An amide compound having anticancer activity and a preparation method and application thereof

Abstract

The application belongs to the field of pharmaceutical chemistry, and discloses an amide compound with anticancer activity, a preparation method and application thereof, the amide compound is a compound shown in formula I or formula II or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof, a preparation method thereof, and application of the compound in lymphoma treatment or prevention.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to an amide compound with anticancer activity, its preparation method, and its application in the manufacture of drugs for the prevention or treatment of lymphoma. Background Technology

[0002] Lymphoma is a type of malignant tumor originating from the lymphohematopoietic system. It is mainly divided into Hodgkin lymphoma and non-Hodgkin lymphoma, with non-Hodgkin lymphoma having a very high incidence rate. It is characterized by high malignancy, aggressiveness, rapid disease progression, and high recurrence rate. Lymphoma can invade multiple immune and hematopoietic organs throughout the body, including lymph nodes, spleen, and bone marrow. Clinical symptoms are often insidious, making early diagnosis difficult and posing a serious threat to human life and health. Burkitt's lymphoma is a highly aggressive B-cell-derived non-Hodgkin lymphoma. This subtype of lymphoma has extremely rapid tumor cell proliferation and high malignancy, and is more common in adolescents and immunocompromised individuals. The disease progresses rapidly, and without timely and effective intervention, patient survival is significantly shortened, making clinical treatment extremely challenging.

[0003] Currently, the mainstream clinical treatments for lymphoma, especially Burkitt lymphoma, primarily involve combination chemotherapy, targeted therapy, immunotherapy, and hematopoietic stem cell transplantation. Chemotherapy drugs are commonly used as first-line treatments, and while they can inhibit tumor cell proliferation and control disease progression to some extent, they generally have significant limitations: Firstly, traditional chemotherapy drugs have poor specificity, damaging normal hematopoietic and immune cells while killing tumor cells, leading to severe toxic side effects such as bone marrow suppression, gastrointestinal reactions, and decreased immunity, resulting in poor patient tolerance. Secondly, long-term chemotherapy easily induces drug resistance in tumor cells, leading to a gradual decline in treatment effectiveness, and many patients are prone to relapse, making a complete cure difficult. While targeted drugs and immunotherapy are more precise than chemotherapy drugs, they suffer from high costs, limited applicability, and non-response in some patients. Furthermore, there is still a lack of highly effective and low-toxicity specific drugs for Burkitt lymphoma. Hematopoietic stem cell transplantation faces drawbacks such as difficulty in matching donors, significant post-transplant rejection, and high medical barriers, hindering its widespread application.

[0004] CA-46 cells are a classic human Burkitt lymphoma cell line isolated from the ascites fluid of Burkitt lymphoma patients. This cell line is EBV nuclear antigen negative, carries the t(8;14) chromosome translocation, and stably expresses the MYC oncogene. It has characteristics such as rapid proliferation, strong in vitro culture stability, and significant malignant tumor phenotype. It can accurately simulate the in vivo malignant proliferation characteristics of Burkitt lymphoma and is currently the core experimental cell model for screening anti-tumor drugs for lymphoma and evaluating their pharmacological activity. It provides a reliable experimental carrier for the activity screening and mechanism research of lymphoma candidate drugs.

[0005] Small molecule compounds have become a key focus in anti-tumor drug development due to their numerous advantages, including simple structure, controllable synthesis processes, stable physicochemical properties, high bioavailability, ease of modification and optimization, and convenient administration. Compared to macromolecular biological drugs, small molecule compounds have stronger penetrating power, can effectively act on tumor lesions, and have lower production costs, making them suitable for large-scale industrial production. They hold broad research and development prospects in the prevention and treatment of malignant tumors. Currently, small molecule drug candidates for lymphoma still have shortcomings. Most small molecule compounds exhibit weak anti-tumor activity, poor selectivity for lymphoma cells, and poor inhibitory effects on the proliferation of highly aggressive Burkitt lymphoma. Furthermore, some compounds possess potential toxicity, severely hindering their clinical translation and application. Therefore, developing a class of novel small molecule compounds with potent inhibitory activity against Burkitt lymphoma CA-46 cells, high safety, and excellent targeting is crucial to filling existing technological gaps and will have significant clinical value and practical implications for enriching the variety of lymphoma treatment drugs and improving the treatment status of lymphoma patients.

[0006] This invention has prepared a series of novel small molecule compounds. In vitro cell activity tests have shown that these small molecule compounds exhibit excellent inhibitory effects on the proliferation of CA-46 Burkitt lymphoma cells, demonstrating significant antitumor activity and possessing great potential for development as drugs for the prevention or treatment of lymphoma. Based on this, the small molecule compounds provided by this invention can overcome the shortcomings of existing lymphoma treatments, such as high toxicity, strong drug resistance, poor specificity, and limited efficacy. Summary of the Invention

[0007] The purpose of this invention is to provide an amide compound or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs, or any mixture of two or more thereof that have anticancer activity, which can be used for the prevention or treatment of tumors, particularly lymphoma.

[0008] Specifically, the present invention relates to the following aspects: In a first aspect, the present invention provides compounds of Formula I or thereof, stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs, or any mixtures of two or more thereof: , In the formula, R1 and R2 are each independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl, 3-8 membered heterocyclic and 5-14 membered heteroaryl, -C(O)R a C(O)OR b SO2R bThe C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl, 3-8 membered heterocyclic and 5-14 membered heteroaryl are each optionally bound by one or more R f replace; Preferably, R1 and R2 are each independently selected from hydrogen, C1-C6 alkyl, -C(O)R a C(O)OR b The C1-C6 alkyl group is affected by one or more R groups. f replace; More preferably, R1 is selected from hydrogen and C1-C6 alkyl; R2 is selected from hydrogen, C1-C6 alkyl, and -C(O)R. a C(O)OR b ; More preferably, R1 is methyl; R2 is selected from hydrogen, C1-C6 alkyl, -C(O)R a C(O)OR b . R3 and R4 are each independently selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 14 Aryl and 5-14 membered heteroaryl; said C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 14 The aryl and 5-14 heteroaryl groups are each optionally bounded by one or more R groups. f replace; Preferably, R3 and R4 are each independently selected from hydrogen, C1-C6 alkyl, and C3-C7 cycloalkyl; the C1-C6 alkyl and C3-C7 cycloalkyl are optionally converted by one or more R f replace; More preferably, R3 and R4 are each independently selected from hydrogen and C1-C6 alkyl groups; the C1-C6 alkyl group is affected by one or more R3 and R4. f replace; More preferably, R3 and R4 are each independently selected from hydrogen and C1-C6 alkyl groups.

[0009] R5 and R6 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, and C(O)R. e C(O)OR e C(O)NR c R d S(O)R b S(O)2R b S(O)2NR c R d ,NHC(O)R e ,NHC(O)OR eNR c R d OC(O)R e C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 14 aryl and 5-14 membered heteroaryl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 14 The aryl and 5-14 heteroaryl groups are each optionally bounded by one or more R groups. f replace; Preferably, R5 and R6 are each independently selected from hydrogen, deuterium, halogen, and C(O)R. e C(O)OR e C(O)NR c R d ,NHC(O)R e ,NHC(O)OR e NR c R d OC(O)R e C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl and 5-14 heteroaryl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 The aryl and 5-14 heteroaryl groups are each optionally bounded by one or more R groups. f replace; More preferably, R5 and R6 are each independently selected from hydrogen, deuterium, halogen, and C(O)R. e C(O)OR e C1-C6 alkyl groups and C3-C7 cycloalkyl groups, wherein each of the C1-C6 alkyl groups and C3-C7 cycloalkyl groups is optionally surrounded by one or more R groups. f replace; More preferably, R5 and R6 are each independently selected from hydrogen and C(O)R e C(O)OR e C1-C6 alkyl; the C1-C6 alkyl group is affected by one or more R f replace; More preferably, R5 and R6 are each independently selected from hydrogen and C(O)R e C(O)OR e C1-C6 alkyl groups. R7 is selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl; the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Each aryl group is optionally bounded by one or more Rf replace; Preferably, R7 is selected from hydrogen, C1-C6 alkyl, and C3-C7 cycloalkyl; the C1-C6 alkyl and C3-C7 cycloalkyl are each optionally surrounded by one or more R f replace; More preferably, R7 is selected from hydrogen and C1-C6 alkyl groups; the C1-C6 alkyl group is affected by one or more R7 groups. f replace; More preferably, R7 is selected from hydrogen and methoxymethyl.

[0010] X1 is selected from O, S, NR c ; Preferably, X1 is selected from O and S.

[0011] X2 is selected from N and CR. a ; Preferably, X2 is N.

[0012] R a Independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 membered heteroaryl, the C6-C 14 The aryl group and the 5-14 membered heteroaryl group are each optionally fused with a C3-C7 cycloalkyl group or a 5-10 membered heterocyclic group; the C1-C6 alkyl group, C3-C7 cycloalkyl group, C6-C7 cycloalkyl group, and C6-C7 cycloalkyl group are respectively fused with a C3-C7 cycloalkyl group or a C3-C7 cycloalkyl group. 14 Aryl, 5-14 membered heteroaryl and 5-10 membered heterocyclic are each optionally bounded by one or more R f replace; Preferably, R a Independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 heteroaryl groups; the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 heteroaryl groups are each optionally bounded by one or more R groups. f replace; More preferably, R a Independently selected from hydrogen and C1-C6 alkyl groups; the C1-C6 alkyl group is separated by one or more R groups. f replace; More preferably, R a It is independently selected from hydrogen and C1-C6 alkyl groups. R b Independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 membered heteroaryl, the C6-C 14The aryl group and the 5-14 membered heteroaryl group are each optionally fused with a C3-C7 cycloalkyl group or a 5-10 membered heterocyclic group; the C1-C6 alkyl group, C3-C7 cycloalkyl group, C6-C7 cycloalkyl group, and C6-C7 cycloalkyl group are respectively fused with a C3-C7 cycloalkyl group or a C3-C7 cycloalkyl group. 14 Aryl, 5-14 membered heteroaryl and 5-10 membered heterocyclic are each optionally bounded by one or more R f replace; Preferably, R b Independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 heteroaryl groups; the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl groups and 5-14 heteroaryl groups are each optionally influenced by one or more R groups. f replace; More preferably, R b Independently selected from C1-C6 alkyl groups; the C1-C6 alkyl group is affected by one or more R groups. f replace; More preferably, R b Independently selected from C1-C6 alkyl groups.

[0013] R c and R d Each is independently selected from hydrogen, C(O)R g S(O)R h S(O)2R h C(O)NR i R j C(O)OR k C1-C6 alkyl, C3-C7 cycloalkyl and 4-7 membered heterocyclic groups; or R b and R c Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic group; the C1-C6 alkyl, C3-C7 cycloalkyl and 4-7 membered heterocyclic group are each optionally surrounded by one or more R f replace; Preferably, R c and R d Each is independently selected from hydrogen, C(O)R g S(O)R h S(O)2R h C(O)NR i R j C(O)OR k C1-C6 alkyl, C3-C7 cycloalkyl, and 4-7 membered heterocyclic groups; each of the C1-C6 alkyl, C3-C7 cycloalkyl, and 4-7 membered heterocyclic groups is optionally surrounded by one or more R groups. f replace; More preferably, R c and R dEach is independently selected from hydrogen, C(O)R g C1-C6 alkyl, C3-C7 cycloalkyl, and 4-7 membered heterocyclic groups; each of the C1-C6 alkyl, C3-C7 cycloalkyl, and 4-7 membered heterocyclic groups is optionally surrounded by one or more R groups. f replace; More preferably, R c and R d Each is independently selected from hydrogen and C1-C6 alkyl; the C1-C6 alkyl group is converted by one or more R f replace; More preferably, R c and R d Each is independently selected from hydrogen and C1-C6 alkyl groups. R e Independently selected from hydrogen, C1-C6 alkyl, 3-7 membered heterocyclic groups, C6-C 14 aryl and 5-14 membered heteroaryl, wherein the C1-C6 alkyl, 3-7 membered heterocyclic, C2-C6 alkenyl C6-C 14 The aryl and 5-14 heteroaryl groups are each optionally bounded by one or more R groups. f replace; Preferably, R e Independently selected from hydrogen, C1-C6 alkyl, wherein the C1-C6 alkyl group is reacted with one or more R f replace; More preferably, R e It is independently selected from hydrogen and C1-C6 alkyl groups.

[0014] R g Independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 aryl and 5-14 heteroaryl groups; the C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 The aryl and 5-14 heteroaryl groups are each optionally bounded by one or more R groups. f replace; Preferably, R g Independently selected from hydrogen, C1-C6 alkyl; said C1-C6 alkyl group is separated by one or more R f replace; More preferably, R g It is independently selected from hydrogen and C1-C6 alkyl groups.

[0015] R h Independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 heteroaryl groups; the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14The aryl and 5-14 heteroaryl groups are each optionally bounded by one or more R groups. f replace; Preferably, R h Independently selected from C1-C6 alkyl groups; the C1-C6 alkyl group is reacted with one or more R f replace; More preferably, R h It is independently selected from C1-C6 alkyl groups. R i and R j Each is independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, and 4-7 membered heterocyclic groups; or R i and R j Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic group; the C1-C6 alkyl, C3-C7 cycloalkyl and 4-7 membered heterocyclic group are each optionally surrounded by one or more R f replace; Preferably, R i and R j Each is independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, and 4-7 membered heterocyclic groups; the C1-C6 alkyl, C3-C7 cycloalkyl, and 4-7 membered heterocyclic groups are each optionally separated by one or more R groups. f replace; More preferably, R i and R j Each is independently selected from hydrogen and C1-C6 alkyl; the C1-C6 alkyl group is converted by one or more R f replace; More preferably, R i and R j Each is independently selected from hydrogen and C1-C6 alkyl groups. R k Independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 aryl and 5-14 heteroaryl groups; the C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 The aryl and 5-14 heteroaryl groups are each optionally bounded by one or more R groups. f replace; Preferably, R k Independently selected from C1-C6 alkyl groups; the C1-C6 alkyl group is reacted with one or more R f replace; More preferably, R k It is independently selected from C1-C6 alkyl groups. R f Independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, CN, NO2, C(O)R LCO2R p NR n SO2R m S(O)R m SO2R m C(O) NR n R o SO2NR n R o NR n R o NR n C(O)R L C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy, C6-C 14 aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic; wherein the C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic group are each optionally bounded by one or more R r replace; Preferably, R f Independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, CN, NO2, C(O)R L CO2R p C(O) NR n R o NR n R o NR n C(O)R L C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C6-C 14 Aryl; the C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C6-C 14 Each aryl group is optionally bounded by one or more R r replace; More preferably, R f Independently selected from hydrogen, hydroxyl, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C6-C 14 Aryl; the C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C6-C 14 Each aryl group is optionally bounded by one or more R r replace; More preferably, R fIndependently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; wherein each of the C1-C6 alkyl and C1-C6 alkoxy groups is optionally separated by one or more R r replace; More preferably, R f It is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy. R L Independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 heteroaryl groups; Preferably, R L It is independently selected from hydrogen and C1-C6 alkyl groups.

[0016] R m Independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 heteroaryl groups; Preferably, R m It is independently selected from C1-C6 alkyl groups.

[0017] R n and R o Each is independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, and 4-7 membered heterocyclic groups; Or, R n and R o Together with the nitrogen atom it is attached to, it forms a 4-7 membered heterocyclic group; Preferably, R n and R o Each is independently selected from hydrogen and C1-C6 alkyl groups.

[0018] R p Independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 heteroaryl groups; Preferably, R p It is independently selected from hydrogen and C1-C6 alkyl groups.

[0019] R r Independently selected from hydrogen, deuterium, halogen, hydroxyl, CN, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy, C6-C 14 Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic; Preferably, R r It is independently selected from hydrogen, hydroxyl, and C1-C6 alkyl.

[0020] In a second aspect, the amide compounds of the present invention, or their stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs, or any mixture of two or more thereof, wherein the amide compound is a compound represented by Formula II,

[0021] in, R2 is selected from hydrogen, C1-C6 alkyl, -C(O)R a and C(O)OR b ; R3 and R4 are each independently selected from hydrogen and C1-C6 alkyl groups; R5 and R6 are each independently selected from hydrogen, halogens, and C(O)R e C(O)OR e and C1-C6 alkyl groups; R7 is selected from hydrogen and methoxymethyl; X1 is selected from O and S; R a Selected from hydrogen and C1-C6 alkyl groups; R b Selected from hydrogen and C1-C6 alkyl groups; R e Selected from hydrogen and C1-C6 alkyl groups.

[0022] Preferred, R2 is selected from hydrogen and C(O)OR b ; R3 and R4 are each independently selected from hydrogen and C1-C3 alkyl groups; R5 and R6 are each independently selected from hydrogen, halogens, and C(O)OR. e ; R7 is selected from hydrogen and methoxymethyl; X1 is selected from O and S; R b Selected from hydrogen and C1-C4 alkyl groups; R e Selected from hydrogen, methyl, ethyl and propyl.

[0023] In some embodiments, the compounds of the present invention are selected from compounds with the following structures: .

[0024] This invention provides specific examples of amide compounds, including: (1) Tert-butyl((S)-1-((R)-3-(3,5-dichloro-4-(methoxymethoxy)phenyl)-1-(oxazol-2-ylamino)-1-oxopropane-2-ylamino)-3-methyl-1-oxobutane-2-yl)(methyl)carbamate; (2)(2S,3S)-1-((R)-3-(3,5-dichloro-4-(methoxymethoxy)phenyl)-1-(oxazol-2-ylamino)-1-oxopropyl-2-yl)amino)-3-methyl-1-oxopent-2-yl)(methyl)carbamate tert-butyl ester. (3)S)-N-((R)-3-(3,5-dichloro-4-(methoxymethoxy)phenyl)-1-(oxazol-2-ylamino)-1-oxopropyl-2-yl)-3-methyl-2-(methylamino)butyramide; (4)(S)-N-((R)-3-(3,5-dichloro-4-hydroxyphenyl)-1-(oxazol-2-ylamino)-1-oxopropyl-2-yl)-3-methyl-2-(methylamino)butyramide; (5) 5-Oxazolylcarboxylic acid-2-[((R)-2-[(2S,3S)-2-(tert-butoxycarbonylmethylamino)-3-methylpentanoylamino]-3-(3,5-dichloro-4-methoxymethoxyphenyl)propionylamino]ethyl ester; (6)2-[(R)-3-(3,5-dichloro-4-hydroxyphenyl)-2-((2S,3S)-3-methyl-2-methylaminopentanoylamino)propionylamino]oxazol-5-carboxylic acid ethyl ester; (7)(S)-N-[(R)-1-[(5-bromothiazol-2-yl)amino]-3-(3,5-dichloro-4-hydroxyphenyl)-1-oxopropyl-2-yl]-3-methyl-2-(methylamino)butyramide; (8)2-[(R)-3-(3,5-dichloro-4-hydroxyphenyl)-2-((S)-3-methyl-2-methylaminobutamido)propamido]-4-methylthiazol-5-carboxylic acid ethyl ester.

[0025] Thirdly, in some embodiments, the present invention provides methods for preparing some of the amide compounds, the synthetic routes of which are as follows: , or (That is, the case where R1 is H in the formulas SM1, IM-1, and IM-2).

[0026] In the formula, The definitions of R1, R2, R3, R4, R5, R6, R7, X1, and X2 are the same as those in the compounds of Formula I or Formula II mentioned above; Step 1: Compounds SM-1 and SM-2 undergo an acid-amine condensation reaction in the presence of a condensing agent to generate compound IM-1; Step 2: Compound IM-1 undergoes deprotection under alkaline or acidic conditions to generate IM-2; Step 3: Compound IM-2 and compound SM-3 undergo an acid-amine condensation reaction in the presence of a condensing agent to generate compound I; or, in a further step, the protecting group is removed by acid to generate compound I.

[0027] Fourthly, the present invention provides a pharmaceutical composition comprising the compound described herein or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs, or any mixture of two or more thereof, and one or more pharmaceutically acceptable carriers.

[0028] Fifthly, the present invention provides a pharmaceutical formulation comprising the compound described herein, a pharmaceutically acceptable salt, ester, solvate, isomer, any crystal form or racemate thereof, a metabolite thereof, or a mixture thereof as an active ingredient, wherein the formulation is in the form of a solid, semi-solid, liquid, or gaseous formulation.

[0029] In a sixth aspect, the present invention provides the use of the compounds described herein, their pharmaceutically acceptable salts, esters, solvates, isomers, any crystal forms or racemates thereof, their metabolite forms, or mixtures thereof, or the pharmaceutical compositions described herein, in the prevention or treatment of lymphoma.

[0030] Beneficial effects: The novel amide compounds of this invention have been shown through in vitro cell activity verification to have excellent inhibitory effects on the proliferation of CA-46 Burkitt lymphoma cells. They exhibit strong inhibitory activity and significant anti-tumor activity, and have great potential to be developed into drugs for the prevention or treatment of lymphoma, thereby addressing the shortcomings of existing lymphoma treatment drugs, such as large toxic side effects, strong drug resistance, poor targeting, and limited efficacy. Detailed Implementation

[0031] The following embodiments are provided to describe the present invention in more detail. However, these embodiments are provided only to help further understand the present invention and are not intended to limit the present invention. Those skilled in the art should understand that equivalent substitutions or corresponding improvements made to the content of the present invention still fall within the protection scope of the present invention.

[0032] General terms and definitions: Unless otherwise defined, the terms used herein have the same meaning as commonly understood by those skilled in the art. The technical intent used herein refers to technology commonly understood in the art, including variations or equivalent substitutions that are obvious to those skilled in the art. While the following terms are readily understood by those skilled in the art, they are set forth below to better explain the invention.

[0033] The term "isomer" refers to compounds that have the same molecular weight due to having the same number and type of atoms, but different spatial arrangements or configurations of atoms.

[0034] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that, due to having at least one chiral element (including a chiral center, chiral axis, chiral plane, etc.), has a perpendicular asymmetric plane, thereby enabling the rotation of plane-polarized light. Since the compounds of the present invention (or pharmaceutically acceptable salts thereof) comprise asymmetric carbon atoms, they can exist as a single stereoisomer, a racemic mixture, or a mixture of enantiomers and diastereomers. These compounds can be monomorphic compounds, mixtures of racemic mixtures, or mixtures of a single stereoisomer enriched with other enantiomers and / or diastereomers.

[0035] The term "tautomer" (or "tautomer form") refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (or proton transfer tautomers) include (but are not limited to) interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-imine alcohol isomerization, etc. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0036] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include (but are not limited to) salts formed by the reaction of the compound of the present invention with a pharmaceutically acceptable inorganic acid / organic acid / acidic amino acid or inorganic base / organic base / basic amino acid; such salts are also known as acid addition salts or base addition salts.

[0037] The term "polymorph" (or "polymorphic form") refers to the solid crystalline form of a compound or complex. Those skilled in the art can obtain polymorphs of molecules using many known methods. These methods include (but are not limited to) melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. Furthermore, well-known techniques can be used to detect, classify, and identify polymorphs, including (but not limited to) differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction (SCXRD), solid-state nuclear magnetic resonance (NMR), infrared spectroscopy (IR), Raman spectroscopy, and scanning electron microscopy (SEM). This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which can be a single polymorph or a mixture of multiple polymorphs in any proportion.

[0038] The term "eutectic" refers to a multi-component molecular crystal complex formed in the solid state by spontaneous association of two or more chemically independent pure components through non-covalent intermolecular interactions (including hydrogen bonds, van der Waals forces, π-π stacking interactions, dipole interactions, etc.) without the breaking or formation of ionic or covalent bonds. Each component of the complex retains its original chemical molecular structure, without proton transfer or salt bond formation, and the components are regularly arranged in the same lattice system with a fixed stoichiometric ratio. This is distinct from physical mixtures, solvates, and polymorphs, and possesses inherent characteristics such as melting point, solubility, dissolution characteristics, physicochemical stability, and powder properties that differ from those of the individual components.

[0039] The term "solvent" refers to a substance formed by the combination of a compound of the present invention (or a pharmaceutically acceptable salt thereof) with at least one solvent molecule through non-covalent intermolecular forces. Common solvates include (but are not limited to) hydrates (including hemihydrates, monohydrates, dihydrates, trihydrates, etc.), ethanol compounds, acetone compounds, etc. The compounds of the present invention may exist in the form of solvates (preferably hydrates), containing a polar solvent (particularly water, methanol, or ethanol) as a lattice structure element. The amount of polar solvent (particularly water) may be present in stoichiometric or non-stoichiometric form.

[0040] The term "metabolite" refers to a derivative compound formed after the compounds of the present invention are metabolized, for example, by reactions such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, or enzymatic hydrolysis. The present invention covers all possible metabolite forms of the compounds of the present invention, i.e., substances formed in the body of an individual administering the compounds of the present invention. Metabolites of the compounds can be identified using techniques known in the art, and their activity can be characterized experimentally.

[0041] The term "prodrug" refers to a derived compound that, upon administration to an individual, can directly or indirectly provide the compounds of the present invention. Particularly preferred derived compounds or prodrugs are those that, upon administration to an individual, can improve the bioavailability of the compounds of the present invention (e.g., facilitate absorption into the bloodstream) or promote the delivery of the parent compound to its site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention. Furthermore, the present invention also covers compounds of the present invention containing protecting groups. In any process of preparing the compounds of the present invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the present invention. This can be achieved by conventional protecting groups. These protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0042] The terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0043] The term "halogenated" or "halogenated" is defined as including F, Cl, Br, or I.

[0044] The term "alkyl" is defined as a straight-chain or branched saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms. For example, as used herein, the term "C1-6 alkyl" refers to a linear or branched group with 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl). The term "C1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain with 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl). In this invention, the "alkyl" is optionally replaced by one or more (such as one to three) suitable substituents such as halogens (in which case the group is referred to as "haloalkyl") (e.g., -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3, etc.).

[0045] The term “cycloalkyl” refers to a monocyclic or polycyclic (e.g., bicyclic) saturated or partially unsaturated aliphatic monovalent hydrocarbon group (e.g., monocyclic cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.; or bicyclic cycloalkyl, including fused ring, bridged ring or spiro ring, such as decahydronaphthyl, bicyclic [2.2.1]heptyl, spiro [4.5]decyl, etc.).

[0046] The term "heterocyclic alkyl" refers to a monocyclic or polycyclic (e.g., bicyclic) saturated or partially unsaturated aliphatic monovalent hydrocarbon group having one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) and one or more (e.g., 1, 2, 3, or 4) segments each independently selected from O, S, S(=O), S(=O)₂, and NR (R represents a hydrogen atom or substituent, such as alkyl or cycloalkyl). The ring system in a heterocyclic alkyl group can be a fused ring, a bridged ring, or a spirocyclic system. If the valence requirements are met, a heterocyclic alkyl group can be linked to other groups (or segments) through any carbon atom or heteroatom in the ring.

[0047] The term "alkenyl" refers to a hydrocarbon group containing at least one carbon-carbon double bond. Alkenyl groups can be straight-chain or branched.

[0048] The term "alkynyl" refers to a hydrocarbon group containing at least one carbon-carbon triple bond. Alynyl groups can be straight-chain or branched.

[0049] The term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, the term "C6-10 aryl" means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group may optionally be substituted by one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, C1-6 alkyl, etc.).

[0050] The term "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system containing at least one heteroatom, which may be the same or different (the heteroatom is, for example, oxygen, nitrogen, or sulfur), and, in some cases, may be benzo-fused. In some embodiments, the heteroaryl group has 3 to 18 cyclic atoms, preferably 5 to 10. In particular, the heteroaryl group is selected from thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, etc., and their benzo-derived derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo-derived derivatives.

[0051] The term "substitution" refers to the replacement of one or more (e.g., 1, 2, 3, or 4) hydrogen atoms on a specified atom by a selected group, provided that the substitution does not exceed the normal valence of the specified atom in its current state and the substitution forms a stable compound. The number of substituted groups selected is permitted only when such a combination forms a stable compound.

[0052] If a substituent is described as “each independently selected”, then each substituent may be the same as or different from another (other) substituent. The term “one or more” means one or more under reasonable conditions, such as two, three, four, five, or ten.

[0053] The terms "optional" and "optionally" mean the same thing, indicating that something is optional, such as whether the functional group can be substituted or not.

[0054] The term "protecting group" refers to a chemical group that has the following characteristics: 1) It can react with corresponding functional groups to form protected groups; 2) The protected group will be stable under the reaction conditions; 3) Functional groups can be released by removing the protected groups.

[0055] In addition, groups not defined herein follow their usual definitions. Pharmaceutically acceptable salts of the compounds of this invention include their acid addition salts and base addition salts. Examples include salts formed from alkali metals, alkaline earth metals, ammonium, alkylammonium, etc., and salts formed with inorganic or organic acids. These salts can be listed as sodium salts, potassium salts, calcium salts, ammonium salts, aluminum salts, triethylammonium salts, acetates, propionates, butyrates, formates, trifluoroacetates, maleates, tartrates, citrates, stearates, succinates, ethylsuccinates, lactobionates, gluconates, glucohepanoates, benzoates, methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, benzenesulfonates, p-toluenesulfonates, lauryl sulfates, malates, aspartate salts, glutamates, adipates, tris(hydroxymethyl)aminomethane salts, salts formed with cysteine, salts formed with N-acetylcysteine, hydrochlorides, hydrobromide salts, phosphates, sulfates, hydroiodates, nicotinate salts, oxalates, picrates, thiocyanates, undecanoates, salts formed with acrylic acid polymers, and salts formed with carboxyl vinyl polymers, etc.

[0056] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0057] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0058] The present invention further includes, within its scope, prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity, and which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the present invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the desired therapeutically active compounds.

[0059] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention.

[0060] The technical solution of the present invention will be further illustrated below through specific embodiments. Unless otherwise stated, the pharmaceuticals, reagents, materials, instruments, etc., described in the following embodiments can all be obtained through conventional commercial means.

[0061] In the conventional synthesis method and in the examples and intermediate synthesis examples, the meanings of each abbreviation are shown in Table 1 below.

[0062] Table 1. Meanings of Abbreviations

[0063] The structures of the compounds described in the following examples were confirmed by nuclear magnetic resonance (1H-NMR) and / or liquid chromatography-mass spectrometry (LC-MS).

[0064] The nuclear magnetic resonance (¹H-NMR) measurements were performed using a Bruker 400MHz NMR spectrometer. The solvents used were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard was tetramethylsilane (TMS). The abbreviations used in the nuclear magnetic resonance (NMR) data in the following examples have the following meanings: s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: quartet doublet, ddd: double double doublet, ddt: double double triplet, dddd: double double double doublet, m: multiplet, br: broad, J: coupling constant, Hz: Hertz, δ: chemical shift. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) was performed using a Shimadzu LC-2050C chromatograph and a Shimadzu LCMS-2050 mass spectrometer. Unless otherwise specified, the general separation conditions were as follows: Shim pack Scepter C18-120 (4.6 mm × 150 mm × 3.0 μm) column; column temperature: 40℃; flow rate: 1.0 mL / min; detection wavelength: 190 / 220 / 254 nm; mobile phase A: 0.05% formic acid aqueous solution; mobile phase B: 100% acetonitrile; elution gradient: (0-2 min: 70% A, 30% B; 6 min: 20% A, 80% B; 9 min: 5% A, 95% B); mass spectrometry scan range: ±100~1000 Da. All chemical shift (δ) values ​​are given in parts per million (ppm). Column chromatography uses 200-300 mesh silica gel (Sichuan Buster Fine Chemical Co., Ltd.) as the stationary phase. The eluent system (but not limited to) is a petroleum ether / ethyl acetate system and a dichloromethane / methanol system. The volume ratio of the two solvents can be adjusted according to the polarity of the compounds to be separated. Unless otherwise stated, the reaction temperature in the following examples is room temperature (20–30°C). Unless otherwise stated, the reagents used in the following examples were purchased from companies such as SANN Chemical Technology (Shanghai) Co., Ltd., Shanghai BIDE Pharmaceutical Technology Co., Ltd., and Shanghai Haohong Biomedical Technology Co., Ltd.

[0065] Preparation of intermediate compounds: Intermediate a1: Methyl(R)-2-amino-3-(3,5-dichloro-4-(methoxymethoxy)phenyl)propionate

[0066] Step 1: (R)-2-amino-3-(3,5-dichloro-4-hydroxyphenyl)propionic acid (a1-2) Compound a1-1 (10.0 g, 55.2 mmol) was added to a mixed solvent of tetrahydrofuran (100 mL) and sulfolane (100 mL) under nitrogen protection. Sulfonyl chloride (34.0 g, 251.8 mmol) was added dropwise with stirring in an ice bath. After the addition was complete, the temperature was raised to 30 °C and the reaction mixture was reacted for 5 h. After the reaction was complete, the reaction mixture was cooled to 0 °C and poured into a mixed solvent of dichloromethane (400 mL) and petroleum ether (400 mL). The mixture was stirred for 15 min, allowed to stand, and the supernatant was discarded. The lower oily layer was added to dichloromethane (200 mL), stirred at room temperature for 1 h, filtered, and the filter cake was washed with dichloromethane and used directly in the next step.

[0067] MS m / z (ESI): 250.0 [M+H] + Step 2: (R)-2-amino-3-(3,5-dichloro-4-hydroxyphenyl)propionate (a1-3) Compound a1-2 (10.0 g, 35.1 mmol) was added to methanol (150 mL), and thionyl chloride (20.0 g, 168.0 mmol) was slowly added dropwise with stirring in an ice bath. After the addition was complete, the mixture was heated to 60 °C and reacted overnight. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated to dryness under reduced pressure, and used directly in the next step.

[0068] MS m / z (ESI): 264.0 [M+H] + Step 3: Methyl(R)-2-amino-3-(3,5-dichloro-4-(methoxymethoxy)phenyl)propionate (a1) Compound a1-3 (5.0 g, 16.6 mmol) was added to dichloromethane (100 mL), and DIPEA (3.4 g, 26.3 mmol) and MOMBr (2.7 g, 20.0 mmol) were added sequentially under stirring in an ice bath. The reaction was continued under ice bath conditions for 1 h. After the reaction was completed, the reaction solution was quenched with sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined, concentrated to dryness under reduced pressure, and the concentrate was separated by column chromatography to obtain compound a1 (4.1 g), with a yield of 76.8%.

[0069] LC-MS (ESI): m / z 308.0 [M+H] + Example 1: Tert-butyl((S)-1-((R)-3-(3,5-dichloro-4-(methoxymethoxy)phenyl)-1-(oxazol-2-ylamino)-1-oxopropane-2-ylamino)-3-methyl-1-oxobutane-2-yl)(methyl)carbamate (1)

[0070] Step 1: Methyl(R)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutamido)-3-(3,5-dichloro-4-(methoxymethoxy)phenyl)propionate (1-1) Compound c1 (462.0 mg, 2.0 mmol) was added to dichloromethane (20 mL). HATU (912.0 mg, 2.4 mmol) was added with stirring in an ice bath. After reacting for 10 min in an ice bath, DIPEA (516.0 mg, 4.0 mmol) and compound a1 (616.0 mg, 2.0 mmol) were added sequentially, and the reaction was continued in an ice bath for 3 h. After the reaction was complete, the reaction solution was quenched with water, allowed to stand, and separated. The organic layer was concentrated to dryness under reduced pressure, and separated by column chromatography to obtain compound 1-1 (565.0 mg), with a yield of 54.0%.

[0071] MS m / z (ESI): 521.2 [M+H] + Step 2: (R)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutamido)-3-(3,5-dichloro-4-(methoxymethoxy)phenyl)propionic acid (1-2) Compound 1-1 (565.0 mg, 1.3 mmol) was added to a mixed solution of tetrahydrofuran (4 mL) and water (2 mL), and lithium hydroxide (91.0 mg, 3.8 mmol) was added at room temperature. The reaction was allowed to proceed for 1 h. After the reaction was complete, the tetrahydrofuran was concentrated under reduced pressure, and the pH was adjusted to 5-6 with dilute hydrochloric acid. A white solid precipitated out. The solid was filtered, and the filter cake was washed with water and dried to give compound 1-2 (470.0 mg), with a yield of 85.7%.

[0072] MS m / z (ESI): 507.2 [M+H] + Step 3: tert-butyl((S)-1-((R)-3-(3,5-dichloro-4-(methoxymethoxy)phenyl)-1-(oxazol-2-ylamino)-1-oxopropane-2-ylamino)-3-methyl-1-oxobutane-2-yl)(methyl)carbamate (1) Compounds 1-2 (50.7 mg, 0.1 mmol) were added to acetonitrile. TCFH (20 mg, 0.12 mmol) and NMI (10 mg, 0.12 mmol) were added sequentially under ice bath conditions. After reacting for 20 min under ice bath conditions, compound b1 (10.1 mg, 0.12 mmol) was added, and the reaction was continued under ice bath conditions for another 2 h. After the reaction was complete, the reaction solution was purified by column chromatography to obtain compound 1 (5.1 mg), with a yield of 8.9%.

[0073] 1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 7.40 (s, 1H), 7.25 – 7.09 (m,3H), 7.01 (s, 1H), 5.12 (s, 2H), 4.21 – 3.79 (m, 2H), 3.66 (s, 3H), 3.29 –3.12 (m, 1H), 3.01 – 2.86 (m, 1H), 2.79 (s, 3H), 2.25 – 2.15 (m, 1H), 1.25(s, 9H), 0.84 (s, 6H).

[0074] MS m / z (ESI): 573.2 [M+H] + Example 2: (2S,3S)-1-((R)-3-(3,5-dichloro-4-(methoxymethoxy)phenyl)-1-(oxazol-2-ylamino)-1-oxopropyl-2-yl)amino)-3-methyl-1-oxopent-2-yl)(methyl)carbamate tert-butyl ester (2)

[0075] Step 1: (R)-2-((2S,3S)-2-(tert-Butoxycarbonyl)(methyl)amino)-3-methylpentamido)-3-(3,5-dichloro-4-(methoxymethoxy)phenyl)propionate (2-1) Compound 2-1 (1.5 g) was prepared using the same method as compound 1-1, with a yield of 86.9%.

[0076] MS m / z (ESI): 535.2 [M+H] + Step 2: (R)-2-((2S,3S)-2-((tert-Butoxycarbonyl)(methyl)amino)-3-methylpentamido)-3-(3,5-dichloro-4-(methoxymethoxy)phenyl)propionic acid (2-2) Compound 2-2 (1.2 g) was prepared using the same synthetic method as compounds 1-2, with a yield of 82.3%.

[0077] MS m / z (ESI): 521.2 [M+H] + Step 3: tert-butyl((2S,3S)-1-(((R)-3-(3,5-dichloro-4-(methoxymethoxy)phenyl)-1-(oxazol-2-ylamino)-1-oxopropane-2-yl)amino)-3-methyl-1-oxopentane-2-yl)(methyl)carbamate)(2) Compound 2-2 (52.1 mg, 0.1 mmol) was added to dichloromethane (2 mL), and HATU (45.6 mg, 0.16 mmol) was added with stirring in an ice bath. After reacting for 20 min, DIPEA (20.0 mg, 0.16 mmol) and compound b1 (8.4 mg, 0.1 mol) were added sequentially, and the reaction was continued in an ice bath for 1.5 h. After the reaction was completed, the solution was concentrated under reduced pressure and separated by column chromatography to obtain compound 2 (4.5 mg), with a yield of 7.6%.

[0078] 1 H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.23 – 6.95 (m, 4H), 5.14 (s,2H), 4.17 – 4.10 (m, 1H), 4.04 – 3.95 (m, 1H), 3.67 (s, 3H), 3.30 – 3.17 (m,1H), 3.01 – 2.85 (m, 1H), 2.79 (s, 3H), 2.39 – 2.31 (m, 1H), 1.25 (s, 9H), 0.92 – 0.77 (m, 8H).

[0079] MS m / z (ESI): 587.2 [M+H] + Example 3: (S)-N-((R)-3-(3,5-dichloro-4-(methoxymethoxy)phenyl)-1-(oxazol-2-ylamino)-1-oxopropyl-2-yl)-3-methyl-2-(methylamino)butyramide (3)

[0080] Compound 1 (20 mg, 0.035 mmol) was dissolved in DCM (5 mL). The reaction solution was cooled to 0–5 °C, and then 2,6-lutidine (0.5 mL) and TESOTf (0.5 mL) were added sequentially. The mixture was stirred at 0–5 °C for 4 hours. The reaction solution was quenched with 10 mL of saturated ammonium chloride solution, and then 5 mL of DCM was added. After thorough stirring, the mixture was separated into layers. The aqueous phase was extracted once with 10 mL of DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated. The residue was separated using a preparative separation column to obtain product 3 (7.3 mg), with a yield of 44.2%.

[0081] 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.39 (s, 1H), 7.27 – 7.18 (m,3H), 7.00 (s, 1H), 5.13 (s, 2H), 4.89 – 4.69 (m, 1H), 3.66 (s, 3H), 3.34 –3.20 (m, 1H), 3.07 – 2.94 (m, 1H), 2.91 – 2.78 (m, 1H), 2.19 (s, 3H), 2.13 –2.04 (m, 1H), 0.88 – 0.75 (m, 6H).

[0082] MS m / z (ESI): 473.1 [M+H] + Example 4: (S)-N-((R)-3-(3,5-dichloro-4-hydroxyphenyl)-1-(oxazol-2-ylamino)-1-oxopropyl-2-yl)-3-methyl-2-(methylamino)butyramide (4)

[0083] Compound 1 (18 mg, 0.031 mmol) was dissolved in DCM (5 mL), and TFA (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with 10 mL of saturated ammonium chloride solution, and then 5 mL of DCM was added. After thorough stirring, the mixture was separated into aqueous and organic phases. The aqueous phase was extracted twice with 10 mL of DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated. The residue was separated using a preparative separation column to give product 4 (7.3 mg), with a yield of 44.2%.

[0084] 1 H NMR (400 MHz, Chloroform- d ) δ 7.40 (d, J = 1.3 Hz, 1H), 7.19 (s,1H), 7.17 (s, 1H), 7.01 (d, J = 1.3 Hz, 1H), 3.25 (d, J = 5.4 Hz, 1H), 3.08 –2.96 (m, 1H), 2.79 (dd, J= 17.6, 4.4 Hz, 1H), 2.33 (s, 1H), 2.25 – 2.19 (m,1H), 2.18 (s, 3H), 2.13 – 2.06 (m, 1H), 1.02 – 0.92 (m, 6H).

[0085] MS m / z (ESI): 429.1 [M+H] + Example 5: Ethyl 5-oxazolylcarboxylic acid-2-[((R)-2-[(2S,3S)-2-(tert-butoxycarbonylmethylamino)-3-methylpentanoylamino]-3-(3,5-dichloro-4-methoxymethoxyphenyl)propionylamino] ester (5)

[0086] Except for replacing 1-2 in step 3 of Example 1 with 2-2 and replacing b1 in step 3 of Example 1 with 5-1, the remaining steps were the same as in step 3 of Example 1, yielding compound 5 (14 mg) in 8.8%.

[0087] 1 H NMR (400 MHz, Chloroform- d ) δ 7.65 (s, 1H), 7.19 (s, 2H), 5.11 (s,2H), 4.97 – 493 (m, 1H), 4.39 – 4.33 (m, 2H), 4.02 (t, J = 12.0 Hz, 1H), 3.65(s, 3H), 3.35 – 3.14 (m, 2H), 2.99 – 2.87 (m, 2H), 2.79 (s, 3H), 2.10 – 2.04(m, 1H), 1.55 – 1.31 (m, 11H), 1.05 – 0.98 (m, 1H), 0.89 – 0.84 (m, 3H), 0.82 – 0.74 (m, 3H).

[0088] MS m / z (ESI): 659.2 [M+H] + Example 6: 2-[(R)-3-(3,5-dichloro-4-hydroxyphenyl)-2-((2S,3S)-3-methyl-2-methylaminopentanoylamino)propionylamino]oxazole-5-carboxylic acid ethyl ester (6)

[0089] Except for replacing 1 in Example 4 with 5, all other steps were performed according to Example 4, yielding compound 6 (4.7 mg) in a yield of 52%.

[0090] 1 H NMR (400 MHz, Chloroform- d ) δ 7.97 (dd, J = 12.5, 7.7 Hz, 1H), 7.66(d, J = 1.9 Hz, 1H), 7.18 (d, J = 9.0 Hz, 2H), 4.43 – 4.31 (m, 3H), 3.27 – 3.23(m, 1H), 3.04 – 2.96 (m, 1H), 2.93 – 2.81 (m, 1H), 2.17 (s, 3H), 1.44 – 1.34(m, 4H), 1.04 – 0.93 (m, 2H), 0.93 – 0.86 (m, 3H), 0.87 – 0.81 (m, 3H).

[0091] MS m / z (ESI): 515.1 [M+H] + Example 7: (S)-N-[(R)-1-[(5-bromothiazol-2-yl)amino]-3-(3,5-dichloro-4-hydroxyphenyl)-1-oxopropyl-2-yl]-3-methyl-2-(methylamino)butyramide (7)

[0092] Step 1: Compound 2-2 (75 mg, 0.14 mmol) was added to acetonitrile. TCFH (45 mg, 0.16 mmol) and NMI (17 mg, 0.21 mmol) were added sequentially under ice bath conditions. After reacting for 20 min under ice bath conditions, compound b1 (30 mg, 0.17 mmol) was added, and the reaction was continued under ice bath conditions for another 2 h. After the reaction was complete, the reaction solution was purified by column chromatography to obtain compound 1 (16 mg), with a yield of 16.3%.

[0093] MS m / z (ESI): 680.1 [M+H] + Step 2: Except for replacing 1 in Example 4 with 7-2, all other steps were performed in accordance with Example 4 to obtain compound 7 (5.5 mg) with a yield of 62.2%.

[0094] 1 H NMR (400 MHz, DMSO- d 6) δ 8.94 – 8.90 (m, 1H), 7.68 (s, 1H), 7.41 (s, 2H), 4.81 (ddd, J = 11.6, 8.0, 3.6 Hz, 1H), 3.16 – 3.10 (m, 2H), 2.95 –2.79 (m, 1H), 2.39 (s, 3H), 1.94 (dd, J = 15.6, 9.1 Hz, 1H), 0.76 (d, J = 6.8Hz, 6H).

[0095] MS m / z (ESI): 523.0 [M+H] + Example 8: 2-[(R)-3-(3,5-dichloro-4-hydroxyphenyl)-2-((S)-3-methyl-2-methylaminobutamido)propionamido]-4-methylthiazol-5-carboxylic acid ethyl ester (8)

[0096] Except for replacing 7-2 in Example 7 with 8-2, all other steps were performed according to Example 7, yielding compound 8 (7.3 mg) in a yield of 71.7%.

[0097] 1 H NMR (400 MHz, DMSO- d 6) δ 7.37 (s, 2H), 4.73 (ddd, J = 11.5, 7.8, 3.5Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H), 3.67 – 3.56 (m, 1H), 3.11 – 3.07 (m, 2H), 2.57 (s, 3H), 2.36 (s, 3H), 1.80 – 1.71 (m, 1H), 1.40 – 1.30 (m, 3H), 0.70(d, J = 6.9 Hz, 6H).

[0098] MS m / z (ESI): 531.1 [M+H] + Biological evaluation: The present invention will be further described and explained below through experimental examples, but these experimental examples are not intended to limit the scope of the present invention.

[0099] Experimental Example 1: The anti-cell proliferation effect of the compound in the tumor cell line CA-46 was studied using in vitro cell activity experiments.

[0100] 1. Experimental reagents and instruments (1) Human Burkitt lymphoma CA-46 cells; Wuhan Pronosei Life Science Technology Co., Ltd.; (2) Cell Counting Kit-8 (CCK-8) Cell Viability Assay Kit, Brand and Model: Selleck-B34302; (3) SpectraMax M5e multi-function board reader, manufacturer: Molecular Devices; 2. Cell lines and culture methods are shown in Table 2.

[0101] Table 2. Cell lines and culture methods

[0102] The tumor cell lines were cultured in a CO2-free incubator at 37ºC according to the culture conditions shown in Table 2 above. Cells were passaged periodically, and cells in the logarithmic growth phase were used for plating.

[0103] CA-46 cells were cultured routinely in a constant temperature incubator at 37℃, 5% CO2, and saturated humidity. The medium was changed and the cells were passaged regularly. Cells in good growth condition and in the logarithmic growth phase were used for subsequent plating and drug delivery experiments.

[0104] 3. Experimental Methods The in vitro antiproliferative effect of the small molecule compound of this invention on CA-46 cells was detected using the CCK-8 assay. The specific operation steps are as follows: (1) Cell seeding and pre-culture: Logarithmically growing CA-46 cells were used to prepare a homogeneous single-cell suspension, which was then seeded into 96-well sterile cell culture plates. 100 μL of cell suspension was added to each well, and the cells were cultured overnight under normal conditions. Drug intervention was performed when the cell confluence reached 70%–80%. Complete culture medium was used throughout the process. The experiment included blank wells, control wells, and experimental groups with different concentrations of compounds, with three replicates for each group.

[0105] (2) Drug intervention: The working solution of the small molecule compound of the present invention diluted with gradient concentration was added to each experimental group well, and the solvent control group was added with the same volume of complete culture medium containing low concentration of DMSO to ensure that the final concentration of DMSO in the system was non-cytotoxic. The drug was continuously administered and cultured for 48 h.

[0106] (3) Preparation of CCK-8 working solution: Mix CCK-8 stock solution with serum-free RPMI-1640 medium at a volume ratio of 1:9. Prepare and use immediately, and store in the dark.

[0107] (4) Color development incubation: After 48 h of drug treatment, discard the original culture medium in the wells, add 100 μL of freshly prepared CCK-8 working solution to each well, and place the culture plate in a 37℃ constant temperature incubator for 1 to 4 h in the dark.

[0108] (5) Absorbance detection: When the solution in the negative control wells turns a uniform orange-yellow color, take out the 96-well plate and use a SpectraMax M5e plate reader to measure the absorbance OD value of each well at a wavelength of 450 nm and record the experimental data.

[0109] 4. Data Analysis Methods The survival rate of CA-46 cells was calculated based on the measured OD values, using the following formula: Cell viability (%) = [A (Drug+) – A (Black)] / [A (Drug-) – A (Black)]x 100% In the formula: A (Drug+) is the OD value of the experimental well (containing cells, CCK-8, and small molecule compounds); A (Drug-) is the OD value of the control well (containing cells, CCK-8, and no compound); A (Black) is the OD value of the blank well (containing culture medium, CCK-8, and no cells).

[0110] Cell viability at various compound concentrations was calculated using Excel. Dose-response curves were fitted using GraphPad Prism software. Statistical analysis was performed to calculate the minimum cell viability, maximum cell viability, and half-maximal inhibitory concentration (IC50). 50 Key parameters were used to evaluate the antiproliferative activity of small molecule compounds against CA-46 tumor cells.

[0111] 5. Test results are shown in Table 3.

[0112] Table 3. Experimental results on the inhibitory effect of compounds on the proliferation of CA-46 cells.

[0113] As shown in Table 3, the compounds of the present invention have a good inhibitory effect on the proliferation of CA-46 cells, especially compounds 1, 2, 3, and 5, which show stronger and better inhibitory activity.

Claims

1. An amide compound with anticancer activity or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds: 。 2. A pharmaceutical composition, characterized in that: It comprises the amide compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

3. A pharmaceutical preparation, characterized in that: The formulation comprises the compound of claim 1 or a pharmaceutically acceptable salt thereof, and the formulation is a solid, semi-solid, or liquid formulation.

4. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2, or the pharmaceutical preparation of claim 3, in the manufacture of a drug for treating an tumor, wherein the tumor is lymphoma.

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