.00, 117.80, 1 16.80, 111.67, 111.28, 109.47, 55.21, 53.10, 51.67, 26.76.ESI-MS: m / z 555.2[M+H] + ,

[0269] In Example 10, 2-naphthyl ethyl ketone was replaced with p-methoxyphenylacetone, and m-methylphenylhydrazine hydrochloride was replaced with 3,5-dimethylphenylhydrazine hydrochloride. The other raw materials, reagents and preparation methods were the same as in Example 6. The esterification product (Z)-(3-(1-(3,5-dimethylyl)-3-(2-methoxyphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester was retained.

[0270] (Z)-(3-(1-(3,5-dimethylyl)-3-(2-methoxyphenyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan methyl ester (I-39)

[0271]

[0272] 1H NMR (400MHz, DMSO-d6) δ10.87 (s, 1H), 9.17 (s, 1H), 8.64 (d, J=7.5Hz, 1H), 7.52-7.49 (m, 3H ), 7.40 (s, 2H), 7.32 (d, J = 8.0Hz, 1H), 7.17 (d, J = 2.5Hz, 1H), 7.07-7.05 (m, 3H), 6.99 (d, J = 8.8Hz, 2H), 6.56 (d, J=12.6Hz, 1H), 5.95 (d, J=12.6Hz, 1H), 4.63 (q, J=7.6Hz, 1H), 3.81 (d, J=2.1Hz, 3H), 3.61 (s, 3H), 3.25-3.16 (m, 1H), 3.12-3.05 (m, 1H), 2.34 (s, 6H). ESI-MS: m / z 549.2[M+H] + ,

[0273] Example 11: 2-Naphthylacetone was replaced with 4′-cyclohexylacetophenone, and m-methylphenylhydrazine hydrochloride was replaced with m-chlorophenylhydrazine hydrochloride. The remaining raw materials, reagents, and preparation methods were the same as in Example 6. The esterification product (Z)-(3-(1-(3-(m-chlorophenyl)-3-(4-cyclohexylphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester was retained and further hydrolyzed to obtain the product (Z)-(3-(1-(3-(m-chlorophenyl)-3-(4-cyclohexylphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester. (E)-3-(1-(3-(m-chlorophenyl)-3-(4-cyclohexylphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan. The same procedure yields (E)-(3-(1-(3-(m-chlorophenyl)-3-(4-cyclohexylphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester and (E)-(3-(1-(3-(m-chlorophenyl)-3-(4-cyclohexylphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan.

[0274] (Z)-(3-(1-(3-(m-chlorophenyl)-3-(4-cyclohexylphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester (I-40)

[0275]

[0276] 1H NMR (600MHz, DMSO-d6) δ10.87 (d, J=2.4Hz, 1H), 9.22 (s, 1H), 8.66 (d, J=7.5Hz, 1H), 7.89 (t, J=2.1Hz, 1H), 7.76 (ddd, J=8.2, 2.2, 0.9Hz, 1H), 7 .57-7.50 (m, 4H), 7.42 (ddd, J=8.1, 2.0, 0.9Hz, 1H), 7.37-7.32 (m, 3H), 7.18 (d, J=2.2Hz, 1H), 7.06 (ddd, J=8.1, 6.9, 1.2Hz, 1H), 6.99 (ddd, J=7 .9, 7.0, 1.0Hz, 1H), 6.61 (dd, J=12.6, 0.7Hz, 1H), 6.02 (d, J=12.6Hz, 1H), 4.69-4.62 (m, 1H), 3.63 (s, 3H), 3.22 (dd, J=14.6, 5.4Hz, 1H), 3.10 (d d, J=14.6, 8.8Hz, 1H), 2.57 (tt, J=11.6, 3.3Hz, 1H), 1.82 (dq, J=8.9, 3. 0, 2.4Hz, 4H), 1.75-1.70 (m, 1H), 1.50-1.34 (m, 4H), 1.31-1.21 (m, 1H); 13 C NMR (151MHz, DMSO-d6) δ173.13, 166.13, 154.18, 148.52, 140.76, 136.57, 134 .54, 131.94, 131.52, 129.86, 129.19(2C), 128.77, 127.49, 127.47(2C), 126.9 6, 124.21, 121.47, 121.06, 118.92, 118.90, 118.47, 117.64, 116.61, 111.94, 1 10.00, 53.68, 52.40, 44.06, 34.34(2C), 27.50, 26.81(2C), 26.06; ESI-MS: m / z 607.2[M+H] + ESI-HRMS: calcd for C 36 H 36 O3N4Cl[M+H] + 607.2470, found 607.2476.

[0277] (Z)-(3-(1-(3-(m-chlorophenyl)-3-(4-cyclohexylphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan (I-41)

[0278]

[0279] 1 H NMR(600MHz,DMSO-d6)δ12.69(s,1H),10.84(d,J=2.4Hz,1H),9.28(s,1H),8.52(d,J=7.8Hz,1H),7.88(t,J=2.1Hz,1H),7.75(ddd,J=8.2,2.2,0.9Hz,1H),7.59-7.48(m,4H),7.42(ddd,J=8.0,2.1,0.9Hz,1H),7.38-7.34(m,2H),7.34-7.31(m,1H),7.17(d,J=2.1Hz,1H),7.06(ddd,J=8.0,6.9,1.2Hz,1H),6.98(ddd,J=8.0,7.0,1.0Hz,1H),6.58(d,J=12.6Hz,1H),6.02(d,J=12.7Hz,1H),4.61(ddt,J=9.2,4.9,3.2Hz,1H),3.25(dd,J=14.7,4.8Hz,1H),3.07(dd,J=14.7,9.2Hz,1H),2.57(tt,J=11.8,3.3Hz,1H),1.82(td,J=10.4,9.9,5.1Hz,4H),1.75-1.69(m,1H),1.50-1.34(m,4H),1.31-1.22(m,1H); 13 C NMR(151MHz,DMSO-d6)δ174.04,166.01,154.24,148.51,140.77,136.56,134.54,131.94,131.63,129.87,129.21(2C),128.56,127.61,127.47(2C),126.94,124.10,121.41,121.25,118.93,118.86,118.64,117.60,116.65,111.87,110.45,60.23,44.06,34.34(2C),27.56,26.81(2C),26.06;ESI-MS:m / z 593.2[M+H] + ,ESI-HRMS:calcd forC 35 H 34 O3N4Cl[M+H] + 593.2314,found 593.2313.

[0280] (E)-(3-(1-(3-(m-chlorophenyl)-3-(4-cyclohexylphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester (I-42)

[0281]

[0282] 1 H NMR (600MHz, DMSO-d6) δ10.88 (d, J=2.5Hz, 1H), 9.07 (s, 1H), 8.59 (d, J=7.5Hz, 1H), 8.05 (t, J=2.1Hz, 1H), 7.95-7.90 (m, 1H), 7.57 (t , J=8.1Hz, 1H), 7.53 (dd, J=8.0, 3.5Hz, 3H), 7.44-7.41 (m, 1H), 7.39-7.33 (m, 4H), 7.17 (d, J=2.1Hz, 1H), 7.09-7.05 (m, 1H), 7.01-6.9 7 (m, 1H), 6.54 (d, J=15.7Hz, 1H), 4.66-4.59 (m, 1H), 3.62 (s, 3H), 3.21 (dd, J=14.6, 5.4Hz, 1H), 3.11 (dd, J=14.6, 9.0Hz, 1H), 2.57 (t t, J=11.8, 3.3Hz, 1H), 1.86-1.79 (m, 4H), 1.72 (dd, J=13.0, 4.0Hz, 1H), 1.50-1.34 (m, 4H), 1.26 (dddd, J=15.9, 12.6, 8.2, 3.7Hz, 1H); 13 C NMR(151 MHz, DMSO-d6) δ173.06, 165.64, 152.84, 148.65, 140.71, 136.59, 134.54, 13 1.83, 130.05, 129.91, 128.74(2C), 128.29, 127.60(2C), 127.49, 126.96, 12 4.15, 121.86, 121.47, 118.92, 118.78, 118.47, 118.25, 117.56, 111.93, 110 .07, 53.82, 52.35, 44.06, 34.32(2C), 27.47, 26.80(2C), 26.05; ESI-MS: m / z 607.2[M+H] + ESI-HRMS: calcd for C 36 H 36 O3N4Cl[M+H] + 607.2470, found 607.2478.

[0283] (E)-(3-(1-(3-(m-chlorophenyl)-3-(4-cyclohexylphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan (I-43)

[0284]

[0285] 1 H NMR (600MHz, DMSO-d6) δ12.67 (s, 1H), 10.86 (s, 1H), 9.05 (s, 1H), 8.44 (d, J=7.8Hz, 1H), 8.05 (s, 1H), 7.93 (d, J=8 .3Hz, 1H), 7.55 (dd, J=23.6, 7.9Hz, 4H), 7.44-7.32 (m, 5H), 7.18 (s, 1H), 7.07 (t, J=7.5Hz, 1H), 6.99 (t, J=7.5Hz, 1 H), 6.56 (d, J=15.6Hz, 1H), 4.62-4.59 (m, 1H), 3.25 (dd, J=15.1, 4.7Hz, 1H), 3.10 (dd, J=14.7, 9.3Hz, 1H), 2.57 (t , J=12.1Hz, 1H), 1.82 (t, J=13.8Hz, 4H), 1.72 (d, J=13.0Hz, 1H), 1.43 (dq, J=25.5, 12.7Hz, 4H), 1.28-1.21 (m, 1H); 13 C NMR (151MHz, DMSO-d6) δ174.04, 165.56, 152.79, 148.62, 140.72, 136.58, 13 4.54, 131.81, 129.93, 129.73, 128.72(2C), 128.20, 127.63, 127.59(2C), 12 6.93, 124.04, 122.25, 121.41, 118.86, 118.76, 118.64, 118.32, 117.53, 111 .86, 110.54, 53.71, 44.07, 34.31(2C), 27.52, 26.80(2C), 26.05; ESI-MS: m / z 593.2[M+H] + ESI-HRMS: calcd for C 35 H 34 O3N4Cl[M+H] + 593.2314, found 593.2323.

[0286] In Example 12, 2-naphthyl ethylone was replaced with acetone, and m-methylphenylhydrazine hydrochloride was replaced with m-chlorophenylhydrazine hydrochloride. The remaining raw materials, reagents, and preparation methods were the same as in Example 6. The esterification product (Z)-(3-(1-(3-chlorophenyl)-3-phenylethyl-1H-pyrazole-4-yl)acryloyl)-L-tryptophan methyl ester was retained and further hydrolyzed to obtain the product (Z)-(3-(1-(3-chlorophenyl)-3-phenylethyl-1H-pyrazole-4-yl)acryloyl)-L-tryptophan. The same procedure was performed to obtain (E)-(3-(1-(3-chlorophenyl)-3-phenylethyl-1H-pyrazole-4-yl)acryloyl)-L-tryptophan methyl ester and (E)-(3-(1-(3-chlorophenyl)-3-phenylethyl-1H-pyrazole-4-yl)acryloyl)-L-tryptophan.

[0287] (Z)-(3-(1-(3-chlorophenyl)-3-phenylethyl-1H-pyrazole-4-yl)acryloyl)-L-tryptophan methyl ester (I-52)

[0288]

[0289] 1 H NMR (600MHz, Chloroform-d) δ9.11 (s, 1H), 8.02 (s, 1H), 7.75 (d, J=2.0Hz, 1H), 7.58 (dd, J=8.1, 2.1Hz, 1H), 7.51 (d, J= 7.9Hz, 1H), 7.33 (t, J=8.0Hz, 1H), 7.31-7.27 (m, 3H), 7.25-7.24 (m, 1H), 7.23 (s, 1H), 7.22 (d, J=7.1Hz, 1H), 7.19 (d, J= 7.3Hz, 1H), 7.16 (t, J=7.6Hz, 1H), 7.09 (t, J=7.5Hz, 1H), 6.93 (d, J=2.3Hz, 1H), 6.45 (d, J=12.4Hz, 1H), 6.15 (d, J=7.9 Hz, 1H), 5.59 (d, J=12.5Hz, 1H), 5.03 (dt, J=8.6, 5.3Hz, 1H), 3.74 (s, 3H), 3.37 (d, J=5.2Hz, 2H), 3.02 (t, J=2.6Hz, 4H). 13C NMR (151MHz, Chloroform-d) δ172.40, 165.92, 155.02, 141.49, 140.73, 136.07, 135.11, 130.67, 130.31, 128.97, 128.49 (2C), 128.46 (2C), 127.57, 126.34, 126.13, 122.65, 122.35, 119.80, 119.40, 118.51, 118.15, 117.11 , 116.39, 111.25, 110.01, 52.92, 52.47, 35.59, 28.44, 27.62.ESI-MS: m / z 553.2[M+H] + .

[0290] (Z)-(3-(1-(3-chlorophenyl)-3-phenylethyl-1H-pyrazole-4-yl)acryloyl)-L-tryptophan (I-53)

[0291]

[0292] 1 H NMR (600MHz, DMSO-d6) δ12.70 (s, 1H), 10.85 (d, J = 5.2Hz, 1H), 9.25 (d, J = 10.1Hz, 1H), 8.49 (d, J = 7.5Hz, 1H), 7 .79 (s, 1H), 7.67 (d, J = 8.2Hz, 1H), 7.59 (d, J = 8.0Hz, 1H), 7.51 (td, J = 8.2, 2.5Hz, 1H), 7.35 (dt, J = 14.5, 7.5Hz , 2H), 7.29 (d, J=4.4Hz, 4H), 7.18 (d, J=7.8Hz, 2H), 7.07 (t, J=7.2Hz, 1H), 7.00 (q, J=6.9Hz, 1H), 6.61 (d, J=12 .8Hz, 1H), 5.96 (d, J=12.2Hz, 1H), 4.65-4.61 (m, 1H), 3.30-3.24 (m, 1H), 3.12-3.06 (m, 1H), 3.01-2.95 (m, 4H). 13C NMR (151MHz, DMSO-d6) δ173.51, 165.53, 154.57, 141.15, 140.19, 135.94, 133.86, 131.24, 130.43, 128.26 (2C), 128.08 (2C), 127.41, 127.0 1, 125.85, 125.78, 123.44, 120.78, 119.38, 118.23, 118.02, 117.95, 116.58(2C), 111.24, 109.87, 52.93, 34.51, 27.46, 26.98.ESI-MS: m / z 539.2[M+H] +

[0293] (E)-(3-(1-(3-chlorophenyl)-3-phenylethyl-1H-pyrazole-4-yl)acryloyl)-L-tryptophan methyl ester (I-54)

[0294]

[0295] 1 H NMR (600MHz, Chloroform-d) δ8.12 (s, 1H), 7.96 (s, 1H), 7.71 (t, J=1.9Hz, 1H), 7 .57-7.50(m, 2H), 7.47(d, J=15.6Hz, 1H), 7.40-7.33(m, 2H), 7.28(s, 2H), 7.25( s, 1H), 7.23-7.15 (m, 4H), 7.09 (t, J=7.5Hz, 1H), 7.01-6.98 (m, 1H), 6.07-6.01 ( m, 2H), 5.09 (dd, J=8.2, 4.8Hz, 1H), 3.73 (s, 3H), 3.453.34 (m, 2H), 3.05 (s, 4H). 13 C NMR (151MHz, Chloroform-d) δ172.43, 165.48, 153.81, 141.36, 140.47, 136.11, 135.35, 131.11, 130.52, 128.53 (2C), 128.45 (2C), 127.76, 126.64, 126.27, 126.14, 122.77, 122.33, 119.79, 119.33, 119.05, 118.71, 118.36 , 116.79, 111.28, 110.17, 53.17, 52.43, 34.92, 29.23, 27.74.ESI-MS: m / z 553.2[M+H] +

[0296] (E)-(3-(1-(3-chlorophenyl)-3-phenylethyl-1H-pyrazol-4-yl)acryloyl)-L-tryptophan (I-55)

[0297]

[0298] 1 H NMR (600MHz, DMSO-d6) δ10.85 (s, 1H), 8.84 (s, 1H), 8.40 (t, J=6.1Hz, 1H), 7.92 (s, 1H), 7.8 1 (d, J=8.2Hz, 1H), 7.57 (dd, J=8.3, 3.9Hz, 1H), 7.53 (td, J=8.2, 2.3Hz, 1H), 7.39-7.26 (m, 7H), 7.217.15 (m, 2H), 7.06 (t, J=7.5Hz, 1H), 7.00-6.95 (m, 1H), 6.47 (dd, J=16.3, 4.9Hz, 1 H), 4.63 (t, J=7.4Hz, 1H), 3.25 (dd, J=14.1, 6.3Hz, 1H), 3.09 (q, J=7.4Hz, 1H), 3.03 (s, 4H). 13 C NMR (151MHz, DMSO-d6) δ173.45, 165.07, 152.51, 141.14, 140.08, 135.94, 133.85, 131.12, 128.88, 128.31 (3C), 128.11 (2C), 127.05, 1 25.78(2C), 123.35, 120.76, 120.45, 118.20, 118.05, 117.97, 117.65, 116.43, 111.21, 109.90, 53.05, 33.60, 28.64, 27.07.ESI-MS: m / z 539.2[M+H] +

[0299] Example 13

[0300]

[0301] Add (Z)-(3-(3-(4-nitrophenyl)-1-(m-tolyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan methyl ester 28.5 mg (0.05 mmol), methanol (10 mL), iron powder (14 mg (0.25 mmol), and ammonium chloride aqueous solution (8 mg (0.15 mmol)) to a 50 mL pouch and heat under reflux with stirring for 5 h. Remove the iron powder by diatomaceous earth filtration, add water (10 mL), and extract three times with dichloromethane (10 mL). Dry, filter, concentrate, and precipitate by column chromatography in petroleum ether:ethyl acetate = 1:1 to obtain solid (Z)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan methyl ester (27 mg, 100%). Methanol hydrolysis yields (Z)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan. The same procedure yields (E)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester and (E)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan.

[0302] (Z)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester (I-56)

[0303]

[0304] 1 H NMR (600MHz, DMSO-d6) δ10.87 (s, 1H), 9.18 (s, 1H), 8.63 (d, J=7.5Hz, 1H), 7.86 (t, J=2.0Hz, 1H), 7.74 (d, J=8.1Hz, 1H), 7.53 (dt, J=7.9, 4.1Hz, 2H), 7.41-7.30 (m, 2H), 7.28 (d, J=8.0Hz, 2H), 7.19 (s, 1H), 7.07 (t, J=7.5Hz, 1H), 7.00 (t, J=7.4Hz, 1H), 6.68 (d, J=8.0Hz, 2H), 6.59 (d, J=12.5Hz, 1H), 5.98 (d, J =12.6Hz, 1H), 5.40 (s, 2H), 4.66 (q, J = 7.4Hz, 1H), 3.63 (s, 3H), 3.26-3.20 (m, 1H), 3.14-3.07 (m, 1H). 13C NMR (151MHz, DMSO-d6) δ172.53, 165.61, 154.40, 149.09, 140.24, 135.95, 133.87, 131.24, 130.60, 129.43 (2C), 128.69, 126.87, 125.97, 123.58, 120.84, 119.68, 118.71, 118.29, 118.05, 117.85, 116.77, 115.58, 113.52(2C), 111.31, 109.39, 53.04, 51.76, 26.92.ESI-MS: m / z 540.2[M+H] + ESI-HRMS: calcd for C 30 H 26 ClN5O3[M+H] + 540.1797, found 540.1796.

[0305] (Z)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan (I-57)

[0306]

[0307] 1 H NMR (600MHz, DMSO-d6) δ10.85 (s, 1H), 9.23 (s, 1H), 8.48 (d, J = 7.8Hz, 1H), 7.86 (s, 1H), 7.72 (d, J = 8.2Hz, 1H), 7 .57 (d, J=7.9Hz, 1H), 7.53 (t, J=8.1Hz, 1H), 7.39 (dd, J=8.0, 2.0Hz, 1H), 7.33 (d, J=8.1Hz, 1H), 7.28 (d, J=8.2Hz , 2H), 7.18 (s, 1H), 7.06 (t, J=7.5Hz, 1H), 6.99 (t, J=7.4Hz, 1H), 6.68 (d, J=8.2Hz, 2H), 6.57 (d, J=12.6Hz, 1H), 5.98 (d, J=12.6Hz, 1H), 4.61 (td, J=8.4, 4.8Hz, 1H), 3.25 (dd, J=14.7, 4.8Hz, 1H), 3.08 (dd, J=14.7, 9.1Hz, 1H). 13C NMR (151MHz, DMSO-d6) δ173.46, 165.49, 154.44, 149.04, 140.24, 135.93, 133.87, 131.25, 130.71, 129.44 (2C), 128.47, 126.99, 125. 96, 123.46, 120.77, 119.88, 118.74, 118.23, 118.08, 118.01, 116.73, 115.62, 113.53(2C), 111.23, 109.84, 52.92, 26.94.ESI-MS: m / z 526.2[M+H] + ESI-HRMS: calcd for C 29 H 24 ClN5O3[M+H] + 526.1640, found 526.1627.

[0308] (E)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester (I-58)

[0309]

[0310] 1 H NMR (600MHz, DMSO-d6) δ 10.88 (s, 1H), 8.98 (s, 1H), 8.56 (d, J = 7.5Hz, 1H), 8.03 (d, J = 2.5Hz, 1H), 7.91 (d , J=8.2Hz, 1H), 7.577.51 (m, 2H), 7.40 (d, J=7.4Hz, 2H), 7.37-7.33 (m, 1H), 7.32-7.28 (m, 2H), 7.18 (s, 1H ), 7.08 (t, J=7.5Hz, 1H), 7.00 (t, J=7.6Hz, 1H), 6.69 (d, J=8.0Hz, 2H), 6.51 (dd, J=15.7, 2.0Hz, 1H), 5.4 2 (s, 2H), 4.64 (q, J=7.5Hz, 1H), 3.62 (s, 3H), 3.22 (dd, J=14.8, 5.4Hz, 1H), 3.12 (dd, J=14.6, 8.5Hz, 1H). 13C NMR (151MHz, DMSO-d6) δ172.46, 165.13, 152.92, 149.15, 140.18, 135.96, 133.87, 131.13, 129.99, 128.94 (2C), 127.41, 126.87, 125.96, 123.52, 120.84, 120.59, 118.86, 118.29, 117.91, 117.84, 117.18, 116.70, 113.62(2C), 111.30, 109.46, 53.17, 51.71, 26.86.ESI-MS: m / z 540.2[M+H] + ESI-HRMS: calcd for C 30 H 26 ClN5O3[M+H] + 540.1797, found 540.1790.

[0311] (E)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan (I-59)

[0312]

[0313] 1 H NMR (600MHz, DMSO-d6) δ10.85 (s, 1H), 8.96 (s, 1H), 8.40 (d, J=7.8Hz, 1H), 8.02 (s, 1H), 7.90 (d, J=8.2Hz, 1H), 7.59-7.53 (m, 2H), 7.41-7.36 (m, 2H), 7.36-7.32 (m, 2H), 7.30 (d, J=8.0Hz, 2H), 7 .17 (s, 1H), 7.07 (t, J=7.5Hz, 1H), 6.99 (t, J=7.5Hz, 1H), 6.69 (d, J=8.0Hz, 2H), 6.52 (d, J=15.7 Hz, 1H), 4.60 (td, J=8.5, 4.8Hz, 1H), 3.24 (dd, J=14.7, 4.9Hz, 1H), 3.09 (dd, J=14.6, 9.5Hz, 1H). 13C NMR (151MHz, DMSO-d6) δ173.43, 165.04, 152.89, 149.17, 140.18, 135.94, 133.86, 131.12, 129.67, 128.93 (2C), 127.31, 126.98, 125. 93, 123.41, 120.94, 120.78, 118.85, 118.23, 118.00, 117.90, 117.23, 116.68, 113.59(2C), 111.23, 109.90, 53.02, 26.89.ESI-MS: m / z 526.2[M+H] + ESI-HRMS: calcdfor C 29 H 24 ClN5O3[M+H] + 526.1640, found 526.1632.

[0314] Example 14

[0315]

[0316] (Z)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester (54 mg, 0.1 mmol), anhydrous DMF (8 mL), and DIPEA (39 mg, 0.3 mmol) were added to a 50 mL two-necked flask. Under nitrogen protection, 1-bromo-2-(2-bromoethoxy)ethane (30 mg, 0.13 mmol) was added, and the mixture was stirred at 75 °C for 6 h. Water (10 mL) and ethyl acetate (10 mL) were added and extracted three times. The mixture was dried, filtered, and concentrated. Column chromatography with petroleum ether:ethyl acetate = 1:1 yielded solid (Z)-(3-(1-(3-chlorophenyl)-3-(4-morpholinophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester (16 mg, 27%). Methanol hydrolysis yields (Z)-(3-(1-(3-chlorophenyl)-3-(4-morpholinophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan. The same procedure yields (E)-(3-(1-(3-chlorophenyl)-3-(4-morpholinophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester and (E)-(3-(1-(3-chlorophenyl)-3-(4-morpholinophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan.

[0317] (Z)-(3-(1-(3-chlorophenyl)-3-(4-morpholinophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester (I-60)

[0318]

[0319] 1 H NMR (600MHz, CDCl3) δ9.10 (s, 1H), 8.06 (s, 1H), 7.80 (s, 1H), 7.64 (d, J=8.1Hz, 1H ), 7.57 (s, 2H), 7.50 (d, J = 7.7Hz, 1H), 7.33 (t, J = 8.0Hz, 1H), 7.24 (d, J = 8.0Hz, 2H) , 7.09 (dt, J=29.3, 7.2Hz, 4H), 6.92 (s, 1H), 6.66 (s, 1H), 6.33-6.23 (m, 1H), 5.71 ( s, 1H), 5.04 (d, J=5.5Hz, 1H), 3.94 (s, 4H), 3.75 (s, 3H), 3.37 (s, 2H), 3.27 (s, 4H). 13 C NMR (151MHz, CDCl3) δ171.81, 165.35, 153.71, 140.01, 135.44, 134.48, 130.19, 129.68 (2C), 129.48 (2C), 126.85, 125.90 (2C), 122.05, 121.7 3(2C),119.18,118.83(2C),118.70,117.79,116.54,115.28,110.65(2 C), 109.29, 65.98(2C), 52.29, 51.90, 48.96, 29.07, 26.91.ESI-MS: m / z 610.2[M+H] + ESI-HRMS: calcd for C 34 H 32 ClN5O4[M+H] + 610.2216, found 610.2195.

[0320] (Z)-(3-(1-(3-chlorophenyl)-3-(4-morpholinophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan (I-61)

[0321]

[0322] 1H NMR (600MHz, DMSO-d6) δ12.74 (s, 1H), 10.85 (s, 1H), 9.27-9.24 (m, 1H), 8.50 (d, J=7.6Hz, 1H), 7.88 (s, 1H), 7.77-7.72 ( m, 1H), 7.58 (dd, J=8.2, 2.9Hz, 1H), 7.54 (t, J=8.1Hz, 1H), 7.48 (d, J=8.4Hz, 2H), 7.41 (d, J=7.9Hz, 1H), 7.33 (d, J=8.0Hz , 1H), 7.19 (s, 1H), 7.08-7.04 (m, 3H), 6.99 (t, J=7.5Hz, 1H), 6.58 (d, J=12.5Hz, 1H), 6.04-5.99 (m, 1H), 4.62 (dd, J=8.5 , 5.0Hz, 1H), 3.77 (t, J=4.6Hz, 3H), 3.26 (dd, J=14.7, 4.8Hz, 1H), 3.21-3.17 (m, 4H), 3.08 (ddd, J=14.8, 9.5, 3.6Hz, 1H). 13 C NMR (151MHz, DMSO-d6) δ173.48, 165.42, 153.67, 150.90, 140.19, 135.93 ,133.90,131.27,130.88,129.33(2C),128.13,127.01,126.14,123.46, 122.04, 120.77, 120.35, 118.22, 118.21, 118.02, 116.86, 115.86, 114.5 6(2C), 111.23, 109.87, 65.87(2C), 52.97, 47.78(2C), 26.96.ESI-MS: m / z 596.2 [M+H] + ESI-HRMS: calcd for C 33 H 30 ClN5O4[M+H] + 596.2059, found 596.2044.

[0323] (E)-(3-(1-(3-chlorophenyl)-3-(4-morpholinophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester (I-62)

[0324]

[0325] 1H NMR (600MHz, CDCl3) δ8.09 (s, 1H), 7.79 (s, 1H), 7.68-7.56 (m, 4H), 7.56-7.48 (m, 2H), 7.44-7.35 (m, 2H), 7.28 (s, 2H), 7.21-7. 15(m, 2H), 7.14-7.06(m, 2H), 7.05-6.94(m, 1H), 6.16(s, 1H), 5.10(s, 1H), 3.97(s, 4H), 3.73(s, 3H), 3.40(s, 2H), 3.26(s, 4H). 13 CNMR (151MHz, CDCl3) δ172.51, 165.42, 140.38, 136.18, 135.39, 130.62(2C), 129.75(2C), 127.75, 126.90(2C), 123.07, 122.23(3C), 119.69( 2C), 119.50(2C), 118.67(2C), 118.09, 117.04, 111.42(2C), 109.99, 72 .14, 70.92, 61.73, 53.00, 52.54, 29.70, 27.76.ESI-MS: m / z610.2[M+H] + ESI-HRMS: calcd for C 34 H 32 ClN5O4[M+H] + 610.2216, found 610.2188.

[0326] (E)-(3-(1-(3-chlorophenyl)-3-(4-morpholinophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan (I-63)

[0327]

[0328] 11H NMR (600 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.00 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.04 (s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.59 - 7.47 (m, 4H), 7.43 - 7.36 (m, 1H), 7.36 - 7.32 (m, 2H), 7.17 (s, 1H), 7.10 - 7.04 (m, 3H), 6.98 (t, J = 7.5 Hz, 1H), 6.54 (d, J = 15.7 Hz, 1H), 4.59 (dt, J = 8.9, 4.8 Hz, 1H), 3.76 (t, J = 4.8 Hz, 4H), 3.25 (dd, J = 14.7, 4.5 Hz, 1H), 3.19 (t, J = 4.9 Hz, 4H), 3.15 - 3.06 (m, 1H). 13 13C NMR (151 MHz, DMSO-d6) δ 173.54, 164.90, 152.15, 150.95, 140.13, 135.93, 133.88, 131.15, 129.27, 128.82 (2C), 127.51, 127.05, 126.11, 123.38, 122.13, 121.46, 120.74, 118.20, 118.02, 117.52, 116.80, 114.65 (2C), 114.47, 111.20, 110.02, 65.86 (2C), 53.20, 47.74 (2C), 26.93. ESI-MS: m / z 596.2 [M+H] + , ESI-HRMS: calcd for C 33 H 30 ClN5O4 [M+H] + 596.2059, found 596.2041.

[0329] Example 15

[0330]

[0331] (Z)-(3-(1-(3-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan methyl ester (55 mg, 0.1 mmol), dichloromethane (5 mL), and boron tribromide (5 mL) were added to a 50 mL round-bottom flask and stirred at room temperature for 5 h. The reaction was quenched with methanol, and column chromatography with dichloromethane:methanol = 20:1 yielded solid (Z)-(3-(1-(3-chlorophenyl)-3-(4-hydroxyphenyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan methyl ester (37 mg, 67%). Hydrolysis with methanol yielded (Z)-(3-(1-(3-chlorophenyl)-3-(4-hydroxyphenyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan. The same operation yields (E)-(3-(1-(3-chlorophenyl)-3-(4-hydroxyphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester and (E)-(3-(1-(3-chlorophenyl)-3-(4-hydroxyphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan.

[0332] (Z)-(3-(1-(3-chlorophenyl)-3-(4-hydroxyphenyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan methyl ester (I-64)

[0333]

[0334] 1 H NMR (600MHz, DMSO-d6) δ10.87 (s, 1H), 9.74 (s, 1H), 9.21 (s, 1H), 8.65 (d, J=7.5Hz, 1H), 7.89 (s, 1H), 7. 76 (d, J=8.2Hz, 1H), 7.57-7.52 (m, 2H), 7.47-7.38 (m, 3H), 7.38-7.33 (m, 1H), 7.19 (s, 1H), 7.07 (t, J=7 .4Hz, 1H), 7.00 (t, J=7.4Hz, 1H), 6.91 (d, J=8.0Hz, 2H), 6.59 (d, J=12.6Hz, 1H), 6.01 (d, J=12.5Hz, 1H) , 4.66 (dq, J=16.0, 7.4Hz, 1H), 3.64 (s, 3H), 3.24 (dd, J=14.6, 5.4Hz, 1H), 3.12 (dd, J=14.4, 8.3Hz, 1H). 13C NMR (151MHz, DMSO-d6) δ172.50, 165.55, 157.76, 153.78, 140.17, 135.95, 133.90, 131.25, 130.73, 129.92 (2C), 128.34, 126.88, 126.15, 123.58, 122.35, 120.84, 120.11, 118.29, 118.17, 117.85, 116.90, 115.77, 115.33(2C), 111.31, 109.38, 53.05, 51.76, 26.92.ESI-MS: m / z 541.2[M+H] + ESI-HRMS: calcd for C 30 H 25 ClN4O4[M+H] + 541.1637, found 541.1621.

[0335] (Z)-(3-(1-(3-chlorophenyl)-3-(4-hydroxyphenyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan (I-65)

[0336]

[0337] 1 H NMR (600MHz, DMSO-d6) δ12.68 (s, 1H), 10.84 (s, 1H), 9.74 (s, 1H), 9.26 (s, 1H), 8.50 (d, J=7.7Hz, 1H), 7. 88 (d, J=2.2Hz, 1H), 7.74 (d, J=8.3Hz, 1H), 7.63-7.50 (m, 2H), 7.47-7.39 (m, 3H), 7.33 (d, J=8.4Hz, 1H), 7 .18(s, 1H), 7.10-7.04(m, 1H), 7.04-6.97(m, 1H), 6.90(d, J=8.0Hz, 2H), 6.57(d, J=12.6Hz, 1H), 6.01(d , J=12.6Hz, 1H), 4.62 (td, J=8.8, 5.1Hz, 1H), 3.26 (dd, J=14.8, 5.1Hz, 1H), 3.08 (dd, J=14.8, 9.0Hz, 1H). 13C NMR (151MHz, DMSO-d6) δ173.45, 165.43, 157.74, 153.83, 140.18, 135.93, 133.90, 131.27, 130.85, 129.94 (2C), 129.44, 128.13, 127.00, 12 6.15, 123.46, 122.36, 120.77, 120.31, 118.22, 118.01, 116.86, 115.8 0, 115.32(2C), 111.23, 109.84, 52.93, 26.94.ESI-MS: m / z527.2[M+H] + ESI-HRMS: calcd for C 29 H 23 ClN4O4[M+H] + 527.1481, found 527.1460.

[0338] (E)-(3-(1-(3-chlorophenyl)-3-(4-hydroxyphenyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan methyl ester (I-66)

[0339]

[0340] 1 H NMR (600MHz, DMSO-d6) δ10.99 (s, 1H), 9.90 (s, 1H), 9.03 (s, 1H), 8.63 (d, J=7.5Hz, 1H), 8.04 (s, 1H), 7 .92 (d, J=8.2Hz, 1H), 7.58-7.50 (m, 2H), 7.44 (d, J=7.9Hz, 2H), 7.40 (d, J=8.0Hz, 1H), 7.38-7.33 (m, 2 H), 7.20 (s, 1H), 7.07 (t, J=7.6Hz, 1H), 6.99 (t, J=7.5Hz, 1H), 6.94 (d, J=7.9Hz, 2H), 6.55 (d, J=15.7H z, 1H), 4.63 (q, J=7.3Hz, 1H), 3.62 (s, 3H), 3.22 (dd, J=14.7, 5.2Hz, 1H), 3.13 (dd, J=14.6, 9.3Hz, 1H). 13C NMR (151MHz, DMSO-d6) δ172.44, 165.10, 157.90, 152.35, 140.10, 135.96, 133.89, 131.16, 129.62, 129.42 (2C), 127.64, 126.84, 126.15, 123.6 0, 122.40, 120.97, 120.80, 118.27, 118.02, 117.79, 117.38, 116.81, 11 5.48(2C), 111.33, 109.38, 53.22, 51.71, 26.83.ESI-MS: m / z541.2[M+H] + ESI-HRMS: calcd for C 30 H 25 ClN4O4[M+H] + 541.1637, found 541.1622.

[0341] (E)-(3-(1-(3-chlorophenyl)-3-(4-hydroxyphenyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan (I-67)

[0342]

[0343] 1 H NMR (600MHz, DMSO-d6) δ12.60 (s, 1H), 10.85 (d, J = 2.4Hz, 1H), 9.76 (s, 1H), 9.00 (s, 1H), 8.42 (d, J = 7.9Hz, 1 H), 8.04 (s, 1H), 7.92 (d, J=8.3Hz, 1H), 7.59-7.51 (m, 2H), 7.47-7.43 (m, 2H), 7.41 (dd, J=7.9, 1.9Hz, 1H), 7. 38-7.32 (m, 2H), 7.17 (d, J=2.5Hz, 1H), 7.07 (t, J=7.5Hz, 1H), 6.99 (t, J=7.5Hz, 1H), 6.94-6.89 (m, 2H), 6.5 3(d, J=15.7Hz, 1H), 4.60 (tt, J=8.3, 3.8Hz, 1H), 3.24 (dd, J=14.7, 4.7Hz, 1H), 3.09 (dd, J=15.0, 9.6Hz, 1H). 13C NMR (151MHz, DMSO-d6) δ173.42, 164.96, 157.81, 152.29, 140.12, 135.95, 133.89, 131.15, 129.44 (2C), 129.34, 127.55, 126.98, 126. 13, 123.41, 122.49, 121.29, 120.78, 118.23, 118.03, 118.00, 117.43, 116.81, 115.44(2C), 111.24, 109.90, 53.04, 26.89.ESI-MS: m / z 527.2[M+H] + ESI-HRMS: calcd for C 29 H 23 ClN4O4[M+H] + 527.1481, found 527.1464.

[0344] Example 16

[0345]

[0346] In a 50 mL round-bottom flask, (E)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester (I-58, 73 mg, 0.135 mmol), anhydrous DMF (10 mL), HATU (77 mg, 0.202 mmol), DIPEA (67 μL, 0.405 mmol), and 3-(2-((tert-butoxycarbonyl)amino)ethoxy)propionic acid (35 mg, 0.16 mmol) were added and stirred overnight at room temperature. The mixture was then extracted three times with water (20 mL) and ethyl acetate (20 mL), dried, filtered, and concentrated. Column chromatography with petroleum ether:ethyl acetate (1:1) yielded solid I-58-Linker-NHBoc. I-58-Linker-NHBoc, anhydrous dichloromethane (2 mL), and trifluoroacetic acid (2 mL) were then added to a 50 mL round-bottom flask and stirred at room temperature for 1 h. The mixture was then extracted three times with sodium bicarbonate aqueous solution (5 mL) and dichloromethane (5 mL), dried, filtered, and concentrated before being added to the next reaction step. Anhydrous DMF (10 mL), HATU (68 mg, 0.178 mmol), DIPEA (60 μL, 0.365 mmol), and thalidomide acetic acid (48 mg, 0.144 mmol) were added and stirred overnight at room temperature. The mixture was then extracted three times with water (10 mL) and ethyl acetate (10 mL), dried, filtered, and concentrated. Column chromatography with dichloromethane:methanol (20:1) yielded solid I-58-PROTAC2, which was hydrolyzed with p-methyl ester to give I-59-PROTAC2.

[0347] I-58-PROTAC2(I-68)

[0348]

[0349] 1 H NMR(600MHz,DMSO-d6)δ11.12(s,1H),10.87(s,1H),10.12(s,1H),9.05(s,1H),8.59(d,J=7.6Hz,1H),8.078.02(m,2H),7.93(d,J=8.3Hz,1H),7.80(t,J=7.9Hz,1H),7.74(d,J=8.2Hz,2H),7.61-7.50(m,4H),7.47(d,J=7.3Hz,1H),7.43(d,J=8.1Hz,1H),7.41-7.32(m,3H),7.18(s,1H),7.07(t,J=7.6Hz,1H),6.99(t,J=7.6Hz,1H),6.53(d,J=15.7Hz,1H),5.12(dd,J=12.9,5.4Hz,1H),4.78(s,2H),4.63(q,J=7.5Hz,1H),3.74(t,J=6.4Hz,2H),3.62(s,3H),3.49(t,J=6.0Hz,2H),3.42-3.37(m,2H),3.22(dd,J=14.9,5.3Hz,1H),3.18(s,1H),3.11(dd,J=14.7,8.9Hz,1H),2.89(ddd,J=18.1,14.1,5.4Hz,1H),2.64-2.53(m,4H). 13C NMR(151MHz,DMSO-d6)δ172.60,172.42,169.72,169.21,166.77,166.55,165.27,164.98,154.84,151.76,140.05,139.43,136.73,135.95,133.90,132.86,131.19,129.41,128.50(2C)127.83,126.85,126.31(2C),123.52,121.24,120.83,120.18,118.95(2C),118.29,118.14,117.83,117.55,116.92,116.61,115.86,111.29,109.43,68.43,67.35,66.21,64.75,53.18,51.72,48.63,36.91,30.78,26.86,21.83.ESI-MS:m / z 969.2[M+H] + ,

[0350] I-59-PROTAC2(I-69)

[0351]

[0352] 1 H NMR(600MHz,DMSO-d6)δ12.61(s,1H),10.84(s,1H),10.14(s,1H),9.03(s,1H),8.49-8.41(m,1H),8.05(s,1H),7.97-7.86(m,2H),7.81-7.73(m,2H),7.60-7.55(m,4H),7.49-7.40(m,2H),7.39-7.33(m,2H),7.29-7.25(m,1H),7.23-7.14(m,2H),7.07(t,J=7.5Hz,1H),6.99(t,J=7.5Hz,1H),6.82(s,1H),6.54(d,J=15.7Hz,1H),4.64-4.49(m,3H),4.33(q,J=8.0,7.5Hz,1H),3.72(t,J=6.3Hz,2H),3.47(t,J=6.0Hz,2H),3.33-3.30(m,6H),3.27-3.16(m,1H),3.09(dd,J=14.8,9.2Hz,1H),2.60(q,J=6.9Hz,2H). 13C NMR (151MHz, DMSO-d6) δ173.55, 173.39, 173.05, 171.85, 170.18, 169.23, 166.26, 164.91, 154.36, 151.76 ,140.06,139.43,135.94,134.61,133.90,131.18,130.89,129.85,129.62,129.08,128.53(2C),127.77, 126.97, 126.42, 126.29, 123.41, 121.61, 120.78, 120.27, 118.98(2C), 118.23, 118.13, 118.00, 117.63, 1 16.92, 111.23, 109.88, 68.41, 66.23, 59.59, 53.03, 52.04, 36.91, 31.33, 26.89, 20.89, 20.60.ESI-MS: m / z 955.2[M+H] + ,

[0353] Example 17

[0354] Replace (E)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester with (z)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester, and replace 3-(2-((tert-butoxycarbonyl)amino)ethoxy)propionic acid with N-Boc-3-[2-(2-aminoethoxy)ethoxy]propionic acid. The remaining raw materials, reagents, and preparation methods are the same as in Example 16, yielding product I-56-PROTAC1 (I-70).

[0355] I-56-PROTAC1(I-70)

[0356]

[0357] 11H NMR (600 MHz, DMSO-d6) δ 11.12 (s, 1H), 10.95 (s, 1H), 10.29 (s, 1H), 9.20 (s, 1H), 8.74 - 8.70 (m, 1H), 8.10 - 8.07 (m, 1H), 7.89 (s, 1H), 7.83 - 7.75 (m, 4H), 7.58 - 7.50 (m, 4H), 7.48 (d, J = 7.2 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.34 (d, J = 8.1 Hz, 1H), 7.20 (s, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.99 (t, J = 7.4 Hz, 1H), 6.60 (d, J = 12.5 Hz, 1H), 6.04 (d, J = 12.6 Hz, 1H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 4.80 (s, 2H), 4.64 (q, J = 7.5 Hz, 1H), 3.72 (t, J = 6.3 Hz, 2H), 3.63 (s, 3H), 3.56 - 3.52 (m, 4H), 3.47 (t, J = 5.7 Hz, 2H), 3.31 (q, J = 5.8 Hz, 2H), 3.25 - 3.15 (m, 2H), 3.11 (dd, J = 14.6, 8.8 Hz, 1H), 2.90 (ddd, J = 18.0, 13.9, 5.5 Hz, 1H), 2.63 - 2.57 (m, 4H). 13 13C NMR (151 MHz, DMSO-d6) δ 172.62, 172.49, 169.72, 169.34, 166.75, 166.57, 165.50, 165.27, 154.84, 153.21, 140.11, 139.46, 136.76, 135.94, 133.89, 132.86, 131.29, 130.88, 128.92 (2C), 128.09, 126.84, 126.29, 126.20, 123.64, 120.79, 120.48, 120.15, 118.82 (2C), 118.26 (2C), 117.80, 117.02, 116.55, 115.95, 115.83, 111.32, 109.32, 69.44, 69.39, 68.65, 67.29, 66.47, 53.09, 51.76, 48.63, 38.23, 37.01, 30.78, 26.87, 21.83. ESI-MS: m / z 1013.2 [M + H] + ,

[0358] Example 18

[0359] Replace (E)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester with (Z)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester, and use the same raw materials, reagents and preparation methods as in Example 16 to obtain product I-58-PROTAC1 (I-71), which is then hydrolyzed to obtain I-59-PROTAC1 (I-72).

[0360] I-58-PROTAC1(I-71)

[0361]

[0362] 1 H NMR (600MHz, DMSO-d6) δ11.12 (s, 1H), 10.87 (s, 1H), 10.13 (s, 1H), 9.05 (s, 1H), 8. 58 (d, J=7.6Hz, 1H), 8.05 (s, 1H), 8.027.99 (m, 1H), 7.93 (d, J=8.3Hz, 1H), 7.79 (t, J =8.0Hz, 1H), 7.75 (d, J = 8.3Hz, 2H), 7.597.55 (m, 3H), 7.52 (d, J = 8.0Hz, 1H), 7.48 ( d, J=7.1Hz, 1H), 7.43 (d, J=8.1Hz, 1H), 7.41-7.33 (m, 3H), 7.18 (s, 1H), 7.07 (t, J=7 .5Hz, 1H), 6.99 (t, J=7.4Hz, 1H), 6.53 (d, J=15.4Hz, 1H), 5.12 (dd, J=12.9, 5.4Hz, 1H), 4.79 (s, 2H), 4.63 (q, J=7.4Hz, 1H), 3.72 (t, J=6.3Hz, 2H), 3.62 (s, 3H), 3.54 (d , J=5.3Hz, 4H), 3.47 (t, J=5.7Hz, 2H), 3.31 (q, J=5.8Hz, 2H), 3.25-3.16 (m, 2H), 3. 11 (dd, J=14.8, 8.8Hz, 1H), 2.89 (ddd, J=18.2, 13.8, 5.4Hz, 1H), 2.62-2.57 (m, 4H). 13C NMR(151MHz,DMSO-d6)δ172.61,172.42,169.71,169.29,166.73,166.56,165.27,164.99,154.81,151.78,140.05,139.45,136.74,135.95,133.91,132.86,131.19,129.40,128.53(2C),127.85,126.86,126.37,126.31,123.52,121.24,120.84,120.15,118.94(2C),118.29,118.14,117.83,117.57,116.92,116.58,115.85,111.29,109.43,69.45,69.39,68.66,67.31,66.44,53.18,51.72,48.63,38.23,37.05,30.78,26.86,21.86.ESI-MS:m / z 1013.2[M+H] + ,

[0363] I-59-PROTAC1(I-72)

[0364]

[0365] 11H NMR (600 MHz, DMSO-d6) δ 10.85 (s, 1H), 10.15 (s, 1H), 9.04 (s, 1H), 8.74 (d, J = 8.0 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.05 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.62 - 7.55 (m, 4H), 7.48 - 7.37 (m, 3H), 7.37 - 7.32 (m, 2H), 7.28 (d, J = 8.6 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 7.19 - 7.16 (m, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 9.4 Hz, 1H), 6.54 (d, J = 15.4 Hz 1H), 4.64 - 4.50 (m, 3H), 4.33 (t, J = 8.7 Hz, 1H), 3.72 (q, J = 5.0, 3.9 Hz, 2H), 3.54 - 3.50 (m, 5H), 3.48 - 3.43 (m, 3H), 3.42 - 3.35 (m, 2H), 3.30 (t, J = 5.6 Hz, 2H), 3.24 (dd, J = 14.6, 4.7 Hz, 1H), 3.15 - 3.05 (m, 1H), 2.60 (t, J = 6.4 Hz, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 173.56, 173.40, 173.06, 170.18, 169.29, 167.58, 167.43, 164.91, 154.35, 151.76, 140.06, 139.45, 135.94, 134.61, 133.91, 131.18, 129.83, 129.08, 128.53 (2C), 127.78, 126.98, 126.41, 126.29, 124.55, 123.41, 121.62, 120.78, 120.25, 118.95 (2C), 118.23, 118.13, 118.00, 117.63, 116.92, 115.56, 111.23, 109.89, 69.40, 69.36, 68.61, 67.73, 66.44, 53.03, 52.03, 38.22, 37.04, 31.33, 26.89, 20.89. ESI-MS: m / z 999.2 [M+H] + ,

[0366] Example 19

[0367] Replace (E)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester with (Z)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester, and use the same raw materials, reagents and preparation methods as in Example 16 to obtain product I-56-PROTAC2 (I-73), which is then hydrolyzed to obtain I-57-PROTAC2 (I-74).

[0368] I-56-PROTAC2(I-73)

[0369]

[0370] 13 C NMR (151MHz, Chloroform-d) δ171.93, 170.46, 169.60, 168.04, 167.96, 166.18, 165.62, 165.42, 153.47, 152. 99, 139.85, 137.81, 136.51, 135.49, 134.49, 132.72, 130.08, 129.73, 128.87 (2C), 128.72, 127.07, 126.63, 1 25.99, 122.21, 121.58, 119.58, 119.08(2C), 119.06, 118.73, 117.80, 117.11, 116.68, 116.50, 115.30, 115.2 4, 110.65, 108.95, 69.15, 66.90, 66.29, 65.24, 51.92, 48.64, 38.16, 37.59, 30.64, 26.83, 21.86.ESI-MS: m / z 969.2[M+H] + ,

[0371] I-57-PROTAC2(I-74)

[0372]

[0373] 11H NMR (600 MHz, DMSO-d6) δ 12.70 (s, 1H), 10.85 (s, 1H), 10.12 (s, 1H), 9.27 (s, 1H), 8.53 (d, J = 7.8 Hz, 1H), 7.89 (s, 1H), 7.78 - 7.73 (m, 3H), 7.59 - 7.50 (m, 4H), 7.49 - 7.44 (m, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.30 - 7.20 (m, 2H), 7.18 (s, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.83 (s, 1H), 6.59 (d, J = 12.5 Hz, 1H), 6.03 (d, J = 12.6 Hz, 1H), 4.64 - 4.49 (m, 3H), 4.37 - 4.28 (m, 1H), 3.72 (t, J = 6.4 Hz, 2H), 3.48 (t, J = 6.0 Hz, 2H), 3.42 - 3.37 (m, 1H), 3.33 - 3.30 (m, 4H), 3.25 (dd, J = 14.9, 4.8 Hz, 1H), 3.18 (s, 1H), 3.08 (dd, J = 14.8, 9.2 Hz, 1H), 2.60 (q, J = 7.1 Hz, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 173.55, 173.44, 173.06, 170.18, 169.25, 166.90, 166.27, 165.38, 154.36, 153.27, 140.13, 139.35, 135.93, 134.62, 133.91, 131.30, 130.95, 129.86, 129.62, 129.01 (2C), 127.91, 126.98, 126.30 (2C), 123.47, 122.17, 120.77, 120.64, 120.27, 118.86 (2C), 118.31, 118.23, 118.00, 116.98, 115.99, 111.23, 109.82, 68.38, 67.76, 66.25, 64.75, 52.94, 52.16, 36.92, 31.23, 26.89, 20.60. ESI-MS: m / z 955.2 [M+H] + ,

[0374] Example 20

[0375] (N-Boc-3-[2-(2-aminoethoxy)ethoxy]propionic acid was replaced with 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaheptadecane-17-acid, and the other required raw materials, reagents and preparation methods were the same as in Example 17, to obtain product I-56-PROTAC3 (I-75), which was then hydrolyzed to obtain I-57-PROTAC3 (I-76).

[0376] I-56-PROTAC3(I-75)

[0377]

[0378] 1 H NMR (600MHz, DMSO-d6) δ11.12 (s, 1H), 10.87 (s, 1H), 10.12 (s, 1H), 9.21 (s, 1H), 8. 66(d, J=7.5Hz, 1H), 8.02-7.99(m, 1H), 7.96(s, 1H), 7.90(s, 1H), 7.82-7.78(m, 1H ), 7.77-7.73 (m, 2H), 7.58-7.52 (m, 4H), 7.49 (d, J = 7.3Hz, 1H), 7.40 (dd, J = 20.4, 8 .3Hz, 2H), 7.33 (d, J=8.1Hz, 1H), 7.19 (s, 1H), 7.07 (t, J=7.6Hz, 1H), 7.00 (t, J=7. 5Hz, 1H), 6.61 (d, J=12.5Hz, 1H), 6.02 (d, J=12.6Hz, 1H), 5.12 (dd, J=12.9, 5.6Hz, 1H), 4.78 (s, 2H), 4.66 (q, J=7.5Hz, 1H), 3.72 (t, J=6.3Hz, 2H), 3.63 (s, 3H), 3.54- 3.49(m, 8H), 3.46(t, J=5.8Hz, 2H), 3.42-3.37(m, 1H), 3.33-3.29(m, 1H), 3.23(dd , J=14.7, 5.4Hz, 1H), 3.10 (dd, J=14.7, 8.8Hz, 1H), 2.90 (s, 2H), 2.64-2.53 (m, 4H). 13C NMR(151MHz,DMSO-d6)δ172.60,172.49,169.70,169.28,166.72,166.56,165.48,165.27,162.14,154.80,153.20,140.11,139.38,136.76,135.94,133.90,132.86,131.29,130.88,128.98(2C),128.12,126.86,126.30,126.26,123.58,120.83,120.44,120.15,118.81(2C),118.27,117.84,117.01,116.59,115.94,115.87,111.30,109.36,69.56,69.53,69.45,68.64,67.32,66.44,64.75,53.05,51.77,48.64,37.05,35.62,30.69,26.91,21.83.ESI-MS:m / z 1057.2[M+H] + ,

[0379] I-57-PROTAC3(I-76)

[0380]

[0381] 11H NMR (600 MHz, DMSO-d6) δ 12.64 (s, 1H), 10.84 (d, J = 2.5 Hz, 1H), 10.13 (s, 1H), 9.27 (s, 1H), 8.52 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.84 (t, J = 5.7 Hz, 1H), 7.75 (d, J = 8.2 Hz, 3H), 7.56 (q, J = 8.1 Hz, 4H), 7.48 - 7.40 (m, 2H), 7.37 - 7.26 (m, 2H), 7.22 - 7.16 (m, 2H), 7.06 (t, J = 7.5 Hz, 1H), 6.99 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 11.6 Hz, 1H), 6.59 (d, J = 12.5 Hz, 1H), 6.03 (d, J = 12.6 Hz, 1H), 4.64 - 4.55 (m, 3H), 4.32 (q, J = 6.2, 5.4 Hz, 1H), 3.72 (t, J = 6.2 Hz, 2H), 3.51 (d, J = 19.9 Hz, 9H), 3.44 (t, J = 5.9 Hz, 2H), 3.42 - 3.37 (m, 1H), 3.30 (t, J = 5.5 Hz, 1H), 3.28 - 3.23 (m, 1H), 3.18 (s, 1H), 3.08 (dd, J = 14.7, 9.1 Hz, 1H), 2.89 (s, 1H), 2.60 (t, J = 6.3 Hz, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 173.56, 173.44, 171.85, 170.18, 169.29, 167.44, 166.22, 165.38, 154.35, 153.27, 140.13, 139.38, 135.93, 134.61, 133.91, 131.30, 131.00, 129.84, 129.60, 129.02 (2C), 127.90, 126.98, 126.29, 124.56, 123.47, 120.77, 120.64, 120.25, 118.82 (2C), 118.31, 118.23, 118.00, 116.98, 115.98, 115.56, 111.23, 109.82, 69.51, 69.42, 69.37, 68.54, 67.74, 66.45, 64.75, 52.93, 52.03, 37.06, 31.33, 28.70, 26.93, 20.89. ESI-MS: m / z 1043.2 [M + H] + ,

[0382] Example 21

[0383] Replace (Z)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester with (E)-(3-(3-(4-aminophenyl)-1-(3-chlorophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester, and use the same raw materials, reagents and preparation methods as in Example 20 to obtain product I-56-PROTAC3 (I-77), which is then hydrolyzed to obtain I-57-PROTAC3 (I-78).

[0384] I-58-PROTAC3(I-77)

[0385]

[0386] 1 H NMR (600MHz, DMSO-d6) δ11.12 (s, 1H), 10.87 (s, 1H), 10.14 (s, 1H), 9.05 (s, 1H), 8.5 9(d, J=7.6Hz, 1H), 8.05 (s, 1H), 8.00 (t, J=5.8Hz, 1H), 7.93 (d, J=8.3Hz, 1H), 7.82- 7.74(m, 3H), 7.60-7.55(m, 3H), 7.53(d, J=8.0Hz, 1H), 7.49(d, J=7.3Hz, 1H), 7.43( d, J=8.1Hz, 1H), 7.40-7.33 (m, 3H), 7.18 (s, 1H), 7.07 (t, J=7.6Hz, 1H), 6.99 (t, J=7 .5Hz, 1H), 6.53(d, J=15.7Hz, 1H), 5.12(dd, J=12.9, 5.4Hz, 1H), 4.78(s, 2H), 4.64( q, J=7.5Hz, 1H), 3.72 (t, J=6.3Hz, 2H), 3.62 (s, 3H), 3.51 (d, J=10.4Hz, 9H), 3.45 (t , J=5.8Hz, 2H), 3.42-3.37 (m, 1H), 3.333.29 (m, 1H), 3.22 (dd, J=14.8, 5.3Hz, 1H), 3 .12 (dt, J=14.7, 8.8Hz, 1H), 2.90 (td, J=16.3, 14.1, 5.5Hz, 1H), 2.66-2.52 (m, 4H). 13C NMR(151MHz,DMSO-d6)δ172.60,172.42,169.70,169.28,166.71,166.56,165.26,164.98,154.81,151.79,140.04,139.47,136.74,135.95,133.90,132.86,131.18,129.40,128.53(2C),127.85,126.86,126.37,126.30,123.52,121.25,120.83,120.14,118.93(2C),118.29,118.13,117.83,117.56,116.92,116.58,115.86,111.29,109.43,69.55,69.53,69.44,68.64,67.31,66.43,64.75,53.43,53.18,51.71,48.64,37.04,30.78,26.86,21.83.ESI-MS:m / z1057.2[M+H] + ,

[0387] I-59-PROTAC3(I-78)

[0388]

[0389] 1H NMR (600MHz, DMSO-d6) δ12.63 (s, 1H), 10.84 (d, J=2.3Hz, 1H), 10.15 (s, 1H ), 9.03 (s, 1H), 8.43 (d, J = 8.0Hz, 1H), 8.05 (d, J = 2.2Hz, 1H), 7.967.86 (m, 1 H), 7.84 (t, J=5.8Hz, 1H), 7.77 (d, J=8.2Hz, 2H), 7.57 (td, J=6.2, 4.7, 2.3H z, 4H), 7.487.40 (m, 2H), 7.397.29 (m, 2H), 7.297.19 (m, 2H), 7.18 (d, J=7.4 Hz, 1H), 7.07 (t, J=7.5Hz, 1H), 6.99 (t, J=7.5Hz, 1H), 6.82 (d, J=11.6Hz, 1 H), 6.54 (d, J=15.7Hz, 1H), 4.654.55 (m, 3H), 4.32 (q, J=6.7, 5.8Hz, 1H), 3. 72(t, J=6.2Hz, 2H), 3.543.47(m, 8H), 3.463.42(m, 2H), 3.373.34(m, 5H), 3 .323.27(m, 1H), 3.273.20(m, 1H), 3.153.04(m, 1H), 2.60(t, J=6.4Hz, 2H). 13 CNMR (151MHz, DMSO-d6) δ173.56, 173.40, 173.05, 169.29, 167.44, 166.22, 165.69, 164.911, 154.35, 151.76, 140 .06, 139.46, 135.94, 134.61, 133.90, 131.18, 130.89, 129.83, 129.59, 129.08, 128.53(2C), 127.78, 126.98, 126. 41, 126.29, 124.56, 123.41, 121.61, 120.78, 118.95(2C), 118.23, 118.13, 118.00, 117.63, 116.92, 111.23, 109.8 8, 69.51, 69.41, 69.36, 68.54, 67.73, 67.56, 66.43, 53.03, 52.03, 48.43, 37.04, 31.33, 26.89, 20.89.ESI-MS: m / z 1042.2[M+H] + ,

[0390] Comparative Example 1

[0391] (E)-(3-(3-(naphthyl-2-yl)-1-phenyl-1H-pyrazole-4-yl)acryloyl)-L-tryptophan

[0392] (Compare with compound 1)

[0393]

[0394] The required raw materials, reagents and preparation methods are the same as those in Example 64 of CN 110746355 A, to obtain the comparative compound 1(E)-(3-(3-(naphthyl-2-yl)-1-phenyl-1H-pyrazol-4-yl)acryloyl)-L-tryptophan. 1 H NMR (400MHz, Methanol-d4) δ8.68 (s, 1H), 8.14 (d, J=1.6Hz, 1H), 8.03-7.86 (m, 6H), 7.83 (dd, J=8.5, 1 .7Hz, 1H), 7.68 (d, J=15.7Hz, 1H), 7.60 (d, J=7.9Hz, 1H), 7.58-7.53 (m, 4H), 7.40 (t, J=7.4Hz, 1H), 7. 33 (d, J=8.1Hz, 1H), 7.12 (s, 1H), 7.09 (t, J=7.5Hz, 1H), 7.04-6.95 (m, 1H), 6.55 (d, J=15.7Hz, 1H), 4. 87-4.83 (m, 4H), 3.44 (dd, J=14.8, 4.5Hz, 1H), 3.26 (dd, J=14.7, 7.3Hz, 1H). MS (ESI, m / z): 525.0 [MH] - .

[0395] Comparative Example 2

[0396] (Z)-(3-(3-(naphthyl-2-yl)-1-phenyl-1H-pyrazole-4-yl)acryloyl)-L-tryptophan

[0397] (Compare with compound 2)

[0398]

[0399] The required raw materials, reagents and preparation methods are described in Example 64 of CN 110746355 A, which yielded the comparative compound 2(Z)-(3-(3-(naphthyl-2-yl)-1-phenyl-1H-pyrazole-4-yl)acryloyl)-L-tryptophan. 1H NMR (400MHz, DMSO-d6) δ10.70 (s, 1H), 9.44 (s, 1H), 8.12 (s, 1H), 8.04 (d, J=8.1Hz, 2H), 8.007.97 (m, 1H), 7 .88 (d, J=8.1Hz, 2H), 7.79 (dd, J=8.5, 1.8Hz, 2H), 7.59-7.52 (m, 6H), 7.37 (t, J=7.4Hz, 1H), 7.31-7.23 (m, 1 H), 7.10 (s, 1H), 6.99 (dd, J=8.1, 6.9Hz, 1H), 6.88 (t, J=7.4Hz, 1H), 6.57 (d, J=12.5Hz, 1H), 6.00 (d, J=12. 6Hz, 1H), 4.34-4.27 (m, 1H), 3.16 (d, J=4.7Hz, 1H), 3.02 (dd, J=14.7, 7.4Hz, 1H). MS (ESI, m / z): 527.2[M+H] + .

[0400] Comparative Example 3

[0401] (Z)-(3-(3-(2-naphthyl)-1-(m-tolyl)-1H-4-pyrazolyl)acryloyl)-L-tryptophan (comparative compound 3)

[0402] Compare compound 3 with compound (I-1) in Example 6.

[0403]

[0404] Comparative Example 4

[0405] By replacing m-methylphenylhydrazine hydrochloride with o-methylphenylhydrazine hydrochloride, and using the same raw materials, reagents and preparation methods as in Example 6, the comparative compound 4(Z)-(3-(3-(2-naphthyl)-1-(o-tolyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan was obtained.

[0406] (Z)-(3-(3-(2-naphthyl)-1-(o-tolyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan (Comparative compound 4)

[0407]

[0408] 1H NMR (600MHz, DMSO-d6) δ12.49 (s, 1H), 10.84 (d, J = 2.4Hz, 1H), 8.98 (d, J = 0.5Hz, 1H), 8.49 (d, J = 7.8Hz, 1H), 8.15-8.09 (m, 1H) , 8.05-8.01 (m, 2H), 8.00-7.95 (m, 1H), 7.76 (dd, J=8.5, 1.7Hz, 1H), 7.60-7.53 (m, 3H), 7.48-7.36 (m, 4H), 7.32 (dt, J=8.1, 0. 9Hz, 1H), 7.17 (d, J=2.4Hz, 1H), 7.05 (ddd, J=8.1, 6.9, 1.2Hz, 1H), 6.97 (ddd, J=8.0, 7.0, 1.1Hz, 1H), 6.76-6.71 (m, 1H), 6.01 (d, J=12.7Hz, 1H), 4.58 (ddd, J=9.2, 7.8, 4.9Hz, 1H), 3.24 (dd, J=14.7, 4.5Hz, 1H), 3.06 (dd, J=14.7, 9.1Hz, 1H), 2.30 (s, 3H); 13 C NMR (151MHz, DMSO-d6) δ174.05, 172.49, 166.19, 153.03, 139.62, 136.56, 135.67 ,133.31,133.22,132.98,131.93,130.27,129.08,129.02,128.73,128.63,128.3 1, 128.07, 127.61, 127.36, 127.15, 126.98, 126.09, 124.07, 121.40, 120.29, 118. 85, 118.62, 115.31, 111.86, 110.48, 53.51, 27.55, 18.45; ESI-MS: m / z541.2[M+H] + ESI-HRMS: calcd for C 34 H 29 O3N3[M+H] + 541.2234, found 541.2234.

[0409] Comparative Example 5

[0410] By replacing m-methylphenylhydrazine hydrochloride with p-methylphenylhydrazine hydrochloride, and using the same raw materials, reagents and preparation methods as in Example 6, the comparative compound 5(Z)-(3-(3-(2-naphthyl)-1-(p-tolyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan was obtained.

[0411] (Z)-(3-(3-(2-naphthyl)-1-(p-tolyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan (Comparative compound 5)

[0412]

[0413] 1 H NMR (600MHz, DMSO-d6) δ12.68 (s, 1H), 10.86 (d, J = 2.4Hz, 1H), 9.29 (s, 1H), 8.53 (d, J = 7.8Hz, 1H), 8.12 (d, J = 1.7Hz, 1 H), 8.09-8.02 (m, 2H), 7.99 (dt, J=7.1, 3.6Hz, 1H), 7.79 (dd, J=8.4, 1.7Hz, 1H), 7.74-7.70 (m, 2H), 7.63-7.56 (m, 3H), 7.34 (dd, J=8.2, 6.2Hz, 3H), 7.19 (d, J=2.2Hz, 1H), 7.07 (t, J=7.3Hz, 1H), 7.00 (t, J=7.4Hz, 1H), 6.70 (d, J=12.6Hz, 1H ), 6.03 (d, J=12.6Hz, 1H), 4.66-4.61 (m, 1H), 3.27 (dd, J=14.7, 4.8Hz, 1H), 3.09 (dd, J=14.7, 9.2Hz, 1H), 2.37 (s, 3H); 13 C NMR (151MHz, DMSO-d6) δ174.09, 166.15, 153.49, 137.45, 136.74, 136.58, 133. 29, 133.05, 131.38, 130.58 (2C), 130.15, 128.76, 128.65, 128.29, 128.09, 127. 63, 127.60, 127.06 (2C), 127.02, 124.10, 121.42, 120.83, 119.20 (2C), 118.88 , 118.65, 116.44, 111.89, 110.50, 53.57, 27.57, 20.98; ESI-MS: m / z541.2[M+H] + ESI-HRMS: calcd for C 34 H 29 O3N4[M+H] + 541.2234, found 541.2233.

[0414] Comparative Example 6 replaced 2-naphthylacetone with p-nitroacetophenone and m-methylphenylhydrazine hydrochloride with m-chlorophenylhydrazine hydrochloride. The other required raw materials, reagents, and preparation methods were the same as in Example 6, yielding comparative compound 6(Z)-(3-(1-(3-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan and comparative compound 7(E)-(3-(1-(3-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan

[0415] (Z)-(3-(1-(3-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan (Comparative compound 6)

[0416]

[0417] 1 H NMR (600MHz, DMSO-d6) δ12.52 (s, 1H), 10.84 (s, 1H), 9.23 (s, 1H), 8.57 (d, J=7.8Hz, 1H), 8.38-8.30 (m, 2H), 7.98-7. 88 (m, 3H), 7.79 (ddd, J=8.2, 2.2, 0.9Hz, 1H), 7.56 (t, J=8.0Hz, 2H), 7.46 (ddd, J=8.1, 2.0, 0.9Hz, 1H), 7.32 (dd, J=8. 0, 1.0Hz, 1H), 7.17 (d, J=2.2Hz, 1H), 7.05 (ddd, J=8.1, 7.0, 1.2Hz, 1H), 6.98 (ddd, J=7.9, 6.9, 1.0Hz, 1H), 6.65 (d, J =12.5Hz, 1H), 6.11 (d, J = 12.5Hz, 1H), 4.63-4.56 (m, 1H), 3.24 (dd, J = 14.7, 4.8Hz, 1H), 3.07 (dd, J = 14.7, 9.1Hz, 1H); 13C NMR(151 MHz, DMSO-d6) δ173.96, 165.63, 151.46, 147.64, 140.53, 138.89, 136.56, 134.61, 132.10, 131.98, 130.06 (2C), 127.81, 127.61, 1 27.42, 124.38(2C), 124.11, 122.82, 121.41, 119.23, 118.86, 118.64, 117.90, 117.35, 111.86, 110.39, 53.56, 27.58; ESI-MS: m / z 556.1[M+H]+, ESI-HRMS: calcd forC 29 H 23 O5N4Cl[M+H] + 556.1382, found 556.1381.

[0418] (E)-(3-(1-(3-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan (Comparative compound 7)

[0419]

[0420] 1 H NMR (600MHz, DMSO-d6) δ12.71 (s, 1H), 10.86 (s, 1H), 9.12 (s, 1H), 8.48 (d, J=7.8Hz, 1H), 8.38 (d, J=8.4 Hz, 2H), 8.08 (s, 1H), 7.94 (dd, J=14.1, 8.2Hz, 3H), 7.62-7.54 (m, 2H), 7.46 (d, J=8.0Hz, 1H), 7.38 (d, J= 15.6Hz, 1H), 7.34 (d, J=8.1Hz, 1H), 7.17 (s, 1H), 7.07 (t, J=7.5Hz, 1H), 6.98 (t, J=7.5Hz, 1H), 6.57 (d, J =15.7Hz, 1H), 4.62 (dt, J=12.5, 6.2Hz, 1H), 3.25 (dd, J=14.8, 4.8Hz, 1H), 3.09 (dd, J=14.7, 9.3Hz, 1H); 13C NMR (151MHz, DMSO-d6) δ173.98, 165.29, 150.22, 147.77, 140.46, 138.91, 136.58, 134.61, 131.90, 129.75 (2C), 129.31, 128.88, 127. 61, 127.46, 124.58 (2C), 124.07, 123.46, 121.42, 119.07, 119.02, 118.87, 118.63, 117.83, 111.87, 110.47, 53.69, 27.54; ESI-MS: m / z 556.1[M+H] + ESI-HRMS: calcd for C 29 H 23 O5N4Cl[M+H] + 556.1382, found 556.1384.

[0421] Comparative Example 7

[0422] Replace 2-naphthyl ethyl ketone with p-ethyl acetophenone, replace m-methylphenylhydrazine hydrochloride with m-chlorophenylhydrazine hydrochloride, and use the same raw materials, reagents and preparation methods as in Example 6. Retain the esterification product (Z)-(3-(1-(3-(m-chlorophenyl)-3-(4-ethylphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan methyl ester, and further hydrolyze it to obtain the comparative compound 8(Z)-(3-(1-(3-(m-chlorophenyl)-3-(4-ethylphenyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan.

[0423] (Z)-(3-(1-(3-(m-chlorophenyl)-3-(4-ethylphenyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan methyl ester (Comparative compound 8)

[0424]

[0425] 1H NMR (600MHz, DMSO-d6) δ10.87 (d, J=2.4Hz, 1H), 9.22 (s, 1H), 8.67 (d, J=7.5Hz, 1H), 7.89 (t, J=2.1Hz, 1H), 7.77 (ddd, J=8.2, 2 .2, 0.9Hz, 1H), 7.57-7.51 (m, 4H), 7.42 (ddd, J=8.0, 2.1, 0.9Hz, 1H), 7.38-7.31 (m, 3H), 7.18 (d, J=2.3Hz, 1H), 7.06 (ddd, J=8 .1, 6.9, 1.2Hz, 1H), 6.99 (ddd, J=7.9, 6.9, 1.0Hz, 1H), 6.60 (d, J=12.5Hz, 1H), 6.02 (d, J=12.6Hz, 1H), 4.66 (ddd, J=8.9, 7.5, 5.4Hz, 1H), 3.63 (s, 3H), 3.22 (dd, J=14.6, 5.4Hz, 1H), 3.10 (dd, J=14.6, 8.8Hz, 1H), 2.71-2.65 (m, 2H), 1.23 (t, J=7.6Hz, 3H); 13 CNMR (151MHz, DMSO-d6) δ173.12, 166.12, 154.18, 144.77, 140.76, 136.57, 134.54, 131.93, 131.53, 129.70, 129.20 (2C), 128.74, 128.56 (2C), 127.49, 126.97, 124.22, 121.47, 121.07, 118.92(2C), 118.47, 117.67, 116.63, 111.94, 110.00, 53.68, 52.40, 28.45, 27.54, 16.00; ESI-MS: m / z 553.2[M+H] + ESI-HRMS: calcd for C 32 H 30 O3N4Cl[M+H] + 553.2001, found 553.2013.

[0426] Comparative Example 8

[0427] I-8-PROTAC (Comparative compound 9)

[0428]

[0429] In a 50 mL round-bottom flask, (E)-(3-(1-(3-chlorophenyl)-3-(2-naphthyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan (I-8, 184 mg, 0.33 mmol), anhydrous DMF (10 mL), HATU (194 mg, 0.5 mmol), DIPEA (112 μL, 0.66 mmol), and tert-butyl 2-(2-(2-aminoethoxy)ethoxy)ethylcarbamate (127 mg, 0.5 mmol) were added and stirred at room temperature for 6 h. Water (60 mL) and dichloromethane (20 mL) were added, and the mixture was extracted three times. The extract was dried, filtered, and concentrated. Column chromatography with dichloromethane:methanol (20:1) yielded a yellow oil, I-8-Linker-NHBoc (260 mg, 99%). 1 H NMR (400MHz, Chloroform-d) δ8.68 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 8.00 (d, J=3.7Hz, 2H), 7.95-7.84 (m , 3H), 7.79 (d, J=8.2Hz, 1H), 7.69 (dd, J=18.3, 11.1Hz, 2H), 7.51 (q, J=4.3Hz, 2H), 7.43-7.31 (m, 2H), 7.2 9 (d, J=7.7Hz, 1H), 7.19-7.06 (m, 2H), 6.62 (s, 1H), 6.35 (d, J=15.5Hz, 1H), 6.15 (s, 1H), 5.95 (s, 1H), 5.0 5(s, 1H), 4.93-4.74(m, 1H), 3.68-3.01(m, 7H), 3.04-2.91(m, 5H), 2.88-2.85(m, 2H), 1.48-1.33(m, 9H).

[0430] I-8-Linker-NHBoc, dichloromethane (4 mL), and trifluoroacetic acid (1 mL) were added to a 50 mL round-bottom flask and stirred at room temperature for 1 h. The pH was adjusted to alkaline with sodium hydroxide aqueous solution, and the mixture was extracted three times with dichloromethane (5 mL). The extract was dried, filtered, concentrated, and then the next step (189 mg, 0.27 mmol), DMF (10 mL), DIPEA (90 μL, 0.54 mmol), and thalidomide F (68.7 mg, 0.25 mmol) were added. The mixture was stirred and refluxed for 2 h. Water (30 mL) was added, and the mixture was extracted three times with dichloromethane (10 mL). The extract was dried, filtered, and concentrated. Column chromatography with dichloromethane:methanol = 20:1 yielded a yellow oily substance, I-8-PROTAC (50 mg, 20%).

[0431] 11H NMR (600 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.81 (s, 1H), 9.07 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.16 (s, 1H), 8.09 (s, 2H), 8.04 (dd, J = 13.8, 6.9 Hz, 2H), 7.99 - 7.94 (m, 2H), 7.78 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 7.6 Hz, 3H), 7.52 (t, J = 7.8 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.17 - 7.14 (m, 1H), 7.05 (t, J = 7.9 Hz, 2H), 7.00 (d, J = 6.9 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 6.58 (d, J = 16.3 Hz, 2H), 5.76 (s, 1H), 5.05 (dd, J = 12.9, 5.5 Hz, 1H), 4.65 (q, J = 7.9 Hz, 1H), 3.60 - 3.40 (m, 10H), 3.26 - 3.17 (m, 2H), 3.15 - 3.10 (m, 1H), 3.03 - 2.96 (m, 1H), 2.91 - 2.84 (m, 2H), 2.73 (s, 2H), 2.61 - 2.56 (m, 1H); 13 13C NMR (151 MHz, DMSO-d6) δ 172.64, 171.59, 169.92, 168.75, 167.11, 164.66, 162.16, 151.92, 146.17, 140.04, 135.99, 135.89, 132.70, 132.54, 131.88, 131.20, 129.33, 128.76, 128.20, 128.10, 127.93, 127.50, 127.18, 127.13, 126.54, 126.48, 126.42, 125.91, 123.45, 122.19, 120.67, 118.37, 118.23, 118.08, 118.02, 117.16, 117.00, 111.09, 110.47, 110.05, 109.04, 69.46 (2C), 68.75, 68.69, 54.74, 53.51, 48.38, 41.49, 30.81, 27.86, 21.96; ESI-MS: m / z 969.2 [M+Na] + .

[0432] Comparative Example 9

[0433] Replacing (E)-(3-(1-(3-chlorophenyl)-3-(2-naphthyl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan with (Z)-(3-(1-(3-chlorophenyl)-3-(5,6,7,8-tetrahydronaphthyl-2-yl)-1H-pyrazol-4-yl)acryloyl)-L-tryptophan, and using the same raw materials, reagents, and preparation methods as in Comparative Example 8, yielded product I-25-PROTAC.

[0434] I-25-PROTAC (Comparative compound 10)

[0435]

[0436] 1 H NMR (600MHz, DMSO-d6) δ11.09 (s, 1H), 10.82-10.79 (m, 1H), 9.23 (s, 1H), 8. 43 (d, J=8.0Hz, 1H), 8.16 (t, J=5.7Hz, 1H), 7.96 (s, 1H), 7.88 (s, 1H), 7.77-7 .72 (m, 1H), 7.66 (d, J = 7.9Hz, 1H), 7.53 (t, J = 7.6Hz, 2H), 7.39 (d, J = 8.1Hz, 1 H), 7.30 (d, J=8.1Hz, 1H), 7.27 (d, J=6.4Hz, 2H), 7.17 (d, J=8.6Hz, 2H), 7.10 6.94 (m, 3H), 6.58-6.50 (m, 2H), 6.00 (d, J=12.6Hz, 1H), 5.05 (dd, J=12.8, 5. 5Hz, 1H), 4.65 (td, J=8.5, 5.1Hz, 1H), 3.59-3.45 (m, 5H), 3.43-3.37 (m, 3H), 3.28-3.21 (m, 2H), 3.14 (dd, J=14.6, 5.2Hz, 1H), 2.98 (dd, J=14.5, 9.2Hz, 1H ), 2.89 (s, 3H), 2.81-2.74 (m, 4H), 2.73 (s, 3H), 1.77 (dd, J=7.2, 3.6Hz, 4H); 13C NMR(151 MHz, DMSO-d6) δ172.62, 171.71, 169.90, 168.74, 167.11, 165.33, 162.14, 153.58, 146.17, 140.14, 137.03, 136 .81, 135.98, 135.87, 133.90, 131.88, 131.21, 130.73, 128.99, 128.93, 127.23, 127.11, 126.19, 125.70, 123.5 3,121.11,120.66,118.40,118.12,118.00,117.16,116.88,116.09,111.08,110.46,110.02,109.05,69.48,6 9.45,68.76,68.70,53.43,48.38,41.48,35.61,30.81,30.60,28.60,28.47,27.86,22.49,21.97; ESI-MS: m / z 973.3[M+Na] + .

[0437] Comparative Example 10

[0438] Replacing (E)-(3-(1-(3-chlorophenyl)-3-(2-naphthyl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan with (E)-(3-(1-(3-chlorophenyl)-3-(5,6,7,8-tetrahydronaphthyl-2-yl)-1H-pyrazole-4-yl)acryloyl)-L-tryptophan, and using the same raw materials, reagents, and preparation methods as in Comparative Example 8, yielded product I-26-PROTAC.

[0439] I-26-PROTAC (Comparative compound 11)

[0440]

[0441] 1H NMR (600MHz, DMSO-d6) δ11.10 (s, 1H), 10.82-10.80 (m, 1H), 8.98 (s, 1H), 8.29 (d , J=8.2Hz, 1H), 8.09 (t, J=5.7Hz, 1H), 8.03 (q, J=3.3, 2.2Hz, 1H), 7.96 (s, 3H), 7. 79 (d, J=7.3Hz, 1H), 7.73 (t, J=8.8Hz, 1H), 7.65-7.62 (m, 1H), 7.56-7.52 (m, 1H), 7.41(dd, J=8.1, 2.1Hz, 1H), 7.33-7.30(m, 2H), 7.27-7.22(m, 1H), 7.19-7.14(m, 1H), 7.10-6.99 (m, 2H), 6.97 (t, J=7.4Hz, 1H), 6.58 (t, J=5.8Hz, 1H), 6.53 (d, J= 15.7Hz, 1H), 5.17 (dd, J=12.9, 5.4Hz, 1H), 4.64 (td, J=8.5, 5.1Hz, 1H), 3.62-3.4 7(m, 5H), 3.45-3.38(m, 3H), 3.27-3.18(m, 2H), 3.16-3.10(m, 1H), 3.02-2.95(m, 1H), 2.91-2.86(s, 3H), 2.79-2.74(m, 4H), 2.73-2.72(s, 3H), 1.84-1.67(s, 4H);

[0442] Effect Example 1: Affinity test results of some compounds with Bcl-xL, Bcl-2, and Mcl-1

[0443] A 26-amino acid peptide, BidBH3 (amino acids 79-104: QEDIIRNIARHLAQVGDSMDRSIPPG), was synthesized and labeled with 6-carboxyfluorescein succinimide (FAM) at the N-terminus as a fluorescent tag (FAM-Bid). His-Bcl-xL protein, His-Bcl-2 protein, or His-Mcl-1 protein, along with the target small molecule compound, were dissolved in phosphate buffer solution and incubated at 37°C in the dark for 30 minutes. Then, the FAM-Bid peptide was added, mixed, and incubated at 37°C in the dark for another 20 minutes. The final concentrations of His-Bcl-XL protein, His-Bcl-2 protein, His-Mcl-1 protein, and FAM-Bid peptide were 230 nM, 425 nM, 200 nM, and 10 nM, respectively. The final concentrations of the compounds in the system were 1 nM, 10 nM, 100 nM, 1 μM, 10 μM, 50 μM, and 100 μM. 60 μl of each reaction solution was added to a 384-well plate (three parallel groups), and fluorescence polarization was immediately detected using a microplate reader. The fluorescence polarization value (mP) was measured at an emission wavelength of 535 nm generated by excitation at 485 nm. Two control groups were also established: one control group contained only Bcl-xL, Bcl-2, or Mcl-1 and FAM-Bid (equivalent to 0% inhibition rate), and the other control group contained only FAM-Bid peptide. The protein inhibition rate was calculated based on the polarization values ​​of the control groups and the tested compounds. The IC50 was calculated by plotting the protein inhibition rate against the logarithm of the compound concentration. 50 The competitive inhibition constant Ki between the compound and the protein was calculated using the formula Ki = [I]50 / ([L]50 / Kd + [P]0 / Kd + 1). In the formula, [I]50 is the compound concentration when the protein inhibition rate is 50%, [L]50 is the free FAM-Bid concentration when the protein inhibition rate is 50%, Kd is the dissociation constant between the target protein and the FAM-Bid peptide, and [P]0 is the free protein concentration when the protein inhibition rate is 0%. Specific results are shown in Table 1.

[0444] Table 1. Effects of the compounds of this invention on Bcl-X L The competitive inhibition constant K between Bcl-2 and Mcl-1 proteins i

[0445]

[0446]

[0447] NA indicates inactivity.

[0448] As can be seen from the table above, the phenylpyrazole compounds provided by Benming can effectively and selectively inhibit the key protein MCL-1 in the apoptosis process at the molecular level.

[0449] Efficacy Example 2: Inhibitory activity of some compounds on several tumor cell lines

[0450] Human plasmacytosis leukemia cells H929 and human acute lymphoblastic leukemia cells RS4;11 were cultured in RPMI 1640 medium containing 10% fetal bovine serum, human myeloid monocytic leukemia cells MV-4-11 were cultured in IMDM medium containing 10% fetal bovine serum, and human embryonic kidney cells 293T cells were cultured in DMEM medium containing 10% fetal bovine serum. Cells were seeded in 96-well plates at concentrations of 8000 cells / 100 μL for H929 and MV-4-11, 16000 cells / 100 μL for RS4;11, and 10000 cells / 100 μL for 293T cells. The zero-adjustment group only received culture medium. Compounds were added to 96-well plates at five different concentrations (40 μM, 20 μM, 10 μM, 5 μM, and 2.5 μM, with three replicates for each concentration), and then incubated at 37°C in a CO2 incubator for 48 hours. 10 μL of LCK-8 solution was added to each well and incubated at 37°C for 2 hours. The absorbance of each well was measured at 450 nm using a microplate reader. Cell viability was calculated as (experimental group absorbance - zero-adjustment group absorbance) / (control group absorbance - zero-adjustment group absorbance). The IC50 was calculated by plotting cell viability against the logarithm of the compound concentration. 50 Values. See Tables 2 and 3 for specific results.

[0451] Table 2. Cytotoxicity test results of the compounds of the present invention on H929, MV-4-11, RS4;11 and 293T cell lines.

[0452]

[0453]

[0454] / indicates no test data.

[0455] As can be seen from the table above, the phenylpyrazole compounds provided by Benming have significant killing effects and high selectivity against cancer cells, especially human plasma cell leukemia cells H929 and human myeloid monocytic leukemia cells MV-4-11.

[0456] Efficacy Example 3: Intracellular Kinetics Study of Compound I-66

[0457] MV-4-11 cells were seeded in 6-well cell culture plates at a density of 1.2 × 10⁶ cells per well. All cells were incubated with 40 μM I-66 (5‰ DMSO). Cells from one well were collected at the following time points (0, 1, 2, 3, 5, 7, and 8 h) and immediately centrifuged at 4 °C and 200 g for 5 min. The supernatant was used as the extracellular component for LC-MS / MS quantitative analysis. Cell pellets were lysed for 30 min in RIPA lysis buffer (50 mM Tris, pH 7.4, 150 mM NaCl, 1% Triton X-100, 0.1% SDS, 1% sodium deoxycholate). After lysis, cells were centrifuged at 12000 rpm for 20 min, and the supernatant was collected as the intracellular component for LC-MS / MS analysis. The percentage of intracellular or extracellular compounds was calculated using the following formula:

[0458]

[0459] MV-4-11 cells were co-incubated with 40 μM I-66, and the intracellular and extracellular contents of I-66 and its carboxylic acid form (i-67) were accurately measured at 0, 1, 2, 3, 5, and 8 hours. As shown in Table 4, I-66 and I-67 were not present in the cells at 0 h, indicating complete exposure to the extracellular environment. After 1 h of incubation with I-66, I-67 was detected only intracellularly, accounting for 20% of the total weight. The absence of I-66 intracellularly confirms that I-66 is completely hydrolyzed into carboxylic acid I-67 after entering the cell, thus exerting its intracellular biological effects. With prolonged I-66 treatment, the intracellular weight of I-67 increased rapidly over time. Accompanied by apoptosis and cell death, the original intracellular I-67 was converted to extracellular I-67 and detected, resulting in a slow decrease in the proportion of I-67 in viable cells.

[0460] Table 4

[0461]

[0462] This experiment, through dynamic monitoring of the amount of compounds within living cells, elucidated that I-66 has good membrane permeability and is completely hydrolyzed into I-67 within the cell to exert its biological functions.

Claims

1. A phenylpyrazole compound as shown in Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof, in, R a For R 1 -(CH2) m -or The value of m is 0; The R mentioned 1 For being an R 1-1 Substituted phenyl; The R mentioned 1-1 Independently -NH2, -OH, C1-C4 alkoxy, heteroatom selected from N and / or O, 5-6 membered heterocyclic alkyl or 3-8 membered cycloalkyl with 1 to 2 heteroatoms; R b1 R b2 and R b3 Independently H or halogen; R c It is H or C1-C4 alkyl; R d for Indicates Z configuration, E configuration, or a mixture thereof; Chiral carbons marked with "*" are in the S configuration, R configuration, or a mixture thereof.

2. The phenylpyrazole compound of formula I as described in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, It meets one or two of the following conditions: (1) The R 1-1 Independently -NH2, -OH, or a 3-8 membered cycloalkyl group; or, the R... 1-1 Independently, it is a C1-C4 alkoxy or a 5-6 membered heterocyclic alkyl group; (2) The R b1 R b2 and R b3 One of them is a halogen, and the rest are H.

3. The phenylpyrazole compound of formula I as described in claim 2, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R b2 For halogens, R b1 and R b3 For H.

4. The phenylpyrazole compound of formula I as described in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, It meets one or more of the following conditions: (1) The R 1-1 Independently located at the ortho, meta, or para position of the "phenyl-pyrazole linkage site"; (2) When R 1-1 When the alkoxy group is C1-C4, the C1-C4 alkoxy group is methoxy, ethoxy, propoxy, or butoxy; (3) When R 1-1 When the 3-8 membered cycloalkyl group is a cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl group; (4) When R b1 R b2 and R b3 When it is a halogen on its own, the halogen is fluorine, chlorine, bromine or iodine; (5) When R c When the alkyl group is C1 to C4, the C1 to C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

5. The phenylpyrazole compound of formula I as described in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, It meets one or more of the following conditions: (1) The R 1-1 It is independently located at the para position of the "phenyl-pyrazole linkage site"; (2) When R 1-1 When the C1-C4 alkoxy group is a C1-C4 alkoxy group, the C1-C4 alkoxy group is a methoxy group; (3) When R 1-1 When it is a 3-8 membered cycloalkyl group, the 3-8 membered cycloalkyl group is cyclohexyl; (4) When R 1-1 When it is a 5-6 membered heterocyclic alkyl group, the 5-6 membered heterocyclic alkyl group is a morpholino group; (5) When R b1 R b2 and R b3 When it is a halogen on its own, the halogen is chlorine.

6. The phenylpyrazole compound of formula I as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, It is either Option 1 or Option 2 as follows; Option 1: R a For R 1 -(CH2) m -; The value of m is 0; The R mentioned 1 For being an R 1-1 Substituted phenyl; The R mentioned 1-1 Independently -NH2, -OH or 3-8 membered cycloalkyl; R b1 R b2 and R b3 Independently H or halogen; R c It is H or C1-C4 alkyl; Option 2: R a For R 1 -(CH2) m -; The value of m is 0; The R mentioned 1 For being an R 1-1 Substituted phenyl; The R mentioned 1-1 The C1-C4 alkoxy group or heteroatom is selected from N and / or O, and the number of heteroatoms is 1 to 2; R b1 R b2 and R b3 Independently H or halogen; R c It is H or C1 to C4 alkyl.

7. The phenylpyrazole compound of formula I as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, It meets one or two of the following conditions: (1) The R a for (2) for 8. The phenylpyrazole compound of formula I as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, It is any of the following compounds:

9. A compound as shown in Formula II, its stereoisomer, or a pharmaceutically acceptable salt thereof, in, X is L is End a is connected to Y, and end b is connected to X; n1 is 1, 2, 3, 4 or 5; L 1 It can be -O- or -S-; Y is R b1 R b2 R b3 R c and R d The definition is as described in any one of claims 1-8; L 3 -R 3 -(CH2) m -;-(CH2) m - The end is connected to pyrazole; The value of m is 0; The R mentioned 3 It is phenyl; L is connected to L 3 The adjacent, meta, or para position of the pyrazole linkage site; Indicates Z configuration, E configuration, or a mixture thereof; Chiral carbons marked with "*" are in the S configuration, R configuration, or a mixture thereof.

10. The compound of formula II as claimed in claim 9, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, It meets one or two of the following conditions: (1) The L 1 -O-; (2) The L is connected to L 3 Parallel to the pyrazole linker site.

11. The compound of formula II as claimed in claim 9, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, The n1 mentioned is 1, 2 or 3.

12. The compound of formula II as claimed in claim 9, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, It meets one or more of the following conditions: (1) X is (2) The L mentioned above is (3) The Y mentioned is 13. The compound of formula II as claimed in claim 9, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, It is as follows: II-a Among them, R c R b1 R b2 R b3 and R d The definition is as described in any one of claims 9-12; n can be 1, 2, 3, 4 or 5.

14. The compound of formula II as claimed in any one of claims 9-12, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, It is any of the following compounds:

15. A method for preparing a compound of formula I as described in any one of claims 1 to 8, characterized in that, It includes method 1 or method 2; Method 1 includes the following steps: in an organic solvent, in the presence of a catalyst, compound III and compound IV are subjected to an amidation reaction as shown below to obtain compound I. Among them, R a R b1 R b2 R b3 and R d The definition is as described in any one of claims 1-8; Method 2, which includes the following steps: in an organic solvent, "R" c Compound I, which is a C1-C4 alkyl group, undergoes the hydrolysis reaction shown below to give "R". c Compound I, which is H”, is acceptable; Among them, R a R b1 R b2 R b3 and R d The definition is as described in any one of claims 1-8.

16. The method for preparing the compound of formula I as described in claim 15, characterized in that, The reaction conditions of methods 1 and 2 satisfy one or more of the following conditions: (1) In method 1, the organic solvent is an amide solvent; (2) In Method 1, the catalyst is one or more of N,N'-diisopropylethylamine, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; (3) In method 1, the molar ratio of compound III to compound IV is 1:1 to 1:2; (4) In method 2, the organic solvent is an ether solvent; (5) In method 2, the hydrolysis is carried out in the presence of an alkali, which is an alkali metal hydroxide.

17. The method for preparing the compound of formula I as described in claim 16, characterized in that, The reaction conditions of methods 1 and 2 satisfy one or more of the following conditions: (1) In method 1, the organic solvent is N,N-dimethylformamide; (2) In method 2, the organic solvent is tetrahydrofuran; (3) In method 2, the hydrolysis is carried out in the presence of an alkali, which is NaOH.

18. The method for preparing the compound of formula I as described in claim 15, characterized in that, Further steps include the following: Among them, R a R b1 R b2 and R b3 As described in claim 15; R e It is a C1 to C4 alkyl group; Step 1: In an organic solvent and in the presence of a catalyst, compound VIII and compound IX undergo a condensation reaction as shown to obtain compound VII. Step 2: In an organic solvent and in the presence of a catalyst, compound VII is reacted with a disubstituted formamide in the manner shown by the Wilsmayer-Hacker formylation reaction to obtain compound V. Step 3: In an organic solvent and in the presence of a base, compound IV and compound V undergo the addition-elimination reaction shown to obtain compound III.

19. The method for preparing the compound of formula I as described in claim 18, characterized in that, In step one, it satisfies one or two of the following conditions: (1) The organic solvent is an alcohol solvent; (2) The catalyst is acetic acid.

20. The method for preparing the compound of formula I as described in claim 19, characterized in that, In step one, the organic solvent is ethanol.

21. The method for preparing the compound of formula I as described in claim 18, characterized in that, In step two, it satisfies one or more of the following conditions: (1) The organic solvent is a formamide solvent; (2) The disubstituted formamide is N,N-dimethylformamide; (3) The catalyst is POCl3; (4) The molar ratio of compound VII to the catalyst is 1:2 to 1:

5.

22. The method for preparing the compound of formula I as described in claim 21, characterized in that, In step two, it satisfies one or both of the following conditions: (1) The organic solvent is N,N-dimethylformamide; (2) The molar ratio of compound VII to the catalyst is 1:

4.

23. The method for preparing the compound of formula I as described in claim 18, characterized in that, In step three, it satisfies one or more of the following conditions: (1) The R e It is ethyl; (2) The organic solvent is an ether solvent; (3) The molar ratio of compound V to compound VI is 1:2 to 1:

3.

24. The method for preparing the compound of formula I as described in claim 23, characterized in that, In step three, it must satisfy one or two of the following conditions: (1) The organic solvent is tetrahydrofuran; (2) The molar ratio of compound V to compound VI is 1:2.

2.

25. A method for preparing a compound of formula II as described in any one of claims 13-14, characterized in that, It includes the following steps: in a solvent, under the action of a catalyst, compound II-b reacts with compound II-c to obtain a compound as shown in formula II-a; Among them, R b1 R b2 R b3 R c and R d The definition is as described in any one of claims 9-14; n can be 1, 2, 3, 4 or 5.

26. The method for preparing the compound of formula II as described in claim 25, characterized in that, The reaction is subject to one or more of the following conditions: (1) The solvent is a formamide solvent; (2) The catalyst is N,N'-diisopropylethylamine; (3) The molar ratio of compound II-b to compound II-c is 1:1 to 1:1.

5.

27. The method for preparing the compound of formula II as described in claim 26, characterized in that, The solvent is N,N-dimethylformamide.

28. The method for preparing the compound of formula II as described in claim 25, characterized in that, Further steps include the following: Among them, R b1 R b2 R b3 R c and R d The definition is as described in claim 25; n is 1, 2, 3, 4 or 5; Step 1: In a solvent, in the presence of a base and a condensing agent, compound II-e reacts with compound II-f to give the compound shown in formula II-d; Step 2: In a solvent, compound II-d is deprotected to obtain the compound shown in formula II-b.

29. The method for preparing the compound of formula II as described in claim 28, characterized in that, In step one, it satisfies one or more of the following conditions: (1) The solvent is a formamide solvent; (2) The catalyst is N,N'-diisopropylethylamine and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate; (3) The molar ratio of compound II-e to compound II-f is 1:1 to 1:1.

5.

30. The method for preparing the compound of formula II as described in claim 29, characterized in that, In step one, it satisfies one or two of the following conditions: (1) The solvent is N,N-dimethylformamide; (2) The molar ratio of compound II-e to compound II-f is 1:1.1 to 1:1.

2.

31. The method for preparing the compound of formula II as described in claim 28, characterized in that, In step two, it satisfies one or both of the following conditions: (1) The solvent is a haloalkane solvent; (2) The reagent for removing the protecting group is an acid reagent.

32. The method for preparing the compound of formula II as described in claim 31, characterized in that, In step two, it satisfies one or both of the following conditions: (1) The solvent is dichloromethane; (2) The reagent for removing the protecting group is trifluoroacetic acid.

33. A pharmaceutical composition comprising substance A, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient; wherein substance A is a compound of formula I as claimed in any one of claims 1-8 or a compound of formula II as claimed in any one of claims 9-14.

34. The use of a substance A, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a BCL-2 antiapoptotic protein inhibitor or in the preparation of a medicament for the treatment and / or prevention of diseases associated with BCL-2 antiapoptotic protein; The substance A is a compound of formula I as described in any one of claims 1-8 or a compound of formula II as described in any one of claims 9-14.

35. The application as described in claim 34, characterized in that, The "BCL-2 anti-apoptotic protein" mentioned is BCL-X. L One or more of the proteins BCL-2 and MCL-1.

36. The application as described in claim 35, characterized in that, The "BCL-2 anti-apoptotic protein" mentioned above is MCL-1.

37. The application as described in claim 34, characterized in that, The "diseases associated with BCL-2 anti-apoptotic protein" mentioned are cancer.

38. The application as described in claim 37, characterized in that, The cancer mentioned is leukemia.

39. The application as described in claim 38, characterized in that, The leukemia mentioned refers to human acute lymphoblastic leukemia or human plasma cell leukemia.

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