CN115124528A - Pyrrolopyridine compound and preparation method and medical application thereof - Google Patents
Pyrrolopyridine compound and preparation method and medical application thereof Download PDFInfo
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- CN115124528A CN115124528A CN202210850237.3A CN202210850237A CN115124528A CN 115124528 A CN115124528 A CN 115124528A CN 202210850237 A CN202210850237 A CN 202210850237A CN 115124528 A CN115124528 A CN 115124528A
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- Prior art keywords
- ring
- compound
- pharmaceutically acceptable
- phenyl
- solvate
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- -1 Pyrrolopyridine compound Chemical class 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 15
- 239000012453 solvate Substances 0.000 claims abstract description 15
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 8
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 7
- 201000007270 liver cancer Diseases 0.000 claims abstract description 7
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 7
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims abstract description 6
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 claims abstract description 6
- 208000008839 Kidney Neoplasms Diseases 0.000 claims abstract description 6
- 206010038389 Renal cancer Diseases 0.000 claims abstract description 6
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 claims abstract description 6
- 201000010982 kidney cancer Diseases 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 12
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 12
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical group C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 25
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to a pyrrolopyridine compound, a preparation method and medical application thereof, belonging to the technical field of pharmaceutical chemistry and pharmacotherapeutics. The compound, isomer, hydrate, solvate or pharmaceutically acceptable salt thereof shown in the formula I has good PAK5 inhibitory activity, can be used for preparing medicines for treating diseases related to serine/threonine kinase PAK5, and specifically has strong anti-tumor activity on tumor cells such as kidney cancer cells, liver cancer cells, colorectal cancer cells and breast cancer cells.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry and pharmacotherapeutics, and particularly relates to a pyrrolopyridine compound. The compounds can be used for preparing medicines for diseases related to PAK 5. The invention also relates to a preparation method of the compounds and a pharmaceutical composition containing the compounds.
Background
Pyrrole [2,3-b ] pyridine is an important nitrogen-containing heterocyclic compound, has a structure similar to indole and purine, becomes a biological electron isostere of the latter two compounds, and has wide application in the fields of medicines, pesticides and the like. The compound containing the pyrrolopyridine structure in the natural product is an important alkaloid and has the physiological activities of resisting cancer, resisting bacteria, resisting psychosis and the like. The pyrrolopyridine derivative has a protein kinase inhibition effect, and has potential biological activity and medicinal value in aspects of histamine resistance, dopamine resistance and the like. With the continuous research, the anti-tumor small molecules with the pyrrolopyridine as the skeleton are approved by FDA to be on the market. Vemurafenib (Vemurafenib), a selective inhibitor of BRAF at half inhibitory concentrations up to 31nM, was FDA approved for the treatment of advanced metastatic or surgically unresectable melanoma 8 months 2011. GSK1070916 is an ATP competitive aurora kinase inhibitor taking pyrrolopyridine as a framework, the Ki of the inhibitor to aurora kinase B and aurora kinase C is 0.38 +/-0.29 nM and 1.5 +/-0.4 nM respectively, and the evaluation experiment of the tumor proliferation inhibition activity shows that the half inhibition concentration of GSK1070916 to lung cancer cells is 7nM, and the proliferation of the tumor cells is effectively inhibited. Xenograft tumor experiments show that GSK1070916 can inhibit the phosphorylation of histone H3 of Colo205 and HL-60 of human colon cancer, and the small molecule is in a clinical phase I experiment at present.
The anti-tumor target PAK5 is proved to play an important role in the aspects of invasion, metastasis, proliferation, survival, apoptosis and the like of tumor cells, so the development of inhibitors thereof is considered to be an effective strategy for tumor treatment, however, the class II PAKs inhibitors are mostly in the stage of biological test research. However, based on a large number of research results in molecular biology and structural biology, the discovery and development of class II PAKs inhibitors, particularly selective class II PAKs inhibitors, are in a rapid development stage, and it is expected that a new generation of antitumor drugs, particularly the protein crystal structure of PAK5, will be developed, and it is believed that the development of PAK5 inhibitors will be imperative.
Therefore, how to provide a protein kinase inhibitor which can effectively inhibit the activity of PAK5 is a problem to be solved by those skilled in the art.
Disclosure of Invention
The invention aims to obtain a class of pyrrolopyridine compounds by utilizing a fragment-based drug design principle based on silk/threonine kinase PAK5 on the basis of the prior art, and pharmacological experiments prove that the class of pyrrolopyridine compounds has good PAK5 inhibitory activity and particularly has strong anti-tumor activity on tumor cells such as kidney cancer cells, liver cancer cells, colorectal cancer cells, breast cancer cells and the like.
The invention also aims to provide a preparation method of the pyrrolopyridine compound.
The invention also aims to provide the application of the pyrrolopyridine compound in the aspect of medicine, in particular to the application in the aspect of preparing medicines for treating diseases related to the serine/threonine kinase PAK 5; wherein the related diseases of the serine/threonine kinase PAK5 are colorectal cancer, liver cancer, gastric cancer, breast cancer, renal cancer or cervical cancer.
The technical scheme of the invention is as follows:
a compound, isomer, hydrate, solvate or pharmaceutically acceptable salt thereof represented by formula I:
wherein the content of the first and second substances,
R 1 represents hydrogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy, acryloyl, propenyl, or tert-butoxycarbonyl;
R 2 represents hydrogen, hydroxy, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy, halogen or trifluoromethyl;
L 1 represents-CH 2 -、-CO-NH-、-CO-NH-CH 2 -c (oh) -, vinyl, ethynyl, nitrogen atom, hydrazide or sulfonyl hydrazide groups;
n represents 0, 1 or 2;
ring A represents piperidine, piperazine, morpholine, pyrrole or furan;
ring B represents phenyl or a five-membered nitrogen-containing heterocycle;
ring C represents phenyl, naphthyl or biphenyl;
and ring D represents an oxygen atom, phenyl, cyclopentane, cyclohexane, pyridine or pyrimidine.
In a preferred embodiment, R 1 Represents hydrogen, methyl, ethyl, methoxy or ethoxy.
In a more preferred embodiment, R 1 Represents a methyl group.
In a preferred embodiment, R 2 Represents hydrogen, hydroxy, methyl, ethyl, methoxy or ethoxy.
In a more preferred embodiment, R 2 Represents hydrogen, hydroxy or methoxy.
In a preferred embodiment, L 1 represents-CH 2 -、-CO-NH-、-CO-NH-CH 2 -c (oh) -, vinyl, ethynyl or hydrazide groups.
In a more preferred embodiment, L 1 represents-CH 2 -、-CO-NH-、-CO-NH-CH 2 -c (oh) -or ethynyl.
In a preferred embodiment, n represents 0 or 1.
In a more preferred embodiment, n represents 0.
In a preferred embodiment, ring a represents piperidine, piperazine or morpholine.
In a more preferred embodiment, ring a represents piperidine.
In a preferred embodiment, ring B represents phenyl, pyrazole, oxazole, thiazole, imidazole or pyrrole.
In a more preferred embodiment, ring B represents pyrazole.
In a preferred embodiment, ring C represents phenyl.
In a preferred embodiment, ring D represents an oxygen atom, phenyl, cyclopentane, cyclohexane, pyridine or pyrimidine.
In a more preferred embodiment, ring D represents an oxygen atom, phenyl, cyclopentane, cyclohexane or pyridine.
Further, R 1 Represents a methyl group; r 2 Represents hydrogen, hydroxy or methoxy; l is 1 represents-CH 2 -、-CO-NH-、-CO-NH-CH 2 -c (oh) -or ethynyl; n represents 0; ring A represents piperidine; ring B represents pyrazole; ring C represents phenyl; and ring D represents an oxygen atom, phenyl, cyclopentane, cyclohexane or pyridine.
Still further, the compound, isomer, hydrate, solvate or pharmaceutically acceptable salt thereof of formula I, wherein the compound is selected from:
in a preferred embodiment, when ring A represents piperidine, ring B represents pyrazole, ring C represents phenyl, L 1 Represents ethynyl and R 1 When representing methyl, the preparation method of the compound shown in the general formula I comprises the following steps:
the intermediates or the target compounds mentioned in the present invention can be purified according to conventional isolation techniques and converted into addition salts with pharmaceutically acceptable acids as required.
Unless otherwise indicated, the following terms used in the specification and claims have the meanings discussed below:
"pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:
(1) salified with an acid by reaction of the free base of the parent compound with an inorganic or organic acid, including hydrochloric, hydrobromic, nitric, phosphoric, metaphosphoric, sulfuric, sulfurous, perchloric, and the like, the organic acid includes acetic acid, trifluoroacetic acid, propionic acid, acrylic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, ascorbic acid, camphoric acid, benzoic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, cinnamic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, aspartic acid, stearic acid, mandelic acid, succinic acid, glutaric acid, or malonic acid, and the like.
(2) The acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or is complexed with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, quinine, or the like.
"pharmaceutical composition" refers to the combination of one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, with another chemical ingredient, such as a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration process to an animal.
"pharmaceutically acceptable carrier" or "pharmaceutically acceptable carrier" refers to inactive ingredients in a pharmaceutical composition that do not cause significant irritation to an organism and do not interfere with the biological activity and properties of the administered compound, such as, but not limited to: calcium carbonate, calcium phosphate, various sugars (e.g., lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic or methacrylic polymers, gelatin, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil or hydrogenated or polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil, and the like.
"alkyl" means a saturated aliphatic radical of 1 to 20 carbon atoms, including straight and branched chain radicals (a numerical range referred to herein, e.g., "1 to 20", means that the radical, in this case alkyl, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). More preferably, the alkyl group is a medium size alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, and the like. Preferably, alkyl is lower alkyl having 1 to 8 or 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, and the like. Alkyl groups may be substituted or unsubstituted. When substituted alkyl, the substituent is preferably one or more, more preferably 1 to 3, most preferably 1 or 2 substituents.
A nitrogen-containing five-membered heterocyclic ring denotes a monocyclic ring of 5 ring atoms, containing one, two, three or four N heteroatoms, the remaining ring atoms being C, for example pyrazole, oxazole, thiazole, imidazole or pyrrole.
"hydroxy" means an-OH group.
"trifluoromethyl" means-CF 3 A group.
"alkoxy" means-O- (unsubstituted alkyl) and-O- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
"halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
The invention provides a pharmaceutical composition, which takes the compound, isomer, hydrate, solvate or pharmaceutically acceptable salt thereof as an active ingredient or a main active ingredient, and is assisted by a pharmaceutically acceptable carrier.
The compound, the isomer, the hydrate, the solvate or the pharmaceutically acceptable salt thereof can be applied to the preparation of drugs for diseases related to the serine/threonine kinase PAK5, wherein the diseases related to the serine/threonine kinase PAK5 are colorectal cancer, liver cancer, gastric cancer, breast cancer, renal cancer or cervical cancer.
By adopting the technical scheme of the invention, the advantages are as follows:
1. the compound provided by the invention has better inhibiting effect on human colon cancer HCT-116 cells, human renal clear cell carcinoma 786O cells, human breast cancer MCF-7 cells and human liver cancer HepG2 cells. Wherein, compound III 5 The half inhibition concentration of the composition on four tumor cells is in nanomolar level, and the inhibition effect is superior to Sunitinib; under the concentration of 1 mu M, the survival rate of the HK-2 cells of the human renal cortex proximal convoluted tubule epithelial cells of normal cells is close to 80 percent, which shows that the derivative taking the pyrrolopyridine as the framework has stronger inhibiting effect on tumor cells and better biological safety.
2. Homogeneous time-resolved fluorescence (HTRF) STK-S2 kit (62ST2PEB, Cisbio) was used to evaluate the inhibitory effect of the target compounds on PAK5 protein, overall at nanomolar levels. Wherein the compound III 5 IC for PAK5 50 8. + -. 0.40 nM.
3. HepG2 xenograft tumor nude mouse experiment proves that target compound III 5 The tumor volume and tumor weight of the group are obviously smaller than those of a positive control medicine group, and the tumor inhibition rate reaches 91.21 percent
4. After the administration, no pathological structural change is seen in the HE stained section of heart, liver, spleen, lung and kidney tissues of the nude mice, which indicates that the compound III 5 Has better biological safety.
Drawings
FIG. 1 is a graph showing the effect of compound III5 on the survival of HK-2 normal cells; wherein, compound III 5 The survival rate of the HK-2 cells of the human renal cortex proximal tubular epithelial cells of the normal cells is close to 80 percent when the concentration of the HK-2 cells is 1 mu M;
FIG. 2 is a compoundInhibition of HepG2 nude mouse graft tumor model by object III 5; in FIG. 2, A is a photograph of a tumor of a nude mouse taken off 16 days after administration to each treatment group; in FIG. 2B is a curve showing the change in tumor volume after administration; in FIG. 2, C is a curve showing the change in tumor weight after administration; object Compound III 5 The tumor volume and the tumor weight of the group are obviously smaller than those of a positive control medicine group, and the tumor inhibition rate reaches 91.21%;
FIG. 3 is a graph showing the body weight change of nude mice during administration; wherein, the influence of the three high, medium and low dose groups of the compound III5 on the body weight of the nude mice is small, which indicates that the compound has small toxicity;
FIG. 4 is the effect of Compound III5 on normal tissues in nude mice; wherein, after the administration is finished, no pathological structural change is seen in the HE stained section of heart, liver, spleen, lung and kidney tissues of a nude mouse, which indicates that the compound III5 has low toxicity
Detailed Description
The technical solutions in the embodiments of the present invention will be described clearly and completely below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In view of the wide variety of the pyrrolopyridine compounds protected by the invention, the applicant only lists some of the compounds, and other compounds can achieve the following technical effects.
EXAMPLE 1 Compound III 5 The structural formula and the detailed preparation method are as follows:
the preparation method comprises the following steps:
synthesis of 4- (4- (1-hydro-pyrrolo [2,3-b ] pyridin-5-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (10)
Weighing raw materials of 5-bromo-7 azaindole (3.94g,20mmol) and 1- (1-tert-butoxycarbonyl) -piperidyl-4-borate-pyrazole (8.67g,24mmol), putting into a eggplant-shaped bottle, and weighing Pd (PPh) 3 ) 4 (1.2g,1mmol),Na 2 CO 3 (4.24g,40mmol) was charged into 10mL of mixed solvent (dioxane: water ═ 4:1), dissolved with stirring, reacted under nitrogen, 80 ℃ and monitored by TLC (DCM: MeOH ═ 30: 1). After the reaction is finished, extracting the reaction liquid, drying and concentrating an organic phase, preparing sand by silica gel, and performing column chromatography separation (DCM: MeOH is 50:1) to obtain a yellow solid. 1 H NMR(400MHz,CDCl 3 )δ9.39(s,1H),8.43(s,1H),8.00(d,J=2.0Hz,1H),7.80(d,J=2.4Hz,1H),7.68(d,J=1.2Hz,1H),7.33–7.30(m,1H),4.34–4.31(m,1H),2.97–2.87(m,2H),2.22–2.16(m,2H),2.01–1.96(m,2H),1.86–1.80(m,2H),1.48(s,9H).
Synthesis of 4- (4- (3-iodo-1-hydro-pyrrolo [2,3-b ] pyridin-5-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (11)
Weighing 10(3.67g,10mmol) of raw material, putting into a eggplant-shaped bottle, dissolving with dichloromethane, standing at room temperature, starting stirring, after 5min, weighing N-iodosuccinimide (2.7g,12mmol) in batches for multiple times, putting in batches, finishing the adding within 30min, continuing stirring, monitoring by TLC (DCM: MeOH ═ 30:1), quenching reaction after the reaction is finished, extracting with ethyl acetate, drying and concentrating an organic phase, preparing sand by silica gel, performing column chromatography (DCM: MeOH ═ 50:1), and separating to obtain a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ12.07(s,1H),8.55(d,J=2.0Hz,1H),8.43(s,1H),8.00(s,1H),7.82(d,J=2.0Hz,1H),7.70(d,J=2.5Hz,1H),4.42–4.33(m,1H),4.09–4.02(m,2H),2.99–2.89(m,2H),2.11–2.05(m,2H),1.86–1.78(m,2H),1.43(s,9H).
Synthesis of 4- (4- (3-iodo-1-methyl-benzenesulfonyl-1-hydro-pyrrolo [2,3-b ] pyridin-5-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (12)
Weighing raw material 11(4.93g,10mmol) and putting into a solanaceous bottle, dissolving with 10mL DMF, placing in an ice bath, starting stirring, weighing sodium hydride (287.97mg,12mmol) in batches for multiple times, finishing the batch charging for 30min, continuing stirring for 1h, weighing p-methylbenzenesulfonyl chloride (2.29g,12mmol) and putting, continuing stirring, monitoring by TLC (DCM: MeOH ═ 50:1), after the reaction is finished, transferring the reaction liquid into ice water, stirring for 30min, carrying out suction filtration, washing filter residues with water, and obtaining an off-white solid. 1 H NMR(400MHz,DMSO-d 6 )δ8.65(d,J=2.0Hz,1H),8.45(s,1H),8.07(s,1H),8.02(d,J=1.4Hz,1H),7.98(s,1H),7.96(s,1H),7.86(d,J=2.1Hz,1H),7.58(d,J=8.3Hz,1H),7.42–7.35(m,1H),4.37–4.26(m,1H),2.48–2.44(m,2H),2.37–2.34(m,2H),2.28(s,3H),2.04–1.97(m,2H),1.79–1.73(m,2H),1.37(s,9H).
Synthesis of 3-iodo-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -1-methyl-benzenesulfonyl-1H-pyrrolo [2,3-b ] pyridine (13)
Weighing raw material 12(3.24g,5mmol), putting into a eggplant-shaped bottle, dissolving with methanol, stirring at room temperature, taking hydrochloric acid, slowly dropping to excess, monitoring by TLC (DCM: MeOH ═ 20:1), and after the reaction is finished, concentrating the reaction solution to prepare the next reaction.
Synthesis of 3-iodo-5- (1- (1-methyl-piperidin-4-yl) -1H-pyrazol-4-yl) -1-methyl-benzenesulfonyl-1H-pyrrolo [2,3-b ] pyridine (14)
Dissolving the raw material 13 with methanol, adding a stirrer, starting stirring at room temperature, adding a catalytic amount of acetic acid, taking 7mL of formaldehyde solution, dropwise and slowly adding the formaldehyde solution, continuously stirring at room temperature for 2 hours, directly extracting the reaction liquid, and drying and concentrating an organic phase to obtain a white solid.
Putting the white solid into a 25mL eggplant-shaped bottle, dissolving the white solid in methanol, weighing sodium cyanoborohydride (378mg,1.2mmol) in batches for multiple times, adding the sodium cyanoborohydride in batches, stirring at room temperature, monitoring by TLC (DCM: MeOH ═ 20:1), quenching the reaction liquid after the reaction is finished, extracting, drying and concentrating an organic phase, preparing sand by silica gel, and separating by column chromatography (MeOH: DCM ═ 50:1) to obtain the white solid. 1 H NMR(400MHz,CDCl 3 )δ8.57(d,J=2.1Hz,1H),8.10(d,J=8.4Hz,2H),7.87(s,1H),7.81(s,1H),7.75(s,1H),7.67(d,J=2.1Hz,1H),7.31(d,J=7.8Hz,2H),4.23–4.17(m,1H),3.06–3.00(m,2H),2.39(s,3H),2.38(s,3H),2.23–2.20(m,2H),2.14–2.09(m,2H),1.30–1.24(m,2H).
Synthesis of 1- ((3-bromo-phenyl) ethynyl) cyclohexyl-1-ol (III) 5a )
Weighing m-bromoiodobenzene (1.41g,5mmol), 1-ethynylcyclohexanol (745.1mg,6mmol), cuprous iodide (95.23mg,0.5mmol), triethylamine (1.01g,10mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (183mg,0.25mmol) and 5mL of tetrahydrofuran were dissolved and reacted at 70 ℃ under nitrogen. TLC monitoring (PE: EA is 5:1), extracting reaction liquid after the reaction is finished, drying and concentrating an organic phase, preparing sand by silica gel, and performing column chromatography separation (PE: EA is 5:1) to obtain a yellow solid. 1 H NMR(400MHz,CDCl 3 )δ7.58(t,J=1.8Hz,1H),7.44(m,1H),7.35(m,1H),7.17(t,J=8.0Hz,1H),2.08–1.95(m,4H),1.64–1.56(m,6H).
Synthesis of 1- (3-boronic acid ester-phenyl) -ethynyl-cyclohexan-1-ol (III) 5b )
Weighing III 5a (1.4g,5mmol), pinacol diboron (1.52g,6mmol), potassium acetate (981.42mg,10mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (183mg,0.25mmol) was dissolved in 5mL DMSO and reacted at 90 ℃ under nitrogen. TLC monitoring (PE: EA: 5:1), ready for reactionAfter that, the reaction solution is extracted, the organic phase is dried and concentrated, silica gel is used for preparing sand, and column chromatography separation is carried out (PE: EA is 5:1), so as to obtain white solid. 1 H NMR(400MHz,CDCl 3 )δ7.91(s,1H),7.76(m,1H),7.54(m,1H),7.34(t,J=7.5Hz,1H),1.78–1.72(m,4H),1.63–1.54(m,6H),1.37(s,12H).
1- ((3- (5- (1- (1-methyl-piperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2, 3-b)]Synthesis of pyridin-3-yl) phenyl) ethynyl) cyclohexyl-1-ol (III) 5 )
Weighing raw material III 5b (200g,0.35mmol), 14(140mg,0.14mmol), sodium carbonate (75mg,0.70mmol) were put into a 100ml round bottom flask, tetrakis (triphenylphosphine) palladium (40mg,0.035mmol) was weighed into a reaction flask, dissolved in a mixed solvent (dioxane: water: 4:1) under nitrogen, reacted at 80 ℃, monitored by TLC (DCM: MeOH ═ 20:1), after the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried, concentrated, granulated on silica gel, and separated by column chromatography (DCM: MeOH ═ 40:1) to give a pale white solid.
The product obtained in the previous step (100mg,0.15mmol) and potassium carbonate (23mg,0.15mmol) were put into a 50ml round-bottom flask, dissolved in a mixed solvent (methanol: water ═ 4:1), refluxed at 60 ℃ for 5 hours, monitored by TLC (DCM: MeOH ═ 15:1), and after completion of the reaction, the reaction solution was extracted with ethyl acetate, dried and concentrated in an organic phase, granulated on silica gel, and separated by column chromatography (DCM: MeOH ═ 40:1) to obtain a white solid.
Compound III 5 White solid product, 0.512g, yield 65.07%. 1 H NMR(400MHz,MeOD)δ8.50(d,J=2.0Hz,1H),8.38(d,J=2.0Hz,1H),8.20(s,1H),7.92(s,1H),7.77–7.68(m,3H),7.46(t,J=7.7Hz,1H),7.35(m,J=7.7Hz,1H),4.25(m,J=5.1Hz,1H),3.23(s,1H),3.05(d,2H),2.37(s,3H),2.28(t,J=3.3Hz,2H),2.23–2.11(m,4H),2.02(d,2H),1.78(d,J=4.3Hz,1H),1.69(t,3H),1.63(d,J=7.2Hz,1H),1.35(s,1H),1.30(s,1H).HRMS(ESI)m/z[M-H] + :478.2607,found:478.2593.Retention time 2.612min,HPLC purity=98.255%.
EXAMPLE 2 Compound III 4 The structural formula and the detailed preparation method are as follows:
the preparation method comprises the following steps:
wherein III 4a With reference to example 1, 1-ethynylcyclohexanol was replaced with 1-ethynylcyclopentanol, and the synthetic route was as follows:
m-bromoiodobenzene (1.41g,5mmol), 1-ethynylcyclopentanol (660.94mg,6mmol), cuprous iodide (95.23mg,0.5mmol), triethylamine (1.01g,10mmol), [1,1' -bis (diphenylphosphino) ferrocene ], palladium dichloride (183mg,0.25mmol), tetrahydrofuran dissolved, displaced with nitrogen for 5min, reacted at 70 ℃ overnight. TLC detection (PE: EA is 5:1) until the raw material completely reacts, extracting the reaction solution, drying and concentrating the organic phase, preparing sand from silica gel, and performing column chromatography separation (PE: EA is 5:1) to obtain a yellow solid.
Wherein III 4b Reference example 1, the synthetic route is as follows:
weighing III 4a (1.2g,5mmol), pinacol diboron (1.52g,6mmol), potassium acetate (981.42mg,10mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (183mg,0.25mmol), 5mL DMSO, nitrogen protection, 90 ℃ reaction. TLC monitoring (PE: EA is 5:1), extracting reaction liquid after the reaction is finished, drying and concentrating an organic phase, preparing sand by silica gel, and performing column chromatography separation (PE: EA is 5:1) to obtain a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.89(d,J=1.6Hz,1H),7.72(m,1H),7.50(m,1H),7.30(t,J=7.6Hz,1H),2.03(m,4H),1.86–1.84(m,2H),1.81–1.74(m,2H),1.34(s,12H).
Wherein III 4 Reference example 1, the synthetic route is as follows:
weighing raw material III 4b (198mg,0.63mmol), 14(300mg,0.53mmol), sodium carbonate (112mg,1.06mmol) were put into a 100ml eggplant-shaped bottle, tetrakis (triphenylphosphine) palladium (31mg,0.026mmol) was weighed into a reaction bottle, dissolved in a mixed solvent (dioxane: water ═ 4:1), reacted at 80 ℃, monitored by TLC (DCM: MeOH ═ 20:1), after the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried and concentrated, silica gel was made into sand, and column chromatography was performed (DCM: MeOH ═ 40:1) to obtain a white solid.
Adding the product (100mg,0.16mmol) obtained in the previous step and potassium carbonate (72mg,0.48mmol) into a 50ml round-bottom flask, dissolving with a mixed solvent (methanol: water ═ 4:1), refluxing at 60 ℃ for 5h, monitoring by TLC (DCM: MeOH ═ 15:1), extracting the reaction solution with ethyl acetate after the reaction is finished, drying and concentrating the organic phase, preparing sand with silica gel, and separating by column chromatography (DCM: MeOH ═ 40:1) to obtain a white solid III 4 。
1- ((3- (5- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2, 3-b)]Pyridin-3-yl) phenyl) ethynyl) cyclopentan-1-ol (III) 4 ) 0.37g of white solid, yield 50.07%, 1 H NMR(400MHz,MeOD)δ8.48(d,J=2.0Hz,1H),8.36(d,J=2.0Hz,1H),8.18(s,1H),7.91(s,1H),7.72-7.65(m,3H),7.43(t,J=7.7Hz,1H),7.32(d,J=7.7Hz,1H),3.21(s,1H),3.07-2.99(m,2H),2.35(s,3H),2.31-2.22(m,2H),2.19-2.12(m,4H),2.03(d,J=6.5Hz,4H),1.90-1.76(m,4H).HRMS(ESI)m/z[M-H] + :464.2456,found:464.2430.Retention time 2.55min,HPLC purity=97.681%.
EXAMPLE 3 Compound III 1 The structural formula and the detailed preparation method are as follows:
(3-bromophenyl) methanol (935.18mg,5mmol), pinacol diboron (1.52g,6mmol), potassium acetate (981.42mg,10mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (183mg,0.25mmol) and 5mL of DMSO were weighed out and dissolved in nitrogen to react at 90 ℃. TLC monitoring (PE: EA is 5:1), extracting reaction liquid after the reaction is finished, drying and concentrating an organic phase, preparing sand by silica gel, and performing column chromatography separation (PE: EA is 5:1) to obtain a white solid.
Wherein III 1 Reference example 1, the synthetic route is as follows:
weighing raw material III 1b (150mg,0.64mmol), 14(300mg,0.53mmol), sodium carbonate (112mg,1.06mmol) were put into a 100ml round bottom flask, tetrakis (triphenylphosphine) palladium (31mg,0.026mmol) was weighed into a reaction flask, dissolved in a mixed solvent (dioxane: water ═ 4:1), reacted at 80 ℃ under nitrogen protection, monitored by TLC (DCM: MeOH ═ 20:1), after the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried, concentrated, made into silica gel, and separated by column chromatography (DCM: MeOH ═ 40:1) to obtain a pale yellow solid.
The product from the previous step (150mg,0.28mmol), potassium carbonate (129mg,0.84mmol) were charged into a 50ml round bottom flask, dissolved in mixed solvent (methanol: water ═ 4:1), refluxed at 60 ℃ for 5h, monitored by TLC (DCM: MeOH ═ 15: 1). After the reaction was completed, ethyl acetate was extracted, the organic phase was dried, concentrated, silica gel-granulated, and separated by column chromatography (DCM: MeOH ═ 40:1) to give a white solid powder.
(3- (5- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) phenyl) methanol (III) 1 ) White solid powder, 0.131gThe yield is 68.11 percent, 1 H NMR(400MHz,CDCl 3 )δ10.74(s,1H),8.54(s,1H),8.24(d,J=1.8Hz,1H),7.97(s,1H),7.78(d,J=0.7Hz,1H),7.66(d,J=2.0Hz,1H),7.61–7.57(m,1H),7.50–7.45(m,2H),7.33(d,J=7.7Hz,1H),4.80(s,2H),4.32–4.26(m,1H),2.25–2.17(m,4H),1.87(s,4H).HRMS(ESI)m/z[M-H] + :386.1986,found:386.2004.Retention time 2.091min,HPLC purity=98.713%.
EXAMPLE 4 Compound III 2 The structural formula and the detailed preparation method are as follows:
the preparation method comprises the following steps:
the compound 14 was prepared as in example 1, the synthetic route is as follows:
(3-bromophenyl) methanol (935.18mg,5mmol), pinacol diboron (1.52g,6mmol), potassium acetate (981.42mg,10mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (183mg,0.25mmol) and 5mL of DMSO were weighed out and dissolved in nitrogen to react at 90 ℃. TLC monitoring (PE: EA is 5:1), extracting reaction liquid after the reaction is finished, drying and concentrating an organic phase, preparing sand by silica gel, and performing column chromatography separation (PE: EA is 5:1) to obtain a white solid.
Wherein III 2b Reference example 1, the synthetic route is as follows:
3-Borate-benzoic acid (496.17mg,2mmol), 3-amino-2-methoxy-pyridine (297.94mg,2.4mmol), HATU (564.65mg,2,4mmol), DIPEA (516.97mg,4mmol), 3mL DMF were weighed, dissolved, stirred at room temperature, monitored by TLC (PE: EA ═ 1:1), and after the reaction was completed, the reaction solution was extracted, the organic phase was dried and concentrated, and silicon was addedAnd (4) preparing sand by gluing, and performing column chromatography separation (PE: EA is 1:1) to obtain a white solid. 1 H NMR(400MHz,CDCl 3 ):δ8.72(d,J=9.6Hz,1H),8.42(s,1H),8.28(s,1H),7.99(d,J=9.1Hz,2H),7.90(d,J=1.9Hz,1H),7.51(t,J=7.6Hz,1H),6.95(dd,J=7.8,5.0Hz,1H),4.05(s,3H),3.97(s,1H),1.36(s,12H).
Wherein III 2 Reference example 1, the synthetic route is as follows:
weighing raw material III 2b (227mg,0.64mmol), 14(300mg,0.53mmol), sodium carbonate (112mg,1.06mmol) are put into a 100ml round bottom flask, tetrakis (triphenylphosphine) palladium (31mg,0.026mmol) is weighed into a reaction bottle, dissolved by a mixed solvent (dioxane: water ═ 4:1), protected by nitrogen, reacted at 80 ℃, monitored by TLC (DCM: MeOH ═ 20:1), after the reaction is finished, the reaction solution is extracted by ethyl acetate, an organic phase is dried, concentrated, granulated by silica gel, and separated by column chromatography (DCM: MeOH ═ 40:1), so that a light yellow solid is obtained.
Adding the product (150mg,0.23mmol) obtained in the previous step and potassium carbonate (106mg,0.69mmol) into a 50ml round-bottom flask, dissolving with a mixed solvent (methanol: water ═ 4:1), refluxing at 60 ℃ for 5h, monitoring by TLC (DCM: MeOH ═ 15:1), extracting the reaction solution with ethyl acetate after the reaction is finished, drying and concentrating the organic phase, preparing sand with silica gel, and separating by column chromatography (DCM: MeOH ═ 40:1) to obtain white solid powder III 2 。
N- (2-methoxypyridin-3-yl) -3- (5- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) benzamide (III) 2 ) White solid, 0.62g, yield 61.37%, 1 H NMR(400MHz,CDCl 3 )δ10.75(s,1H),8.78(dd,J=7.8,1.7Hz,1H),8.63(d,J=2.0Hz,1H),8.49(s,1H),8.30(d,J=2.0Hz,1H),8.20(t,J=1.8Hz,1H),8.06(s,1H),7.92–7.76(m,4H),7.65–7.60(m,2H),6.98(dd,J=7.8,5.0Hz,1H),4.04(s,3H),2.51(s,3H),2.36–2.14(m,4H).HRMS(ESI)m/z[M-H] + :506.2304,found:506.2322.Retention time 2.439min,HPLC purity=98.867%.
EXAMPLE 5 Compound III 3 The structural formula and the detailed preparation method are as follows:
the preparation method comprises the following steps:
weighing (3-bromophenyl) formic acid (1.05g,5mmol), pinacol diboron (1.52g,6mmol), potassium acetate (981.42mg,10mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (183mg,0.25mmol), dissolving in DMSO (5 mL), and reacting at 90 ℃ under nitrogen protection. TLC (PE: EA: 5:1), extracting the reaction solution after the reaction is finished, drying and concentrating an organic phase, preparing sand by silica gel, and performing column chromatography separation (PE: EA: 5:1) to obtain a yellow solid.
Wherein III 3b Reference example 1, the synthetic route is as follows:
3-boronate-benzoic acid (496.17mg,2mmol), 2-amino-1- (329.24mg,2.4mmol), HATU (564.65mg,2,4mmol), DIPEA (516.97mg,4mmol) and 3mL of DMF were weighed and dissolved, stirred at room temperature, monitored by TLC (PE: EA ═ 1:1), and after the reaction was completed, the reaction solution was extracted, the organic phase was dried and concentrated, and subjected to silica gel sand preparation and column chromatography (PE: EA ═ 1:1) to obtain a white solid. 1 H NMR(400MHz,CDCl 3 ):δ8.13(t,J=1.4Hz,1H),7.98–7.91(m,2H),7.47–7.34(m,6H),6.91(s,1H),3.94–3.86(m,1H),3.56–3.48(m,1H),1.35(s,12H).
Wherein III 2 Reference example 1, the synthetic route is as follows:
weighing raw material III 3b (235mg,0.64mmol), 14(300mg,0.53mmol), sodium carbonate (112mg,1.06mmol) were put into a 100ml round bottom flask, tetrakis (triphenylphosphine) palladium (31mg,0.026mmol) was weighed into a reaction flask, dissolved in a mixed solvent (dioxane: water ═ 4:1), reacted at 80 ℃ under nitrogen protection, monitored by TLC (DCM: MeOH ═ 20:1), and after the reaction was completed, the reaction solution was extracted with ethyl acetate, and the organic phase was dried, concentrated, made into silica gel, and separated by column chromatography (DCM: MeOH ═ 40:1) to obtain a pale yellow solid.
Adding the product (150mg,0.22mmol) obtained in the previous step and potassium carbonate (101mg,0.66mmol) into a 50ml round-bottom flask, dissolving with a mixed solvent (methanol: water ═ 4:1), refluxing at 60 ℃ for 5h, monitoring by TLC (DCM: MeOH ═ 15:1), extracting the reaction solution with ethyl acetate after the reaction is finished, drying and concentrating the organic phase, preparing sand with silica gel, and separating by column chromatography (DCM: MeOH ═ 40:1) to obtain white solid powder III 3 。
(S) -N- (2-hydroxy-2-phenylethyl) -3- (5- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) benzamides (III) 3 ) White solid, 0.33g, yield 51.98%, 1 H NMR(400MHz,CDCl 3 )δ8.48(d,J=2.0Hz,1H),8.36(d,J=2.0Hz,1H),8.18(s,1H),7.92(s,1H),7.71–7.65(m,3H),7.44(t,J=7.7Hz,1H),7.32(d,J=7.7Hz,1H),7.17–7.11(m,5H),5.36(s,1H),5.34(s,1H),4.30(t,J=6.7Hz,1H),3.49(s,2H),2.54(d,J=16.0Hz,4H),2.00(d,J=6.6Hz,4H).HRMS(ESI)m/z[M-H] + :519.2508,found:519.2521.Retention time 2.105min,HPLC purity=98.397%.
the following are some of the pharmacological tests and results of representative compounds of the invention:
1. CCK-8 method for detecting proliferation inhibition effect of target compound on tumor cells
Tumor cells are digested by trypsin, the cells are counted by a cell counting plate, 100 mu L PBS is added into 36 holes around a 96-hole plate to prevent water evaporation, and 5000-10000 cells are paved in each other hole. Cell plasterAfter the wall, complete medium containing the specified concentration of compound was added and the mixture was left at 37 ℃ with 5% CO 2 Culturing in a cell culture box for 48 h. After 48 hours, the culture medium in a 96-well plate is discarded, and 90 mu L of complete culture medium and 10 mu L of CCK-8 solution are added into each well in a dark place and mixed evenly. The 96-well plate was placed in a cell incubator for 0.5,1,2,4h incubation. The OD value was measured with the wavelength of the microplate reader set at 450nm, and the experiment was repeated three times. Relative inhibition rate (OD control-OD experimental group)/(OD control-OD blank group) × 100%. Calculating IC according to the Kouzhou's method 50 The value, i.e., the drug concentration at which the cell growth inhibition rate was 50%. The specific growth inhibitory effect is shown in table 1.
TABLE 1 Effect of Compounds on the antiproliferative potential of different tumor cell lines
The CCK-8 experimental results in table 1 show that the compound provided by the invention has obvious proliferation inhibition effects on human colorectal cancer cells HCT-116, human breast cancer cells MCF-7, human kidney cancer cells 786O and human liver cancer cells HepG 2.
Wherein the compound III 2 Half maximal inhibitory concentrations on MCF-7 cells and 786O cells were 0.44 and 0.83. mu.M, respectively; compound III 4 Half maximal inhibitory concentration to 786O cells was 0.95 μ M; compound III 5 The half inhibition concentrations of HCT-116 cells, MCF-7 cells, 786O cells and HepG2 cells are respectively 0.44 mu M, 0.27 mu M, 0.65 mu M and 0.45 mu M, and the inhibition effect is superior to positive control drugs of Sunitinib and 5-fluorouracil (5-FU), which indicates that the derivative taking pyrrolopyridine as a framework provided by the invention has stronger inhibition effect on tumor cells and achieves the nanomolar level as a whole.
2. HTRF KinEASE kit for investigating inhibitory effect of compound on PAK5 kinase activity
The method comprises the following two steps: the first step is an enzymatic reaction step in which the PAK5 kinase substrate-2-biotin complex is incubated with the enzyme and ATP is added to start the enzymatic reaction. The second step is that the monitoring reagent captures the phosphorylated substrate. The resultant TR-FRET signalAdding Eu labeled in proportion to phosphorylation level 3+ Antibodies to Cryptate and streptavidin-XL 665 terminate kinase activity. Inhibition rate ═ max-test)/(max-min) × 100% ("max" means no compound control and "min" means no compound no kinase control).
We evaluated the inhibitory effect of compounds on PAK5 kinase using the HTRF KinEASE kit. The inhibition rate of the compound on PAK5 reaches 50% under the condition of 100nM, and the compound III under the condition of 1 mu M 1 、III 2 、III 3 The inhibition rate of PAK5 is more than 80%, and other compounds not shown have similar effect. We select compounds III4 and III5 with better inhibition effect to evaluate half inhibition, and find that the compound III 4 、III 5 Half-inhibitory concentrations of PAK5 reached 14nM and 8nM, respectively, similar to the positive control sunitinib (results are shown in table 2).
TABLE 2 inhibitory Activity of the Compounds on PAK5 kinase
a The results are expressed as Mean ± standard deviation (Mean ± SD) for the concentration of compound corresponding to half inhibition of kinase activity, which was repeated three times.
3. CCK-8 method for determining cytotoxicity of compound on normal cells
Normal human tubular epithelial cells HK-2 in logarithmic growth phase in the pancreatin dish were counted on a counter plate and seeded in a 96-well plate. 3000-6000 cells were plated in each well except the peripheral wells which were only added with 200. mu.L PBS; set 4 duplicate wells, add 100 μ Ι _ of complete medium of 10% FBS per well; after the cells are attached to the wall, the culture medium in a 96-well plate is discarded by reversing, the culture medium containing compounds with different concentrations is added, the mixture is placed at 37 ℃ and 5 percent CO 2 Culturing for 48h in an incubator; discarding the old culture medium in the 96-well plate after 48h, adding 90 mu L of serum-free culture medium and 10 mu L of CCK-8 solution into each well, uniformly mixing, and keeping out of the sun; putting into an incubator for continuous incubation for 0.5,1,2 and 4 hours; reading at 450 using a microplate readerOptical Density (OD) was measured at nm wavelength, in triplicate.
We examined the target compound III by the CCK-8 method 5 And III 4 The cytotoxicity to HK-2, a normal human tubular epithelial cell, is shown in FIG. 1. The survival rates of HK-2 cells in groups III4 and III5 are 70.48 percent and 76.33 percent respectively when the concentration of the compound is 1 mu M, which is higher than the cell survival rate of 63.75 percent of 5-FU; when the concentration of the compound is 5 mu M, the cell survival rate of the III4 and III5 groups is 30 percent, which is close to 34.95 percent of the 5-FU group, and the difference has statistical significance, thereby indicating that the compound has better safety. Other compounds of the invention also have similar effects.
4. In vivo tumor inhibition effect of compound is investigated by adopting xenograft tumor nude mouse model
For further evaluation of the object Compound III 5 Anti-tumor effect in animals. We evaluated the in vivo tumor suppression effect of compound III5 using in vivo experiments with HepG2 cell nude mouse subcutaneous tumors. 30 BALB/C nude mice (male, SPF grade, 18-22g) were inoculated subcutaneously into the right axilla of each nude mouse at 5X 10 6 Individual HepG2 cells, established tumor bearing animal model. The subcutaneous tumors grow to 100- 3 Then, the nude mice were randomly divided into 5 groups, namely a control group (Vehicle), a positive control drug sunitinib (20mg/kg) group and a target compound III 5 High, medium, and low concentration groups (50mg/kg, 35mg/kg, and 20 mg/kg). The administration was carried out by tail vein injection once a day for 16 days, and the tumor size and body weight of each nude mouse were measured every day to determine the major diameter (a) and the minor diameter (b) of the tumor in the mouse. Nude mice were sacrificed 16 days after administration using a decapitation method, tumor tissues and normal tissues were taken out, and hematoxylin-eosin staining (H) was performed&E) In that respect According to the tumor volume calculation formula: 1/2 × a × b 2 And calculating the tumor volume and obtaining the tumor inhibition rate, and simultaneously performing statistical t-test analysis. The results are shown in FIGS. 2-4.
FIG. 2A is a graph of tumors in nude mice. As shown in the figure, compound III 5 The group showed a significant reduction in tumor size compared to the placebo group. At the same dose, 20mg/k of Compound III 5 The tumor size of the administration group is equivalent to the treatment effect of the positive control drug sunitinib group. Height ofConcentration of Compound III 5 The tumor volume in the administered group (50mg/kg) was minimal, indicating that a dose-dependent relationship exists.
Fig. 2B is a graph of tumor volume change. As shown in the figure, the tumor volume of the blank group increased exponentially with time, whereas the tumor volume of the administered group was significantly smaller than that of the control group. At the same dosing concentration, Compound III 5 Compared with the positive control drug group, the tumor inhibition rate of the group is improved to a certain extent, and the group is in a dose dependent relationship.
Fig. 2C is a graph of tumor weight change. As shown in the figure, the tumor weight was reduced to a different extent in the administered group than in the blank group. At the same dosing concentration, Compound III 5 The average tumor weight of the administered group is reduced by 0.15g compared with that of the positive control drug sunitinib group. The tumor weight is reduced along with the increase of the administration dosage, and when the administration dosage is 50mg/kg, the tumor inhibition rate reaches 91.21 percent.
FIG. 3 is a graph showing the body weight change of each group of tumor-bearing nude mice during the administration period. As shown, no significant change in body weight occurred during the administration period in nude mice, indicating that compound III5 has low toxicity.
FIG. 4 is a section of normal tissues of nude mice stained by HE after the end of administration, in which hematoxylin dye stains mainly the nucleus of tumor cells bluish purple, and eosin dye stains mainly the cytoplasm and extracellular matrix red. The results show that each group has a relatively compact cell mass, the cell nucleus is complete, the cell morphology is normal, and the compound III5 does not cause pathological damage to the heart, liver, spleen, lung, kidney and other major organs of a nude mouse and has biosafety in vivo.
The above examples are only intended to illustrate the technical solution of the present invention, and not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications of the technical solutions described in the foregoing embodiments are still possible, or some technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. A compound, isomer, hydrate, solvate or pharmaceutically acceptable salt thereof of formula I:
wherein the content of the first and second substances,
R 1 represents hydrogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy, acryloyl, propenyl, or tert-butoxycarbonyl;
R 2 represents hydrogen, hydroxy, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy, halogen or trifluoromethyl;
L 1 represents-CH 2 -、-CO-NH-、-CO-NH-CH 2 -c (oh) -, vinyl, ethynyl, nitrogen atom, hydrazide or sulfonyl hydrazide;
n represents 0, 1 or 2;
ring A represents piperidine, piperazine, morpholine, pyrrole or furan;
ring B represents phenyl or a five-membered nitrogen-containing heterocycle;
ring C represents phenyl, naphthyl or biphenyl;
and ring D represents an oxygen atom, phenyl, cyclopentane, cyclohexane, pyridine or pyrimidine.
2. A compound, isomer, hydrate, solvate or pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Represents hydrogen, methyl, ethyl, methoxy or ethoxy; preferably, R 1 Represents a methyl group; r 2 Represents hydrogen, hydroxy, methyl, ethyl, methoxy or ethoxy; preferably, R 2 Represents hydrogen, hydroxy or methoxy.
3. A compound, isomer, hydrate, solvate or pharmaceutically acceptable salt thereof according to claim 1, wherein L 1 represents-CH 2 -、-CO-NH-、-CO-NH-CH 2 -c (oh) -, ethenyl, ethynyl or hydrazide; preferably, L 1 Represent-CH 2 -、-CO-NH-、-CO-NH-CH 2 -c (oh) -or ethynyl; n represents 0 or 1; preferably, n represents 0.
4. A compound, isomer, hydrate, solvate or pharmaceutically acceptable salt thereof according to claim 1, wherein ring a represents piperidine, piperazine or morpholine; preferably, ring a represents piperidine; ring B represents phenyl, pyrazole, oxazole, thiazole, imidazole or pyrrole; preferably, ring B represents pyrazole.
5. The compound, isomer, hydrate, solvate or pharmaceutically acceptable salt thereof according to claim 1, wherein ring C represents phenyl; ring D represents an oxygen atom, phenyl, cyclopentane, cyclohexane, pyridine or pyrimidine; preferably, ring D represents an oxygen atom, phenyl, cyclopentane, cyclohexane or pyridine.
6. A compound, isomer, hydrate, solvate or pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Represents a methyl group; r 2 Represents hydrogen, hydroxy or methoxy; l is a radical of an alcohol 1 represents-CH 2 -、-CO-NH-、-CO-NH-CH 2 -c (oh) -or ethynyl; n represents 0; ring A represents piperidine; ring B represents pyrazole; ring C represents phenyl; and ring D represents an oxygen atom, phenyl, cyclopentane, cyclohexane or pyridine.
8. a process for the preparation of the compound according to claim 1,
when ring A represents piperidine, ring B represents pyrazole, ring C represents phenyl, L 1 Represents ethynyl and R 1 When representing methyl, the preparation method of the compound shown in the general formula I comprises the following steps:
9. a pharmaceutical composition comprising a compound, isomer, hydrate, solvate or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 as an active ingredient or as a main active ingredient, in association with a pharmaceutically acceptable carrier.
10. Use of a compound, isomer, hydrate, solvate or pharmaceutically acceptable salt thereof according to any of claims 1-7 for the manufacture of a medicament for the treatment of a disease associated with the serine/threonine kinase PAK 5; preferably, the silk/threonine kinase PAK 5-related disease is colorectal cancer, liver cancer, gastric cancer, breast cancer, renal cancer or cervical cancer.
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CN101027302A (en) * | 2004-07-27 | 2007-08-29 | Sgx药物公司 | Pyrrolo-pyridine kinase modulators |
CN109069516A (en) * | 2016-02-01 | 2018-12-21 | 哈佛学院校长同事会 | Small molecule for mouse satellite cell Proliferation |
CN112243439A (en) * | 2018-06-13 | 2021-01-19 | 百济神州有限公司 | Pyrrolo [2,3-B ] pyridines or pyrrolo [2,3-B ] pyrazines as HPK1 inhibitors and uses thereof |
US20210040091A1 (en) * | 2018-03-01 | 2021-02-11 | The Trustees Of Columbia University In The City Of New York | Compounds, compositions, and methods for suppressing toxic endoplasmic reticulum stress |
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CN101027302A (en) * | 2004-07-27 | 2007-08-29 | Sgx药物公司 | Pyrrolo-pyridine kinase modulators |
CN109069516A (en) * | 2016-02-01 | 2018-12-21 | 哈佛学院校长同事会 | Small molecule for mouse satellite cell Proliferation |
US20210040091A1 (en) * | 2018-03-01 | 2021-02-11 | The Trustees Of Columbia University In The City Of New York | Compounds, compositions, and methods for suppressing toxic endoplasmic reticulum stress |
CN112243439A (en) * | 2018-06-13 | 2021-01-19 | 百济神州有限公司 | Pyrrolo [2,3-B ] pyridines or pyrrolo [2,3-B ] pyrazines as HPK1 inhibitors and uses thereof |
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