CN116535395B - 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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CN116535395B
CN116535395B CN202210094416.9A CN202210094416A CN116535395B CN 116535395 B CN116535395 B CN 116535395B CN 202210094416 A CN202210094416 A CN 202210094416A CN 116535395 B CN116535395 B CN 116535395B
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indazole
carboxamide
trifluoromethyl
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acid
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CN116535395A (en
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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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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 monoADP ribotransferase activity. The MonoPARP family of proteins is closely related to the development of cancer, inflammation and neurodegenerative diseases. PARP7 is one of the members of the monoPARP protein family, a novel negative regulator of nucleic acid sensors in cells, which 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 low oral bioavailability, and its in vivo efficacy in animals shows that RBN-2397 alone has difficulty in anti-tumor action, 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 2 are each independently selected from hydrogen, C 1～C6 alkyl, substituted C 3～C6 cycloalkyl or heterocycloalkyl, cyano, halogen, difluoromethyl, trifluoromethyl, or R 1 and R 2 together with the carbon atom to which they are attached form C 3～C6 cycloalkyl; the substituent of the C 3～C6 cycloalkyl is selected from hydrogen, methyl, trifluoromethyl, 2-difluoroethyl, methoxy, halogen, cyano, amino, methylamino, dimethylamino, diethylamino, acetamido, hydroxyl, acetoxy, carboxyl or methoxycarbonyl, and one or more substituents;
A 1 is selected from-NH-, -O-, -CH 2-、C3～C6 cycloalkyl or heterocycloalkyl or a 5-10 membered aromatic or heteroaromatic ring; wherein any position of the C 3～C6 cycloalkyl or heterocycloalkyl or 5-10 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 is selected from:
wherein R 3、R4 or R 5 are 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, alkyl of C 1～C6, alkoxy of C 1～C6, hydroxy, methoxy, amino, methylamino, dimethylamino, acetamido, carboxy, methoxycarbonyl or nitro.
Preferably, in the above structure:
n is selected from 0,1,2 or 3;
R 1 or R 2 are each independently selected from hydrogen, methyl, fluoro or ethyl; when R 1 and R 2 are different, the carbon atom connected with R 1 and R 2 is in a racemization configuration, an R configuration or an S configuration;
A 1 is selected from:
Wherein each X 1、X2 or X 3 is independently selected from CH or N, R 6 is selected from one or more of hydrogen, halogen, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, trifluoromethanesulfonyl, methanesulfonyl, cyano, hydroxy, amino, methylamino, dimethylamino, diethylamino, acetamido, carboxamido, nitro, methoxy or ethoxy;
a 2 is selected from:
r is selected from:
Wherein Y 1 and Y 2 each independently represent CH or N, R 7 is selected from one or more of hydrogen, trifluoromethyl, methyl, fluoro, chloro, bromo, cyano, methoxy, methylsulfonyl, 2-difluoroethyl or 4-trifluoromethylphenyl.
More preferably, in the above structure:
R 1 or R 2 are each independently selected from hydrogen or methyl, and when R 1 and R 2 are different, the carbon atom to which R 1 and R 2 are attached is in the racemic configuration;
A 1 is selected from:
a 2 is 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 and A 1、Y1、Y2、R1、R2、R4、R5、R7 are 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 the activity of PARP7 enzyme, and the value of the enzyme inhibition IC 50 is optimally less than 50nM, so as to reach the nanomolar concentration level; the compound has inhibition effect on various tumor cells, and the tumor cell inhibition IC 50 value is optimally less than 50nM, so that the nanomolar concentration level is reached;
(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). 5mL of water was added, extraction was performed with ethyl acetate (6 mL. Times.2), the pH of the aqueous layer was adjusted to 4 with dilute hydrochloric acid, a white solid was precipitated, suction filtration was performed, the filter cake was washed with 5mL of water, the filter cake was collected, and the filter cake was dried in vacuo 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, the reaction was completed after heating 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, 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), yield 81％.ESI-MS[M+H]+333.2;1H NMR(300MHz,DMSO-d6)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)
Tert-butyl 4- (5-trifluoromethylpyrimidin-2-yl) piperazine-1-carboxylate (3.3 g,10.0 mmol) was dissolved in 15mL dichloromethane and 10mL trifluoroacetic acid was added and after stirring at room temperature for 0.5 hours, the reaction was monitored by thin layer chromatography (V dichloromethane: V methanol=15:1) to completion. 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 obtaining yield 90.1％.ESI-MS[M+H]+233.1;1H NMR(300MHz, DMSO-d6)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 a white solid (I-1), yield 73.7％. ESI-MS[M+H]+448.2;1H NMR(300MHz,DMSO-d6)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:
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 2PO4, 45g NaCl and 5.311g Na 2HPO4·12H2 O are respectively weighed and dissolved in 500mL deionized water, the pH of the system is adjusted to 7.4, the system is sterilized at 121 ℃ for 30 minutes, and the system is cooled and placed at 4 ℃ for standby.
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 100% DMSO, and then 10 times of dilution is carried out by 1X PARPbuffer to prepare a compound working solution of 10X.
(3) The experimental steps are as follows:
a. the day before the experiment, thawing on ice 5X histone mixture;
1X history mix formulation, 5X histone mixture was formulated as 1X histone mixture using 1X PBS; mu.L 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 of Opti-PARP 10X Assay mix and 10. Mu.L of 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;
Adding 50 mu L of mixed solution per well to a test plate according to ELISA ECL Substrate A and ELISA ECL Substrate B in a 1:1 mixed kit, immediately performing Luminence detection by using Nivo, and reading a Luminescence value (RLU);
Calculating the enzyme rate: % Enzyme activity= (RLU (Sample) -RLU (Blank))/(RLU (pos ctrl) -RLU (Blank)) ×100%; enzyme inhibition = 1-% Enzyme Activity IC 50 fitting was performed using PRISM GRAPHPAD software, with specific results shown in table 1 below.
TABLE 1 enzyme inhibition activity data for PARP7 by test compounds
Examples IC50 Examples IC50
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. Gtoreq.0.05. Mu.M and < 0.5. Mu.M.
As shown in table 1, all the test compounds of the present invention showed good inhibitory activity against PARP7 enzyme, and IC 50 values reached nanomolar levels. Wherein examples 3, 8, 9, 11-17, 19-25, 28, 29 and 31-38 each have an IC 50 value of less than 0.05. Mu.M that inhibits PARP7 enzyme activity.
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 μl of reaction buffer (Tris-HCl, pH 8.0), NAD +, biotin-labeled activated DNA, PARP-1 enzyme and inhibitor; 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 was performed using PRISM GRAPHPAD software using normalized dose response fitting to calculate the concentration required to inhibit PARP1 enzyme activity (IC 50) by 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 IC50
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 is placed in a constant temperature incubator with 4.5% CO 2 at 37 ℃ for cultivation, and 20 mu L of 1.0% MTT thiazole blue solution is added into each well 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 by using a multifunctional enzyme-labeled instrument, and calculating IC 50 value according to modified kou method: lgIC 50 =xm-I [ P- (3-Pm-Pn)/4 ], and 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. Gtoreq.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 log phase were plated in 96-well plates and incubated overnight in a 5% co 2 incubator at 37 ℃ until adherent. Cells were co-treated with dose-titrated PARP7 inhibitor and 50 μg/mL DMXAA for 24 hours and the supernatant was collected, treated by ELISA (R & D, mouse IFN-beta DuoSet Elisa) according to the kit instructions and the results are seen in figure 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 0min, 2 min, 5min, 10min, 20 min, 30min, 60min, 2 hr, 4 hr, 6 hr, 8 hr, respectively, centrifuged (3000 rpm/5 min), and the supernatant was collected for analysis using LC-MS-MS, and the results were analyzed using 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, 24 mice with tumor sizes in the range of 55-75mm 3 (average tumor size 63mm 3) were selected and randomly divided into 4 groups of 6 mice based on their tumor volumes. 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, mice with 100-188mm 3 tumors 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 a pharmaceutically acceptable salt thereof:
Wherein:
n is selected from 0, 1, 2, 3 or 4;
m is selected from 0 or 1;
r 1 or R 2 are each independently selected from hydrogen, C 1～C6 alkyl, halogen;
When R 1 and R 2 are different, the carbon atom connected with R 1 and R 2 is in a racemization configuration, an R configuration or an S configuration;
A 1 is selected from: -CH2-；
a 2 is selected from:
wherein R 3、R4 or R 5 are each independently selected from hydrogen, methyl;
r is selected from: y 1 and Y 2 each independently represent CH or N, R 7 is selected from one or more of hydrogen, trifluoromethyl, methyl, fluoro, chloro, bromo, cyano, methoxy.
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 2 are each independently selected from hydrogen, methyl, fluoro or ethyl; when R 1 and R 2 are different, the carbon atom connected with R 1 and R 2 is in a racemization configuration, an R configuration or an S configuration;
A 1 is selected from: -CH2-；
a 2 is selected from:
r is selected from:
3. the 2H-indazole-7-carboxamide compound according to claim 1 or 2, characterized in that in said structure:
R 1 or R 2 are each independently selected from hydrogen or methyl, and when R 1 and R 2 are different, the carbon atom to which R 1 and R 2 are attached is in the racemic configuration;
A 1 is selected from:
a 2 is selected from:
4. a 2H-indazole-7-carboxamide compound, characterized in that it is selected from any one of the following:
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).
5. 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.
6. A process for the preparation of a 2H-indazole-7-carboxamide compound according to any one of claims 1 to 5, 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 and A 1、Y1、Y2、R1、R2、R4、R5、R7 are defined as 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.
7. The preparation method according to claim 6, wherein the compound IV is prepared from the compound II by dissolving II and III in a solvent, and adding an acid binding agent for substitution reaction; wherein the reaction solvent is N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether or acetonitrile; the acid binding agent is sodium carbonate, potassium carbonate, triethylamine or N, N-diisopropylethylamine;
Preparing a compound V from the compound IV, namely dissolving the IV in a solvent, and adding an aqueous solution of alkali for hydrolysis reaction to obtain the compound V; wherein the reaction solvent is THF, methanol, acetonitrile or a mixed solvent of any two; the alkali is sodium hydroxide, lithium hydroxide or potassium hydroxide;
preparing a compound I from a compound V, namely dissolving the compound V in a solvent, adding a condensing agent, and then adding alkali and a compound VI for condensation reaction to obtain the compound I; wherein the solvent is dichloromethane, THF, DMF, 1, 4-dioxane, ethylene glycol dimethyl ether or acetonitrile; the condensing agent is selected from N, N ' -carbonyldiimidazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, N, N ' -dicyclohexylcarbodiimide, N, N ' -diisopropylcarbodiimide, 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate, benzotriazol-1-yl-oxy-tripyrrolidinyl hexafluorophosphate; the base is triethylamine, sodium carbonate, potassium carbonate or DIPEA.
8. A pharmaceutical composition comprising a 2H-indazole-7-carboxamide compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.
9. Use of a 2H-indazole-7-carboxamide compound according to any of claims 1 to 5 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.
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