CN115433167B - Benzo-heterocyclic compound with Snail inhibitory activity, preparation method thereof, pharmaceutical composition and medical application - Google Patents

Benzo-heterocyclic compound with Snail inhibitory activity, preparation method thereof, pharmaceutical composition and medical application Download PDF

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CN115433167B
CN115433167B CN202211407379.9A CN202211407379A CN115433167B CN 115433167 B CN115433167 B CN 115433167B CN 202211407379 A CN202211407379 A CN 202211407379A CN 115433167 B CN115433167 B CN 115433167B
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methyl
benzo
thio
methoxypropoxy
methylpyridin
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CN115433167A (en
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刘洁
傅蓉
钟文艺
徐进宜
吴照球
曾召兰
臧晨孜
邓力
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China Pharmaceutical University
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Abstract

The invention discloses benzo-heterocyclic compounds with Snail inhibition activity and derivatives thereof or stereoisomers, solvates, prodrugs, metabolites, deuterons, pharmaceutically acceptable salts or co-crystals thereof, and a preparation method, a pharmaceutical composition and application thereof, wherein the application is to prepare medicines for treating and/or preventing diseases related to Snail inhibition or Snail inhibitors. The inhibitor, the derivative thereof and the pharmaceutical composition have strong affinity with Snail protein, have good affinity with the Snail protein at micromolar concentration level, can effectively inhibit the activity of the Snail, have good inhibition effect on cells, and have the highest cell inhibition rate of more than 99% when the administration concentration is 5 mu M; and the prepared medicine has wide action target and can be used for treating and/or preventing various diseases related to inhibition of Snail activity.

Description

Benzo-heterocyclic compound with Snail inhibitory activity, preparation method thereof, pharmaceutical composition and medical application
Technical Field
The invention relates to the technical field of biological pharmacy, in particular to a benzo-heterocycle compound with Snail inhibitory activity, a preparation method, a pharmaceutical composition and medical application thereof.
Background
Zinc finger proteins in eukaryotes can selectively bind to specific target structures, and play an important role in the life processes of gene expression regulation, cell differentiation, embryonic development and the like. Snail as a zinc finger transcription factor occupies a central position in the morphogenesis process of various organisms. The Snail is combined with a downstream target gene promoter through a zinc finger structure in a protein structure, participates in the processes of downstream gene transcription, inhibition of chromatin structure formation and the like, and enables an organism to maintain normal biological functions. Under the condition of normal organism, the expression level of Snail is very low; however, in tumor patients, expression of Snail is strongly associated with staging of the tumor, cancer metastasis and poor prognosis.
Studies have shown that Snail can participate in tumor progression in several ways: the Snail can promote the tumor metabolism reprogramming and endow the tumor cell with the characteristics of stem cells, thereby promoting the drug resistance, the recurrence and the metastasis of the tumor cell; snail triggers epithelial-mesenchymal transition by inhibiting the expression of cell adhesion proteins, thereby promoting the metastasis of tumor cells; the Snail can activate p53 mediated apoptosis resistance pathway and inhibit tumor cell apoptosis.
Therefore, snail plays a key role in the development and development process of tumors, and the development of Snail inhibitors can make inhibition of expression of Snail proteins an effective strategy for inhibiting tumor development.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to solve the technical problem of providing a benzo-heterocycle compound with Snail inhibitory activity and a derivative thereof.
The invention also aims to solve the technical problem of providing a preparation method of the benzo-heterocycle compound with Snail inhibitory activity and the derivative thereof.
The invention also aims to solve the technical problem of providing a pharmaceutical composition containing the benzo-heterocycle compound with Snail inhibitory activity and derivatives thereof.
The invention finally aims to solve the technical problem of providing the application of the benzo-heterocycle compound with Snail inhibition activity and the derivative thereof in preparing medicines for treating and/or preventing diseases related to Snail inhibition.
The technical scheme is as follows: in order to solve the technical problems, the invention provides a benzo-heterocycle compound and/or a derivative or a pharmaceutically acceptable salt or a co-crystal thereof shown as a general formula I:
Figure 712726DEST_PATH_IMAGE001
，
wherein the content of the first and second substances,
x is selected from NH, O and S;
y is selected from NH, O, S, -SO-, -CONH-, -COO-, -NHCO-and-OCO-;
z is selected from NH, O and S;
g is selected from CH and N;
n is 0, 1,2, 3, 4;
ring A is selected from the group consisting of: 6-10 membered aromatic ring, 5-10 membered heteroaromatic ring, 8-15 membered bicyclic fused ring, 3-10 membered heterocyclic group, C3-C8 cycloalkyl group;
each R is 1 、R 2 、R 3 、R 4 、R 5 Each independently selected from the group consisting of: H. halogen, -CN, -OH, -NH 2 Substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 3-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, -CONHR 6 、-CONH(CH 2 ) m NH(CH 2 ) p CH 3 、-CONH(CH 2 ) m O(CH 2 ) p CH 3 、-COR 6 、-CONR 6 Het、-COR 6 Het、-COOR 6 、-NHR 6 、-NH(CH 2 ) 1- 10 Het、-NH(CH 2 ) 1-10 OR 6 、-NHCOOR 6 、-NHCOOHet、-NHCONHR 6 、-NHCONHHet、-OR 6 、-O(CH 2 ) 1-10 NR 6 、-O(CH 2 ) 1-10 Het or-O (CH) 2 ) 1-10 OR 6 (ii) a Said Het may be optionally substituted with: halogen, -CN, -OH, -CF 3 、-OCF 3 、-OR 6 、-SH、-SR 6 、-NH 2 、-NHR 6 、-N(R 6 ) 2 、-NHCOR 6 、-NHSO 2 R 6 、-NHSO 2 R 6 、-COR 6 、-COOR 6 、-CONHR 6 、-CON(R 6 ) 2 、-CONH(CH 2 ) 1-10 N(R 6 ) 2 、-CON(R 6 ) 2 、-CONH(CH 2 ) 1-10 N(R 6 ) 2 ；
R 6 Selected from the group consisting of: H. halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of N, S and O;
m and p are each independently 1,2, 3, 4, 5, 6;
het is selected from the group consisting of piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, morpholinyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, piperazinyl, substituted piperazinyl, pyrazinyl or pyridazinyl, or from the group consisting of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo [ 2 ]b][1 ,4]Dioxane group or benzo [ 2 ]d][1 ,3]A bicyclic heterocycle of dioxolanyl, each of said monocyclic or bicyclic heterocycle optionally substituted with 1,2 or 3 substituents, each substituent independently selected from the group consisting of halogen, haloalkyl, hydroxy, alkyl, alkoxy, a C3-C8 aliphatic carbocycle, tetrahydropyrrolyl, morpholinyl, alkoxymorpholinyl, piperazinyl, piperidinyl, or alkylaminopiperidinyl; the alkyl is a straight chain or branched chain saturated hydrocarbon group with 1-6 carbon atoms(ii) a Or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms to which a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms is bonded; the alkoxy group is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms to which a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms is attached, wherein each carbon atom is optionally substituted with oxygen; the alkylamino group is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms to which a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms is attached, wherein each carbon atom is optionally substituted by nitrogen;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, methylsulfonyl, oxo (= O), -CN, hydroxy, carboxy, C1-C6 amido (- = C (= O) -NHCH 3 or-NH-C (= O) CH 3 )、-N(CH 3 ) 2 Or a substituted or unsubstituted group selected from: C1-C6 alkyl, C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, - (CH) 2 ) -C6-C10 aryl, - (CH) 2 ) - (5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O), -5-10 membered heteroarylene having 1-3 heteroatoms selected from N, S and O) - (C1-C6 alkyl), 3-12 membered heterocyclyl (including monocyclic, spiro, bridged or fused rings) having 1-3 heteroatoms selected from the group N, S and O, and said substituents are selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkylene-OH, C1-C6 alkoxy, oxo, -S (O) 2 CH 3 -CN, -OH, C6-C10 aryl, 3-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, -C = OCHNHCH 3 、-C=OCH 2 OH；
Wherein the derivative comprises a stereoisomer, a hydrate, a metabolite, a deuteron, a solvate or a pharmaceutically acceptable salt or a eutectic crystal.
Wherein, the compound is selected from any one of the following compounds: 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (5-methyl-1)H-pyrazol-3-yl) -1H-benzo [ 2 ]d]Imidazole-7-amine (3),N- (2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -1H-benzo [ 2 ]d]Imidazol-7-yl) -5-methylisothiazol-3-amine (4),N- (1,5-dimethyl-1H-pyrazol-3-yl) -2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -1H-benzo [ 2 ]d]Imidazole-7-amine (6), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N-phenyl-1H-benzo [ 2 ]d]Imidazole-7-amine (7), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (pyridin-3-yl) -1H-benzo [ 2 ]d]Imidazole-7-amine (8), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (5-methyl-1)H-1,2,4-triazol-3-yl) -1H-benzo [ 2 ]d]Imidazole-7-amine (9), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (2-methyl-2H-tetrazol-5-yl) -1H-benzo [ 2 ]d]Imidazole-7-amine (10), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (pyridin-2-yl) -1H-benzo [ 2 ]d]Imidazole-7-amine (11), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (piperidin-4-yl) -1H-benzo [ 2 ]d]Imidazole-7-amine (12), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (4-methylpyridin-2-yl) -1H-benzo [ 2 ]d]Imidazole-7-amine (13), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (3-methylpyridin-2-yl) -1H-benzo [ 2 ]d]Imidazole-7-amine (14), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (3-methoxypyridin-2-yl) -1H-benzo [ 2 ]d]Imidazole-7-amines (15),N- (3-fluoropyridin-2-yl) -2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -1H-benzo [ 2 ]d]Imidazole-7-amine (16), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (5-methyl-1)H-pyridineAzol-3-yl) -1H-benzo [ 2 ]d]Imidazole-6-amines (17),N- (2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -1H-benzo [ 2 ]d]Imidazol-6-yl) -5-methylisothiazol-3-amine (18), 2- ((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methoxy)N- (5-methyl-1H-pyrazol-3-yl) -1H-benzo [ 2 ]d]Imidazole-7-amines (20),N- (2- ((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methoxy) -1H-benzo [ 2 ]d]Imidazol-7-yl) -5-methylisothiazol-3-amine (21), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (5-methyl-1)H-pyrazol-3-yl) benzo [ 2 ]d]Oxazol-7-amines (23),N- (4-methoxyphenyl) -2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -1H-benzo [ 2 ]d]Imidazol-7-amine (24), N- (4-fluorophenyl) -2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -1H-benzo [ d]Imidazole-7-amine (25), 2- ((3- (3-methoxypropoxy) -2-methylbenzyl) thio) -N- (5-methyl-1H-pyrazol-3-yl) -1H-benzo [ 2 ]d]Imidazole-7-amines (26),N- (2- ((3- (3-methoxypropoxy) -2-methylbenzyl) thio) -1H-benzo [ 2 ]d]Imidazol-7-yl) -5-methylisothiazol-3-amine (27), 2- (((4- (4-methoxyphenoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (5-methyl-1)H-pyrazol-3-yl) -1H-benzo [ 2 ]d]Imidazole-7-amines (30),N- (5-methyl-1)H-pyrazol-3-yl) -2- (((3-methyl-4-morpholinopyridin-2-yl) methyl) thio) -1H-benzo [ 2 ]d]Imidazol-7-amine (31), 6- (((7- ((5-methyl-1)H-pyrazol-3-yl) amino) -1H-benzo [ 2 ]d]Imidazol-2-yl) thio) methyl) -N-phenylnicotinamide (32),N-phenyl-6- (((7- (pyridin-2-ylamino) -1)H-benzo [ 2 ]d]Imidazol-2-yl) thio) methyl) nicotinamide (33).
Wherein the pharmaceutically acceptable salt is a salt formed by the benzo-heterocycle compound or the derivative thereof and an acid or a base, the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid, and the base is an inorganic base containing an alkali metal cation, an alkaline earth metal cation or an ammonium cation salt.
The invention further provides a pharmaceutical composition, and the pharmaceutical composition comprises the benzo-heterocycle compound and/or the derivative or the pharmaceutically acceptable salt or the eutectic crystal thereof.
One or more embodiments of the present invention provide that the pharmaceutical composition of the present invention comprises the compound of formula (I) or the specific structure or its stereoisomer, solvate, metabolite, deuteride, pharmaceutically acceptable salt, co-crystal or prodrug thereof and one or more pharmaceutically acceptable carriers and/or excipients.
One or more embodiments of the invention provide application of the benzo-heterocycle compound and/or the derivative or the pharmaceutically acceptable salt or the cocrystal thereof or the pharmaceutical composition in preparation of a Snail inhibitor or a drug for treating and/or preventing diseases related to Snail.
One or more embodiments of the present invention provide compounds of formula (I) or the specific structures described above or stereoisomers, solvates, generations, deuterions, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, for use in the treatment of diseases associated with Snail or as Snail inhibitors.
Wherein the disease associated with Snail comprises lung cancer, melanoma, liver cancer, kidney cancer, leukemia, prostate cancer, thyroid cancer, skin cancer, pancreatic cancer, rectal cancer, colon cancer, ovarian cancer, testicular cancer, breast cancer, bladder cancer, gall bladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, gastrointestinal cancer, astrocytoma, neuroblastoma, glioma, schwannoma, mesothelioma, non-insulin dependent diabetes mellitus or an autoimmune disease.
The benzo-heterocyclic compound and the derivative thereof with Snail inhibitory activity can be added with a pharmaceutically acceptable carrier to prepare common medicinal preparations, such as tablets, capsules, syrup, suspending agents and injections, and common medicinal auxiliary materials such as spices, sweeteners, liquid or solid fillers or diluents and the like can be added.
One or more embodiments of the present invention provide a method of inhibiting Snail comprising contacting a compound of formula (I) of the present invention or the specific structures described above or stereoisomers, solvates, metabolites, deuterons, pharmaceutically acceptable salts, co-crystals or prodrugs thereof or the composition of the present invention with a subject in need thereof.
One or more embodiments of the present invention provide methods of treating diseases associated with Snail comprising administering a compound of formula (I) of the present invention or the specific structures described above or stereoisomers, solvates, metabolites, deuterons, pharmaceutically acceptable salts, co-crystals or prodrugs thereof or a composition of the present invention to a subject in need thereof.
Has the advantages that: compared with the prior art, the invention has the following advantages: the inhibitor, the derivative and the pharmaceutical composition have strong affinity with Snail protein, have good affinity with Snail protein at micromolar concentration level, can effectively inhibit the Snail activity, have good inhibition effect on cells, and have the highest cell inhibition rate of more than 99% when the administration concentration is 5 mu M; and the prepared medicine has wide action target and can be used for treating and/or preventing various diseases related to inhibition of Snail activity.
Detailed Description
Example 1 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (5-methyl-1)H-pyrazol-3-yl) -1H-benzo [ 2 ]d]Synthesis of imidazol-7-amine (Compound 3)
Figure 620377DEST_PATH_IMAGE002
(1) Synthesis of Compound 3-1
Dissolving 3-bromo-2-nitroaniline (5 g) in acetone (30 mL), adding sodium hydroxide (1.38 g), stirring for 10min, adding benzyl bromide (4.73 g), reacting at room temperature for 3 h, evaporating the solvent, pulping with petroleum ether, and performing suction filtration to obtain a yellow solid 5.9 g, wherein the yield is as follows: 83.38 percent. 1 H NMR (300 MHz, DMSO-d6) δ 7.36 (d, J = 5.4 Hz, 4H), 7.32–7.23 (m, 1H), 7.25–7.11 (m, 2H), 6.93 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 4.44 (t, J = 3.1 Hz, 2H).
(2) Synthesis of Compound 3-2
Under the protection of nitrogen, compound 3-1 (3 g) is dissolved in toluene, 5-methyl-1H-pyrazol-3-amine (1.42 g), cesium carbonate (4.77 g), palladium acetate (109.6 mg), 1,1 '-binaphthyl-2,2' -bis-diphenylphosphine (608 mg), reaction at 100 ℃ is carried out for 18H, after the reaction is finished, diatomite is filtered, the filtrate is evaporated to dryness, water is added into the residue, an organic layer is extracted by ethyl acetate, the organic layer is washed by saturated salt water and then dried by anhydrous sodium sulfate, standing is carried out, the solvent is evaporated to dryness, column chromatography is carried out (petroleum ether: ethyl acetate = 1:1), orange red solid mg is obtained, and the yield: 19.6 percent. 1 H NMR (300 MHz, Chloroform-d) δ 8.96 (s, 1H), 8.73 (t, J = 5.6 Hz, 1H), 7.68 (dd, J = 7.3, 1.1 Hz, 1H), 7.53 (t, J = 7.3 Hz, 1H), 7.41–7.17 (m, 5H), 6.96 (dd, J = 7.4, 1.2 Hz, 1H), 6.11 (s, 1H), 4.51 (dt, J = 5.5, 1.0 Hz, 2H), 2.30 (s, 3H).
(3) Synthesis of Compound 3-3
Compound 3-2 (620 mg) was dissolved in methanol (10 mL) under hydrogen, reacted at room temperature for 16 h, the reaction solution was filtered with celite, the filtrate was evaporated to dryness of the solvent, the obtained solid was washed with the solvent (petroleum ether: ethyl acetate = 4:1) to give 350 mg as a pale yellow solid, yield: 89.81%. 1 H NMR (300 MHz, Chloroform-d) δ 7.99 (s, 1H), 7.36 (dd, J = 8.0, 1.3 Hz, 1H), 6.63 (t, J = 7.9 Hz, 1H), 6.44 (dd, J = 7.6, 1.2 Hz, 1H), 6.06 (s, 1H), 4.74 (s, 2H), 4.49 (dd, J = 51.7, 7.2 Hz, 2H), 2.30 (s, 3H).
(4) Synthesis of Compounds 3-4
Dissolving the compound 3-3 (300 mg) in ethanol, adding potassium hydroxide (83 mg) and carbon disulfide (113 mg), reacting at 90 ℃ for 12 h, cooling to room temperature after the reaction is finished, and performing suction filtration to obtain a yellow solid 300 mg, wherein the yield is as follows: 82.86%. 1 H NMR (300 MHz, Chloroform-d) δ 8.43 (s, 1H), 7.44–7.34 (m, 2H), 7.27 (dd, J = 5.4, 4.5 Hz, 1H), 6.06 (s, 1H), 2.30 (s, 3H).
(5) Synthesis of Compound 3
Dissolving compound 3-4 (100 mg) in acetonitrile (10 mL), adding sodium hydroxide (110 mg), adding 2-chloromethyl-3-methyl-4- (3-methoxypropoxy) pyridine hydrochloride (113 mg), reacting at room temperature for 5h, evaporating the solvent after the reaction is finished, adding water, extracting with ethyl acetate, combining the organic phases, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, standing, concentrating, and performing column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain a white solid 102 mg, yield: 57.05%. 1 H NMR (300 MHz, Chloroform-d6) δ 8.30 (s, 1H), 8.03 (d, J = 4.9 Hz, 1H), 7.74 – 7.34 (m, 3H), 6.82 (d, J = 4.9 Hz, 1H), 6.06 (s, 1H), 4.64 (s, 2H), 4.11 (t, J = 6.2 Hz, 2H), 3.56 (t, J = 6.4 Hz, 2H), 3.19 (s, 3H), 2.30 (s, 3H), 2.19 (s, 3H), 2.02 (p, J = 6.3 Hz, 2H).
Example 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (pyridin-2-yl) -1H-benzo [ 2 ]d]Synthesis of imidazol-7-amine (Compound 11)
Figure 550287DEST_PATH_IMAGE003
(1) Synthesis of Compound 11-1
Dissolving 3-bromo-2-nitroaniline (5 g) in acetone (30 mL), adding sodium hydroxide (1.38 g), stirring for 10min, adding benzyl bromide (4.73 g), reacting at room temperature for 3 h, evaporating the solvent, pulping with petroleum ether, and performing suction filtration to obtain a yellow solid 5.9 g, wherein the yield is as follows: 83.38 percent. 1 H NMR (300 MHz, DMSO-d6) δ 7.36 (d, J = 5.4 Hz, 4H), 7.32–7.23 (m, 1H), 7.25–7.11 (m, 2H), 6.93 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 4.44 (t, J = 3.1 Hz, 2H).
(2) Synthesis of Compound 11-2
Under the protection of nitrogen, compound 11-1 (1 g) is dissolved in toluene, and 2-aminopyridine (460) is addedmg), cesium carbonate (1.6 g), palladium acetate (37 mg), 1,1 '-binaphthyl-2,2' -bis-diphenylphosphine (203 mg), reaction at 100 ℃ of 18 h, after the reaction is finished, diatomaceous earth is filtered, the filtrate is evaporated to dryness, water is added to the residue, extraction is performed with ethyl acetate, the organic layers are combined, washing is performed with saturated brine, then drying is performed with anhydrous sodium sulfate, standing is performed, the solvent is evaporated to dryness, column chromatography is performed (petroleum ether: ethyl acetate = 1:1), and orange-red solid 720 mg is obtained, yield: 69.03%. 1 H NMR (300 MHz, Chloroform-d) δ 10.34 (s, 1H), 8.52 (t, J= 5.5 Hz, 1H), 8.35 (dd, J = 5.3, 2.0 Hz, 1H), 8.09 (dd, J = 5.6, 1.8 Hz, 1H), 7.66 (dd, J = 8.4, 1.2 Hz, 1H), 7.62 (ddd, J = 8.3, 7.3, 2.0 Hz, 1H), 7.44 (ddd, J = 8.3, 7.2, 1.9 Hz, 1H), 7.25 (t, J = 8.4 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.92 (ddd, J = 7.3, 4.9, 1.0 Hz, 1H), 6.66 (ddd, J = 7.2, 5.1, 1.0 Hz, 1H), 6.52 (d, J = 8.3 Hz, 1H), 6.29 (dd, J = 8.5, 1.2 Hz, 1H), 4.53 (d, J = 5.5 Hz, 2H).
(3) Synthesis of Compound 11-3
Compound 11-2 (500 mg) was dissolved in methanol (10 mL) under hydrogen, reacted at room temperature for 16 h, the reaction solution was filtered with celite, the filtrate was evaporated to dryness of the solvent, and the obtained solid was washed with a solvent (petroleum ether: ethyl acetate = 1:3) to give 250 mg as a pale yellow solid, yield: 79.99 percent. 1 H NMR (300 MHz, Chloroform-d) δ 8.27 (s, 1H), 8.19 (dd, J = 4.3, 1.7 Hz, 1H), 7.65 (td, J = 7.3, 1.6 Hz, 1H), 7.36 (dd, J = 8.1, 1.2 Hz, 1H), 6.97–6.81 (m, 2H), 6.63 (t, J = 7.9 Hz, 1H), 6.44 (dd, J = 7.6, 1.2 Hz, 1H), 4.74 (s, 2H), 4.49 (dd, J = 51.7, 7.2 Hz, 2H).
(4) Synthesis of Compound 11-4
Dissolving the compound 11-3 (200 mg) in ethanol, adding potassium hydroxide (56.04 mg) and carbon disulfide (76.03 mg), reacting at 90 ℃ for 12 h, cooling to room temperature after the reaction is finished, and performing suction filtration to obtain a yellow solid 162 mg, wherein the yield is as follows: 66.94%. 1 H NMR (300 MHz, Chloroform-d) δ 7.60- 7.56 (m, 2H), 7.43 (t, J = 1.4 Hz, 1H), 7.11-7.04 (m, 2H), 6.25-6.18 (m, 2H).
(5) Synthesis of Compound 11
Compound 11-4 (50 mg) was dissolved in methanol (10 mL), sodium hydroxide (20 mg) was added, 2-chloromethyl-3-methyl-4- (3-methoxypropoxy) pyridine hydrochloride (57 mg) was added, 5h was reacted at room temperature, after the reaction was completed, the solvent was evaporated, water was added, extraction was performed with ethyl acetate, organic phase was combined, washing was performed with saturated sodium chloride, drying was performed with anhydrous sodium sulfate, standing, concentration, and column chromatography (petroleum ether: ethyl acetate = 1:3) was performed to obtain 56 mg as a white solid, yield: 62.31 percent. 1 H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.20 (d, J = 5.7 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.67–7.48 (m, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.07 (t, J = 7.9 Hz, 1H), 7.02–6.90 (m, 2H), 6.75 (t, J = 6.2 Hz, 1H), 4.68 (s, 2H), 4.46 (s, 1H), 3.48 (td, J = 6.2, 1.8 Hz, 3H), 3.36 (s, 3H), 2.20 (s, 3H), 2.14 (s, 2H).
Example 3N- (4-fluorophenyl) -2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -1H-benzo [ 2 ]d]Synthesis of imidazol-7-amine (Compound 25)
Figure 885191DEST_PATH_IMAGE004
(1) Synthesis of Compound 25-1
Dissolving 3-bromo-2-nitroaniline (5 g) in acetone (30 mL), adding sodium hydroxide (1.38 g), stirring for 10min, adding benzyl bromide (4.73 g), reacting at room temperature for 3 h, evaporating the solvent, pulping with petroleum ether, and performing suction filtration to obtain a yellow solid 5.9 g, wherein the yield is as follows: 83.38 percent. 1 H NMR (300 MHz, DMSO-d6) δ 7.36 (d, J = 5.4 Hz, 4H), 7.32-7.23 (m, 1H), 7.25 - 7.11 (m, 2H), 6.93 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 4.44 (t, J = 3.1 Hz, 2H).
(2) Synthesis of Compound 25-2
Under the protection of nitrogen, compound 25-1 (1 g) is dissolved in toluene, and para-fluoroaniline (471 m) is addedg) Cesium carbonate (1.6 g), palladium acetate (37 mg), 1,1 '-binaphthyl-2,2' -bis-diphenylphosphine (203 mg), reaction at 100 ℃ of 18 h, after the reaction is finished, diatomaceous earth is filtered, the filtrate is evaporated to dryness in solvent, the residue is extracted with ethyl acetate, the organic layers are combined, the residue is washed with saturated brine, dried with anhydrous sodium sulfate, left to stand, the solvent is evaporated to dryness, column chromatography is performed (petroleum ether: ethyl acetate = 1:1), and orange-red solid 778 mg is obtained, yield: 70.83 percent. 1 H NMR (300 MHz, Chloroform-d) δ 9.96 (s, 1H), 8.83 (s, 1H), 7.46–7.32 (m, 6H), 7.30 (d, J = 1.4 Hz, 1H), 7.28–7.27 (m, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.07 (t, J = 8.4 Hz, 1H), 6.38 (dd, J = 8.4, 1.2 Hz, 1H), 6.06 (dd, J = 8.5, 1.3 Hz, 1H), 4.52 (d, J = 5.5 Hz, 2H).
(3) Synthesis of Compound 25-3
Compound 25-2 (770 mg) was dissolved in methanol (12 mL) under hydrogen, reacted at room temperature for 16 h, the reaction solution was filtered through celite, the solvent was evaporated from the filtrate, and the resulting solid was washed with the solvent to give a tan solid 452 mg, yield: 91.15 percent. 1 H NMR (300 MHz, DMSO-d6) δ 6.98 (s, 1H), 6.88 (t, J = 8.9 Hz, 1H), 6.63–6.55 (m, 2H), 6.38–6.25 (m, 3H), 4.45 (s, 4H).
(4) Synthesis of Compound 25-4
Dissolving the compound 25-3 (100 mg) in ethanol, adding potassium hydroxide (26 mg) and carbon disulfide (35 mg), reacting at 90 ℃ for 12 h, cooling to room temperature after the reaction is finished, and performing suction filtration to obtain a yellow solid 82 mg, wherein the yield is as follows: 68.7 percent. 1 H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.37 (s, 1H), 7.13–6.96 (m, 4H), 6.87–6.73 (m, 2H), 6.57 (dd, J = 7.6, 1.2 Hz, 1H).
(5) Synthesis of Compound 25
Dissolving compound 25-4 (50 mg) in methanol (10 mL), adding sodium hydroxide (20 mg), adding 2-chloromethyl-3-methyl-4- (3-methoxypropoxy) pyridine hydrochloride (70 mg), reacting at room temperature for 10 h, evaporating the solvent after the reaction is finished, adding water, extracting with ethyl acetate, combining the organic phase, washing with saturated sodium chloride, drying with anhydrous sodium sulfateDrying, standing, concentration, then column chromatography (petroleum ether: ethyl acetate = 1:3) gave 76 mg as a white solid, yield: 89.88%. 1 H NMR (300 MHz, DMSO-d6) δ 12.65 (s, 1H), 12.42 (s, 0H), 8.23 (d, J = 5.6 Hz, 1H), 8.05 (s, 1H), 7.25 (dd, J = 8.6, 5.0 Hz, 2H), 7.08 (t, J = 8.9 Hz, 2H), 7.03–6.83 (m, 3H), 4.67 (s, 2H), 4.15–4.04 (m, 2H), 3.48 (t, J = 6.2 Hz, 2H), 3.25 (s, 3H), 2.20 (d, J = 5.4 Hz, 3H), 1.99 (s, 2H).
In a similar operation to example 1, the following compounds were prepared:
TABLE 1
Figure 736604DEST_PATH_IMAGE005
Figure 418252DEST_PATH_IMAGE006
Figure 562440DEST_PATH_IMAGE007
Figure 507393DEST_PATH_IMAGE008
Figure 141375DEST_PATH_IMAGE009
Figure 95556DEST_PATH_IMAGE010
Figure 498593DEST_PATH_IMAGE011
Figure 942344DEST_PATH_IMAGE012
EXAMPLE 4 affinity assay of Compounds for Snail proteins (MST molecular interaction)
1. Preparing consumables: capillary, GFP-tagged recombinant Snail protein (Monolith NT.115; from NanoTemper Technologies), 0.2 mL, 1.5 mL, 10 mL, 50mL pipette, PBS (0.01M, pH =7.4, containing 0.05% Tween 20), DMSO, pipette tip.
2. The experimental principle is as follows: the microcalorimetric electrophoresis (MST) technique analyzes interactions between biomolecules by measuring molecular movement in a microscopic temperature gradient field. The technology can measure the change of the moving speed caused by the change of the molecular size, the charge and the hydration layer, and has extremely high sensitivity.
3. Experimental procedures and methods: preparing the compounds in the table 2 into 2.5mM DMSO mother liquor, taking 4 mu L, adding into 100 mu LPBS, observing the dissolution condition, and ensuring the compounds to be dissolved at the highest concentration; preparing 4% DMSO PBS solution, diluting the compound mother solution step by step, and mixing; adding protein with the same volume, centrifuging, and standing for 10min; operating on the machine, and continuously measuring for 2 times.
4. The experimental results are as follows: the results are shown in Table 2.
Figure 502769DEST_PATH_IMAGE013
As shown in Table 2, the compounds 3, 11 and 25 have affinity effect on Snail protein, the affinity ability is in micromolar concentration level, the affinity effect is obvious, and the inhibition effect is favorably exerted.
EXAMPLE 5 in vitro determination of the antitumor Activity of Compounds
1. The experimental principle is as follows: CCK-8 method using novel water-soluble tetrazolium salt 2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfophenyl) -2HThe tetrazolium monosodium salt colorimetric detection product for rapidly and sensitively detecting the activity of the cells can be reduced into orange yellow water-soluble formazan by dehydrogenase of the cells in the presence of an electronic carrier, and the generated formazan amount is in direct proportion to the activity of the cells. The stronger the cell activity, the more the color becomesThe darker the color; the weaker the cell activity, the lighter the color. The shade of color and cell viability are linear for the same cells.
2. Experimental procedures and methods: 100. Mu.L of suspension per well (about 1X 10 per well) were inoculated in 96-well plates 4 HCT-116 cells, HCT-116 cells purchased from ATCC, USA); after 4 h was stabilized, different concentrations (1 μ M, 2.5 μ M, 5 μ M) of media containing the compounds prepared according to the invention (DMEM, 5% FBS; thermo Fisher Scientific, # 10099-147) were added, respectively, and after 24 h, 10 μ L of CCK8 solution (from Solarbio) was added per well; culturing the culture plate in an incubator for 2 hours; measuring absorbance at 450nm by using a microplate reader; and (3) calculating the cell viability: the OD values of each replicate were averaged and the inhibition (%) = (test well OD-blank OD)/(control well OD-blank OD) × 100%.
3. The experimental results are as follows: the results are shown in Table 3.
Figure 290334DEST_PATH_IMAGE014
As shown in Table 3, at a concentration of 5 μ M, all the representative compounds have an inhibitory effect on HCT-116 cell lines, the inhibitory rate is over 70 percent, even can reach over 95 percent, and the inhibitory effect is obvious.

Claims (4)

1. Benzo-heterocyclic compounds, characterized in that said compounds are, in particular, optionally selected from any of the following compounds: 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (5-methyl-1)H-pyrazol-3-yl) -1H-benzo [ 2 ]d]Imidazole-7-amines (3),N- (2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -1H-benzo [ 2 ]d]Imidazol-7-yl) -5-methylisothiazol-3-amine (4),N- (1,5-dimethyl-1H-pyrazol-3-yl) -2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -1H-benzo [ 2 ]d]Imidazole-7-amine (6), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N-phenyl-1H-benzo [ 2 ]d]Imidazole-7-amine (7), 2- (((4- (3-methoxypropoxy) -3-methylpyridine)-2-yl) methyl) thio-N- (pyridin-3-yl) -1H-benzo [ 2 ]d]Imidazole-7-amine (8), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) one-substituted acidsN- (5-methyl-1)H-1,2,4-triazol-3-yl) -1H-benzo [ 2 ]d]Imidazole-7-amine (9), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (2-methyl-2H-tetrazol-5-yl) -1H-benzo [ 2 ]d]Imidazole-7-amine (10), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (pyridin-2-yl) -1H-benzo [ 2 ]d]Imidazole-7-amine (11), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (piperidin-4-yl) -1H-benzo [ 2 ]d]Imidazole-7-amine (12), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) propanoic acidN- (4-methylpyridin-2-yl) -1H-benzo [ 2 ]d]Imidazole-7-amine (13), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (3-methylpyridin-2-yl) -1H-benzo [ 2 ]d]Imidazole-7-amine (14), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (3-methoxypyridin-2-yl) -1H-benzo [ 2 ]d]Imidazole-7-amines (15),N- (3-fluoropyridin-2-yl) -2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -1H-benzo [ 2 ]d]Imidazole-7-amine (16), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (5-methyl-1)H-pyrazol-3-yl) -1H-benzo [ 2 ]d]Imidazole-6-amines (17),N- (2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -1H-benzo [ 2 ]d]Imidazol-6-yl) -5-methylisothiazol-3-amine (18), 2- ((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methoxy)N- (5-methyl-1H-pyrazol-3-yl) -1H-benzo [ 2 ]d]Imidazole-7-amines (20),N- (2- ((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methoxy) -1H-benzo [ 2 ]d]Imidazol-7-yl) -5-methylisothiazol-3-amine (21), 2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (5-methyl-1)H-pyrazol-3-yl) benzo [ 2 ]d]Oxazol-7-amines (23),N- (4-methoxyphenyl) -2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl)Thio) -1H-benzo [ 2 ]d]Imidazol-7-amine (24), N- (4-fluorophenyl) -2- (((4- (3-methoxypropoxy) -3-methylpyridin-2-yl) methyl) thio) -1H-benzo [ d]Imidazol-7-amine (25), 2- ((3- (3-methoxypropoxy) -2-methylbenzyl) thio) -N- (5-methyl-1H-pyrazol-3-yl) -1H-benzo [ 2 ]d]Imidazole-7-amines (26),N- (2- ((3- (3-methoxypropoxy) -2-methylbenzyl) thio) -1H-benzo [ 2 ]d]Imidazol-7-yl) -5-methylisothiazol-3-amine (27), 2- (((4- (4-methoxyphenoxy) -3-methylpyridin-2-yl) methyl) thio) -N- (5-methyl-1)H-pyrazol-3-yl) -1H-benzo [ 2 ]d]Imidazol-7-amine (30),N- (5-methyl-1)H-pyrazol-3-yl) -2- (((3-methyl-4-morpholinopyridin-2-yl) methyl) thio) -1H-benzo [ 2 ]d]Imidazol-7-amine (31), 6- (((7- ((5-methyl-1)H-pyrazol-3-yl) amino) -1H-benzo [ 2 ]d]Imidazol-2-yl) thio) methyl) -N-phenylnicotinamide (32),N-phenyl-6- (((7- (pyridin-2-ylamino) -1)H-benzo [ 2 ]d]Imidazol-2-yl) thio) methyl) nicotinamide (33).
2. Use of a benzo-heterocycle according to claim 1 for the manufacture of a Snail inhibitor or for the manufacture of a medicament for the treatment and/or prevention of a Snail-related disease.
3. The use according to claim 2, wherein the disease associated with Snail comprises lung cancer, melanoma, liver cancer, kidney cancer, leukemia, prostate cancer, thyroid cancer, skin cancer, pancreatic cancer, rectal cancer, colon cancer, ovarian cancer, testicular cancer, breast cancer, bladder cancer, gall bladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, gastrointestinal cancer, astrocytoma, neuroblastoma, glioma, schwannoma, mesothelioma, non-insulin dependent diabetes mellitus or an autoimmune disease.
4. Use according to claim 2, wherein the pharmaceutical dosage form comprises tablets, capsules, syrups, suspensions or injections.
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