CN116535395A - 2H-indazole-7-carboxamide compounds, preparation method, pharmaceutical composition and application - Google Patents

2H-indazole-7-carboxamide compounds, preparation method, pharmaceutical composition and application Download PDF

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CN116535395A
CN116535395A CN202210094416.9A CN202210094416A CN116535395A CN 116535395 A CN116535395 A CN 116535395A CN 202210094416 A CN202210094416 A CN 202210094416A CN 116535395 A CN116535395 A CN 116535395A
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indazole
carboxamide
trifluoromethyl
acid
piperazin
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徐云根
郝海平
邹毅
古宏峰
汪勇
严文昕
朱启华
王洪
黄磊
苏宇佩
许文博
杨解平
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China Pharmaceutical University
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a 2H-indazole-7-carboxamide compound, a preparation method, a pharmaceutical composition and application. The structure of the compound is shown as a formula (I), and the compound comprises an isomer, pharmaceutically acceptable salt or a mixture thereof.The compound and the pharmaceutical composition thereof have excellent pharmacokinetic properties in vivo, have high-efficiency inhibition effect on PARP7 and various tumor cells, and the prepared antitumor drug can exert good drug effect at molecular level and cell level, can promote the release of immune factors, and particularly has excellent antitumor activity in vivo; in addition, the preparation method of the compounds is simple, convenient and feasible.

Description

2H-indazole-7-carboxamide compounds, preparation method, pharmaceutical composition and application
Technical Field
The invention relates to a 2H-indazole-7-carboxamide compound, a preparation method, a pharmaceutical composition and application thereof, in particular to a 2H-indazole-7-carboxamide compound which is used as a PARP7 inhibitor and has anti-tumor activity, a preparation method, a pharmaceutical composition and application thereof.
Background
Studies have shown that most PARP family members of the human body exhibit mono adp ribose transferase activity. The monoprp protein family is closely related to the development of cancer, inflammation and neurodegenerative diseases. PARP7 is one of the members of the monoprop protein family, a novel negative regulator of nucleic acid sensors in cells that is overexpressed in a variety of tumor cells. Since cancer cells can "harbor" the immune system by inhibiting interferon signaling with PARP-7, many cancer cells rely on PARP-7 to survive. It was found that inhibiting PARP7 restores intracellular interferon signaling, restores the innate and adaptive immunity of the body, and thereby inhibits the growth of cancer cells. PARP7 inhibitors exhibit a durable tumor growth inhibiting effect in cancer models such as lung cancer, colorectal cancer and the like.
No PARP-7 inhibitor is approved to be marketed, RBN-2397 developed by Ribon company is the first compound with strong inhibition activity and selectivity to PARP-7, and clinical phase I study (NCT 04053673) is currently entered. However, RBN-2397 has high in vivo clearance, resulting in low in vivo exposure and oral bioavailability, and its in vivo efficacy in animals suggests that RBN-2397 alone is difficult to exert an antitumor effect, and it must be combined with CYP450 inhibitors to reduce its clearance rate.
Disclosure of Invention
The invention aims to: aiming at the defects of poor pharmacokinetic property, difficult single drug action and the like of the existing compounds, the invention aims to provide a class of 2H-indazole-7-carboxamide compounds with excellent anti-tumor activity and pharmacokinetic property, a preparation method, a pharmaceutical composition and application.
The technical scheme is as follows: as a first aspect to which the present invention relates, the 2H-indazole-7-carboxamide compounds of the present invention have the structure of formula (I), said compounds comprising an isomer, a pharmaceutically acceptable salt thereof or a mixture thereof:
wherein:
n is selected from 0, 1, 2, 3 or 4;
m is selected from 0 or 1;
R 1 or R is 2 Are independently selected from hydrogen, C 1 ～C 6 Alkyl, substituted C 3 ～C 6 Cycloalkyl or heterocycloalkyl, cyanoA radical, halogen, difluoromethyl, trifluoromethyl, or R 1 And R is 2 Together with the carbon atoms to which they are attached form C 3 ～C 6 Cycloalkyl; the C is 3 ～C 6 The substituent of the cycloalkyl is selected from hydrogen, methyl, trifluoromethyl, 2-difluoroethyl, methoxy, halogen, cyano, amino, methylamino, dimethylamino, diethylamino, acetamido, hydroxy, acetoxy, carboxyl or methoxycarbonyl, and one or more of the substituents;
A 1 selected from the group consisting of-NH-, -O-, -CH 2 -、C 3 ～C 6 Cycloalkyl or heterocycloalkyl or a 5-to 10-membered aromatic or heteroaromatic ring; wherein the C 3 ～C 6 Cycloalkyl or heterocycloalkyl or any position of a 5-to 10-membered aromatic or heteroaromatic ring is substituted with one or more of the following groups: hydrogen, halogen, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, trifluoromethanesulfonyl, methanesulfonyl, cyano, hydroxy, amino, methylamino, dimethylamino, diethylamino, acetamido, carboxamido, nitro, methoxy or ethoxy;
A 2 selected from:
wherein R is 3 、R 4 Or R is 5 Each independently selected from hydrogen, methyl, trifluoromethyl, cyano, hydroxy, methoxy, amino, methylamino, dimethylamino, acetamido, carboxyl, or methoxycarbonyl;
r is selected from aryl, heteroaryl or 1, 3-benzodioxan substituted at any position with one or more of the following groups: hydrogen, halogen, cyano, trifluoromethyl, 2-difluoroethyl, C 1 ～C 6 Alkyl, C of (2) 1 ～C 6 Alkoxy, hydroxy, methoxy, amino, methylamino, dimethylamino, acetamido, carboxyl, methoxycarbonyl or nitro.
Preferably, in the above structure:
n is selected from 0, 1, 2 or 3;
R 1 or R is 2 Each independently selected from hydrogen, methyl, fluoro or ethyl; when R is 1 And R is 2 Different from R 1 And R is 2 The carbon atoms are racemized, R-shaped or S-shaped;
A 1 selected from:
wherein X is 1 、X 2 Or X 3 Each independently selected from CH or N, R 6 Selected from one or more of hydrogen, halogen, methyl, ethyl, isopropyl, difluoromethyl, difluoromethylsulfonyl, trifluoromethyl, trifluoromethylsulfonyl, methanesulfonyl, cyano, hydroxy, amino, methylamino, dimethylamino, diethylamino, acetamido, carboxamido, nitro, methoxy or ethoxy;
A 2 selected from:
r is selected from:
wherein Y is 1 And Y 2 Each independently represents CH or N, R 7 Selected from one or more of hydrogen, trifluoromethyl, methyl, fluoro, chloro, bromo, cyano, methoxy, methanesulfonyl, 2-difluoroethyl or 4-trifluoromethylphenyl.
More preferably, in the above structure:
R 1 or R is 2 Independently selected from hydrogen or methyl, when R 1 And R is 2 Different from R 1 And R is 2 The carbon atoms connected are in racemization configuration;
A 1 selected from:
A 2 selected from:
preferably, in the above structure:
r is selected from:
more specifically, the 2H-indazole-7-carboxamide compound is selected from any one of the following compounds:
the pharmaceutically acceptable salt of the 2H-indazole-7-carboxamide compound is a salt of the compound with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, or ferulic acid.
As a second aspect of the present invention, the preparation method of the 2H-indazole-7-carboxamide compound described above is:
the compound (II) and the compound (III) are subjected to substitution, hydrolysis and acylation reaction to obtain a compound (I);
wherein m, n, A 1 、Y 1 、Y 2 、R 1 、R 2 、R 4 、R 5 、R 7 Is as defined above;
specifically, the compound II is used for preparing the compound IV by dissolving II and III in a solvent, and adding an acid binding agent for substitution reaction. The reaction solvent is N, N-Dimethylformamide (DMF), N-dimethylacetamide, tetrahydrofuran (THF), 1, 4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably DMF; the acid binding agent is sodium carbonate, potassium carbonate, triethylamine or N, N-Diisopropylethylamine (DIPEA), preferably potassium carbonate.
The compound IV is prepared by dissolving the IV in a solvent, and adding an aqueous solution of alkali for hydrolysis reaction. The reaction solvent is THF, methanol, acetonitrile or a mixed solvent of any two, preferably a mixed solvent of THF and methanol; the base is sodium hydroxide, lithium hydroxide or potassium hydroxide, preferably sodium hydroxide.
The compound I is prepared from the compound V by dissolving the compound V in a solvent, adding a condensing agent, and then adding alkali and the compound VI for condensation reaction. The solvent is dichloromethane, THF, DMF, 1, 4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably DMF; the condensing agent is selected from the group consisting of N, N ' -Carbonyldiimidazole (CDI), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 1-Hydroxybenzotriazole (HOBT), N, N ' -Dicyclohexylcarbodiimide (DCC), N, N ' -Diisopropylcarbodiimide (DIC), 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea Hexafluorophosphate (HATU), benzotriazol-N, N, N ', N ' -tetramethylurea Hexafluorophosphate (HBTU), benzotriazol-1-yl-oxy-tripyrrolidinyl (PyBop), preferably EDCI and HOBT; the base is triethylamine, sodium carbonate, potassium carbonate or DIPEA, preferably DIPEA.
And (3) salifying the corresponding acid with the compound (I) prepared by the method to obtain pharmaceutically acceptable salts of the compound.
As a third aspect to which the present invention relates, a pharmaceutical composition comprises the above 2H-indazole-7-carboxamide compound and a pharmaceutically acceptable carrier.
The 2H-indazole-7-carboxamide compound can be added with pharmaceutically acceptable carriers to prepare common medicinal preparations, such as tablets, capsules, syrup, suspending agents or injection, and the preparations can be added with common medicinal auxiliary materials such as perfume, sweetener, liquid/solid filler, diluent and the like.
As a third aspect of the present invention, the 2H-indazole-7-carboxamide compounds and pharmaceutical compositions thereof described above may be prepared as PARP7 inhibitor medicaments; more specifically, as an antitumor drug, it is particularly useful for treating cancers such as lung squamous cell carcinoma, colon cancer, breast cancer, etc.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
(1) The 2H-indazole-7-carboxamide compound has excellent in vivo pharmacokinetic properties, remarkably improves half-life, in vivo exposure and bioavailability, and has remarkable advantages of patent medicine;
(2) The compound has excellent in-vivo pharmacodynamic properties, and can realize better tumor inhibition activity by lower dosage; the release of immune factors can be promoted, the combined medication is not needed, and the obvious curative effect can be realized by singly taking the medicines;
(3) The compounds can effectively inhibit PARP7 enzyme activity and inhibit IC 50 The value is optimally less than 50nM, reaching nanomolar concentration levels; and has inhibiting effect on various tumor cells,tumor cell inhibition IC 50 The value is optimally less than 50nM, reaching nanomolar concentration levels;
(4) The compounds and the pharmaceutical compositions thereof have wide application and can be prepared into antitumor drugs; the medicine can exert the medicine effect at the molecular level and the cellular level, and particularly has more excellent in vivo pharmacokinetics and pharmacodynamics properties;
(5) The preparation method of the compound is simple, convenient and feasible.
Drawings
FIG. 1 is a graph showing the promotion of interferon release by a compound of the present invention;
FIG. 2 shows the antitumor effect in 14-day mice of the compounds of the present invention;
FIG. 3 shows the antitumor effect of the compounds of the present invention in 21-day mice.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
Example 1: synthesis of 2- (3-oxo-3- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl) propyl) -2H-indazole-7-carboxamide (I-1)
Synthesis of ethyl 3- (7-carbamoyl-2H-indazol-2-yl) propionate (IV-1)
The compound 1H-indazole-7-carboxamide (II) (161.2 mg,1.0 mmol) was dissolved in 3mL DMF, followed by ethyl 3-bromopropionate (III-1) (199.1 mg,1.1 mmol), reacted for 2 hours at 90 ℃, monitored by thin layer chromatography (V dichloromethane: V methanol=15:1) for completion, extracted with 10mL of water, ethyl acetate (8 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, and the filtrate concentrated. The crude product was purified by column chromatography on silica gel (V petroleum ether: V ethyl acetate=1:2) to give 251.1mg of yellow oil (IV-1) in 96.1% yield. ESI-MS [ M+H ]] + 262.1。
Synthesis of 3- (7-carbamoyl-2H-indazol-2-yl) propionic acid (V-1)
Compound IV-1 (234.9 mg,0.9 mmol) was dissolved in 3mL of tetrahydrofuran, 3mL of methanol was added, and 2mL of 5mol/L aqueous sodium hydroxide solution was added, and the reaction was completed after the addition, at room temperature for 1 hour, as monitored by thin layer chromatography (V petroleum ether: V ethyl acetate=1:1). Adding water5mL, ethyl acetate (6 mL. Times.2) extraction, pH adjustment of the aqueous layer to 4 with dilute hydrochloric acid, precipitation of a white solid, suction filtration, washing of the filter cake with 5mL of water, collection of the filter cake, and vacuum drying to give 200.5mg of a white solid (V-1) in 95.5% yield. ESI-MS [ M+H ]] + 234.1
Synthesis of 4-tert-butyl-1- (5-iodopyrimidin-2-yl) piperazine carboxylic acid ester (VI-1-1)
2-chloro-5-iodopyrimidine (7.2 g,0.03 mol) was dissolved in 25mL of N-methylpyrrolidone (NMP), tert-butyl piperazine-1-carboxylate (5.6 g,0.03 mol) and potassium carbonate (8.3 g,0.06 mol) were added sequentially, and the mixture was heated to 80℃and reacted for 5 hours. The reaction was monitored by thin layer chromatography (V petroleum ether: V ethyl acetate=8:1), 100mL of water was added, ethyl acetate (30 ml×4) was extracted, the organic phases were combined, and washed successively with saturated aqueous saline solution (40 ml×3), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The crude product was purified by column chromatography on silica gel (V petroleum ether: V ethyl acetate=15:1) to give 11.7g of yellow solid (VI-1-1) in 100% yield. ESI-MS [ M+H ]] + 391.0
Synthesis of tert-butyl 4- (5-trifluoromethylpyrimidin-2-yl) piperazine-1-carboxylate (VI-1-2)
4-tert-butyl-1- (5-iodopyrimidin-2-yl) piperazine carboxylate (11.7 g,0.03 mol) was dissolved in 25mL NMP, cuprous iodide (1.2 g,0.06 mol) was added, methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (11.6 g,0.06 mol) was slowly added dropwise at room temperature under nitrogen protection, after the addition was completed, the reaction was allowed to proceed to 100℃for 8 hours, thin layer chromatography (V petroleum ether: V dichloromethane: V methanol=15:10:2) was monitored for completion, 100mL water was added, ethyl acetate (40 mL. Times.4) was extracted, and the combined organic phases were washed with saturated brine solution (40 mL. Times.3), dried over anhydrous sodium sulfate, suction filtered, concentrated, and the crude product was purified by silica gel column chromatography (V dichloromethane: V methanol=30:1) to give 8.2g pale yellow solid (VI-1-2) in 81% yield. ESI-MS [ M+H ]] + 333.2； 1 H NMR(300MHz,DMSO-d 6 )δ8.72(s, 2H),3.87–3.77(m,4H),3.47–3.37(m,4H),1.47(s,9H).
2- (piperazin-1-yl) -5-trifluoromethyl pyrimidine (VI-1)
4- (5-Trifluoromethylpyrimidin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (3.3 g,10.0 mmol) was dissolved in 15mL dichloromethane and 10mL trifluoroacetic acid was added at room temperatureAfter stirring for 0.5 h, the reaction was monitored to be complete by thin layer chromatography (V dichloromethane: V methanol=15:1). Concentrating, adjusting pH to 7-8 with saturated sodium bicarbonate aqueous solution, adding dichloromethane 15mL×5, extracting, mixing organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, vacuum filtering, concentrating to obtain white solid (VI-1) 2.1g, and yield 90.1%. ESI-MS [ M+H ]] + 233.1； 1 H NMR(300MHz, DMSO-d 6 )δ8.52(s,2H),3.87–3.77(m,4H),3.47–3.37(m,4H),1.75(s,1H).
Synthesis of 2- (3-oxo-3- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl) propyl) -2H-indazole-7-carboxamide (I-1)
Compound V-1 (186.6 mg,0.8 mmol) was dissolved in 4mL of DMF, HOBT (135.1 mg,1.0 mmol) and EDCI (165.1 mg,1.0 mmol) were added sequentially, reacted at room temperature for 0.5 hours, and VI-1 (186.4 mg,0.8 mmol) and DIPEA (387.1 mg,3.0 mmol) were added and reacted at room temperature for 3 hours, and the reaction was completed as monitored by thin layer chromatography (V petroleum ether: V ethyl acetate=1:1). 10mL of water was added, extraction was performed with ethyl acetate (8 mL. Times.3), the organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (V petroleum ether: V ethyl acetate=1:2) to give 264.1mg of white solid (I-1) in 73.7% yield. ESI-MS [ M+H ]] + 448.2； 1 H NMR(300MHz,DMSO-d 6 )δ8.72(s,2H),8.63(s,1H),8.55(s, 1H),8.01–7.92(m,2H),7.82(s,1H),7.21-7.14(m,1H),4.76(t,J＝6.7Hz,2H),3.86-3.73 (m,4H),3.60-3.50(m,4H),3.17(t,J＝6.7Hz,2H).
Referring to the preparation of example 1, the following compounds were prepared:
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example 39: enzyme inhibitory Activity of Compounds against PARP7
Experimental materials: PARP7 Chemiluminescent Assay Kit, BPS Bioscience; DMSO, national drug, nivo, perkinElmer.
The experimental method comprises the following steps:
(1) Solution and buffer preparation:
10X PBS formulation: 720mg KH was weighed out separately 2 PO 4 45g NaCl and 5.311g Na 2 HPO 4 ·12H 2 O was dissolved in 500mL deionized water, the pH of the system was adjusted to 7.4, sterilized at 121℃for 30 minutes, cooled and placed at 4℃for further use.
1X PBS formulation: 10 XPBS was diluted 10-fold with deionized water, i.e., 1 part 10 XPBS was diluted with 9 parts deionized water.
Wash buffer preparation: 1 XPBS contained 0.05% Tween-20.
1X PARP buffer preparation: (on-line) 10X PARP buffer was diluted 10-fold with deionized water and placed on ice for use.
(2) Preparing the concentration of a compound working solution:
according to the detection requirement, the compound to be detected is diluted to the required concentration by using 100% DMSO, and then 10 times of dilution is carried out by using 1X PARPbuffer, so as to prepare 10X compound working solution.
(3) The experimental steps are as follows:
a. the day before the experiment, thawing 5X histone mixture on ice;
1 Xhistory mix formulation, 5X histone mixture was formulated as 1X histone mixture using 1 XPBS; mu.L of 1X histone mixture per well was taken into the test plate and incubated overnight at 4 ℃;
c. 100 μ L Blocking buffer per well was added to the test plate and incubated for 90 minutes at 25 ℃;
d. after the incubation is finished, the liquid in the test plate is dried, and the plate is repeatedly washed for 3 times;
e. 2.5 mu L of compound working solution is taken from each hole and added into a test plate according to an experimental layout; adding 1X PARP buffer with 10% DMSO in corresponding volume into Positive control well (Positive control), and adding 1X PARP buffer with corresponding volume into Blank control (Blank);
f. after complete enzyme solubilization, the zymogen solution was diluted to 6 ng/. Mu.L with 1 XPARP buffer;
g. mu.L of enzyme solution per well was added to the test well plate, and 1 XPARP buffer was added to the blank wells at a corresponding volume, at which time the enzyme amount was 60ng per well. Note that: this step requires operation on ice;
h. to each well of the test plate, 12.5. Mu.L of master mix (12.5. Mu.L of master mix including 1.25. Mu.L 10X PARP buffer,1.25. Mu.L Opti-PARP 10X Assay mix and 10. Mu.L water) was added; the test plate sealing film is placed at 25 ℃ for incubation for 60 minutes;
i. after incubation, the liquid in the test plate is dried, and the plate is repeatedly washed for 3 times;
j. diluting the strepavidin-HRP in the kit by 50 times with a Blocking buffer solution, adding 25 mu L of each hole into a test plate, and incubating for 30 minutes at 25 ℃;
k. after incubation, the liquid in the test plate is dried, and the plate is repeatedly washed for 3 times;
50 mu L of the mixture per well was added to the test plate according to ELISA ECL Substrate A and ELISA ECL Substrate B in the 1:1 mix kit, and Luminescence values (RLU) were read immediately using Nivo for Luminecen detection;
calculating the enzyme rate: % Enzyme activity= (RLU (Sample) -RLU (Blank))/(RLU (pos ctrl) -RLU (Blank)) ×100%; enzyme inhibition = 1-% Enzyme Activity IC was performed using Prism GraphPad software 50 Fitting, specific results are shown in table 1 below.
TABLE 1 enzyme inhibition activity data for PARP7 by test compounds
Examples IC 50 Examples IC 50
1 ++ 20 +++
2 ++ 21 +++
3 +++ 22 +++
4 ++ 23 +++
5 ++ 24 +++
6 ++ 25 +++
7 ++ 26 ++
8 +++ 27 ++
9 +++ 28 +++
10 ++ 29 +++
11 +++ 30 ++
12 +++ 31 +++
13 +++ 32 +++
14 +++ 33 +++
15 +++ 34 +++
16 +++ 35 +++
17 +++ 36 +++
18 ++ 37 +++
19 +++ 38 +++
Note that: "+". ++'s is IC (integrated circuit) 50 < 0.05. Mu.M; "++" is IC 50 More than or equal to 0.05 mu M and less than 0.5 mu M.
As shown in Table 1, all the test compounds of the present invention showed good inhibitory activity against PARP7 enzyme, IC 50 Values all reached nanomolar concentration levels. Wherein examples 3,8, 9, 11 to 17, 19 to 25, 28, 29 and 31 to 38 are ICs inhibiting PARP7 enzyme activity 50 The values were all less than 0.05. Mu.M.
Example 40: enzyme inhibitory Activity of Compounds against PARP1
Experimental reagent: PARP-1 enzyme activity assay kit was purchased from BPS Bioscience.
The experimental method comprises the following steps: compound samples were dissolved in DMSO to prepare 10mM stock solutions, and then the compounds were added to the screening system at a concentration ranging from 0.1nM to 10 μm, diluted according to a 3-fold gradient, and two wells were made for each concentration. Taking out 96-well plates which are pre-coated with histone, adding the following enzyme reaction systems and inhibitors with different concentrations into each well, wherein the steps comprise: 50. Mu.L of reaction buffer (Tris-HCl, pH 8.0), NAD + Biotin-labeled activated DNA, PARP-1 enzyme and inhibitors; after 1 hour of reaction at room temperature, 50. Mu.L of avidin-labeled HRP was added to each well and reacted for 30 minutes; a further 100. Mu.L of HRP substrate was added and the chemiluminescent value was detected on a SpectraMax M instrument.
The inhibition of PARP1 enzyme activity was calculated as (Lu control-Lu treatment/Lu control) ×100%. Nonlinear regression using normalized dose response fitting using Prism GraphPad software calculated for PARP1 enzyme activity (IC 50 ) The concentration required to inhibit 50%.
The activity data of the positive control selected from the commercially available PARP1/2 inhibitor Olaparib are shown in Table 2.
TABLE 2 enzyme inhibition Activity data of Compounds against PARP1
Examples IC 50
20 1.23nM
23 0.82nM
Olaparib 2.2nM
The above results indicate that some of the compounds of the present invention have not only strong enzyme inhibitory activity against PARP7, but also strong enzyme inhibitory activity against PARP 1.
Example 41: antiproliferative activity of compounds on tumor cells
The experimental process comprises the following steps:
a. plating a set of cancer cell lines cultured to log phase into 96-well plates at a pre-specified density in a medium containing fetal bovine serum;
b. cells were treated with compound or vehicle (DMSO) after 24 hours and day 0 plates were collected for analysis;
c. after application, the 96-well plate was placed at 37℃with 4.5% CO 2 Culturing in a constant temperature incubator, and adding 20 mu L of 1.0% MTT thiazole blue solution into each hole after 6 days;
d. continuously placing the mixture in a constant temperature incubator, sucking away the supernatant culture solution after 4 hours, adding 150 mu L of DMSO into each hole, and uniformly mixing the mixture on a decoloring shaking table until crystals are dissolved;
e. measuring absorbance at 570nm with multifunctional enzyme-labeled instrument, and calculating IC according to modified kou method 50 Value: lgIC 50 ＝Xm-I[P-(3-Pm-Pn)/4]Specific results are shown in table 3 below.
TABLE 3 antiproliferative activity data of test compounds on tumor cells
Cell lines Example 20 (IC) 50 :nM) Example 23 (IC) 50 :nM)
NCI-H1373 +++ +++
HCC-827 ++ ++
SW-1990 ++ ++
SH-SY5Y ++ ++
CFPAC-1 +++ +++
Note that: "+". ++'s is IC (integrated circuit) 50 < 0.05. Mu.M; "++" is IC 50 0.05. Mu.M and < 0.5. Mu.M).
The data show that the invention of example 20 (I-20) and example 23 (I-23) has better inhibition effect on proliferation of various tumor cells.
Example 42: compounds for promoting interferon release
Interferon- β levels were induced by PARP7 inhibitors on RAW264.7 in the presence of STING agonist DMXAA. RAW264.7 cells grown to logarithmic phase were plated in 96-well plates at 37℃with 5% CO 2 Incubate overnight in incubator until adherent. Cells were treated with dose-titrated PARP7 inhibitor and 50 μg/mL DMXAA for 24 hours and the supernatant was collected by ELISA (R&D, mouse IFN-beta DuoSet Elisa) was processed according to the kit instructions and the results are shown in FIG. 1.
As can be seen from FIG. 1, the compound of the invention can obviously promote the release of interferon beta, thus being applicable to the immunotherapy of tumors, and the release amount is better than that of a positive medicament RBN-2397.
Example 43: in vivo pharmacokinetic studies in mice of Compounds
The experimental process comprises the following steps: male Balb/c mice were selected for 6, 3, oral administration (10 mg/kg), 3 intravenous injection (1 mg/kg), blood samples were collected for 0 min, 2 min, 5 min, 10 min, 20 min, 30 min, 60 min, 2h, 4 h, 6 h, 8 h, respectively, centrifuged (3000 rpm), and the supernatant was collected for analysis using LC-MS-MS, and the results were analyzed using the winnonlin software, and specific results are shown in Table 4 below.
TABLE 4 pharmacokinetic data of test compounds in Balb/c mice
/>
IV: represents intravenous injection, PO: indicating administration by lavage.
Experimental results show that the compounds of example 8 (I-8) and example 20 (I-20) of the present invention have good pharmacokinetic properties in Balb/c mice.
Example 44: in vivo efficacy study in mice of Compounds
(1) BALB/c mice were inoculated subcutaneously with CT26 cells on the right flank to develop tumors. Four days after tumor inoculation, tumor sizes of 55-75mm were selected 3 (average tumor size 63 mm) 3 ) 24 mice in the range and based on their tumor volume, were randomly divided into 4 groups of 6 mice each. The dosing was started the next day after the randomization (day of randomization was defined as day 0), compound RBN-2397 (500 mg/kg, 1 time per day, 14 consecutive days of gavage), compound I-8 (100 mg/kg, 1 time per day, 14 consecutive days of gavage), compound I-20 (100 mg/kg, 1 time per day, 14 consecutive days of gavage), compound I-23 (100 mg/kg, 1 time per day, 14 consecutive days of gavage), and tumor sizes were measured three times per week during dosing, respectively. The whole study was terminated on day 14 and the efficacy results are shown in figure 2.
As can be seen from FIG. 2, the compounds I-8, I-20 and I-23 of the present invention have remarkable antitumor activity in mice, and compared with the positive drug RBN-2397, the compounds I-8, I-20 and I-23 of the present invention can exert better antitumor effect at lower doses.
(2) SCID CB17 mice were inoculated subcutaneously with NCI-H1373 cells on the right flank to develop tumors. After 5 days of tumor growth, will have a length of 100-188mm 3 Tumor mice were randomized into treatment groups, with an average tumor volume of 181mm 3 . The treatment was started the second day after the randomization (day of randomization was defined as day 0) and was performed by gavage vehicle (50% Labrasol) or compound RBN-2397 (30 mg/kg) or compound I-20 (30 mg/kg) for 21 days once a day. Tumor size was measured 1 time every three days during dosing. The whole study was terminated on day 21 and the efficacy results are shown in figure 3.
As can be seen from FIG. 3, the compound I-20 of the present invention has very obvious antitumor effect in mice and is superior to the positive drug RBN-2397.

Claims (10)

1. A 2H-indazole-7-carboxamide compound, characterized by having the structure of formula (I), said compound comprising an isomer, a pharmaceutically acceptable salt thereof or a mixture thereof:
wherein:
n is selected from 0, 1, 2, 3 or 4;
m is selected from 0 or 1;
R 1 or R is 2 Are independently selected from hydrogen, C 1 ～C 6 Alkyl, substituted C 3 ～C 6 Cycloalkyl or heterocycloalkyl, cyano, halogen, difluoromethyl, trifluoromethyl, or R 1 And R is 2 Together with the carbon atoms to which they are attached form C 3 ～C 6 Cycloalkyl; the C is 3 ～C 6 The substituents of the cycloalkyl group are selected from hydrogen, methyl, trifluoromethyl, 2-difluoroEthyl, methoxy, halogen, cyano, amino, methylamino, dimethylamino, diethylamino, acetamido, hydroxy, acetoxy, carboxyl, or methoxycarbonyl, said substituent being one or more;
A 1 selected from the group consisting of-NH-, -O-, -CH 2 -、C 3 ～C 6 Cycloalkyl or heterocycloalkyl or a 5-to 10-membered aromatic or heteroaromatic ring; wherein the C 3 ～C 6 Cycloalkyl or heterocycloalkyl or any position of a 5-to 10-membered aromatic or heteroaromatic ring is substituted with one or more of the following groups: hydrogen, halogen, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, trifluoromethanesulfonyl, methanesulfonyl, cyano, hydroxy, amino, methylamino, dimethylamino, diethylamino, acetamido, carboxamido, nitro, methoxy or ethoxy;
A 2 selected from:
wherein R is 3 、R 4 Or R is 5 Each independently selected from hydrogen, methyl, trifluoromethyl, cyano, hydroxy, methoxy, amino, methylamino, dimethylamino, acetamido, carboxyl, or methoxycarbonyl;
r is selected from aryl, heteroaryl or 1, 3-benzodioxan substituted at any position with one or more of the following groups: hydrogen, halogen, cyano, trifluoromethyl, 2-difluoroethyl, C 1 ～C 6 Alkyl, C of (2) 1 ～C 6 Alkoxy, hydroxy, methoxy, amino, methylamino, dimethylamino, acetamido, carboxyl, methoxycarbonyl or nitro.
2. The 2H-indazole-7-carboxamide compound according to claim 1, characterized in that in said structure:
n is selected from 0, 1 or 2;
R 1 or R is 2 Each independently selected from hydrogen, methyl, fluoro or ethyl; when R is 1 And R is 2 Different from R 1 And R is 2 The carbon atoms are racemized, R-shaped or S-shaped;
A 1 selected from:
-NH- -CH 2 -
wherein X is 1 、X 2 Or X 3 Each independently selected from CH or N, R 6 Selected from one or more of hydrogen, halogen, methyl, ethyl, isopropyl, difluoromethyl, difluoromethylsulfonyl, trifluoromethyl, trifluoromethylsulfonyl, methanesulfonyl, cyano, hydroxy, amino, methylamino, dimethylamino, diethylamino, acetamido, carboxamido, nitro, methoxy or ethoxy;
A 2 selected from:
r is selected from:
wherein Y is 1 And Y 2 Each independently represents CH or N, R 7 Selected from one or more of hydrogen, trifluoromethyl, methyl, fluoro, chloro, bromo, cyano, methoxy, methanesulfonyl, 2-difluoroethyl or 4-trifluoromethylphenyl.
3. The 2H-indazole-7-carboxamide compound according to claim 1 or 2, characterized in that in said structure:
R 1 or R is 2 Independently selected from hydrogen or methyl, when R 1 And R is 2 Different from R 1 And R is 2 The carbon atoms connected are in racemization configuration;
A 1 selected from:
-CH 2 -
A 2 selected from:
4. the 2H-indazole-7-carboxamide compound according to claim 1 or 2, characterized in that in said structure:
r is selected from:
5. 2H-indazole-7-carboxamide compounds according to claim 1 or 2, characterized in that they are selected from any of the following compounds:
2- (3-oxo-3- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl) propyl) -2H-indazole-7-carboxamide (I-1),
2- (3- (4- (5-cyanopyrimidin-2-yl) piperazin-1-yl) -3-oxopropyl) -2H-indazole-7-carboxamide (I-2),
2- (3-oxo-3- ((1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) amino) propyl) -2H-indazole-7-carboxamide (I-3),
2- (3- (methyl (1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) amino) -3-oxopropyl) -2H-indazole-7-carboxamide (I-4),
2- (3- (methyl (1- (5- (trifluoromethyl) pyrimidin-2-yl) azetidin-3-yl) amino) -3-oxopropyl) -2H-indazole-7-carboxamide (I-5),
2- (3-oxo-3- ((1- (5- (trifluoromethyl) pyrimidin-2-yl) azetidin-3-yl) amino) propyl) -2H-indazole-7-carboxamide (I-6),
2- (3- (4- (2, 2-difluorobenzo [ d ] [1,3] dioxa-5-yl) piperazin-1-yl) -3-oxopropyl) -2H-indazole-7-carboxamide (I-7),
2- (4-oxo-4- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl) butyl) -2H-indazole-7-carboxamide (I-8),
2- (4- (4- (5-cyanopyrimidin-2-yl) piperazin-1-yl) -4-oxobutyl) -2H-indazole-7-carboxamide (I-9),
2- (4-oxo-4- ((1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) amino) butyl) -2H-indazole-7-carboxamide (I-10),
2-4- (methyl (1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) amino) -4-oxobutyl) -2H-indazole-7-carboxamide (I-11),
2- (4- (methyl (1- (5- (trifluoromethyl) pyrimidin-2-yl) azetidin-3-yl) amino) -4-oxobutyl) -2H-indazole-7-carboxamide (I-12),
2- (4-oxo-4- ((1- (5- (trifluoromethyl) pyrimidin-2-yl) azetidin-3-yl) amino) butyl) -2H-indazole-7-carboxamide (I-13),
2- (4- (4- (5-methylpyrimidin-2-yl) piperazin-1-yl) -4-oxobutyl) -2H-indazole-7-carboxamide (I-14),
2- (4- (4- (5-fluoropyrimidin-2-yl) piperazin-1-yl) -4-oxobutyl) -2H-indazole-7-carboxamide (I-15),
2- (4-oxo-4- (4- (5- (trifluoromethyl) pyridin-2-yl) piperazin-1-yl) butyl) -2H-indazole-7-carboxamide (I-16),
2- (4-oxo-4- (4- (5- (trifluoromethyl) pyrazin-2-yl) piperazin-1-yl) butyl) -2H-indazole-7-carboxamide (I-17),
2- (4- (4- (2, 2-difluorobenzo [ d ] [1,3] dioxa-5-yl) piperazin-1-yl) -4-oxobutyl) -2H-indazole-7-carboxamide (I-18),
(E) -2- (4-oxo-4- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl) but-2-en-1-yl) -2H-indazole-7-carboxamide (I-19),
2- (5-oxo-5- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl) pentyl) -2H-indazole-7-carboxamide (I-20),
2- (5- (4- (5-methylpyrimidin-2-yl) piperazin-1-yl) -5-oxopentyl) -2H-indazole-7-carboxamide (I-21),
2- (4- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) -2H-indazole-7-carboxamide (I-22),
2- (3- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) -2H-indazole-7-carboxamide (I-23),
2- (4-oxo-4- (3- (5- (trifluoromethyl) pyrimidin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) butyl) -2H-indazole-7-carboxamide (I-24).
2- (1-oxo-1- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl) propan-2-yl) -2H-indazole-7-carboxamide (I-25)
2- (2- (4- (2, 2-difluorobenzo [ d ] [1,3] dioxa-5-yl) piperazin-1-yl) -2-oxoethane) -2H-indazole-7-carboxamide (I-26)
2- (1- (4- (2, 2-difluorobenzo [ d ] [1,3] dioxa-5-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2H-indazole-7-carboxamide (I-27)
2- (2-oxo-2- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl) ethyl) -2H-indazole-7-carboxamide (I-28)
2- (1- (4- (5-methylpyrimidin-2-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2H-indazole-7-carboxamide (I-29)
2- (1- (4- (5-fluoropyrimidin-2-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2H-indazole-7-carboxamide (I-30)
2- (1-fluoro-2-oxo-2- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl) ethyl) -2H-indazole-7-carboxamide (I-31)
2- (1-oxo-1- (4- (5- (trifluoromethyl) pyridin-2-yl) piperazin-1-yl) propan-2-yl) -2H-indazole-7-carboxamide (I-32)
2- (1-oxo-1- (4- (5- (trifluoromethyl) pyridin-2-yl) piperazin-1-yl) propan-2-yl) -2H-indazole-7-carboxamide (I-33)
2- (1-oxo-1- (3- (5- (trifluoromethyl) pyrimidin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) propan-2-yl) -2H-indazole-7-carboxamide (I-34)
2- (1-oxo-1- (3- (5- (trifluoromethyl) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) propan-2-yl) -2H-indazole-7-carboxamide (I-35)
2- (1-oxo-1- (8- (5- (trifluoromethyl) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) propan-2-yl) -2H-indazole-7-carboxamide (I-36)
2- (1-oxo-1- (8- (5- (trifluoromethyl) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) propan-2-yl) -2H-indazole-7-carboxamide (I-37)
2- (1-oxo-1- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl) butan-2-yl) -2H-indazole-7-carboxamide (I-38).
6. The 2H-indazole-7-carboxamide compound according to claim 1 or 2, characterized in that said pharmaceutically acceptable salt is a salt of said compound with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid or ferulic acid.
7. A process for the preparation of a 2H-indazole-7-carboxamide compound according to any one of claims 1 to 6, characterized in that said process comprises:
the compound (II) and the compound (III) are subjected to substitution, hydrolysis and acylation reaction to obtain a compound (I);
wherein m, n, A 1 、Y 1 、Y 2 、R 1 、R 2 、R 4 、R 5 、R 7 Is as defined in any one of claims 1 to 5;
and (3) salifying the corresponding acid with the compound (I) prepared by the method to obtain pharmaceutically acceptable salts of the compound.
8. A pharmaceutical composition comprising a 2H-indazole-7-carboxamide compound according to any of claims 1 to 6 and a pharmaceutically acceptable carrier.
9. Use of a 2H-indazole-7-carboxamide compound according to any of claims 1 to 6 or a pharmaceutical composition according to claim 8 for the preparation of a PARP7 inhibitor medicament.
10. The use according to claim 9, wherein the medicament is an anti-tumour medicament.
CN202210094416.9A 2022-01-26 2022-01-26 2H-indazole-7-carboxamide compounds, preparation method, pharmaceutical composition and application Pending CN116535395A (en)

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Citations (5)

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CN101415686A (en) * 2006-04-03 2009-04-22 P.安杰莱蒂分子生物学研究所 Amide substituted indazole and benzotriazole derivatives as poly(ADP-ribose)polymerase (PARP) inhibitors
CN109810098A (en) * 2017-11-21 2019-05-28 中国药科大学 The bis- target spot inhibitor of PARP-1 and PI3K containing phthalazines -1 (2H) -one structure
WO2020223229A1 (en) * 2019-04-29 2020-11-05 Ribon Therapeutics, Inc. Solid forms of a parp7 inhibitor
CN112424188A (en) * 2018-04-30 2021-02-26 里邦医疗公司 Pyridazinones as PARP7 inhibitors
CN113045582A (en) * 2021-02-05 2021-06-29 中国药科大学 PARP-1/PI3K double-target inhibitor or pharmaceutically acceptable salt thereof, and preparation method and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101415686A (en) * 2006-04-03 2009-04-22 P.安杰莱蒂分子生物学研究所 Amide substituted indazole and benzotriazole derivatives as poly(ADP-ribose)polymerase (PARP) inhibitors
CN109810098A (en) * 2017-11-21 2019-05-28 中国药科大学 The bis- target spot inhibitor of PARP-1 and PI3K containing phthalazines -1 (2H) -one structure
CN112424188A (en) * 2018-04-30 2021-02-26 里邦医疗公司 Pyridazinones as PARP7 inhibitors
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