CN111454327A - NAMPT protein degradation targeting chimera and preparation method and application thereof - Google Patents

NAMPT protein degradation targeting chimera and preparation method and application thereof Download PDF

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CN111454327A
CN111454327A CN202010255728.4A CN202010255728A CN111454327A CN 111454327 A CN111454327 A CN 111454327A CN 202010255728 A CN202010255728 A CN 202010255728A CN 111454327 A CN111454327 A CN 111454327A
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phenyl
compound
pyridin
carboxamide
ethyl
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盛春泉
董国强
吴颖
何世鹏
程俊飞
黄亚辉
陈树强
武善超
李兴麟
马俊辉
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Second Military Medical University SMMU
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
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Abstract

The invention relates toThe technical field of medicine, in particular to a NAMPT protein degradation targeting chimera which is a compound of a general formula (i) and/or (ii) or a pharmaceutically acceptable salt thereof. The invention also relates to a preparation method and application of the NAMPT protein degradation targeting chimera. The compound of the invention shows good NAMPT enzyme inhibition activity, can reduce the levels of intracellular and extracellular NAMPT protein through ubiquitin proteasome pathway, realizes the inhibition of tumor, has certain broad-spectrum anti-tumor activity, can obviously inhibit the growth of tumor, and can be applied to NAMPT mediated tumor diseases.
Figure DDA0002437243970000011

Description

NAMPT protein degradation targeting chimera and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a NAMPT protein degradation targeting chimera and a preparation method and application thereof.
Background
The tumor cells have higher proliferation rate and energy requirement compared with normal cells, so that NAMPT is in a high expression state and is an important target in anti-tumor research, recently, documents report that NAMPT can be secreted out of cells, has cytokine-like effect, can activate NF-KB pathway, PI3K-MAPK pathway and phosphorylation of downstream AKT, ERK and GSK3 β, up-regulates gene expression and protein production of VEGF and metalloproteinases MMPs, up-regulates expression of SDF-1, has increased affinity to chemokine receptors 3982 and 7, promotes proliferation and tumor cell invasion, inhibits tumor cell invasion and metastasis, and promotes immune cell proliferation, and also has the functions of inhibiting activity of NAMPT-4656, inhibiting activity of cell proliferation, inhibiting activity of cell-IDT-2-NI, and promoting cell proliferation, inhibiting activity of cell proliferation, inhibiting cell proliferation, and promoting cell proliferation of immune cell proliferation.
Currently, clinical NAMPT inhibitors include FK866 and CHS828, which inhibit tumor growth by specifically and non-competitively inhibiting NAMPT proteins. However, NAMPT inhibitors alone can cause problems. One is that after the NAMPT target is inhibited, the level of the NAMPT protein can be up-regulated by negative feedback of cells, so that higher concentration of the inhibitor is needed to reach the original inhibition level, and the high concentration of the inhibitor can cause toxic and side effects and drug resistance. Secondly, upregulation of NAMPT protein levels may lead to upregulation of extracellular NAMPT, contributing to the development of tumor immune escape. Clinical studies have shown that FK866 and CHS828 have a poor tumor suppression effect at low doses and cause dose-limiting toxic thrombocytopenia and gastrointestinal toxic side effects at high doses. This is also why FK866 has been in a state of stasis after the clinical second phase trial.
Therefore, whether the advantages of the protein degradation targeting chimera can be utilized or not is considered, the NAMPT inhibitor MS7 derivative is used as a parent compound, the protein degradation targeting chimera targeting NAMPT is designed and synthesized, the NAMPT level in the cells is directly regulated and controlled, the NAD level in the cells is reduced, and the cells are exhausted and died. We also considered whether it could reduce NAMPT secretion by lowering intracellular NAMPT levels, down-regulate extracellular NAMPT protein levels, and thereby inhibit tumor growth, invasion and metastasis.
No report is found about the NAMPT protein degradation targeting chimera of the invention at present.
Disclosure of Invention
The first purpose of the invention is to provide a NAMPT protein degradation targeting chimera aiming at the defects of the prior art.
The second purpose of the invention is to provide the preparation method of the NAMPT protein degradation targeting chimera, aiming at the defects of the prior art.
A third object of the present invention is to address the deficiencies of the prior art by providing the use of NAMPT protein degradation targeting chimeras as described above.
A fourth object of the present invention is to provide a pharmaceutical composition for overcoming the disadvantages of the prior art.
In order to achieve the first purpose, the invention adopts the technical scheme that:
a NAMPT protein degradation targeting chimera is a compound shown in general formula (i) and/or (ii) or a pharmaceutically acceptable salt thereof,
Figure BDA0002437243950000021
wherein X is selected from any one of the following groups,
Figure BDA0002437243950000031
y is selected from nitrogen atom, oxygen atom, piperazinyl, piperidinyl, heterocyclic group or any linking group thereof, wherein n is 0-3,
Figure BDA0002437243950000041
z is selected from saturated or unsaturated straight-chain alkyl with 1-14 carbon atoms, oxa-chain, phenyl, heterocyclic group or any chaining group, wherein n is 0-3, and the heterocyclic group is piperazinyl, pyrrolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;
Figure BDA0002437243950000051
r is selected from any of the following forms:
Figure BDA0002437243950000052
preferably, the compound is:
1) (2S,4R) -1- ((S) -3, 3-dimethyl-2- (4- (4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) butyrylamino) butyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
2) (2S,4R) -1- ((S) -3, 3-dimethyl-2- (5- (4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl ] sulfonyl) piperazin-1-yl) methyl) benzamido) pentanamide) butyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
3) (2S,4R) -1- ((S) -3, 3-dimethyl-2- (6- (4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) hexa-amino) butyryl) -4-hydroxy-N- ((S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
4) (2S,4R) -1- ((S) -3, 3-dimethyl-2- (7- (4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) heptanamido) butyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
5) (2S,4R) -1- ((S) -3, 3-dimethyl-2- (8- (4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) meta-amino) butyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
6) (2S,4R) -1- ((S) -3, 3-dimethyl-2- (4- (3- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) butanamide) butyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
7) (2S,4R) -1- ((S) -3, 3-dimethyl-2- (5- (3- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl ] sulfonyl) piperazin-1-yl) methyl) benzamido) pentanamide) butyryl) -4-hydroxy-N- ((S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
8) (2S,4R) -1- ((S) -3, 3-dimethyl-2- (6- (3- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) hexa-amino) butyryl) -4-hydroxy-N- ((S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl ] pyrrolidine-2-carboxamide;
9) (2S,4R) -1- ((S) -3, 3-dimethyl-2- (7- (3- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) heptamido) butyryl) -4-hydroxy-N- ((S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
10) (2S,4R) -1- ((S) -3, 3-dimethyl-2- (8- (3- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) meta-amino) butyryl) -4-hydroxy-N- ((S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
11) (2R,4S) -1- ((R) -3, 3-dimethyl-2- (4- (2- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) butanamide) butyryl) -4-hydroxy-N- ((R) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
12) (2S,4R) -1- ((S) -3, 3-dimethyl-2- (5- (2- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) pentanamide) butyryl) -4-hydroxy-N- ((S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
13) (2S,4R) -1- ((S) -3, 3-dimethyl-2- (6- (2- (2- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) phenyl) acetamido) amino) butyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
14) (2S,4R) -1- ((S) -3, 3-dimethyl-2- (7- (2- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) heptanamido) butyryl) -4-hydroxy-N- ((S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
15) (2S,4R) -1- ((S) -3, 3-dimethyl-2- (8- (2- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) meta-amino) butyryl) -4-hydroxy-N- ((S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
16) (2S,4R) -1- ((S) -15- (tert-butyl) -1, 13-dioxo-1- -1- (4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl ] sulfonyl) piperazin-1-yl) methyl) phenyl) -5,8, 11-trioxazole-2, 14-diazahexane-16-acyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
17) (2S,4R) -1- ((S) -18- (tert-butyl) -1, 16-dioxo-1- (4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) phenyl-5, 8,11, 14-tetraoxa-2, 17-diazaododecane-19-acyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
18) (2R,3S,4R,5S) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -4-cyano-N- (2-methoxy-4- ((2- (2- (4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) ethoxy) ethyl) carbamoyl) phenyl) -5-neopentylpyrrolidine-2-carboxamide;
19) (2R,3S,4R,5S) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -4-cyano-N- (2-methoxy-4- ((1-oxo-1- (4- (((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) phenyl) -6,9, 12-triox-2-azapentadecan (15-yl) carbamoyl) phenyl) -5-neotripyrrolidine-2-carboxamide;
20) n- (2- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) oxy) acetamide) ethoxy) ethyl) -4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfo) piperazin-1-yl) methyl) benzamide;
21) n- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) oxy) -2-oxy-7, 10, 13-trioxa-3-azahexadecan-16-yl) -4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamide;
22) (2S,4R) -1- ((S) -15- (tert-butyl) -1, 13-dioxo-1- -1- (4- (4- ((E) -3- (pyridine-3-acyl) acrylamido) butyl) piperidine-1-carbonyl) phenyl) -5,8, 11-trioxazole-2, 14-diazahexane-16-acyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide; (ii) a
23) (2S,4R) -1- ((S) -15- (tert-butyl) -1, 13-dioxo-1- -1- (4- (4- ((E) -3- (pyridine-3-acyl) acrylamido) butyl) piperidine-1-carbonyl) phenyl) -5,8, 11-trioxazole-2, 14-diazahexane-16-acyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
24) (2R,4S) -1- ((R) -2- (tert-butyl) -4-carbonyl-14- (5- (4- (4- ((E) -3- (pyridin-3-yl) acrylamido) butyl) piperidine-1-carbonyl) phenyl) -1H-1,2, 3-triazol-1-yl) -6,9, 12-trioxazole-3-azabicyclodecanoyl) -4-hydroxy-N- ((R) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
25) (2R,4S) -1- ((R) -2- (tert-butyl) -4-carbonyl-18- (5- (4- (4- ((E) -3- (pyridin-3-yl) acrylamido) butyl) piperidine-1-carbonyl) phenyl) -1H-1,2, 3-triazol-1-yl) -6,9,13, 16-tetraoxa-3-azaoctadecanoyl) -4-hydroxy-N- ((R) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.
Preferably, said pharmaceutically acceptable salts comprise the acid addition salts of the compounds of general formula (i) and/or (ii) with the following acids: hydrochloric, hydrobromic, sulphuric, lactic, citric, phosphoric, methanesulphonic, benzenesulphonic, p-toluenesulphonic, naphthalenesulphonic, tartaric, pyruvic, acetic, maleic or succinic acid, fumaric, salicylic, phenylacetic, mandelic acid.
In order to achieve the second object, the invention adopts the technical scheme that:
a process for the preparation of a compound of formula (i) as described above, comprising the steps of:
a. compounds I and Y in CH2Cl2Adding TEA to react at room temperature to obtain a compound II;
b. compound II in CH2Cl2Reacting under the catalysis of hydrogen, palladium and carbon to obtain a compound III;
c. compound III and X are dissolved in CH2Cl2Reacting at room temperature to obtain a compound IV;
d. dissolving the compound IV, Z, HATU and DIPEA in DMF, and reacting at room temperature to obtain a compound V;
e. dissolving the compound V, Z, HATU and DIPEA in DMF, and reacting at room temperature to obtain a compound VI;
a compound I:
Figure BDA0002437243950000081
compound II:
Figure BDA0002437243950000082
compound III:
Figure BDA0002437243950000091
compound IV:
Figure BDA0002437243950000092
compound V:
Figure BDA0002437243950000093
compound VI:
Figure BDA0002437243950000094
wherein HATU is 2- (7-benzotriazole oxide) -N, NN ', N' -tetramethyluronium hexafluorophosphate, DIPEA N, N-diisopropylethylamine, CH2Cl2Dichloromethane, DMF, and TEA are triethylamine; compound R, I, X, Y, Z is commercially available.
A process for the preparation of a compound of formula (ii) as described above, comprising the steps of:
a. dissolving compounds VII and X, HATU and DIPEA in CH2Cl2Neutralizing or dissolving CDI or TCDI in dichloromethane, and reacting at room temperature to obtain VIII;
b. dissolving VIII in CH2Cl2Adding TFA to react at room temperature to obtain a compound IX;
c. dissolving the compound IX, Y, HATU and DIPEA in DMF, and reacting at room temperature to obtain a compound X;
d. dissolving the compound, X, HATU and DIPEA in DMF, and reacting at room temperature to obtain a compound XI;
e. dissolving a compound XI, R, HATU and DIPEA in DMF, and reacting at room temperature to obtain a compound XII;
compound VII:
Figure BDA0002437243950000095
compound VIII:
Figure BDA0002437243950000101
compound IX:
Figure BDA0002437243950000102
compound X:
Figure BDA0002437243950000103
compound XII
Figure BDA0002437243950000104
Compound XI:
Figure BDA0002437243950000105
wherein HATU is 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate, DIPEA is N, N-diisopropylethylamine, and CH2Cl2For dichloromethane, DMF for dimethylformamide, TFA for trifluoroacetic acid, compounds R, VI, X, Y, Z are commercially available.
In order to achieve the third object, the invention adopts the technical scheme that:
use of a compound of formula (i) and/or (ii) as described in any of the above, or a pharmaceutically acceptable salt thereof, in the preparation of a NAMPT protein inhibitor and a degradation agent.
Use of a compound of formula (i) and/or (ii) as described above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a NAMPT mediated tumour.
Preferably, the NAMPT-mediated tumor comprises lung cancer, liver cancer, kidney cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, skin cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer, myelodysplastic syndromes, lymphomas, esophageal cancer, gastrointestinal cancer, osteosarcoma, tumors of the central or peripheral nervous system.
Use of a compound of formula (i) and/or (ii) as described above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for activating the immune system.
In order to achieve the fourth object, the invention adopts the technical scheme that:
a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and a compound of formula (i) and/or (ii) as described above, or a pharmaceutically acceptable salt thereof.
The invention has the advantages that:
1. the experimental results show that: the compound of the invention shows good NAMPT enzyme inhibition activity, realizes the inhibition of tumor by inhibiting NAMPT protein, has certain broad-spectrum anti-tumor activity, can obviously delay the growth of tumor, and can be applied to NAMPT mediated tumor diseases; can down-regulate the level of extracellular NAMPT protein, activate the immune system, and has dual effects of chemotherapy and immunotherapy.
2. The compound of the invention is used as a NAMPT protein degradation targeting chimera reported for the first time, and has further development and research values.
3. The preparation method is simple and convenient, good in repeatability and high in yield.
Drawings
Figure 1 is the effect of proteolytic degradation targeting chimeric molecules on intracellular NAMPT protein expression.
Figure 2 is the effect of proteolytic degradation targeting chimeric molecules on extracellular NAMPT protein expression.
FIG. 3 shows the inhibitory effect of proteolytic degradation targeting chimeric molecules and positive drugs MS7 and FK866 on nude mouse CT26 transplantable tumor model.
FIG. 4 is a graph showing the inhibitory effect of proteolytic degradation targeting chimeric molecules and positive drugs MS7 and FK866 on the BalB/C CT26 transplantable tumor model.
Detailed Description
The invention will be further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Furthermore, it should be understood that various changes and modifications can be made by those skilled in the art after reading the disclosure of the present invention, and equivalents fall within the scope of the appended claims.
In the present invention, the reagents and raw materials used in the following examples are commercially available. Chemical raw materials are purchased from companies such as Bide, Tatan, Henss, etc.; the cells and biological materials are obtained from the companies such as leaf organisms and ceramic organisms.
Process for the preparation of the compounds referred to in the examples1H NMR，13The C NMR and MS data are detailed in Table 1. The numbers 1-25 in Table 1 are compound numbers, corresponding not only to the numbers in Table 1, but also to example 1-25 to prepare the specific compound.
TABLE 1 preferred Compounds1H NMR，13C NMR and MS data
Figure BDA0002437243950000121
Figure BDA0002437243950000131
Figure BDA0002437243950000141
Figure BDA0002437243950000151
Figure BDA0002437243950000161
Figure BDA0002437243950000171
Figure BDA0002437243950000181
Figure BDA0002437243950000191
Figure BDA0002437243950000201
Figure BDA0002437243950000211
Figure BDA0002437243950000221
Figure BDA0002437243950000231
Figure BDA0002437243950000241
Figure BDA0002437243950000251
Figure BDA0002437243950000261
Figure BDA0002437243950000271
Figure BDA0002437243950000281
Figure BDA0002437243950000291
Figure BDA0002437243950000301
Figure BDA0002437243950000311
Figure BDA0002437243950000321
Figure BDA0002437243950000331
Figure BDA0002437243950000341
Figure BDA0002437243950000351
Figure BDA0002437243950000361
EXAMPLE 1 Synthesis of Compound 1
The preparation method comprises the following steps:
synthesis of tert-butyl 4- ((4-nitrophenyl) sulfonyl) piperazine-1-carboxylate:
p-nitrobenzenesulfonyl chloride (2.21g, 10.0mmol), 1-Boc-piperazine (2.79g, 15.0mmol) were dissolved in CH2Cl2(10m L), TEA (2m L) was added dropwise to the solution, and the mixture was stirred at room temperature for 1.5 hours, the reaction mixture was thoroughly mixed with 2N hydrochloric acid solution 50m L, the organic phase was collected after separation, and the solvent was evaporated to dryness to obtain a white solid (3.51 g) with a yield of 95%.1H NMR(600MHz,DMSO-d6):7.78(d,J＝20.78Hz,1H),7.67(d,J＝20.78Hz,1H),3.40-3.37(m,4H),2.89-2.85(m,4H),1.34(s,9H).
Step b.Synthesis of tert-butyl 4- ((4-aminophenyl) sulfonyl) piperazine-1-carboxylate:
the compound tert-butyl 4- ((4-nitrophenyl) sulfonyl) piperazine-1-carboxylate (3.51g, 9.46mmol) was dissolved in dry CH2Cl2(30m L) was stirred overnight at room temperature under the action of palladium on carbon hydrogen at room temperature, and then filtered through celite, and the filtrate was concentrated to give 3.16g of a white solid in 98% yield.1H NMR(600MHz,DMSO-d6):7.32(d,J＝8.50,2H),6.63(d,J＝8.50,2H),6.12(s,1H),3.36(t,J＝4.64,4H),2.71(t,J＝5.02,4H).
Step c.Synthesis of tert-butyl 4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazine-1-carboxylate:
the compound tert-butyl 4- ((4-aminophenyl) sulfonyl) piperazine-1-carboxylate (3.15g, 9.24mmol) and thiocarbonyldiimidazole (2.47g, 13.8mmol) were dissolved in dry CH2Cl2(15m L), the reaction was carried out at room temperature for 2 hours, and then 3-aminomethylpyridine (1.00g, 9.24mmol) was added thereto and the reaction was carried out at room temperature for 2 hours, whereupon a large amount of white solid was aspirated, followed by suction filtration to obtain 4.17g of a white solid in 92% yield.1H-NMR(600MHz,DMSO-d6):8.56-8.55(m,1H),8.43(dd,J＝1.52,J＝1.91,1H),7.89-7.86(m,1H),7.74-7.69(m,4H),7.42-7.39(m,1H),4.88(s,2H)，3.48(s,4H)，2.94(t，J＝5.03,4H),1.39(s,9H).
Step d.Synthesis of 1- (4- (piperazin-1-ylsulfonyl) phenyl) -3- (pyridin-3-ylmethyl) thiourea:
compound 4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazine-1-carboxylic acid tert-butyl ester (4.00g, 8.14mmol) was dissolved in dry CH2Cl2(10m L), TFA (2m L) was added thereto, the mixture was reacted at room temperature overnight, the reaction mixture was mixed with saturated brine (20m L), and the organic phase was concentrated to give 2.95g of a white solid with a yield of 93%. 1H-NMR (600MHz, DMSO-d)6):10.13(s,1H),8.61(s,1H),8.58-8.56(m,1H),8.49-8.46(m,1H),7.82(d,J＝8.80,2H),7.77-7.74(m,1H),7.66(d,J＝8.74,2H),7.49(d,J＝8.27,2H),7.39-7.34(m,3H),4.79(d,J＝5.30,2H),4.30(s,1H),3.77-3.34(m,4H),3.03-2.86(m,4H).
Step e.4 synthesis of- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzoic acid:
the compound 1- (4- (piperazin-1-ylsulfonyl) phenyl) -3- (pyridin-3-ylmethyl) thiourea (2.90g, 7.42mmol) and methyl 4-bromomethylbenzoate (2.03g, 8.90mmol) were dissolved in dry CH2Cl2(10m L), TEA (2m L) was added and the mixture was reacted at room temperature for 2 hours, stirred at room temperature for 3 hours, and then purified by silica gel column chromatography (eluent, dichloromethane/methanol ═ 100/1) to obtain 3.20g of a white solid, and the obtained compound was dissolved in THF/MeOH/H2To O (V/V: 3/2/1,50m L) L iOH (586mg, 24.4mmol) was added and reacted at room temperature for 2 hours, after the organic phase was evaporated, pH was adjusted to about 3 with 1N hydrochloric acid solution, and a large amount of white solid was precipitated and filtered off, whereby 3.00g of white solid was obtained with a yield of 96%.1H NMR(600MHz,DMSO-d6):12.91(s,1H),10.13(s,1H),8.64(s,1H),8.55-8.59(m,1H),8.47(dd,J＝1.04,4.58Hz,1H),7.80-7.83(m,2H),7.78-7,83(m,2H),7.76-7.78(m,1H),7.65(d,J＝7.64Hz,2H),7.48(d,J＝7.61Hz,1H),7.41(t,J＝7.92,15.43Hz,1H),7.38(dd,J＝4.69,7.81Hz,1H),4.79(d,J＝5.42Hz,2H),3.54(s,2H),2.89(s,4H),2.45(s,4H).
Step f.4 synthesis of- (4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamide) butyric acid:
the compound 4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzoic acid (300mg, 0.57mmol), methyl butyrate (58mg, 0.57mmol), HATU (325mg, 0.86mmol), DIPEA (110mg, 0.86mmol) were dissolved in dry DMF (10m L), stirred at room temperature for 2H, the reaction was poured into saturated sodium chloride solution 100m L, extracted with ethyl acetate (20m L× 3), the organic phases were combined and washed with saturated brine 20m L to remove residual DMF, dried over anhydrous sodium sulfate and concentrated, purified by silica gel column chromatography (eluent dichloromethane/methanol ═ 100/1) to give 310mg of white solid, which was dissolved in THF/MeOH/H to give 310mg of product2To O (V/V: 3/2/1,50m L), L iOH (58mg, 2.40mmol) was added and reacted at room temperature for 2 hours, after the organic phase was evaporated, pH was adjusted to about 3 with 1N hydrochloric acid solution, and a large amount of white solid was precipitated and filtered off with suction to obtain 250mg of white solid, yield 86%.1H NMR(600MHz,DMSO-d6):10.75(s,1H),9.27(s,1H),8.56(d，J＝1.56Hz，1H)，8.49(t，J＝5.72，11.00Hz，1H)，8.46(dd,J＝1.10，4.62Hz,1H)，7.84(d，J＝8.58Hz,2H),7.76(d，J＝7.99Hz，1H),7.71(d,J＝8.71Hz，2H),7.25-7.39(m，5H),4.78(d,J＝4.36Hz，2H)，3.54(s，2H),3.30(q,J＝6.53Hz，2H)，2.84(s，4H),2.39(s，4H),2.16(t，J＝7.26Hz，2H)，1.56-1.63(m，2H).
Step g. (2S,4R) -synthesis of 1- ((S) -3, 3-dimethyl-2- (4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamide) butanamide) butyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide:
compound 4- (4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamide) butyric acid (300mg, 0.49mmol), and compound (2S,4R) -1- ((S) -2-amino-3, 3-dimethylbutanol) -4-hydroxy-N- ((S) -1- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (217mg, 0.49mmol), HATU (279mg, 0.74mmol), DIPEA (95mg, 0.74mmol) were dissolved in dry DMF (10m L), stirred at room temperature for 2h, the reaction was poured into saturated sodium chloride solution 100m L, extracted with ethyl acetate (20m L× 3), the organic phases were combined and the remaining DMF was washed with saturated brine 20m L, dried over anhydrous sodium sulfate, concentrated, purified by silica gel column chromatography (eluent 100/4, dichloromethane/methanol ═ 110mg, yield 22%.
EXAMPLES 2-17 Synthesis of Compounds 2-17
The operation and the charge were the same as in example 1.
EXAMPLE 18 Synthesis of Compound 18
The preparation method comprises the following steps:
step a synthesis of (E) -N- (4- (piperidin-4-yl) butyl) -3- (3-pyridyl) acrylamide:
the compound tert-butyl 4- (4-aminobutyl) piperidine-1-carboxylate (2.56g, 10.0mmol) was reacted with (E) -3- (3-pyridine) acrylic acid (1.49g, 10.0mmol), HATU (5.70g, 15.0mmol), DIPEA (1.90g, 15.0mmol) in dry DMF (20m L) at room temperature for 2h, the reaction was poured into saturated sodium chloride solution 200m L, extracted with ethyl acetate (30m L× 3), the organic phases were combined and washed with saturated brine 30m L to remove residual DMF, dried over anhydrous sodium sulfate and concentrated, purified by silica gel column chromatography (eluent dichloromethane/methanol ═ 100/4) to give 3.10g of white solid, which was dissolved in dry CH2Cl2To (30m L) was added TFA (6m L), and the mixture was reacted at room temperature overnight, followed by mixing the reaction mixture with saturated brine (20m L), followed by separation of layers and concentration of the organic phase to obtain 2.00g of a white solid with a yield of 90%.1H NMR(CD3OD，600MHz):8.84，(s,1H),8.63(s，1H)，7.90(s，1H)，7.75(s，1H)，7.66(d,J＝1.4Hz,1H),7.55(s，1H)，7.03(d，J＝1.4Hz,1H)，3.49-3.59(m，4H),2.69-2.8(m,2H),1.72-1.81(m,2H),1.52(t,J＝1.4Hz,2H)，1.50(s，2H)，1.49(q，J＝2.4Hz，2H),1.19(t,J＝1.6Hz,2H).
Step b. (E) -4- (4- (4- (3- (3-pyridyl) acrylamide) butyl) piperidine-1-carbonyl) benzoic acid
Compound (E) -N- (4- (piperidin-4-yl) butyl) -3- (3-pyridyl) acrylamide (1.00g, 3.48mmol), terephthalic acid (578mg, 3.48mmol), HATU (1.98g, 5.22mmol), DIPEA (673mg, 5.22mmol) were dissolved in dry DMF (10m L) and reacted at room temperature for 2h,the reaction mixture was poured into a saturated sodium chloride solution (200 m L), extracted with ethyl acetate (20m L× 3), the organic phases were combined and washed with saturated brine (30m L) to remove residual DMF, dried over anhydrous sodium sulfate and concentrated, and purified by silica gel column chromatography (eluent, dichloromethane/methanol 100/6) to give 1.21g of a white solid with a yield of 80%.1H NMR(DMSO-d6,300MHz):12.71(s,1H),8.84(s,1H),8.64(s，1H),8.63(s,1H),8.13(dd,J＝7.3,1.2Hz,4H),7.98(s,1H),7.66(d,J＝5.3Hz,1H),7.55(s,1H),7.03(d,J＝5.3Hz,1H),3.29-3.49(m,4H),3.30(t,J＝1.4Hz,2H),1.68-1.88(m,4H),1.29-1.54(m,7H).
Step c synthesis of (E) -1-oxo-1- (4- (4- (4- (3- (pyridin-3-yl) acrylamide) butyl) piperidine-1-carbonyl) phenyl) -5,8, 11-triazine-2-azatridecane-13-carboxylic acid:
the compounds tert-butyl 2- (2- (2-aminoethoxy) ethoxy) acetate (263mg, 1.00mmol) and (E) -4- (4- (4- (3- (3-pyridyl) acrylamide) butyl) piperidine-1-carbonyl) benzoic acid (435mg, 1.00mmol), HATU (570mg, 1.50mmol), DIPEA (194mg, 1.50mmol) were dissolved in dry DMF (10m L), reacted at room temperature for 2h, the reaction solution was poured into saturated sodium chloride solution 200m L, extracted with ethyl acetate (20m L× 3), the organic phases were combined and the residual DMF was washed with saturated brine 30m L, dried over anhydrous sodium sulfate and concentrated, purified by silica gel column chromatography (eluent dichloromethane/methanol ═ 100/2) to give 380mg of a white solid, which was dissolved in dry CH2Cl2To (10m L) was added TFA (2m L), the reaction mixture was reacted at room temperature overnight, and the reaction mixture was concentrated to give a white solid, which was directly used in the next step with a yield of 100%.1H NMR(CD3OD,600MHz):12.80(s，1H)，8.84(s,1H),8.66(s,1H),8.63(s,1H),8.40(s,1H),8.16(s,4H),7.88-7.98(m,1H),7.66(d,J＝5.3Hz,1H)，7.55(s,1H),7.03(d,J＝5.3Hz,1H),3.40-3.49(m,4H),3.10-3.26(m,16H),2.50-2.89(m，8H)，1.65-1.75(m,4H).
Step d synthesis of (2S,4R) -1- ((S) -15- (tert-butyl) -1, 13-dioxo-1- (4- (4- ((E) -3- (pyridin-3-yl) acrylamide) butyl) piperidine-1-carbonyl) phenyl) -5,8, 11-trioxa-2, 14-diazacyclohexadecan-16-acyl) -4-hydroxy-N- ((S) -1- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide:
compound (E) -1-oxo-1- (4- (4- (4- (3- (pyridin-3-yl) acrylamide) butyl) piperidine-1-carbonyl) phenyl) -5,8, 11-triazine-2-azatridecane-13-carboxylic acid (150mg,0.24mmol), (2S,4R) -1- ((S) -2-amino-3, 3-dimethylbutanol) -4-hydroxy-N- ((S) -1- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (107mg, 0.24mmol), HATU (136mg, 0.36mmol), DIPEA (46mg, 0.36mmol) were dissolved in dry DMF (6m L), reacted at room temperature for 2h, the reaction solution was poured into saturated sodium chloride solution 50m L, extracted with ethyl acetate (15m 32), the organic phases were combined and washed with saturated brine to remove residual DMF from sodium sulfate, dried without water, concentrated by chromatography, purified by silica gel column chromatography (53936 mg/90 mg) to obtain a white solid.
EXAMPLE 19 Synthesis of Compound 19
The operation and the charge were the same as in example 18.
EXAMPLE 20 Synthesis of Compound 20
The preparation method comprises the following steps:
step a Synthesis of (E) -N- (4- (1- (4-ethynylbenzoyl) piperidin-4-yl) butyl) -3- (pyridin-3-yl) acrylamide
The compound (E) -N- (4- (piperidin-4-yl) butyl) -3- (3-pyridyl) acrylamide (1.00g, 3.48mmol), p-4-ethynylbenzoic acid (508mg, 3.48mmol), HATU (1.98g, 5.22mmol), DIPEA (673mg, 5.22mmol) were dissolved in dry DMF (10m L) and reacted at room temperature for 2h, the reaction solution was poured into saturated sodium chloride solution 200m L, extracted with ethyl acetate (20m L× 3), the organic phases were combined and washed with saturated brine 30m L to remove residual DMF, dried over anhydrous sodium sulfate and concentrated, and purified by silica gel column chromatography (eluent, dichloromethane/methanol ═ 100/6) to give 920mg of white solid yield, 64%.1H NMR(CD3OD,600MHz):12.71(s,1H),8.84(s,1H),8.64(s,1H),8.63(s，1H),8.13(dd,J＝7.3,1.2Hz,4H),7.98(s,1H),7.66(d,J＝5.3Hz，1H)，7.55(s,1H),7.03(d,J＝5.3Hz,1H),3.29-3.49(m,4H),3.30(t,J＝1.4Hz,2H),3.04(s,1H),1.68-1.88(m,4H),1.29-1.54(m,7H).
Step b Synthesis of (E) -tert-butyl 2- (2- (2- (5- (4- (4- (4- (3- (pyridin-3-yl) acrylamido) butyl) piperidine-1-carbonyl) phenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) acetate
Compound (E) -N- (4- (1- (4-ethynylbenzoyl) piperidin-4-yl) butyl) -3- (pyridin-3-yl) acrylamide (400mg, 0.96mmol), sodium ascorbate (19mg, 0.096mmol), tert-butyl 2- (2- (2-azidoethoxy) ethoxy) ethoxyacetate (277mg, 0.96mmol), and copper sulfate (15mg, 0.096mmol) were dissolved in tert-butanol/water (V/V ═ 1/1,20m L) and reacted overnight at room temperature, whereupon a white solid precipitated and was filtered off with suction to obtain 480mg of a white solid with a yield of 36%.1HNMR(CD3OD,600MHz):12.80(s,1H),8.84(s,1H),8.66(s,1H),8.63(s,1H),8.40(s,1H),8.16(s,4H),8.02(s,1H),7.88-7.98(m,1H),7.66(d,J＝5.3Hz,1H),7.55(s,1H),7.03(d,J＝5.3Hz,1H),3.40-3.49(m,4H),3.09-3.28(m,14H),2.50-2.89(m,8H),1.65-1.75(m,4H)，1.42(s,9H).
The rest of the operation was the same as the charging of example 18.
EXAMPLE 21 Synthesis of Compound 21
The operation and the charge were the same as in example 20.
Example 22 testing of the Compounds of the invention for NAMPT inhibitory Activity
First, experiment method
Step a: sample testing liquid preparation: 50mM Tris HCl (pH 7.5), 12.5mM MgCl20.4mM PRPP (phosphoribosyl pyrophosphate), 2mMATP, 30. mu.g/m L ethanol dehydrogenase, 10. mu.g/m L NMNAT (nicotinamide mononucleotide adenyl transferase), 1.5% ethanol, 2mM DTT (dithiothreitol), 0.02% BSA, 2. mu.g/m L NAMPT.
B, adding 0.5 mu L of compound and 20 mu L of sample test solution with different concentrations into a 96-well plate;
c, after incubation for 5min at room temperature, adding 0.2 mu M NAM solution 4.5 mu L;
step d: incubating at 37 deg.C for 15min, and heating at 95 deg.C for 1min to terminate reaction;
e, placing the reaction solution on ice for cooling, adding 20 percent acetophenone 10 mu L and 2M KOH solution 10 mu L, placing the mixture on the ice for 2min by vortex, adding 88 percent formic acid 45 mu L, and incubating the mixture for 10min at 37 ℃;
step f: fluorescence values at an excitation wavelength of 382nm and an emission wavelength of 445nm were measured using a microplate reader.
Step g: according to the formula: a ═ R/(1+ (C/IC50) S) + B (where a is the enzyme activity and C is the compound concentration, R, IC50S, B for parameters to be fitted), the curve of enzyme activity versus compound concentration was fitted in origiN software to obtain the IC of the compound50。
Second, experimental results
IC of the Compounds of the invention50Values as shown in table 2, the test compounds showed moderate to excellent inhibitory activity.
TABLE 2 inhibitory Activity of the target Compounds on NAMPT (units nmol/L)
Figure BDA0002437243950000421
EXAMPLE 23 in vitro antitumor Activity assay (IC) of Compounds of the invention50)
First, experiment method
Step a inoculation 6 × 103Cells per well (100L) were plated in 96-well plates with 100L of PBS surrounding them;
step b: placing in a cell incubator at 37 deg.C and 5% CO2Culturing for 24h under the condition, removing the culture medium, and adding the FBS-free culture medium 100L;
c, continuously placing the mixture in a cell incubator for culturing for 24 hours, adding the compound to be tested 100L with different concentrations, and setting three-fold holes, placing the mixture in the cell incubator for culturing for 72 hours, removing the culture medium, and adding the culture medium 100L containing 10% CCK 8;
step d: after incubation at 37 ℃ for 40min, the samples were tested for OD at 452nm with a microplate reader.
Step e: IC calculation Using GraphPad simulation50。
Second, experimental results
Half inhibitory concentration IC of compound of the invention on tumor cells50The values are shown in table 3, and the test results show that most compounds exhibit moderate to excellent antitumor activity, with compounds 16, 17, 20-25 being the most active.
TABLE 3 half inhibitory concentration of target Compound cells on tumor cells IC50(Unit. mu. mol/L)
Figure BDA0002437243950000422
Figure BDA0002437243950000431
EXAMPLE 24 Effect of Compounds of the invention on intracellular and extracellular NAMPT protein content
First, experiment method
Step a-cells were treated with 5 × 105Planting the seeds in a 6-well plate (2m L), culturing for 24h, replacing the seeds with a serum-free culture medium, and starving for 24 h;
step b: adding the compound of the invention for incubation for 24 h;
step c: extracting intracellular and extracellular proteins;
step d: taking protein, carrying out electrophoresis (100V,2h), rotating the membrane for about 100min under the condition of 270mA, then sealing the membrane in 5% BSA solution at room temperature for 2h, incubating the primary antibody (1:1000) overnight at 4 ℃, washing the membrane for three times by TBST after recovery, incubating the secondary antibody for 1h at room temperature for 5min each time, washing the membrane for three times by TBST after recovery, incubating the membrane for 5min each time, scanning and developing the membrane by an olyssey two-color infrared laser imaging system, and taking GAPDH as an internal reference.
Third, experimental results
The compounds of the invention are capable of degrading intracellular NAMPT protein (figure 1); the compounds of the invention were able to reduce secretion of NAMPT protein outside the cell (fig. 2).
EXAMPLE 25 in vivo antitumor Activity assay of Compounds of the invention
First, experiment method
Step a, preparing cell suspension by PBS, and inoculating 3 × 105Cells (0.2m L) were added to the subcutaneous tissue of the right axilla of each mouse, and the tumor volume was 100mm3On the left and right sides, mice with over-large tumor volumes and over-small tumor volumes are eliminated and randomly grouped, and the average volume of each group is equivalent;
step b: intraperitoneal injection of physiological saline (blank group) and tested drugsThe tumor length (a), tumor length (b) and mouse body weight were recorded once a day every other day, and the tumor volume V ═ ab was calculated2/2；
Step c: when the tumor volume is increased to 2000mm3The experiment was terminated at the left and right, the mice were sacrificed, and the tumor mass was dissected out and weighed;
step d: tumor inhibition activity was calculated as tumor volume, and the tumor inhibition rate (%) (tumor volume on the last day of administration group for Vt administration group/Vt blank group (volume on the last day of blank group for Vt administration group); tumor inhibition (%) was mt dose/mt blank (mt dose was the tumor volume of the last day of the dose and mt blank was the volume of the last day of the blank), calculated by tumor weight, and statistical difference analysis was performed.
Second, experimental results
The tumor model FK866 group of the immunodeficient mouse has high toxicity, and the mice die completely in the experimental process, but the compound group of the invention does not die and the body weight is not obviously reduced, which proves that the toxicity is low. And the tumor inhibition effect of the compound is better than that of positive controls MS7 and FK 866. NAMPT inhibitors MS7 and FK866 showed comparable tumor suppression rates in the immunodeficient (fig. 3) and immunogenic mouse tumor models (fig. 4), demonstrating that NAMPT inhibitors are unable to activate the immune system. And the tumor inhibition rate in the immunogenic mouse tumor model is superior to that of the immunodeficiency mouse tumor model, so that the compound disclosed by the invention can activate an immune system.
The results of the above examples show that the compound of the invention shows good NAMPT enzyme inhibitory activity, realizes the inhibition of tumor by inhibiting NAMPT protein, has a certain broad-spectrum anti-tumor activity, can obviously delay the growth of tumor, and can be applied to NAMPT mediated tumor diseases; can reduce the level of extracellular NAMPT protein, activate the immune system, have the dual effects of chemotherapy and immunotherapy, and have further development and research values.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and additions can be made without departing from the principle of the present invention, and these should also be considered as the protection scope of the present invention.

Claims (10)

1. A NAMPT protein degradation targeting chimera is characterized in that the NAMPT protein degradation targeting chimera is a compound shown as a general formula (i) and/or (ii) or a pharmaceutically acceptable salt thereof,
Figure FDA0002437243940000011
wherein X is selected from any one of the following groups,
Figure FDA0002437243940000012
y is selected from nitrogen atom, oxygen atom, piperazinyl, piperidinyl, heterocyclic group or any linking group thereof, wherein n is 0-3,
Figure FDA0002437243940000021
z is selected from saturated or unsaturated straight-chain alkyl with 1-14 carbon atoms, oxa-chain, phenyl, heterocyclic group or any chaining group, wherein n is 0-3, and the heterocyclic group is piperazinyl, pyrrolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;
Figure FDA0002437243940000031
r is selected from any of the following forms:
Figure FDA0002437243940000032
2. the NAMPT protein degradation targeting chimera of claim 1, wherein the compound is:
(2S,4R) -1- ((S) -3, 3-dimethyl-2- (4- (4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) butyrylamino) butyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2S,4R) -1- ((S) -3, 3-dimethyl-2- (5- (4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl ] sulfonyl) piperazin-1-yl) methyl) benzamido) pentanamide) butyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2S,4R) -1- ((S) -3, 3-dimethyl-2- (6- (4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) hexa-amino) butyryl) -4-hydroxy-N- ((S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2S,4R) -1- ((S) -3, 3-dimethyl-2- (7- (4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) heptanamido) butyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2S,4R) -1- ((S) -3, 3-dimethyl-2- (8- (4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) meta-amino) butyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2S,4R) -1- ((S) -3, 3-dimethyl-2- (4- (3- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) butanamide) butyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2S,4R) -1- ((S) -3, 3-dimethyl-2- (5- (3- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl ] sulfonyl) piperazin-1-yl) methyl) benzamido) pentanamide) butyryl) -4-hydroxy-N- ((S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2S,4R) -1- ((S) -3, 3-dimethyl-2- (6- (3- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) hexa-amino) butyryl) -4-hydroxy-N- ((S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl ] pyrrolidine-2-carboxamide;
(2S,4R) -1- ((S) -3, 3-dimethyl-2- (7- (3- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) heptamido) butyryl) -4-hydroxy-N- ((S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2S,4R) -1- ((S) -3, 3-dimethyl-2- (8- (3- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) meta-amino) butyryl) -4-hydroxy-N- ((S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2R,4S) -1- ((R) -3, 3-dimethyl-2- (4- (2- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) butanamide) butyryl) -4-hydroxy-N- ((R) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2S,4R) -1- ((S) -3, 3-dimethyl-2- (5- (2- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) pentanamide) butyryl) -4-hydroxy-N- ((S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2S,4R) -1- ((S) -3, 3-dimethyl-2- (6- (2- (2- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) phenyl) acetamido) amino) butyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2S,4R) -1- ((S) -3, 3-dimethyl-2- (7- (2- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) heptanamido) butyryl) -4-hydroxy-N- ((S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2S,4R) -1- ((S) -3, 3-dimethyl-2- (8- (2- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) meta-amino) butyryl) -4-hydroxy-N- ((S) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2S,4R) -1- ((S) -15- (tert-butyl) -1, 13-dioxo-1- -1- (4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl ] sulfonyl) piperazin-1-yl) methyl) phenyl) -5,8, 11-trioxazole-2, 14-diazahexane-16-acyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2S,4R) -1- ((S) -18- (tert-butyl) -1, 16-dioxo-1- (4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) phenyl-5, 8,11, 14-tetraoxa-2, 17-diazaododecane-19-acyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2R,3S,4R,5S) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -4-cyano-N- (2-methoxy-4- ((2- (2- (4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamido) ethoxy) ethyl) carbamoyl) phenyl) -5-neopentylpyrrolidine-2-carboxamide;
(2R,3S,4R,5S) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -4-cyano-N- (2-methoxy-4- ((1-oxo-1- (4- (((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) phenyl) -6,9, 12-triox-2-azapentadecan (15-yl) carbamoyl) phenyl) -5-neotripyrrolidine-2-carboxamide;
n- (2- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) oxy) acetamide) ethoxy) ethyl) -4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfo) piperazin-1-yl) methyl) benzamide;
n- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) oxy) -2-oxy-7, 10, 13-trioxa-3-azahexadecan-16-yl) -4- ((4- ((4- (3- (pyridin-3-ylmethyl) thioureido) phenyl) sulfonyl) piperazin-1-yl) methyl) benzamide;
(2S,4R) -1- ((S) -15- (tert-butyl) -1, 13-dioxo-1- -1- (4- (4- ((E) -3- (pyridine-3-acyl) acrylamido) butyl) piperidine-1-carbonyl) phenyl) -5,8, 11-trioxazole-2, 14-diazahexane-16-acyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide; (ii) a
(2S,4R) -1- ((S) -15- (tert-butyl) -1, 13-dioxo-1- -1- (4- (4- ((E) -3- (pyridine-3-acyl) acrylamido) butyl) piperidine-1-carbonyl) phenyl) -5,8, 11-trioxazole-2, 14-diazahexane-16-acyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2R,4S) -1- ((R) -2- (tert-butyl) -4-carbonyl-14- (5- (4- (4- ((E) -3- (pyridin-3-yl) acrylamido) butyl) piperidine-1-carbonyl) phenyl) -1H-1,2, 3-triazol-1-yl) -6,9, 12-trioxazole-3-azabicyclodecanoyl) -4-hydroxy-N- ((R) -1- (4- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide;
(2R,4S) -1- ((R) -2- (tert-butyl) -4-carbonyl-18- (5- (4- (4- ((E) -3- (pyridin-3-yl) acrylamido) butyl) piperidine-1-carbonyl) phenyl) -1H-1,2, 3-triazol-1-yl) -6,9,13, 16-tetraoxa-3-azaoctadecanoyl) -4-hydroxy-N- ((R) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.
3. The NAMPT protein degradation targeting chimera of claim 1, wherein the pharmaceutically acceptable salt comprises an acid addition salt of a compound of general formula (i) and/or (ii) with: hydrochloric, hydrobromic, sulphuric, lactic, citric, phosphoric, methanesulphonic, benzenesulphonic, p-toluenesulphonic, naphthalenesulphonic, tartaric, pyruvic, acetic, maleic or succinic acid, fumaric, salicylic, phenylacetic, mandelic acid.
4. A process for the preparation of a compound of formula (i) according to claim 1, characterized in that it is as follows:
a. compounds I and Y in CH2Cl2Adding TEA to react at room temperature to obtain a compound II;
b. compound II in CH2Cl2Reacting under the catalysis of hydrogen, palladium and carbon to obtain a compound III;
c. compound III and X are dissolved in CH2Cl2Reacting at room temperature to obtain a compound IV;
d. dissolving the compound IV, Z, HATU and DIPEA in DMF, and reacting at room temperature to obtain a compound V;
e. dissolving the compound V, Z, HATU and DIPEA in DMF, and reacting at room temperature to obtain a compound VI;
a compound I:
Figure FDA0002437243940000061
compound II:
Figure FDA0002437243940000062
compound III:
Figure FDA0002437243940000071
compound IV:
Figure FDA0002437243940000072
compound V:
Figure FDA0002437243940000073
compound VI:
Figure FDA0002437243940000074
wherein HATU is 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate, DIPEA is N, N-diisopropylethylamine, and CH2Cl2Dichloromethane, DMF and TEA are used, respectively.
5. A process for the preparation of a compound of formula (ii) according to claim 1, characterized in that it is prepared as follows:
a. dissolving compounds VII and X, HATU and DIPEA in CH2Cl2Neutralizing or dissolving CDI or TCDI in dichloromethane,reacting at room temperature to obtain VIII;
b. dissolving VIII in CH2Cl2Adding TFA to react at room temperature to obtain a compound IX;
c. dissolving the compound IX, Y, HATU and DIPEA in DMF, and reacting at room temperature to obtain a compound X;
d. dissolving the compound, X, HATU and DIPEA in DMF, and reacting at room temperature to obtain a compound XI;
e. dissolving a compound XI, R, HATU and DIPEA in DMF, and reacting at room temperature to obtain a compound XII;
compound VII:
Figure FDA0002437243940000075
compound VIII:
Figure FDA0002437243940000076
compound IX:
Figure FDA0002437243940000081
compound X:
Figure FDA0002437243940000082
compound XII:
Figure FDA0002437243940000083
compound XI:
Figure FDA0002437243940000084
wherein HATU is 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate, DIPEA is N, N-diisopropylethylamine, and CH2Cl2Dichloromethane, DMF, dimethylformamide, TFA, trifluoroacetic acid.
6. Use of a compound of formula (i) and/or (ii) as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the preparation of a NAMPT protein inhibitor and a degradation agent.
7. Use of a compound of formula (i) and/or (ii) as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of NAMPT mediated tumours.
8. The use of claim 7, wherein the NAMPT mediated neoplasm comprises lung cancer, liver cancer, kidney cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, skin cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer, myelodysplastic syndromes, lymphoma, esophageal cancer, gastrointestinal cancer, osteosarcoma, neoplasms of the central or peripheral nervous system.
9. Use of a compound of formula (i) and/or (ii) as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for activating the immune system.
10. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and a compound of formula (i) and/or (ii) as claimed in any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof.
CN202010255728.4A 2020-04-02 2020-04-02 NAMPT protein degradation targeting chimera and preparation method and application thereof Pending CN111454327A (en)

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