CN107417767B - Dipeptide compound constructed by piperidine or piperazine, preparation method and application thereof - Google Patents

Dipeptide compound constructed by piperidine or piperazine, preparation method and application thereof Download PDF

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CN107417767B
CN107417767B CN201710672899.5A CN201710672899A CN107417767B CN 107417767 B CN107417767 B CN 107417767B CN 201710672899 A CN201710672899 A CN 201710672899A CN 107417767 B CN107417767 B CN 107417767B
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formyl
dipeptide
piperidine
chlorobenzylamine
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CN107417767A (en
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张建康
蔡兆斌
刘寿荣
庄让笑
邵益丹
赵艳梅
席建军
潘旭旺
何若愚
方红英
黄玮玮
孙晶晶
潘金明
柯云玲
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Hangzhou Xixi Hospital
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    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
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    • C07K—PEPTIDES
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    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
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Abstract

The invention designs and synthesizes a series of non-covalent small molecule short peptide proteasome inhibitors with brand-new structures, which are dipeptide compounds constructed by six-membered heterocyclic rings with the structure of general formula (I):

Description

Dipeptide compound constructed by piperidine or piperazine, preparation method and application thereof
Technical Field
The invention relates to the field of medicaments, in particular to a novel dipeptide compound containing a piperidine or piperazine ring in a peptide skeleton, a preparation method and application thereof, and application of the compound in preparation of antitumor medicaments.
Background
Cancer is one of the most highly developed and developing countries, and the number of patients, deaths and deaths is higher in developing countries due to different dietary habits and poor medical and health conditions. In China, 429.2 ten thousand new tumor cases and 281.4 ten thousand death cases are expected in 2015, the morbidity and mortality of various tumors continue to rise, and the treatment of tumors faces a great challenge (CA-cancer. J. Clin.2016,66, 115-132). The high incidence and mortality of the tumor also provide wide market space for tumor treatment drugs, and the market scale of the anti-tumor drugs in the world reaches 600 billion dollars in 2014. This market will continue to expand in the future. The research and development of the anti-tumor drugs in China not only concern the huge market and the economic value of the production in China, but also have great social value, and the research and development of the novel, low-toxicity and high-efficiency anti-tumor drugs is related to the civilian life and has great significance.
The proteasome is a giant protein complex widely distributed in eukaryotic cells, has multiple proteolytic functions, and has a main role in degrading proteins which are not needed by the cells or are misfolded in the cells. Proteasomes participate in cell cycle regulation, apoptosis, cell signal transduction, DNA repair and various physiological functions, and play an important role in cell growth and development. Proteasomes regulate the levels of key proteins (e.g., P53, NF- κ B) that affect cell signaling pathways, thereby regulating various vital activities, and many of these regulatory proteins (e.g., cyclins) play important roles in the growth and development of tumors. The proteasome inhibitor influences the degradation of multiple cyclins in cells by inhibiting the activity of proteasome, and promotes apoptosis.
Proteasome inhibitors are mostly characterized by short peptide structures. At present, three short peptide small-molecule proteasome inhibitors are approved by FDA for marketing and used for treating multiple myeloma, namely boronic acid (ester) peptide compound Bortezomib, ixazoib and epoxy ketone peptide compound Carfilzomib, which further verifies the correctness of proteasome as a tumor treatment target.
The boronic acid peptide and epoxy ketone peptide proteasome inhibitors have a common characteristic and belong to covalent binding inhibitors, and exert an antitumor effect by inhibiting proteasome activity through reversible or irreversible binding of an electrophilic group at a carboxyl terminal in the structure of the inhibitor to proteasome. Due to the unique covalent binding effect, the inhibitor has large toxic and side effects. The non-covalent binding inhibitor is mainly bound with proteasomes through non-covalent bonds such as hydrogen bonds, the ligand and the target protein have higher binding and separation speeds and better tissue distribution characteristics, and the non-covalent binding inhibitor is hopeful to be better applied to solid tumors while treating multiple myeloma.
Disclosure of Invention
Aiming at the defects of the prior art, the technical problems to be solved by the invention are as follows: a series of non-covalent small molecule short peptide proteasome inhibitors with brand-new structures are designed and synthesized, piperidine or piperazine rings are incorporated into a peptide skeleton structure to serve as the structural characteristics of the inhibitors, and the compounds are subjected to proteasome activity inhibition evaluation on molecular and cell levels and proliferation inhibition activity evaluation on tumor cells. The results show that the compounds have stronger proteasome inhibition activity and cell proliferation inhibition activity than covalent binding inhibitors, are novel proteasome inhibitors with great prospects, and are expected to provide a new choice for cancer treatment drugs.
Definition of terms:
the term "aryl" as used herein refers to an all-carbon monocyclic or fused polycyclic group of 5 to 12 carbon atoms having a completely conjugated pi-electron system. Non-limiting examples of aromatic rings are: benzene, naphthalene and anthracene rings. The aromatic ring may be substituted or unsubstituted. The substituents of the aromatic ring are selected from halogen, nitro, amino, cyano, C1-C4Alkyl, halogenated C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Alkylamino, halogenated C1-C4Alkoxy, halogenated C1-C4An alkylamino group.
The inventionThe term "heteroaryl" as used herein refers to an unsaturated carbocyclic ring of 5 to 12 ring atoms in which one or more carbons are replaced by a heteroatom such as oxygen, nitrogen, sulfur, and the like. The heteroaromatic ring may be monocyclic or bicyclic, i.e., formed by the fusion of two rings. Specific heterocyclic aryl groups may be: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl and the like. The heterocyclic aryl group may be substituted or unsubstituted. The substituents of the heterocyclic aryl groups may be selected from halogen, nitro, amino, cyano, C1-C4Alkyl, halogenated C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Alkylamino, halogenated C1-C4Alkoxy, halogenated C1-C4An alkylamino group.
The term "heterocyclyl" as used herein, means a monocyclic or fused ring group having from 5 to 9 ring atoms in the ring, wherein at least one or two ring atoms is selected from the group consisting of N, O, S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are C. These rings may have one or more double bonds, but these rings do not have a completely conjugated pi-electron system. Heterocycloalkyl groups may be substituted or unsubstituted. Examples of the unsubstituted heterocycloalkyl group include a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, and a homopiperazinyl group. The heterocyclic ring may be substituted or unsubstituted. The substituents of the heterocyclic ring are selected from halogen, nitro, amino, cyano, C1-C4Alkyl, halogenated C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Alkylamino, halogenated C1-C4Alkoxy, halogenated C1-C4An alkylamino group.
The term "cycloalkyl" as used herein refers to a saturated monocyclic carbocyclic ring having 3 to 8 carbon atoms. "cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. "cycloalkyl" also includes substituted cycloalkyl. The cycloalkyl group may also be optionally substituted on any available carbon with one or more substituents selected from alkoxy, halogen, and haloalkyl, such as perfluoroalkyl, and the like.
The term "alkoxy" as used herein refers to an-O-alkyl group. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy. "alkoxy" also includes substituted alkoxy. Alkoxy groups may be optionally substituted one or more times with halo.
The term "halogen" as used herein denotes fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
The invention aims to provide a novel dipeptide compound constructed by six-membered heterocyclic rings with the structure of general formula (I):
Figure BDA0001373563720000021
wherein:
R1，R2，R3each independently selected from H, C1-6alkyl-D-RaOf halogenated C1-6alkyl-D-RaAryl, alkylaryl, heteroaryl, alkylheteroaryl, wherein D is selected from O, S, N (R)b)(Rc),CON(Rd),N(Rd)CO,CSN(Rd),N(Rd) CS or deletion;
Rais selected from H, C1-6Alkyl, halogenated C1-6Alkyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl or a deletion;
Rb，Rc，Rdeach independently selected from H, OH, C1-6Alkyl, halogenated C1-6Alkyl and N-terminal protecting groups;
R4，R5each independently selected from H, OH, C1-6Alkyl, halogenated C1-6Alkyl, aralkyl;
R6is selected from C1-6Alkyl, halogenated C1-6Alkyl, carbocyclyl, heterocyclyl, aryl, C1-6Aralkyl radical, C1-6Alkylaryl, heteroaryl, C1-6Heteroaralkyl radical, said R6The above-mentioned group in (1) mayEach independently of the other being halogen, nitro, amino, cyano, C1-6Alkyl, halogenated C1-6Alkyl radical, C1-6Alkoxy, halogenated C1-6Alkoxy is optionally substituted;
x is C or N;
l is selected from
Figure BDA0001373563720000031
Or is absent, wherein ReIs selected from H, C1-6Alkyl, halogenated C1-6An alkyl group;
B1and B2The same or different, are respectively and independently selected from O, S and N (R)f)，C(Rg)(Rh) Or is absent, wherein Rf，RgAnd RhAre respectively and independently selected from H and C1-6Alkyl, halogenated C1-6Alkyl radical, C1-6Alkoxy, halogenated C1-6Alkoxy radical, Rf，RgAnd RhThe same or different;
b is selected from
Figure BDA0001373563720000032
Or is absent, wherein RiIs selected from H, C1-6Alkyl and halogenated C1-6An alkyl group;
R7is selected from H, C1-6Alkyl radical, C1-6Alkenyl radical, C1-6Alkynyl, carbocyclyl, heterocyclyl, aryl, C1-6Aralkyl, heteroaryl, C1-6Heteroaralkyl, which may be substituted by halogen, nitro, amino, cyano, C1-6Alkyl, halogenated C1-6Alkyl radical, C1-6Alkoxy and halogenated C1-6Alkoxy is optionally substituted.
Preferably, B1And B2Are respectively and independently selected from O, S, N (R)f) Or is absent;
Rfis selected from H, C1-6Alkyl, halogenated C1-6Alkyl radical, C1-6Alkoxy, halogenated C1-6An alkoxy group;
b is selected from
Figure BDA0001373563720000033
L is selected from
Figure BDA0001373563720000034
Wherein R iseIs H, C1-6Alkyl or halogenated C1-6An alkyl group;
R6selected from aryl, C1-6Alkylaryl, heteroaryl, C1-6Alkylheteroaryl, said aryl, C1-6Alkylaryl, heteroaryl, C1-6The alkyl heteroaryl groups may each independently be substituted by halogen, nitro, amino, cyano, C1-6Alkyl, halogenated C1-6Alkyl radical, C1-6Alkoxy and halogenated C1-6Alkoxy is optionally substituted.
More preferably, B is1And B2Are respectively and independently selected from N (R)f) Or is absent;
b is selected from
Figure BDA0001373563720000035
R6Selected from aryl or heteroaryl.
Preferably, said aryl group is selected from phenyl, naphthyl, anthracenyl;
C1-6the alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and n-hexane;
the carbocyclyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl;
the heterocyclic radical is selected from tetrahydrofuran, piperidine and piperazine;
heteroaryl is selected from furan, thiophene, oxazole, isoxazole, thiazole, thiadiazole, pyrrole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, benzothiazole, benzofuran, indole, quinoline, isoquinoline, purine.
More specifically, preferred compounds of the invention having the structure of formula (I) are:
n- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine (Ex. 27);
n- [4- (pyrazin-2-ylcarboxamide) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine (Ex. 28);
n- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (Phe-hPhe) -2-chlorobenzylamine (Ex. 29);
n- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (Leu-hPhe) -2-chlorobenzylamine (Ex. 30);
n- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (Ala-hPhe) -2-chlorobenzylamine (Ex.31);
n- [4- (carboxanilido) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine (Ex. 32);
n- [4- (4-fluoroanilinoyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine (Ex. 33);
n- [4- (4-methoxycarboxanilido) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine (Ex. 34);
n- [4- (pyridin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine (Ex. 35);
n- [1- (pyrazine-2-formyl) piperidine-4-formyl ] dipeptide [ Asp (4-pivaloamide) -hPhe ] -2-chlorobenzylamine (Ex. 36);
n- [1- (4-fluorobenzoyl) piperidine-4-formyl ] dipeptide [ Asp (4-pivaloyl amide) -hPhe ] -2-chlorobenzylamine (Ex. 37);
n- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -Leu ] -2-chlorobenzylamine (Ex.38);
n- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloylamide) -Phe ] -2-chlorobenzylamine (Ex.39);
n- [4- (pyrazine-2-formyl) piperazine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -hPhe ] -2-chlorobenzylamine (Ex.40);
n- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -hPhe ] -2, 4-difluorobenzylamine (Ex. 41);
n- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ hPhe-Asp (4-pivaloamide) ] -2-chlorobenzylamine (Ex. 42);
n- [4- (pyridin-3-ylaminoformyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloylamide) -Cys (S-Bn) ] -2-chlorobenzylamine (Ex. 43);
n- [4- (pyridin-3-ylcarbamoyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine (Ex. 44);
n- [4- (thiazol-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine (Ex. 45);
n- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-fluorobenzylamine (Ex. 46);
n- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -4-chlorobenzylamine (Ex.47);
n- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -4-fluorobenzylamine (Ex. 48);
n- [4- (pyrazine-2-formyl) piperazine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine (ex.49);
n- [1- (pyrazine-2-formyl) piperidine-4-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine (Ex. 50);
n- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -Ala ] -2-chlorobenzylamine (Ex.51);
n- [4- (pyrazin-2-ylcarboxamide) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -hPhe ] -2-chlorobenzylamine (Ex. 52);
n- [4- (pyrazine-2-formyl) piperazine-1-formyl ] dipeptide [ Asp (4-pivaloylamide) -Leu ] -2-chlorobenzylamine (ex.53);
n- [4- (thiazol-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -hPhe ] -2-chlorobenzylamine (Ex. 54);
n- [4- (pyridin-3-ylaminoformyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -hPhe ] -2-chlorobenzylamine (Ex. 55);
n- [4- (4-methoxycarboxanilido) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -hPhe ] -2-chlorobenzylamine (Ex. 56);
n- [4- (4-trifluoromethylcarboxanilido) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -hPhe ] -2-chlorobenzylamine (Ex. 57);
n- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -hPhe ] -4-chlorobenzylamine (Ex. 58);
n- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Glu (4-tert-butylamide) -hPhe ] -2-chlorobenzylamine (Ex.59);
n- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Tyr (O-tBu) -hPhe) ] -2-chlorobenzylamine (Ex.60);
n- [4- (pyrazin-2-ylaminoformyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloylamide) -Cys (S-Bn) ] -2-chlorobenzylamine (Ex. 61).
Note: hPhe is homophenylalanine; phe is phenylalanine; leu leucine; ala is alanine; asp is aspartic acid; cys is cysteine; glu is glutamic acid; tyr tyrosine
It is another object of the present invention to provide a process for preparing the above target compound by the steps of:
(1) the compound a protected by the amino Boc and the compound b react under the action of a condensation reagent to obtain a compound c, wherein the selected condensation reagent comprises dicyclohexylcarbodiimide/4-dimethylamino pyridine, dicyclohexylcarbodiimide/1-hydroxybenzotriazole, N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole. The reaction temperature is 0-50 ℃, the reaction time is 2-8 hours, and the crude product can be directly used for the next reaction.
(2) And removing the Boc protecting group from the compound c under an acidic condition to produce a compound d, wherein the acidic condition is HCl ether solution, HCl ethyl acetate solution, HCl methanol solution, HCl dioxane solution and trifluoroacetic acid. The reaction temperature is-10-40 ℃, and the reaction time is 0.5-3 hours. The crude product obtained was used directly in the next reaction.
(3) And (3) reacting the compound d with the compound e under the action of a condensation reagent to obtain a compound I, selecting the condensation reagent and the step (1), and carrying out column chromatography separation on the obtained crude product to obtain a pure product.
The reaction formula is as follows:
Figure BDA0001373563720000051
wherein: r1，R2，R3Each independently selected from H, C1-6alkyl-D-RaOf halogenated C1-6alkyl-D-RaAryl, alkylaryl, heteroaryl, alkylheteroaryl, wherein D is selected from O, S, N (R)b)(Rc),CON(Rd),N(Rd)CO,CSN(Rd),N(Rd) CS or deletion;
Rais selected from H, C1-6Alkyl, halogenated C1-6Alkyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl or a deletion;
Rb，Rc，Rdeach independently selected from H, OH, C1-6Alkyl, halogenated C1-6Alkyl and N-terminal protecting groups;
R4，R5each independently selected from H, OH, C1-6Alkyl, halogenated C1-6Alkyl, aralkyl;
R6is selected from C1-6Alkyl, halogenated C1-6Alkyl, carbocyclyl, heterocyclyl, aryl, C1-6Aralkyl radical, C1-6Alkylaryl, heteroaryl, C1-6Heteroaralkyl radical, said R6Wherein the above groups may be independently substituted by halogen, nitro, amino, cyano, C1-6Alkyl, halogenated C1-6Alkyl radical, C1-6Alkoxy, halogenated C1-6Alkoxy is optionally substituted.
It is another object of the present invention to provide a pharmaceutical composition comprising at least one compound in any of the forms as described above, a stereoisomer or a pharmaceutically acceptable salt of said compound as an active ingredient, together with one or more pharmaceutically acceptable carriers or excipients.
The pharmaceutical composition can be prepared into various pharmaceutical dosage forms, such as oral administration, injection, inhalation, implantation and other administration modes. The injection administration and oral administration modes are preferred, such as injection, freeze-dried powder injection, tablets, capsules or granules and the like.
The pharmaceutical compositions of the present invention and the various formulations of the compositions can be prepared using conventional pharmaceutical carriers.
Another object of the present invention is to provide pharmaceutical uses of the compounds of formula (I) and pharmaceutical compositions containing said compounds. The invention provides the application of the compound with the general formula (I) and the pharmaceutical composition containing the compound in preparing the drugs for treating malignant tumor, neurodegenerative diseases or immunological diseases.
Further, the tumor is selected from myeloma, lymphoma, leukemia, macroglobulinemia, breast cancer, sarcoma, lung cancer, prostate cancer, colon cancer, rectal cancer, kidney cancer, pancreatic cancer, neuroblastoma, glioma, head cancer, neck cancer, thyroid cancer, liver cancer, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, stomach cancer, nasopharyngeal cancer, buccal cancer, oral cancer, gastrointestinal stromal tumor, skin cancer.
Experiments prove that the short peptide non-covalent compound constructed by the hexatomic heterocycle has good proteasome inhibition activity and extremely strong in-vitro proliferation inhibition effect on multiple myeloma cell strains such as RPMI8226, H929, MM-1S and the like. The compound of the invention has the advantages of easily obtained raw materials for synthesis, reasonable route design, mild reaction conditions, high yield of each step, simple and convenient operation and suitability for industrial production.
Drawings
FIG. 1 is a graph showing the inhibitory activity of a partial compound on the proteasome of blood cells.
Detailed Description
The present invention is further illustrated by reference to the following examples, which are intended to be illustrative of the invention and are not to be construed as limiting in any way.
EXAMPLE 11 preparation of- (pyrazine-2-acyl) piperidine-4-carboxylic acid
Figure BDA0001373563720000061
Pyrazine-2-carboxylic acid (1.5g, 12mmol) was dissolved in 40mL of anhydrous dichloromethane, HOBt (1.6g, 12mmol) and EDCI (3.5g, 18mmol) were added, and the reaction was carried out at room temperature for half an hour. Subsequently, compound 1(1.4g, 10mmol) and diisopropylethylamine (3.6mL, 20mmol) were added to the reaction solution and reacted at room temperature for 3 hours. Adding intoDiluting with 30mL of saturated sodium bicarbonate, separating an organic layer, drying with anhydrous sodium sulfate, recovering the solvent, and performing column chromatography separation to obtain 2.3g of a white solid 5 with the yield of 92%.1H NMR(500MHz,CDCl3):δ＝8.88(d,1H,J＝1.0Hz,pyrazine-H),8.61(d,1H,J＝2.5Hz,pyrazine-H),8.52(s,1H,pyrazine-H),4.51(m,1H,CH2),3.91(m,1H,CH2),3.70(s,3H,CH3),3.20(m,1H,CH2),3.09(m,1H,CH2),2.62(m,1H,CH),2.04(m,1H,CH2),1.91(m,1H,CH2),1.81(m,2H,CH2)；ESI-MS:m/z＝250[M+H]+.
Compound 5(1.3g, 5mmol) was dissolved in 10mL of acetone, 20mL of aqueous lithium hydroxide (0.5N) was added dropwise, and the reaction was carried out at room temperature for 0.5 h. And (3) distilling under reduced pressure to remove acetone, adjusting the pH value of the aqueous solution to 2-3 by using 1N HCl, extracting by using ethyl acetate (20mL multiplied by 3), combining organic layers, drying by using anhydrous sodium sulfate, and distilling under reduced pressure to remove a solvent to obtain a white solid 15 which is directly used for the next reaction.
Example 21 preparation of- (4-fluorobenzoyl) piperidine-4-carboxylic acid
Figure BDA0001373563720000071
Synthesis of Compound 6: synthesis and post-treatment of 4-fluorobenzoic acid as a raw material were performed as in example 1 to obtain 2.3g of a white solid with a yield of 87%.1H NMR(500MHz,CDCl3):δ＝7.41(dd,2H,J＝8.5,5.5Hz,Ar-H),7.10(t,2H,J＝8.5Hz,Ar-H),4.48(m,1H,CH2),3.80(m,1H,CH2),3.72(s,3H,CH3),3.06(m,2H,CH2),2.61(m,1H,CH),1.96(m,2H,CH2),1.74(m,2H,CH2)；ESI-MS:m/z＝266[M+H]+.
Synthesis and workup of Compound 16 the same as in example 1 gave white solid 16 which was used directly in the next reaction.
Example 34 preparation of- (pyrazine-2-carboxamido) piperidine
Figure BDA0001373563720000072
Synthesis of compound 7: synthesis and workup of the same as in example 1 using 4-amino-1-Boc-piperidine as a starting material gave 2.7g of a white solid in 88% yield.1H NMR(500MHz,CDCl3):δ＝9.40(s,1H,pyrazine-H),8.75(d,1H,J＝2.0Hz,pyrazine-H),8.52(d,1H,J＝1.5Hz,pyrazine-H),7.72(d,1H,J＝8.0Hz,NH),4.10(m,3H,CH+CH2),2.95(t,2H,J＝13.5Hz,CH2),2.00(d,2H,J＝12.5Hz,CH2),1.46(m,11H,CH2+CH3)；ESI-MS:m/z＝307[M+H]+.
Compound 7(1.5g, 5.0mmol) was dissolved in 15mL of dichloromethane, 8mL of trifluoroacetic acid was added dropwise, and the reaction was carried out at room temperature for 1 hour. The solvent is evaporated under reduced pressure, and diethyl ether is added to precipitate a white solid, and the white solid 17 is obtained by suction filtration and drying and is directly used for the next reaction.
Example 44 preparation of- (pyrazine-2-carboxamido) piperazine
Figure BDA0001373563720000073
Synthesis of Compound 8 Using 1-Boc-piperazine as a starting material, the synthesis and post-treatment were carried out in the same manner as in example 1 to give 2.2g of a white solid with a yield of 76%.1H NMR(500MHz,CDCl3):δ＝8.97(d,1H,J＝1.5Hz,pyrazine-H),8.65(d,1H,J＝2.5Hz,pyrazine-H),8.54(s,1H,pyrazine-H),3.79(t,2H,J＝5.0Hz,CH2),3.62(t,2H,J＝5.0Hz,CH2),3.56(t,2H,J＝5.0Hz,CH2),3.49(t,2H,J＝5.0Hz,CH2),1.47(s,9H,CH3)；ESI-MS:m/z＝293[M+H]+.
Synthesis of Compound 18 Using Compound 8 as a starting material, the same procedure as in example 3 was followed to give white solid 18, which was used directly in the next reaction.
Example 54 preparation of pyrazine-2-carbamoyl) piperidine
Figure BDA0001373563720000081
1- (tert-Butoxycarbonyl) piperidine-4-carboxylic acid (2.8g, 1)2mmol) in a 50mL three-necked flask, N2Under protection, 25mL of anhydrous dichloromethane was added, followed by dropwise addition of pyridine (2.5mL, 30mmol) and thionyl chloride (1.1mL, 14mmol) slowly, and the reaction mixture was left at room temperature for half an hour. Subsequently, 2-aminopyrazine (1.0g, 10mmol) and triethylamine (5.7mL, 40mmol) were dissolved in 15mL of dichloromethane, and the reaction mixture was slowly added dropwise thereto and reacted at room temperature for 6 hours. The reaction mixture was diluted with 30mL of saturated brine, the organic layer was separated, the aqueous layer was extracted with dichloromethane (15 mL. times.3), the organic layers were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and column chromatography was performed to obtain 2.4g of a white solid with a yield of 78%.1H NMR(500MHz,CDCl3):δ＝9.55(s,1H,pyrazine-H),8.35(d,1H,J＝2.0Hz,pyrazine-H),8.23(s,1H,pyrazine-H),7.97(s,1H,NH),4.20(m,2H,CH2),2.81(m,2H,CH2),2.48(m,1H,CH),1.93(d,2H,J＝12.5Hz,CH2),1.76(m,2H,CH2),1.47(s,9H,CH3)；ESI-MS:m/z＝307[M+H]+。
Synthesis of compound 19: the compound 9 was used as a starting material, and the synthesis and post-treatment were carried out as in example 3 to give a white solid 19 which was used directly in the next reaction.
EXAMPLE 64 preparation of- (Phenylcarbamoyl) piperidine
Figure BDA0001373563720000082
Synthesis of compound 10: using aniline as a raw material, the synthesis and post-treatment methods were the same as in example 5, whereby 2.4g of a white solid was obtained with a yield of 86%.1H NMR(500MHz,CDCl3):δ＝7.53(d,2H,J＝5.0Hz,Ar-H),7.34(m,3H,Ar-H+NH),7.12(m,1H,Ar-H),4.21(d,2H,J＝10.0Hz,CH2),2.80(m,2H,CH2),2.41(m,1H,CH),1.90(m,2H,CH2),1.73(m,2H,CH2),1.48(s,9H,CH3)；ESI-MS:m/z＝305[M+H]+。
Synthesis of compound 20: the compound 10 was used as a starting material, and the synthesis and post-treatment were carried out as in example 3 to give a white solid 20 which was used directly in the next reaction.
Example 74 preparation of (4-Fluorophenylcarbamoyl) piperidine
Figure BDA0001373563720000083
Synthesis of compound 11: the synthesis and post-treatment method of 4-fluoroaniline used as the raw material was the same as in example 5, whereby 2.4g of a white solid was obtained with a yield of 75%.1H NMR(500MHz,CDCl3):δ＝7.47(m,2H,Ar-H),7.20(s,1H,NH),7.01(t,2H,J＝8.0Hz,Ar-H),4.18(d,2H,J＝12.0Hz,CH2),2.80(t,2H,J＝12.5Hz,CH2),2.37(m,1H,CH),1.90(d,2H,J＝12.5Hz,CH2),1.75(m,2H,CH2),1.47(s,9H,CH3)；ESI-MS:m/z＝323[M+H]+。
Synthesis of compound 21: using compound 11 as a starting material, the synthesis and the work-up were carried out as in example 3 to give white solid 21, which was used directly in the next reaction.
EXAMPLE 84 preparation of (4-Methoxyanilinoyl) piperidine
Figure BDA0001373563720000091
Synthesis of compound 12: the synthesis and post-treatment method of 4-methoxyaniline as the raw material was the same as example 5, and 2.7g of white solid was obtained with a yield of 85%.1H NMR(500MHz,CDCl3):δ＝7.39(d,2H,J＝8.5Hz,Ar-H),7.38(s,1H,NH),6.83(d,2H,J＝7.5Hz,Ar-H),4.16(d,2H,J＝13.0Hz,CH2),3.77(s,3H,CH3),2.75(m,2H,CH2),2.36(m,1H,CH),1.86(d,2H,J＝12.0Hz,CH2),1.71(m,2H,CH2),1.45(s,9H,CH3)；ESI-MS:m/z＝335[M+H]+。
Synthesis of compound 22: the compound 12 was used as a starting material, and the synthesis and post-treatment were carried out as in example 3 to obtain a white solid 22, which was used directly in the next reaction.
EXAMPLE 94 preparation of pyridine-2-carbamoyl) piperidine
Figure BDA0001373563720000092
Synthesis of compound 13: 2.7g of white solid was obtained in 90% yield from 2-aminopyridine in the same manner as in example 5.1H NMR(500MHz,CDCl3):δ＝8.25(m,3H,pyridine-H+NH),7.74(m,1H,pyridine-H),7.06(dd,1H,J＝6.5,5.0Hz,pyridine-H),4.18(m,2H,CH2),2.79(m,2H,CH2),2.43(m,1H,CH),1.91(d,2H,J＝12.5Hz,CH2),1.74(m,2H,CH2),1.46(s,9H,CH3)；ESI-MS:m/z＝306[M+H]+。
Synthesis of compound 23: using compound 13 as a starting material, the synthesis and the work-up procedure were as in example 3 to give white solid 23, which was used directly in the next reaction.
EXAMPLE 104 preparation of pyridine-3-carbamoyl) piperidine
Figure BDA0001373563720000093
Synthesis of compound 14: using 3-aminopyridine as a starting material, synthesis and post-treatment were carried out in the same manner as in example 5 to obtain 1.9g of a white solid with a yield of 63%.1H NMR(500MHz,CDCl3):δ＝8.61(s,1H,pyridine-H),8.34(d,1H,J＝4.0Hz,pyridine-H),8.28(d,1H,J＝8.5Hz,pyridine-H),7.81(s,1H,NH),7.32(dd,1H,J＝8.5,5.0Hz,pyridine-H),4.19(d,2H,J＝13.0Hz,CH2),2.79(m,2H,CH2),2.50(m,1H,CH),1.91(d,2H,J＝12.0Hz,CH2),1.75(m,2H,CH2),1.46(s,9H,CH3)；ESI-MS:m/z＝306[M+H]+。
Synthesis of compound 24: using compound 14 as a starting material, the synthesis and work-up procedure were as in example 3 to give white solid 24, which was used directly in the next reaction.
EXAMPLE 11 preparation of hPhe-2-chlorobenzylamine
Figure BDA0001373563720000094
Synthesis of compound 27: with 2-chlorobenzylamine and Boc-hPhe as raw material, and the synthesis and post-treatment method are the same as example 1, to obtain white solid. The yield thereof was found to be 88%.1H NMR(500MHz,CDCl3):δ＝7.35(m,2H,Ar-H),7.28(m,2H,Ar-H),7.20(m,3H,Ar-H),7.13(d,2H,J＝7.0Hz,Ar-H),6.52(t,1H,J＝5.0Hz,NH),5.02(d,1H,J＝6.5Hz,NH),4.53(d,2H,J＝6.0Hz,CH2),4.09(m,1H,CH),2.66(m,2H,CH2),2.17(m,1H,CH2),1.92(m,1H,CH2),1.43(s,9H,CH3)；ESI-MS:m/z＝403[M+H]+。
Synthesis of compound 33: using compound 27 as a starting material, the synthesis and the work-up were carried out as in example 3 to give white solid 33, which was used directly in the next reaction.
EXAMPLE 12 preparation of Leu-2-chlorobenzylamine
Figure BDA0001373563720000101
Synthesis of Compound 28, starting from 2-chlorobenzylamine and Boc-Leu, the synthesis and work-up were carried out as described in example 1 to give a white solid. The yield thereof was found to be 65%.1H NMR(500MHz,CDCl3):δ＝7.37(m,2H,Ar-H),7.23(m,2H,Ar-H),6.70(t,1H,J＝5.0Hz,NH),4.93(d,1H,J＝7.5Hz,NH),4.55(t,2H,J＝6.0Hz,CH2),4.15(m,1H,CH),1.70(m,2H,CH2),1.50(m,1H,CH),1.46(s,9H,CH3),0.94(t,6H,J＝7.0Hz,CH3)；ESI-MS:m/z＝355[M+H]+。
Synthesis of compound 34: using compound 28 as a starting material, the synthesis and work-up procedure were as in example 3 to give white solid 34, which was used directly in the next reaction.
EXAMPLE 13 preparation of Phe-2-chlorobenzylamine
Figure BDA0001373563720000102
Synthesis of compound 29: the synthesis and post-treatment methods of 2-chlorobenzylamine and Boc-Phe as raw materials were the same as in example 1 to obtain a white solid. The yield thereof was found to be 95%.1H NMR(500MHz,CDCl3):δ＝7.31(d,1H,J＝7.5Hz,Ar-H),7.17(m,8H,Ar-H),6.25(brs,1H,NH),5.07(brs,1H,NH),4.44(d,2H,J＝6.0Hz,CH2),4.35(m,1H,CH),3.07(m,2H,CH2),1.40(s,9H,CH3)；ESI-MS:m/z＝389[M+H]+。
Synthesis of compound 35: using compound 29 as a starting material, the synthesis and the post-treatment were carried out in the same manner as in example 3 to obtain white solid 35, which was used directly in the next reaction.
EXAMPLE 14 preparation of Asp (4-pivaloylamide) -2-chlorobenzylamine
Figure BDA0001373563720000103
Synthesis of compound 30: 2-chlorobenzylamine and Boc-Asp (4-pivalamide) were used as raw materials, and the synthesis and post-treatment methods were the same as in example 1, to obtain a white solid. The yield thereof was found to be 95%.1H NMR(500MHz,CDCl3):δ＝7.33(m,3H,Ar-H+NH),7.21(m,2H,Ar-H),6.30(d,1H,J＝7.0Hz,NH),6.00(brs,1H,NH),4.51(m,3H,CH+CH2),3.03(m,2H,CH2),2.93(dd,1H,J＝15.0,2.5Hz,CH2),2.56(dd,1H,J＝15.0,6.0Hz,CH2),1.43(s,9H,CH3),0.87(s,9H,CH3)；ESI-MS:m/z＝426[M+H]+。
Synthesis of compound 36: the compound 30 was used as a starting material, and the synthesis and post-treatment were carried out as in example 3 to give a white solid 36 which was used directly in the next reaction.
Example 15 preparation of Cys (S-Bn) -2-chlorobenzylamine
Figure BDA0001373563720000111
Synthesis of compound 31: the synthesis and post-treatment methods of 2-chlorobenzylamine and Boc-Cys (S-Bn) as raw materials were the same as in example 1, to obtain a white solid. The yield thereof was found to be 73%.1H NMR(500MHz,CDCl3):δ＝7.39(m,2H,Ar-H),7.32(m,4H,Ar-H),7.25(m,3H,Ar-H),6.73(brs,1H,NH),5.30(brs,1H,NH),4.56(t,2H,J＝6.0Hz,CH2),4.28(brs,1H,CH),3.71(d,2H,J＝6.0Hz,CH2),2.93(dd,1H,J＝14.0,6.0Hz,CH2),2.77(dd,1H,J＝15.0,6.5Hz,CH2),1.46(s,9H,CH3)；ESI-MS:m/z＝435[M+H]+。
Synthesis of compound 37: using compound 31 as a starting material, the synthesis and the post-treatment were carried out in the same manner as in example 3 to obtain white solid 37, which was used directly in the next reaction.
EXAMPLE 16 preparation of hPhe-2, 4-difluorobenzylamine
Figure BDA0001373563720000112
Synthesis of compound 32: the synthesis and post-treatment methods of 2, 4-difluorobenzylamine and Boc-hPhe used as raw materials were the same as in example 1, and a white solid was obtained. The yield thereof was found to be 84%.1H NMR(500MHz,CDCl3):δ＝7.31(m,3H,Ar-H),7.21(m,1H,Ar-H),7.16(d,2H,J＝7.5Hz,Ar-H),6.83(m,2H,Ar-H),6.59(brs,1H,NH),5.06(brs,1H,NH),4.45(d,2H,J＝6.0Hz,CH2),4.10(brs,1H,CH),2.68(t,2H,J＝7.0Hz,CH2),2.17(m,1H,CH2),1.94(m,1H,CH2),1.44(s,9H,CH3)；ESI-MS:m/z＝405[M+H]+。
Synthesis of compound 38: the compound 32 was used as a starting material, and the synthesis and post-treatment were carried out as in example 3 to obtain a white solid 38, which was used directly in the next reaction.
EXAMPLE 17 preparation of hPhe-hPhe-2-chlorobenzylamine
Figure BDA0001373563720000113
Synthesis of compound 39: the synthesis and post-treatment methods of the compound 33 and Boc-hPhe used as raw materials were the same as those of example 1, and a white solid was obtained. The yield thereof was found to be 87%.1H NMR(500MHz,CDCl3):δ＝7.33-7.26(m,4H,Ar-H),7.25-7.11(m,10H,Ar-H),6.72(brs,1H,NH),6.54(brs,1H,NH),4.85(brs,1H,NH),4.55-4.41(m,3H,CH+CH2),4.01(brs,1H,CH),2.67-2.61(m,4H,CH2),2.24-2.18(m,1H,CH2),2.11-1.96(m,2H,CH2),1.87-1.79(m,1H,CH2),1.41(s,9H,CH3)；ESI-MS:m/z＝564[M+H]+。
Synthesis of compound 49: using compound 39 as a starting material, the synthesis and the post-treatment were carried out in the same manner as in example 3 to obtain white solid 49, which was used directly in the next reaction.
EXAMPLE 18 preparation of Phe-hPhe-2-chlorobenzylamine
Figure BDA0001373563720000114
Synthesis of compound 40: the synthesis and the work-up were carried out in the same manner as in example 1, starting from compound 33 and Boc-Phe, to give a white solid. The yield thereof was found to be 88%.1H NMR(500MHz,CDCl3):δ＝7.35-7.33(m,1H,Ar-H),7.30-7.27(m,3H,Ar-H),7.24-7.13(m,8H,Ar-H),7.10-7.08(d,2H,J＝7.0Hz,Ar-H),6.61(brs,1H,NH),6.36(brs,1H,NH),4.80(brs,1H,NH),4.54-4.40(m,3H,CH+CH2),4.30-4.27(m,1H,CH),3.04(dd,1H,J＝13.5,6.0Hz,CH2),3.02(dd,1H,J＝13.5,6.0Hz,CH2),2.63-2.56(m,2H,CH2),2.20-2.11(m,1H,CH2),1.97-1.92(m,1H,CH2),1.36(s,9H,CH3)；ESI-MS:m/z＝550[M+H]+。
Synthesis of Compound 50 Using Compound 40 as a starting material, the same procedure as in example 3 was followed to give white solid 50, which was used directly in the next reaction.
EXAMPLE 19 preparation of Leu-hPhe-2-chlorobenzylamine
Figure BDA0001373563720000121
Synthesis of compound 41: the synthesis and post-treatment methods of the compound 33 and Boc-Leu used as raw materials were the same as those of example 1, to obtain a white solid. The yield thereof was found to be 71%.1H NMR(500MHz,CDCl3):δ＝7.35-7.27(m,2H,Ar-H),7.24-7.12(m,7H,Ar-H),6.81(brs,1H,NH),6.57(brs,1H,NH),4.72(brs,1H,NH),4.55-4.45(m,3H,CH2+CH),4.03(brs,1H,CH),2.65(m,2H,CH2),2.24-2.22(m,1H,CH2),2.02(m,1H,CH2),1.60(m,2H,CH2),1.43-1.41(m,1H,CH),1.39(s,9H,CH3),0.9 1(t,6H,J＝8.0Hz,CH3)；ESI-MS:m/z＝516[M+H]+。
Synthesis of compound 51: using compound 41 as a starting material, the same synthesis and post-treatment as in example 3 gave white solid 51, which was used directly in the next reaction.
EXAMPLE 20 preparation of Gla-hPhe-2-chlorobenzylamine
Figure BDA0001373563720000122
Synthesis of compound 42: the synthesis and post-treatment methods of compound 33 and Boc-Gla as raw materials were the same as in example 1 to obtain a white solid. The yield thereof was found to be 92%.1H NMR(500MHz,CDCl3):δ＝7.36-7.27(m,4H,Ar-H),7.24-7.13(m,5H,Ar-H),6.75(brs,1H,NH),6.54(brs,1H,NH),4.75(brs,1H,NH),4.53-4.45(m,3H,CH2+CH),4.07(brs,1H,CH),2.67(m,2H,CH2),2.26-2.25(m,1H,CH2),2.03(m,1H,CH2),1.40(s,9H,CH3),1.30(d,3H,J＝6.5Hz,CH3)；ESI-MS:m/z＝474[M+H]+。
Synthesis of compound 52: the compound 42 was used as a starting material, and the synthesis and post-treatment were carried out as in example 3 to obtain a white solid 52 which was used directly in the next reaction.
EXAMPLE 21 preparation of Asp (4-pivaloyl amide) -hPhe-2-chlorobenzylamine
Figure BDA0001373563720000123
Synthesis of compound 43: the synthesis and post-treatment methods of compound 33 and Boc-Asp (4-pivalic amide) used as raw materials were the same as in example 1, and a white solid was obtained. The yield thereof was found to be 76%.1H NMR(500MHz,d6-DMSO):δ＝8.51(t,1H,J＝6.0Hz,NH),8.25(d,1H,J＝8.0Hz,NH),7.82(t,1H,J＝6.0Hz,NH),7.31-7.25(m,6H,Ar-H),7.18-7.16(m,3H,Ar-H),7.09(d,1H,J＝8.0Hz,NH),4.35-4.28(m,3H,CH2+CH),4.20-4.18(m,1H,CH),2.82-2.71(m,2H,CH2),2.66-2.52(m,4H,CH2),2.06-1.99(m,1H,CH2),1.90-1.88(m,1H,CH2),1.37(s,9H,CH3),0.77(s,9H,CH3)；ESI-MS:m/z＝588[M+H]+。
Synthesis of compound 53: using compound 43 as a starting material, the synthesis and the post-treatment were carried out in the same manner as in example 3 to obtain white solid 53, which was used directly in the next reaction.
EXAMPLE 22 preparation of Asp (4-pivaloyl amide) -Leu-2-chlorobenzylamine
Figure BDA0001373563720000131
Synthesis of Compound 44, starting from Compound 34 and Boc-Asp (4-pivalamide), the synthesis and work-up procedure was as in example 1, giving a white solid. The yield thereof was found to be 80%.1H NMR(500MHz,CDCl3):δ＝7.35-7.32(m,2H,Ar-H),7.24-7.20(m,3H,Ar-H+NH),6.90(d,1H,J＝8.0Hz,NH),6.10(d,1H,J＝7.0Hz,NH),5.93(t,1H,J＝6.5Hz,NH),4.51(dd,2H,J＝6.0,2.0Hz,CH2),4.47-4.41(m,2H,CH2),2.96-2.93(m,2H,CH2),2.77(dd,1H,J＝15.0,5.0Hz,CH2),2.66(dd,1H,J＝15.0,6.0Hz,CH2),1.84-1.81(m,1H,CH),1.67-1.55(m,2H,CH2),1.44(s,9H,CH3),0.92(dd,6H,J＝22.0,6.5Hz,CH2),0.87(s,9H,CH3)；ESI-MS:m/z＝539[M+H]+。
Synthesis of compound 54: using compound 44 as a starting material, the synthesis and work-up procedure were as in example 3 to give white solid 54 which was used directly in the next reaction.
EXAMPLE 23 preparation of Asp (4-pivaloylamide) -Phe-2-chlorobenzylamine
Figure BDA0001373563720000132
Synthesis of compound 45: the synthesis and post-treatment methods of compound 35 and Boc-Asp (4-pivalamide) as raw materials were the same as in example 1 to obtain a white solid. The yield thereof was found to be 86%.1H NMR(500MHz,d6-DMSO):δ＝8.59(t,1H,J＝6.0Hz,NH),8.16(d,1H,J＝8.0Hz,NH),7.77(t,1H,J＝6.5Hz,NH),7.43(d,1H,J＝7.5Hz,NH),7.31-7.20(m,7H,Ar-H),7.12(d,1H,J＝7.0Hz,Ar-H),6.92(d,1H,J＝8.0Hz,Ar-H),4.52-4.48(m,1H,CH),4.30-4.24(m,3H,CH+CH2),3.07(dd,1H,J＝13.5,5.0Hz,CH2),2.91(dd,1H,J＝14.0,8.0Hz,CH2),2.83(dd,1H,J＝13.0,6.5Hz,CH2),2.75(dd,1H,J＝13.0,6.0Hz,CH2),2.49-2.39(m,2H,CH2),1.35(s,9H,CH3),0.79(s,9H,CH3)；ESI-MS:m/z＝573[M+H]+。
Synthesis of compound 55: using compound 45 as a starting material, the synthesis and the post-treatment were carried out as in example 3 to obtain white solid 55, which was used directly in the next reaction.
EXAMPLE 24 preparation of Asp (4-pivaloyl amide) -hPhe-2, 4-difluorobenzylamine
Figure BDA0001373563720000133
Synthesis of compound 46: the synthesis and post-treatment methods of the compound 38 and Boc-Asp (4-pivalic amide) used as raw materials were the same as in example 1, and a white solid was obtained. The yield thereof was found to be 69%.1H NMR(500MHz,d6-DMSO):δ＝8.49(t,1H,J＝5.5Hz,NH),8.18(d,1H,J＝8.0Hz,NH),7.83(t,1H,J＝6.0Hz,NH),7.78(t,1H,J＝6.5Hz,NH),7.37-7.15(m,6H,Ar-H),7.06-7.00(m,2H,Ar-H),4.37-4.23(m,3H,CH+CH2),4.18-4.14(m,1H,CH),2.89-2.78(m,2H,CH2),2.63-2.47(m,4H,CH2),2.05-2.02(m,1H,CH2),1.89-1.82(m,1H,CH2),1.38(s,9H,CH3),0.81(s,9H,CH3)；ESI-MS:m/z＝589[M+H]+。
Synthesis of compound 56: the compound 46 was used as a starting material, and the synthesis and the post-treatment were performed as in example 3 to obtain a white solid 56 which was used directly in the next reaction.
EXAMPLE 25 preparation of hPhe-Asp (4-pivaloylamide) -2-chlorobenzylamine
Figure BDA0001373563720000141
Synthesis of compound 47: to combine withThe material 36 and Boc-hPhe were used as raw materials, and the synthesis and post-treatment were the same as in example 1 to obtain white solid. The yield thereof was found to be 71%.1H NMR(500MHz,CDCl3):δ＝8.32(brs,1H,NH),7.77(brs,1H,NH),7.32-7.28(m,4H,Ar-H),7.23-7.18(m,5H,Ar-H),6.19(brs,1H,NH),5.07(brs,1H,NH),4.81(m,1H,CH),4.56-4.44(m,2H,CH2),4.07-4.04(m,1H,CH),3.05-2.97(m,3H,CH+CH2),2.73(t,2H,J＝7.5Hz,CH2),2.55-2.52(m,1H,CH2),2.20-2.18(m,1H,CH2),1.97-1.93(m,1H,CH2),1.39(s,9H,CH3),0.88(s,9H,CH3)；ESI-MS:m/z＝588[M+H]+。
Synthesis of compound 57: the synthesis and the post-treatment of compound 47 were carried out as in example 3 to give white solid 57, which was used directly in the next step.
EXAMPLE 26 preparation of Asp (4-pivaloyl amide) -Cys (S-Bn) -2-chlorobenzylamine
Figure BDA0001373563720000142
Synthesis of compound 48: the synthesis and post-treatment methods of compound 37 and Boc-Asp (4-pivalic amide) used as raw materials were the same as in example 1, and a white solid was obtained. The yield thereof was found to be 55%.1H NMR(500MHz,d6-DMSO):δ＝8.66(t,1H,J＝5.5Hz,NH),8.15(d,1H,J＝8.0Hz,NH),7.75(t,1H,J＝6.0Hz,NH),7.42-7.40(m,1H,Ar-H),7.35-7.33(m,1H,Ar-H),7.31-7.20(m,7H,Ar-H),6.97(d,1H,J＝8.5Hz,NH),4.51(dd,1H,J＝14.0,7.5Hz,CH2),4.35-4.29(m,3H,CH+CH2),3.74(s,2H,CH2),2.83-2.74(m,3H,CH+CH2),2.67-2.63(m,1H,CH2),2.54(dd,1H,J＝14.5,6.5Hz,CH2),2.43(dd,1H,J＝14.5,6.5Hz,CH2),1.33(s,9H,CH3),0.77(s,9H,CH3)；ESI-MS:m/z＝619[M+H]+。
Synthesis of compound 58: using compound 48 as a starting material, the synthesis and work-up procedure were as in example 3 to give white solid 58, which was used directly in the next reaction.
EXAMPLE 27 preparation of N- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine
Figure BDA0001373563720000151
Synthesis of compound 59: compound 49(2.3g, 5mmol) is dissolved in 10mL saturated NaHCO3The mixture of the aqueous solution and 10mL of dichloromethane was cooled to 0 ℃ in an ice bath, and triphosgene (0.5g, 1.7mmol) was added in one portion to react at 0 ℃ for 15 minutes. The organic layer was separated, the aqueous layer was extracted with dichloromethane (10mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate and evaporated to dryness. Compound 19(0.8g, 4mmol) was dissolved in 15mL of dichloromethane, diisopropylethylamine (1.4mL,8mmol) was added, the isocyanate obtained by the above reaction was dissolved in 5mL of dichloromethane, and the solution was added dropwise and reacted at room temperature for 6 hours. After the reaction had stopped, the organic layer was saturated with NaHCO3Aqueous wash (15 mL. multidot.2) saturated NH4Washed with aqueous Cl (15mL x 2), dried over anhydrous sodium sulfate, evaporated to remove the solvent, and separated by column chromatography to give 1.2g of a white solid with a yield of 43%.1H NMR(500MHz,d6-DMSO):δ＝10.77(s,1H,NH),9.34(s,1H,pyrazine-H),8.43-8.39(m,2H,pyrazine-H+NH),8.35(d,1H,J＝2.5Hz,pyrazine-H),8.07(d,1H,J＝7.5Hz,NH),7.41(d,1H,J＝7.0Hz,Ar-H),7.33-7.16(m,13H,Ar-H),6.68(d,1H,J＝7.5Hz,NH),4.36-4.27(m,3H,CH+CH2),4.16-4.03(m,3H,CH+CH2),2.78-2.55(m,7H,CH+CH2),2.05-1.94(m,4H,CH2),1.80(d,2H,J＝11.5Hz,CH2),1.59-1.46(m,2H,CH2)；13C NMR(100MHz,DMSO):δ＝174.72,173.55,172.45,172.10,157.89,149.37,143.02,142.21,141.83,140.06,136.77,136.63,132.44,129.49,129.17,129.00,128.79,128.74,127.50,126.29,126.22,55.03,52.81,43.68,43.63,33.98,33.83,32.40,31.85,28.45,21.51；ESI-MS:m/z＝696.1[M+H]+。
EXAMPLE 28 preparation of N- [4- (pyrazin-2-ylcarboxamide) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine
Figure BDA0001373563720000152
Synthesis of compound 60: synthesis and post-treatment of compound 49 and compound 17 as starting materials were carried out in the same manner as in example 27 to give a white solid. The yield thereof was found to be 39%.1H NMR(500MHz,d6-DMSO):δ＝9.19(d,1H,J＝1.5Hz,pyrazine-H),8.86(d,1H,J＝2.5Hz,pyrazine-H),8.77(d,1H,J＝8.5Hz,NH),8.69(d,1H,J＝2.5Hz,pyrazine-H),8.44(t,1H,J＝6.0Hz,NH),8.03(d,1H,J＝7.0Hz,NH),7.41-7.39(m,1H,Ar-H),7.32-7.24(m,7H,Ar-H),7.22-7.17(m,6H,Ar-H),6.71(d,1H,J＝7.0Hz,NH),4.35-4.28(m,3H,CH+CH2),4.15-4.09(m,1H,CH),4.07-4.02(m,3H,CH2+CH),2.86-2.54(m,6H,CH2),2.05-1.90(m,4H,CH2),1.75(d,2H,J＝11.5Hz,CH2),1.63-1.51(m,2H,CH2)；13C NMR(100MHz,DMSO):δ＝173.53,172.09,162.63,157.81,147.87,145.41,144.07,143.67,142.21,141.84,136.59,132.47,129.51,129.22,129.04,128.80,127.52,126.31,126.23,55.18,52.78,47.18,43.44,43.33,34.14,33.89,32.44,31.84,31.53,21.51；ESI-MS:m/z＝696.1[M+H]+。
EXAMPLE 29 preparation of N- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (Phe-hPhe) -2-chlorobenzylamine
Figure BDA0001373563720000161
Synthesis of compound 61: synthesis and post-treatment of the starting materials, Compound 50 and Compound 19, were carried out in the same manner as in example 27 to give a white solid. The yield thereof was found to be 42%.1H NMR(500MHz,d6-DMSO):δ＝10.74(s,1H,NH),9.33(d,1H,J＝1.5Hz,pyrazine-H),8.40-8.39(m,1H,pyrazine-H),8.36-8.33(m,2H,NH+pyrazine-H),8.19(d,1H,J＝3.0Hz,NH),7.45-7.43(m,1H,Ar-H),7.33-7.25(m,9H,Ar-H),7.20-7.17(m,4H,Ar-H),6.71(d,1H,J＝8.0Hz,NH),4.39-4.34(m,3H,CH2+CH),4.29-4.23(m,1H,CH),4.01-3.96(m,2H,CH2),3.06-3.02(dd,1H,J＝14.0,4.50Hz,CH2),2.94-2.89(dd,1H,J＝13.5,9.50Hz,CH2),2.70-2.51(m,5H,CH+CH2),2.07-1.99(m,1H,CH2),1.95-1.85(m,1H,CH2),1.74-1.71(m,2H,CH2),1.48-1.34(m,2H,CH2)；13C NMR(100MHz,DMSO):δ＝174.66,173.22,172.03,157.64,149.35,143.03,141.84,140.05,139.19,136.75,136.63,129.72,129.53,129.15,129.06,128.81,128.78,128.45,127.55,126.55,126.29,56.56,52.91,43.59,43.50,42.51,37.25,34.16,31.76,28.33；ESI-MS:m/z＝682.1[M+H]+。
EXAMPLE 30 preparation of N- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (Leu-hPhe) -2-chlorobenzylamine
Figure BDA0001373563720000162
Synthesis of compound 62: synthesis and post-treatment of the starting materials of Compound 51 and Compound 19 were carried out in the same manner as in example 27 to give a white solid. The yield thereof was found to be 26%.1H NMR(500MHz,d6-DMSO):δ＝10.77(s,1H,NH),9.34(d,1H,J＝1.0Hz,pyrazine-H),8.40-8.35(m,3H,pyrazine-H+NH),8.01(d,1H,J＝7.5Hz,NH),7.44-7.42(m,1H,Ar-H),7.33-7.27(m,5H,Ar-H),7.19-7.16(m,3H,Ar-H),6.58(d,1H,J＝7.5Hz,NH),4.34(d,2H,J＝6.0Hz,CH2),4.27-4.23(m,1H,CH),4.18-4.13(m,1H,CH),4.06-4.04(m,2H,CH2),2.75-2.58(m,5H,CH+CH2),2.07-1.85(m,2H,CH2),1.76(d,2H,J＝12.0Hz,CH2),1.71-1.64(m,1H,CH),1.64-1.44(m,4H,CH2),0.89(dd,6H,J＝19.0,6.5Hz,CH3)；13C NMR(100MHz,DMSO):δ＝174.71,174.05,172.06,157.87,149.36 143.03,141.84,140.06,136.76,136.63,132.47,129.52,129.22,129.07,128.78,127.52,126.29,53.63,52.74,43.67,43.61,42.57,33.96,31.79,28.44,28.39,24.81,23.53,22.14；ESI-MS:m/z＝648.1[M+H]+。
EXAMPLE 31 preparation of N- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (Ala-hPhe) -2-chlorobenzylamine
Figure BDA0001373563720000163
Synthesis of compound 63: synthesis and post-treatment method by using compound 52 and compound 19 as raw materialsIn the same manner as in example 27, a white solid was obtained. The yield thereof was found to be 36%.1H NMR(500MHz,d6-DMSO):δ＝10.76(s,1H,NH),9.34(d,1H,J＝1.5Hz,pyrazine-H),8.41-8.38(m,2H,NH+pyrazine-H),8.35(d,1H,J＝2.5Hz,pyrazine-H),8.00(d,1H,J＝8.0Hz,NH),7.44-7.42(m,1H,Ar-H),7.33-7.27(m,5H,Ar-H),7.19-7.16(m,3H,Ar-H),6.65(d,1H,J＝6.5Hz,NH),4.34(d,2H,J＝6.0Hz,CH2),4.27-4.23(m,1H,CH),4.15(m,1H,CH),4.04(d,2H,J＝12.5Hz,CH2),2.75-2.53(m,5H,CH+CH2),2.08-1.99(m,1H,CH),1.95-1.87(m,1H,CH),1.77(d,2H,J＝5.0Hz,CH2),1.56-1.45(m,2H,CH2),1.28(d,3H,J＝7.0Hz,CH3)；13C NMR(100MHz,DMSO):δ＝174.71,174.27,172.13,157.71,149.36,143.03,141.86,140.06,136.75,136.66,132.43,129.50,129.16,129.03,128.81,128.78,127.54,126.28,52.74,50.85,43.52,43.48,42.54,33.95,31.85,28.44,28.39,18.14；ESI-MS:m/z＝606.0[M+H]+。
EXAMPLE 32 preparation of N- [4- (Phenylcarbamoyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine
Figure BDA0001373563720000171
Synthesis of compound 64: synthesis and working-up were carried out in the same manner as in example 27 using compound 49 and compound 20 as starting materials to give a white solid. The yield thereof was found to be 58%.1H NMR(500MHz,d6-DMSO):δ＝9.92(s,1H,NH),8.44(t,1H,J＝6.0Hz,NH),8.10(d,1H,J＝7.5Hz,NH),7.61(d,2H,J＝8.0Hz,Ar-H),7.42-7.39(m,1H,Ar-H),7.32-7.18(m,15H,Ar-H),7.03(t,1H,J＝7.5Hz,Ar-H),6.70(d,1H,J＝7.5Hz,NH),4.32(d,2H,J＝6.0Hz,CH2),4.29-4.23(m,1H,CH),4.16-4.04(m,3H,CH+CH2),2.78-2.57(m,7H,CH+CH2),2.03-1.90(m,4H,CH2),1.76(d,2H,J＝11.0Hz,CH2),1.59-1.45(m,2H,CH2)；13C NMR(100MHz,DMSO):δ＝173.59,173.56,172.10,157.90,142.22,141.82,139.79,136.62,132.44,129.50,129.17,129.10,129.01,128.79,128.75,127.51,126.30,126.23,123.50,119.61,55.03,52.81,43.73,43.69,43.27,33.97,33.85,32.40,31.85,28.67；ESI-MS:m/z＝684.1[M+H]+。
EXAMPLE 33 preparation of N- [4- (4-fluoroanilinoyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine
Figure BDA0001373563720000172
Synthesis of compound 65: synthesis and post-treatment of compound 49 and compound 21 were carried out in the same manner as in example 27 to give a white solid. The yield thereof was found to be 49%.1H NMR(500MHz,CDCl3):δ＝7.74(m,2H,NH+NH),7.29-7.27(m,2H,Ar-H),7.25-7.13(m,10H,Ar-H),7.10-7.02(m,6H,Ar-H),6.28(d,1H,J＝8.0Hz,NH),4.98(d,1H,J＝5.0Hz,NH),4.52-4.47(m,2H,CH2+CH),4.42(dd,1H,J＝15.0,6.0Hz,CH2),4.32-4.29(m,1H,CH),4.12-4.06(m,1H,CH),3.80(d,1H,J＝13.5Hz,CH2),3.47(d,1H,J＝13.5Hz,CH2),2.79-2.60(m,6H,CH2),2.24-2.11(m,2H,CH2),2.04-1.98(m,2H,CH2),1.91-1.84(m,2H,CH2),1.45-1.37(m,2H,CH2)；13C NMR(100MHz,DMSO):δ＝173.54,172.10,165.49,165.01,163.03,157.84,142.22,141.83,136.59,132.45,131.59,131.56,130.42,130.33,129.56,129.51,129.18,129.09,129.04,128.78,127.52,126.32,126.24,115.63,115.42,55.09,52.82,47.35,43.45,43.29,34.04,33.95,32.43,31.18,31.79；ESI-MS:m/z＝712.1[M+H]+。
EXAMPLE 34 preparation of N- [4- (4-Methoxyanilinoformyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine
Figure BDA0001373563720000181
Synthesis of compound 66: synthesis and working-up were carried out in the same manner as in example 27 using compound 49 and compound 22 as starting materials to give a white solid. The yield thereof was found to be 45%.1H NMR(500MHz,CDCl3):δ＝7.42-7.28(m,8H,NH+Ar-H),7.26-7.12(m,10H,NH+Ar-H),7.01-6.97(brs,1H,NH),6.84(d,2H,J＝8.5Hz,Ar-H),4.51-4.47(m,3H,CH+CH2),4.25(brs,1H,CH),3.78(s,3H,CH3),3.65-3.58(m,2H,CH2),2.75-2.64(m,6H,CH2),2.37-2.34(m,1H,CH),2.28-2.21(m,1H,CH2),2.19-2.12(m,1H,CH2),2.07-1.96(m,2H,CH2),1.90-1.80(m,2H,CH2),1.73-1.65(m,2H,CH2)；13C NMR(100MHz,DMSO):δ＝173.57,173.07,172.11,157.90,155.55,142.22,141.83,136.63,132.96,132.45,129.50,129.17,129.01,128.79,128.75,127.50,126.30,126.23,121.17,114.24,55.62,55.04,52.82,43.76,43.70,43.16,33.97,33.85,32.41,31.85,28.71；ESI-MS:m/z＝724.1[M+H]+。
EXAMPLE 35 preparation of N- [4- (pyridin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine
Figure BDA0001373563720000182
Synthesis of compound 67: synthesis and post-treatment of compound 49 and compound 23 as starting materials were carried out in the same manner as in example 27 to give a white solid. The yield thereof was found to be 39%.1H NMR(500MHz,CDCl3):δ＝8.73(brs,1H,NH),8.26-8.23(m,2H,pyridine-H),7.78(t,1H,J＝8.5Hz,NH),7.34-7.28(m,4H,Ar-H+pyridine-H),7.25-7.03(m,12H,Ar-H+pyridine-H),6.76(d,1H,J＝8.0Hz,NH),4.80(d,1H,J＝6.0Hz,NH),4.55-4.49(m,3H,CH+CH2),4.23(m,1H,CH),3.72(d,1H,J＝13.0Hz,CH2),3.60(d,1H,J＝13.0Hz,CH2),2.80-2.60(m,6H,CH2),2.46-2.39(m,1H,CH),2.33-2.22(m,1H,CH2),2.17-2.12(m,1H,CH2),2.01-1.95(m,2H,CH2),1.87-1.78(m,2H,CH2),1.72-1.60(m,2H,CH2)；13C NMR(100MHz,DMSO):δ＝174.53,173.57,172.11,157.89,152.60,148.33,142.21,141.82,138.55,136.62,132.44,129.49,129.17,129.01,128.79,128.75,127.50,126.30,126.23,119.73,114.00,55.03,52.81,43.73,43.67,42.76,33.96,33.83,32.40,31.85,28.55,28.52；ESI-MS:m/z＝695.3[M+H]+。
EXAMPLE 36 preparation of N- [1- (pyrazine-2-formyl) piperidine-4-formyl ] dipeptide [ Asp (4-pivaloylamide) -hPhe ] -2-chlorobenzylamine
Figure BDA0001373563720000191
Synthesis of compound 68: the synthesis and post-treatment methods of compound 53 and compound 15 used as raw materials were the same as in example 1, to obtain a white solid. The yield thereof was found to be 45%.1H NMR(500MHz,d6-DMSO):δ＝8.81(d,1H,J＝3.5Hz,pyrazine-H),8.74(d,1H,J＝2.5Hz,pyrazine-H),8.65(s,1H,pyrazine-H),8.54(dd,1H,J＝8.5,5.5Hz,NH),8.32(d,1H,J＝7.5Hz,NH),8.23(d,1H,J＝8.0Hz,NH),7.88(q,1H,J＝6.5Hz,NH),7.41-7.39(m,1H,Ar-H),7.31-7.23(m,5H,Ar-H),7.23-7.14(m,3H,Ar-H),4.61(q,1H,J＝7.5Hz,CH),4.47-4.42(m,1H,CH2),4.36-4.28(m,2H,CH2),4.20-4.14(m,1H,CH2),3.69-3.64(m,1H,CH),3.11-3.07(m,1H,CH2),2.92-2.87(m,1H,CH2),2.79-2.54(m,7H,CH+CH2),2.11-2.04(m,1H,CH2),1.93-1.76(m,2H,CH2),1.66-1.51(m,3H,CH2),0.76(s,9H,CH3)；13C NMR(100MHz,DMSO):δ＝174.22,172.08,171.82,170.31,165.10,150.12,145.85,144.59,143.75,141.71,136.62,132.29,129.42,129.02,128.92,128.89,128.75,127.48,126.32,52.76,50.46,50.08,46.50,41.58,37.67,33.61,32.26,31.71,29.30,29.23,28.53,28.48,27.61；ESI-MS:m/z＝704.1[M+H]+。
EXAMPLE 37 preparation of N- [1- (4-fluorobenzoyl) piperidine-4-formyl ] dipeptide [ Asp (4-pivaloyl amide) -hPhe ] -2-chlorobenzylamine
Figure BDA0001373563720000192
Synthesis of compound 69: the synthesis and post-treatment methods of compound 53 and compound 16 used as raw materials were the same as in example 1, to obtain a white solid. The yield thereof was found to be 42%.1H NMR(500MHz,d6-DMSO):δ＝8.55(t,1H,J＝6.0Hz,NH),8.32(d,1H,J＝8.0Hz,NH),8.23(d,1H,J＝8.0Hz,NH),7.89(t,1H,J＝6.0Hz,NH),7.44-7.40(m,3H,Ar-H),7.32-7.24(m,7H,Ar-H),7.19-7.13(m,3H,Ar-H),4.61(q,1H,J＝8.0Hz,CH),4.48-4.28(m,3H,CH2),4.19-4.16(m,1H,CH2),3.64-3.56(m,1H,CH),3.10-2.99(m,1H,CH2),2.85-2.55(m,7H,CH+CH2),2.11-2.03(m,1H,CH2),1.92-1.81(m,1H,CH2),1.79-1.43(m,5H,CH2),0.76(s,9H,CH3)；13C NMR(100MHz,DMSO):δ＝174.27,172.07,171.81,170.30,168.56,163.87,161.91,141.73,136.61,133.09,132.29,129.74,129.67,129.42,129.01,128.90,128.74,127.48,126.31,115.93,115.76,52.77,50.44,50.07,41.92,41.76,37.66,33.63,32.26,31.72,30.63,27.61,21.19,19.08,14.03；ESI-MS:m/z＝720.1[M+H]+。
EXAMPLE 38 preparation of N- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloylamide) -Leu ] -2-chlorobenzylamine
Figure BDA0001373563720000193
Synthesis of compound 70: synthesis and post-treatment of compound 54 and compound 19 as starting materials were carried out in the same manner as in example 27 to give a white solid. The yield thereof was found to be 27%.1H NMR(500MHz,d6-DMSO):δ＝10.80(s,1H,NH),9.33(d,1H,J＝1.5Hz,pyrazine-H),8.52(t,1H,J＝5.5Hz,NH),8.40(d,1H,J＝1.5Hz,pyrazing-H),8.35(d,1H,J＝2.5Hz,pyrazine-H),8.07(d,1H,J＝8.0Hz,NH),7.78(t,1H,J＝6.0Hz,NH),7.43-7.40(m,1H,Ar-H),7.32-7.26(m,3H,Ar-H),6.71(d,1H,J＝7.0Hz,NH),4.40(q,1H,J＝8.0Hz,CH),4.36-4.26(m,3H,CH+CH2),4.00-3.95(m,2H,CH2),2.86-2.75(m,2H,CH2),2.74-2.50(m,5H,CH+CH2),1.80-1.73(m,2H,CH2),1.66-1.43(m,5H,CH+CH2),0.90(d,3H,J＝6.5Hz,CH3),0.84(d,3H,J＝6.5Hz,CH3),0.80(s,9H,CH3)；13C NMR(100MHz,DMSO):δ＝174.65,172.71,172.70,170.60,157.41,149.36,143.04,140.06,136.73,136.69,132.32,129.41,129.01,128.90,127.51,52.40,51.79,50.16,43.52,43.43,42.48,37.83,32.29,28.40,28.35,27.64,24.68,23.61,21.80；ESI-MS:m/z＝671.2[M+H]+。
EXAMPLE 39 preparation of N- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloylamide) -Phe ] -2-chlorobenzylamine
Figure BDA0001373563720000201
Synthesis of compound 71: synthesis and post-treatment of the compound 55 and the compound 19 as starting materials were carried out in the same manner as in example 27 to give a white solid. The yield thereof was found to be 45%.1H NMR(500MHz,d6-DMSO):δ＝10.80(s,1H,NH),9.34(d,1H,J＝1.5Hz,pyrazine-H),8.57(t,1H,J＝6.0Hz,NH),8.40(dd,1H,J＝2.5,1.5Hz,pyrazing-H),8.35(d,1H,J＝2.5Hz,pyrazine-H),8.16(d,1H,J＝8.0Hz,NH),7.76(t,1H,J＝6.0Hz,NH),7.43-7.41(m,1H,Ar-H),7.30-7.18(m,7H,Ar-H),7.17-7.15(m,1H,Ar-H),6.66(d,1H,J＝7.5Hz,NH),4.49-4.44(m,1H,CH),4.38(q,1H,J＝8.0Hz,CH2),4.32(d,2H,J＝5.5Hz,CH2),4.00-3.91(m,2H,CH+CH2),3.10(dd,1H,J＝14.0,5.0Hz,CH2),2.93(dd,1H,J＝13.5,8.0Hz,CH2),2.85(dd,1H,J＝13.0,6.5Hz,CH2),2.77(dd,1H,J＝14.0,5.5Hz,CH2),2.73-2.50(m,3H,CH+CH2),2.52-2.43(m,2H,CH2),1.80-1.75(m,2H,CH2),1.49-1.41(m,2H,CH2),0.80(s,9H,CH3)；13C NMR(100MHz,DMSO):δ＝174.71,172.62,171.53,170.60,157.38,149.30,143.08,140.08,138.25,136.71,136.40,132.30,129.60,129.39,129.05,128.95,128.62,127.52,126.79,54.76,52.40,50.17,43.45,43.35,42.43,37.80,37.38,32.29,28.35,28.30,27.60；ESI-MS:m/z＝705.1[M+H]+。
EXAMPLE 40 preparation of N- [4- (pyrazine-2-formyl) piperazine-1-formyl ] dipeptide [ Asp (4-pivaloylamide) -hPhe ] -2-chlorobenzylamine
Figure BDA0001373563720000202
Synthesis of compound 72: synthesis and working-up were carried out in the same manner as in example 27 using compound 53 and compound 18 as starting materials to obtain a white solid. The yield thereof was found to be 79%.1H NMR(500MHz,d6-DMSO):δ＝8.86(d,1H,J＝1.5Hz,pyrazine-H),8.77(d,1H,J＝1.5Hz,pyrazine-H),8.69(dd,1H,J＝2.5,1.5Hz,pyrazing-H),8.52(t,1H,J＝6.0Hz,NH),8.27(d,1H,J＝7.5Hz,NH),7.82(t,1H,J＝6.0Hz,NH),7.43-7.41(m,1H,Ar-H),7.33-7.25(m,5H,Ar-H),7.20-7.15(m,3H,Ar-H),6.89(d,1H,J＝8.0Hz,NH),4.47(q,1H,J＝7.5Hz,CH),4.32(d,2H,J＝6.0Hz,CH2),4.20-4.16(m,1H,CH),3.65-3.60(m,2H,CH2),3.47-3.32(m,6H,CH2),2.85-2.76(m,2H,CH2),2.70-2.53(m,4H,CH2),2.10-2.02(m,1H,CH2),1.94-1.88(m,1H,CH2),0.79(s,9H,CH3)；13C NMR(100MHz,DMSO):δ＝172.73,172.14,170.59,165.37,157.46,149.56,146.05,145.02,143.68,141.84,136.67,132.35,129.44,129.08,128.94,128.87,128.74,127.49,126.28,52.88,52.44,50.16,46.77,44.24,43.67,42.07,37.89,33.72,32.28,31.77,27.63；ESI-MS:m/z＝705.1[M+H]+。
EXAMPLE 41 preparation of N- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -hPhe ] -2, 4-difluorobenzylamine
Figure BDA0001373563720000211
Synthesis of compound 73: synthesis and post-treatment of compound 56 and compound 19 as starting materials were carried out in the same manner as in example 27 to give a white solid. The yield thereof was found to be 38%.1H NMR(500MHz,d6-DMSO):δ＝10.76(s,1H,NH),9.33(d,1H,J＝1.5Hz,pyrazine-H),8.49(t,1H,J＝6.0Hz,NH),8.40(dd,1H,J＝2.5,1.5Hz,pyrazine-H),8.35(d,1H,J＝2.5Hz,pyrazine-H),8.17(d,1H,J＝7.5Hz,NH),7.81(t,1H,J＝6.0Hz,NH),7.35(q,1H,J＝9.0Hz,Ar-H),7.28-7.13(m,6H,Ar-H),7.02(dt,1H,J＝8.5,2.0Hz,Ar-H),6.74(d,1H,J＝7.5Hz,NH),4.42(q,1H,J＝7.0Hz,CH),4.30-4.27(m,2H,CH2),4.17-4.13(m,1H,CH),4.05-3.98(m,2H,CH2),2.85-2.54(m,9H,CH+CH2),2.06-2.03(m,1H,CH2),1.89-1.77(m,3H,CH2),1.53-1.46(m,2H,CH2),0.81(s,9H,CH3)；ESI-MS:m/z＝720.2[M+H]+。
EXAMPLE 42 preparation of N- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ hPhe-Asp (4-pivaloamide) ] -2-chlorobenzylamine
Figure BDA0001373563720000212
Synthesis of compound 74: synthesis and post-treatment of the compound 57 and the compound 19 as starting materials were carried out in the same manner as in example 27 to give a white solid. The yield thereof was found to be 45%.1H NMR(500MHz,d6-DMSO):δ＝10.76(s,1H,NH),9.36(d,1H,J＝1.0Hz,pyrazine-H),8.51(d,1H,J＝8.0Hz,NH),8.40(dd,1H,J＝2.5,1.0Hz,pyrazine-H),8.37-8.35(m,2H,NH+pyrazine-H),7.91(t,1H,J＝6.5Hz,NH),7.39(dd,1H,J＝7.5,1.5Hz,Ar-H),7.30-7.17(m,8H,Ar-H),6.86(d,1H,J＝6.0Hz,NH),4.50(q,1H,J＝6.0Hz,CH),4.36(dd,1H,J＝16.5,6.5Hz,CH2),4.21(dd,1H,J＝16.5,6.5Hz,CH2),4.03-3.98(m,2H,CH2),3.91(q,1H,J＝6.5Hz,CH),2.93(dd,1H,J＝13.0,6.5Hz,CH2),2.84(dd,1H,J＝13.0,6.5Hz,CH2),2.80-2.55(m,7H,CH+CH2),1.97-1.92(m,2H,CH2),1.79-1.73(m,2H,CH2),1.63-1.52(m,2H,CH2),0.79(s,9H,CH3)；ESI-MS:m/z＝718.5[M+H]+。
EXAMPLE 43 preparation of N- [4- (pyridin-3-ylaminoformyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloylamide) -Cys (S-Bn) ] -2-chlorobenzylamine
Figure BDA0001373563720000221
Synthesis of compound 75: the synthesis and the post-treatment methods of compound 58 and compound 24 used as raw materials were the same as in example 27, and a white solid was obtained. The yield thereof was found to be 25%.1H NMR(500MHz,d6-DMSO):δ＝10.10(s,1H,NH),8.72(s,1H,Ar-H),8.64(t,1H,J＝4.5Hz,Ar-H),8.23-8.18(m,2H,Ar-H+NH),8.02(d,1H,J＝8.5Hz,NH),7.75(t,1H,J＝5.5Hz,NH),7.42-7.21(m,10H,Ar-H),6.72(d,1H,J＝6.5Hz,NH),4.48-4.40(m,2H,CH+CH),4.33(d,2H,J＝5.5Hz,CH2),3.97(t,2H,J＝13.5Hz,CH2),3.74(s,2H,CH2),2.84-2.49(m,8H,CH2),1.89(s,1H,CH),1.75-1.72(m,2H,CH2),1.50-1.45(m,2H,CH2),0.78(s,9H,CH3)；ESI-MS:m/z＝749.8[M+H]+。
EXAMPLE 44 preparation of N- [4- (pyridin-3-ylcarbamoyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine
Figure BDA0001373563720000222
Synthesis of compound 76: using the compounds 24 and 49 as raw materials, the synthesis and the post-treatment were carried out in the same manner as in example 27 to obtain a white solid with a yield of 47%. ESI-MS: M/z 696.3[ M + H ]]+。
EXAMPLE 45 preparation of N- [4- (thiazol-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine
Figure BDA0001373563720000223
Synthesis of compound 77: synthesis and working up were carried out as in example 27 using 4- (thiazol-2-ylcarbamoyl) piperidine and 49 as starting materials to give a white solid in 53% yield. ESI-MS: M/z 702.3[ M + H ]]+。
EXAMPLE 46 preparation of N- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -2-fluorobenzylamine
Figure BDA0001373563720000224
Synthesis of compound 78: the synthesis and post-treatment methods of the compound 19 and hPhe-hPhe-2-fluorobenzylamine used as raw materials were the same as in example 27, and a white solid was obtained with a yield of 62%. ESI-MS: M/z 680.8[ M + H ]]+。
EXAMPLE 47 preparation of N- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -4-chlorobenzylamine
Figure BDA0001373563720000231
Synthesis of compound 79: the synthesis and post-treatment methods of the compound 19 and hPhe-hPhe-4-chlorobenzylamine as raw materials were the same as in example 27 to obtain a white solid with a yield of 59%. ESI-MS: M/z 697.3[ M + H ]]+。
EXAMPLE 48 preparation of N- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide (hPhe-hPhe) -4-fluorobenzylamine
Figure BDA0001373563720000232
Synthesis of compound 80: the synthesis and post-treatment methods of the compound 19 and hPhe-hPhe-4-fluorobenzylamine used as raw materials were the same as in example 27, and a white solid was obtained with a yield of 68%. ESI-MS: M/z 680.8[ M + H ]]+。
EXAMPLE 49 preparation of N- [4- (pyrazine-2-formyl) piperazine-1-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine
Figure BDA0001373563720000233
Synthesis of compound 81: using the compounds 18 and 49 as starting materials, the synthesis and the post-treatment were carried out in the same manner as in example 27 to obtain a white solid with a yield of 61%. ESI-MS: M/z 683.3[ M + H ]]+。
EXAMPLE 50 preparation of N- [1- (pyrazine-2-formyl) piperidine-4-formyl ] dipeptide (hPhe-hPhe) -2-chlorobenzylamine
Figure BDA0001373563720000234
Synthesis of compound 82: using the compounds 15 and 49 as raw materials, the synthesis and post-treatment methods were the same as in example 1, to obtain a white solid with a yield of 75%. ESI-MS: M/z 682.3[ M + H ]]+。
EXAMPLE 51 preparation of N- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -Ala ] -2-chlorobenzylamine
Figure BDA0001373563720000235
Synthesis of compound 83: the synthesis and the post-treatment were carried out in the same manner as in example 27 using 19 and Asp (4-pivaloylamide) -Ala-2-chlorobenzylamine as starting materials to obtain a white solid with a yield of 47%. ESI-MS: M/z 630.3[ M + H ]]+。
EXAMPLE 52 preparation of N- [4- (pyrazin-2-ylcarboxamide) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -hPhe ] -2-chlorobenzylamine
Figure BDA0001373563720000241
Synthesis of compound 84: using the compounds 17 and 53 as starting materials, the synthesis and the post-treatment were carried out in the same manner as in example 27 to obtain a white solid with a yield of 44%. ESI-MS: 720.4[ M + H ] M/z]+。
EXAMPLE 53 preparation of N- [4- (pyrazine-2-formyl) piperazine-1-formyl ] dipeptide [ Asp (4-pivaloylamide) -Leu ] -2-chlorobenzylamine
Figure BDA0001373563720000242
Synthesis of compound 85: using the compounds 18 and 54 as starting materials, the synthesis and the post-treatment were carried out in the same manner as in example 27 to obtain a white solid with a yield of 49%. ESI-MS: M/z 658.3[ M + H ]]+。
EXAMPLE 54 preparation of N- [4- (thiazol-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -hPhe ] -2-chlorobenzylamine
Figure BDA0001373563720000243
Synthesis of compound 86: using 53 and 4- (thiazole-2-carbamoyl) piperidine as starting materials, the synthesis and the post-treatment were carried out in the same manner as in example 27 to obtain a white solid with a yield of 38%. ESI-MS: M/z 725.3[ M +H]+。
EXAMPLE 55 preparation of N- [4- (pyridin-3-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -hPhe ] -2-chlorobenzylamine
Figure BDA0001373563720000244
Synthesis of compound 87: using the compounds 24 and 53 as starting materials, the synthesis and the post-treatment were carried out in the same manner as in example 27 to obtain a white solid with a yield of 35%. ESI-MS: M/z 719.3[ M + H ]]+。
EXAMPLE 56 preparation of N- [4- (4-methoxycarboxanilido) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -hPhe ] -2-chlorobenzylamine
Figure BDA0001373563720000245
Synthesis of compound 88: using the compounds 22 and 53 as starting materials, the synthesis and the post-treatment were carried out in the same manner as in example 27 to obtain a white solid with a yield of 66%. ESI-MS: M/z 748.4[ M + H ]]+。
EXAMPLE 57 preparation of N- [4- (4-trifluoromethylcarboxanilido) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -hPhe ] -2-chlorobenzylamine
Figure BDA0001373563720000251
Synthesis of compound 89: using 53 and 4- (4-trifluoromethyl-carboxanilido) piperidine as starting materials, the synthesis and work-up were carried out as in example 27 to give a white solid in 54% yield. ESI-MS: M/z 786.3[ M + H ]]+。
EXAMPLE 58 preparation of N- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloamide) -hPhe ] -4-chlorobenzylamine
Figure BDA0001373563720000252
Synthesis of compound 90: the synthesis and post-treatment methods of the compound 19 and Asp (4-pivaloyl amide) -hPhe-4-chlorobenzylamine as raw materials are the same as those of example 27, and a white solid is obtained with a yield of 39%. ESI-MS: 720.3[ M + H ] M/z]+。
EXAMPLE 59 preparation of N- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Glu (4-tert-butylamide) -hPhe ] -2-chlorobenzylamine
Figure BDA0001373563720000253
Synthesis of compound 91: the synthesis and post-treatment methods of the compound 19 and Glu (4-tert-butylamide) -hPhe-2-chlorobenzylamine as raw materials were the same as in example 27 to obtain a white solid with a yield of 37%. ESI-MS: 720.3[ M + H ] M/z]+。
EXAMPLE 60 preparation of N- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Tyr (O-tBu) -hPhe) ] -2-chlorobenzylamine
Figure BDA0001373563720000254
Synthesis of compound 92: the synthesis and post-treatment methods of the compound 19 and Tyr (O-tBu) -hPhe-2-chlorobenzylamine as raw materials were the same as example 27 to obtain a white solid with a yield of 46%. ESI-MS: M/z 755.3[ M + H ]]+。
EXAMPLE 61 preparation of N- [4- (pyrazin-2-ylcarbamoyl) piperidine-1-formyl ] dipeptide [ Asp (4-pivaloylamide) -Cys (S-Bn) ] -2-chlorobenzylamine
Figure BDA0001373563720000261
Synthesis of compound 93: using the compounds 19 and 58 as starting materials, the synthesis and the post-treatment were carried out in the same manner as in example 27 to obtain a white solid with a yield of 71%. ESI-MS: M/z 752.3[ M + H ]]+。
Experimental example 1 proteasome inhibition Activity test of dipeptides Compound constructed with piperidine or piperazine
The experimental method comprises the following steps: the activity is detected by adopting a fluorogenic substrate Suc-Leu-Leu-Val-Tyr-AMC, the activity inhibition of different compounds on enzyme is observed, and the inhibition effect of the compounds is preliminarily evaluated. The proteasome chymotrypsin (chymotrypsin-like protease) hydrolyzes the Tyr-AMC sequence in the substrate to release the AMC, the fluorescence absorption value of the hydrolyzed AMC product can be detected under the condition that excitation light is 355nm and light is emitted at 460nm, and the inhibition condition of the compound on the proteasome activity is observed. See table 1 for results.
Test example 2 assay for inhibitory Activity of piperidine or piperazine-constructed dipeptides on proliferation of multiple myeloma cell
The experimental method comprises the following steps: detecting cell survival rate by MTT method, i.e. digesting the cells growing at logarithmic growth phase with 0.01% pancreatin, counting at 2.0 × 103Cell density of/well 100ml seeded in 96 well plates in 5% CO2The culture was carried out overnight at 37 ℃ in an incubator. Each compound is provided with six concentration gradients, each concentration is provided with three multiple holes, each concentration is respectively added into the corresponding hole, and 5% CO is added2The cells were incubated at 37 ℃ for 72 hours in an incubator and 20ml of 5mg/ml MTT was added. After incubation for 3 hours at 37 ℃ the supernatant was aspirated, 100ml DMSO was added to dissolve, 550nm (L1) light absorbance was measured using SpectraMAX 340, the reference wavelength was 690nm (L2), the values of (L1-L2) were plotted against the different inhibitor concentrations, and IC was obtained by fitting the formula50. See table 1 for results.
TABLE 1 inhibitory Activity of Compounds on proteasome CT-L and proliferation inhibitory Activity of multiple myeloma cells
Figure BDA0001373563720000262
Figure BDA0001373563720000271
Note: NT-No test
Experimental example 3 inhibitory Activity of dipeptides partially constructed with piperidine or piperazine on blood cell proteasome CT-L
The experimental method comprises the following steps: ICR mice were bled, anticoagulants were added, and compounds of different concentrations were added for incubation (compound to blood volume ratio 1: 50). After 40 minutes, it was centrifuged (1000rpm, 5min) and the supernatant discarded. Lysis was performed by adding 2 volumes of EDTA (5mM, pH 8.0), spinning on a rotator at 4 ℃ for 60 minutes, and then the blood sample was centrifuged (6600rpm, 10min) to remove the bottom precipitate. And (4) carrying out protein concentration determination on the lysed blood sample, and carrying out proteasome activity detection after calibrating to the same protein concentration. The test method was the same as in test example 1. The results are shown in FIG. 1.
The compounds of the invention are all high-efficiency inhibitors of proteasomes, and the activity test result shows that the proteasome inhibition activity of 7 compounds is stronger than that of the marketed compound Carfilzomib, and the compound shows extremely strong proliferation inhibition activity of multiple myeloma cells. Further, the proteasome activity detection of blood and tissue of normal mice shows that the activity of 3 compounds is superior to or equal to that of a positive control. The experiments show that the compounds have excellent anti-tumor application prospect, so that the compounds have good commercial value.

Claims (6)

1. A dipeptide compound constructed from piperidine or piperazine, characterized in that said compound is selected from:
N- [4- (pyrazin-2-ylcarboxamide) piperidine-1-formyl]Dipeptide (hPhe-hPhe) -2-chlorobenzylamine;
N- [4- (Phenylcarbamoyl) piperidine-1-formyl group]Dipeptide (hPhe-hPhe) -2-chlorobenzylamine;
N- [4- (pyridin-2-ylaminoformyl) piperidine-1-formyl]Dipeptide (hPhe-hPhe) -2-chlorobenzylamine;
N- [1- (pyrazine-2-formyl) piperidine-4-formyl]Dipeptide [ Asp (4-pivaloyl amide) -hPhe]-2-chlorobenzylamine;
N- [1- (4-fluorobenzoyl) piperidine-4-formyl group]Dipeptide [ Asp (4-pivaloyl amide) -hPhe]-2-chlorobenzylamine;
N- [4- (pyrazin-2-ylaminoformyl) piperidine-1-formyl]Dipeptide [ Asp (4-pivaloyl)Amine) -Leu]-2-chlorobenzylamine;
N- [4- (pyrazin-2-ylaminoformyl) piperidine-1-formyl]Dipeptide [ Asp (4-pivaloylamide) -Phe]-2-chlorobenzylamine;
N- [4- (pyrazine-2-formyl) piperazine-1-formyl]Dipeptide [ Asp (4-pivaloyl amide) -hPhe]-2-chlorobenzylamine;
N- [4- (pyrazin-2-ylaminoformyl) piperidine-1-formyl]Dipeptide [ Asp (4-pivaloyl amide) -hPhe]-2, 4-difluorobenzylamine;
N- [4- (pyrazin-2-ylaminoformyl) piperidine-1-formyl]Dipeptide [ hPhe-Asp (4-pivaloyl amide)]-2-chlorobenzylamine;
N- [4- (pyridin-3-ylaminoformyl) piperidine-1-formyl]Dipeptide [ Asp (4-pivaloyl amide) -Cys (S-Bn)]-2-chlorobenzylamine;
N- [4- (pyridin-3-ylaminoformyl) piperidine-1-formyl]Dipeptide (hPhe-hPhe) -2-chlorobenzylamine;
N- [4- (Thiazol-2-ylaminoformyl) piperidine-1-formyl]Dipeptide (hPhe-hPhe) -2-chlorobenzylamine;
N- [4- (pyrazin-2-ylaminoformyl) piperidine-1-formyl]Dipeptide (hPhe-hPhe) -2-fluorobenzylamine;
N- [4- (pyrazin-2-ylaminoformyl) piperidine-1-formyl]Dipeptide (hPhe-hPhe) -4-chlorobenzylamine;
N- [4- (pyrazin-2-ylaminoformyl) piperidine-1-formyl]Dipeptide (hPhe-hPhe) -4-fluorobenzylamine;
N- [4- (pyrazine-2-formyl) piperazine-1-formyl]Dipeptide (hPhe-hPhe) -2-chlorobenzylamine;
N- [1- (pyrazine-2-formyl) piperidine-4-formyl]Dipeptide (hPhe-hPhe) -2-chlorobenzylamine;
N- [4- (pyrazin-2-ylaminoformyl) piperidine-1-formyl]Dipeptide [ Asp (4-pivaloylamide) -Ala]-2-chlorobenzylamine;
N- [4- (pyrazin-2-ylcarboxamide) piperidine-1-formyl]Dipeptide [ Asp (4-pivaloyl amide) -hPhe]-2-chlorobenzylamine;
N- [4- (pyridine)Oxazine-2-formyl) piperazine-1-formyl]Dipeptide [ Asp (4-pivaloyl amide) -Leu]-2-chlorobenzylamine;
N- [4- (Thiazol-2-ylaminoformyl) piperidine-1-formyl]Dipeptide [ Asp (4-pivaloyl amide) -hPhe]-2-chlorobenzylamine;
N- [4- (pyridin-3-ylaminoformyl) piperidine-1-formyl]Dipeptide [ Asp (4-pivaloyl amide) -hPhe]-2-chlorobenzylamine;
N- [4- (4-Methoxyanilinoformyl) piperidine-1-formyl]Dipeptide [ Asp (4-pivaloyl amide) -hPhe]-2-chlorobenzylamine;
N- [4- (pyrazin-2-ylaminoformyl) piperidine-1-formyl]Dipeptide [ Asp (4-pivaloyl amide) -hPhe]-4-chlorobenzylamine;
N- [4- (pyrazin-2-ylaminoformyl) piperidine-1-formyl]Dipeptide [ Glu (4-tert-butanamide) -hPhe]-2-chlorobenzylamine;
N- [4- (pyrazin-2-ylaminoformyl) piperidine-1-formyl]Dipeptide [ Tyr (O-tBu) -hPhe)]-2-chlorobenzylamine;
N- [4- (pyrazin-2-ylaminoformyl) piperidine-1-formyl]Dipeptide [ Asp (4-pivaloyl amide) -Cys (S-Bn)]-2-chlorobenzylamine.
2. A pharmaceutical composition comprising as an active ingredient at least one compound according to claim 1, a stereoisomer or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers or excipients.
3. Use of a compound of claim 1, a pharmaceutically acceptable salt, solvate, or pharmaceutical composition of claim 2 in the preparation of an anti-neoplastic drug.
4. Use according to claim 3, characterized in that the neoplasm is myeloma, lymphoma, leukemia.
5. The pharmaceutical composition of claim 2, wherein: the administration mode of the pharmaceutical composition is selected from oral administration, injection, inhalation and implantation.
6. The pharmaceutical composition of claim 2, wherein: the dosage form of the pharmaceutical composition is injection, freeze-dried powder injection, tablet, capsule or granule.
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