CN115785071B - 3-ethynyl-5- (1H-1, 2, 3-triazole-4-yl) -1H-indazole compound and application thereof - Google Patents

3-ethynyl-5- (1H-1, 2, 3-triazole-4-yl) -1H-indazole compound and application thereof Download PDF

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CN115785071B
CN115785071B CN202310024643.9A CN202310024643A CN115785071B CN 115785071 B CN115785071 B CN 115785071B CN 202310024643 A CN202310024643 A CN 202310024643A CN 115785071 B CN115785071 B CN 115785071B
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ethynyl
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CN115785071A (en
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卞金磊
李志裕
刘迈
宫广越
余思弦
胡天星
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China Pharmaceutical University
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Abstract

The invention discloses a 3-ethynyl-5- (1H-1, 2, 3-triazole-4-yl) -1H-indazole compound and application thereof. The compound and the pharmaceutical composition thereof can effectively inhibit the activities of CLK2 protein and DYRK1A protein, can be prepared into medicines for treating osteoarthritis, can exert the efficacy at the molecular level, have more excellent treatment effect, and can reach the nanomolar concentration level optimally. In addition, the preparation method of the compound is simple and convenient and is easy to operate.

Description

3-ethynyl-5- (1H-1, 2, 3-triazole-4-yl) -1H-indazole compound and application thereof
Technical Field
The invention relates to a 3-ethynyl-5- (1H-1, 2, 3-triazole-4-yl) -1H-indazole compound and application thereof, in particular to a 3-ethynyl-5- (1H-1, 2, 3-triazole-4-yl) -1H-indazole compound which can effectively inhibit the activity of CLK2 or DYRK1A protein, a pharmaceutical composition and application thereof.
Background
Osteoarthritis (OA) is characterized by synovial inflammation, cartilage loss, and subchondral bone remodeling. The synovium of OA patients is rich in stem cells, and the inability of articular cartilage to regenerate is not due to insufficient supply of stem cells, but rather due to improper differentiation of stem cells. The Wnt pathway plays a central role in organogenesis, cellular differentiation and tissue remodeling, and aberrant activation or inhibition of the Wnt signaling pathway leads to the onset of the disease. Thus, the Wnt signaling pathway is a potential target for the treatment of osteoarthritis.
The Wnt signaling pathway is a signaling pathway of a set of multiple downstream channels stimulated by ligand protein Wnt and membrane protein receptor binding. Through this pathway, the intracellular activation process of cell surface receptors transmits extracellular signals into the cell. In the canonical Wnt pathway, when the cell membrane surface is free of Wnt proteins, the β -Catenin proteins downstream of it are broken down in the cytoplasm by glycogen synthase 3 (GSK 3) complexes, resulting in their inability to enter the nucleus to initiate transcription of the relevant Wnt genes; when the Wnt protein exists on the surface of the cell membrane, the Wnt protein can inhibit the GSK3 complex, so that the beta-Catenin protein is accumulated in the nucleus, and finally, the transcription of the Wnt channel related genes is started. There is a delicate balance between bone joint homeostasis and Wnt pathway, and this balance is broken, potentially leading to the onset of osteoarthritis.
Protein kinase family CLK (CDC-like kinase) is a bispecific protein kinase that regulates intracellular signal transduction through protein phosphorylation of tyrosine, serine or threonine residues; it can be divided into four subtypes (CLK 1, CLK2, CLK3 and CLK 4), all of which encode a protein C segment that has a highly conserved gene sequence and has the same amino acid sequence of similar structure. CLKs play an important role in alternate splicing. CLKs act as a body temperature sensor that globally controls alternative splicing and gene expression. The activity of CLKs is indeed highly sensitive to physiological temperature changes, which is conferred by structural rearrangements within the kinase activation segment. Inhibition of CLK2 kinase is believed to be a method of improving neuronal function and combating mental disability and autism; inhibition of CLK2 kinase can kill MYC-driven breast tumors, triple negative breast cancers and glioblastomas; inhibition of CLK2 and CLK3 may block HIV-1 production.
Bispecific tyrosine phosphorylation regulated kinase 1A (Dual Specificity Tyrosine Phosphorylation Regulated Kinase a, DYRK 1A) belongs to the DYRK family, which is highly conserved in evolution, in mammals, with five different subtypes of DYRK family, only DYRK1A being located in the DSCR region of human chromosome 21. DYRK1A is expressed from the DYRK1A gene and encodes a mature protein consisting of 763 amino acids, including a protein kinase domain and other specialized structures. Many important proteins can serve as substrates for DYRK1A and are regulated by it to participate in a variety of biological functions in cells. Such as neurodevelopment, cell proliferation and differentiation, tumorigenesis, neurodegenerative diseases, and the like.
At present, a First-in-class small molecule drug SM-04690 developed by Sumumed corporation has been applied to three-phase clinic to treat osteoarthritis, and the specific mechanism is mainly to induce early cartilage formation by inhibiting CLK 2-mediated SR protein phosphorylation; and inhibiting DYRK 1A-mediated SIRT1 and FOXOA phosphorylation to enhance mature chondrocyte function; and can reduce inflammation by inhibiting inflammatory factors such as NF-gamma B and STAT 3. SM04690, although having significant CLK2 inhibitory activity, lacks selectivity for the CLK family, which results in a potential for certain side effects; in addition, the inhibition activity of DYRK1A target is insufficient, and the water solubility is poor, so that the patentability of the drug is to be improved.
Disclosure of Invention
The invention aims to provide a 3-ethynyl-5- (1H-1, 2, 3-triazole-4-yl) -1H-indazole compound with specific CLK2 and DYRK1A protein activity inhibition effect, a pharmaceutical composition and application aiming at the problems of insufficient CLK family selectivity, insufficient DYRK1A target inhibition activity and the like of the existing compounds.
The aim of the invention can be achieved by the following technical scheme:
as a first aspect of the present invention, the 3-ethynyl-5- (1H-1, 2, 3-triazol-4-yl) -1H-indazoles of formula I, isomers, pharmaceutically acceptable salts or mixtures thereof,
wherein R1 is selected from the following groups:
r2 is selected fromFrom the following groups:
according to the invention, through reasonable drug design, serial derivatives are synthesized, and biological activity evaluation shows that the designed compound has obvious CLK2 inhibitory activity, has better selectivity to CLK family members, and has obvious DYRK1A inhibitory activity.
Preferably, the structure of the above compound is as follows:
R 1 selected from H,
R2 is selected from the following groups:
more preferably, the above compound is selected from any one of the following compounds:
pharmaceutically acceptable salts of the above compounds are salts of the above compounds with the following acids: hydrochloric acid, sulfuric acid, phosphoric acid, carbonic acid, nitric acid, hydrobromic acid, hydroiodic acid, maleic acid, fumaric acid, tartaric acid, citric acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, succinic acid, acetic acid, mandelic acid, isobutyric acid or malonic acid.
As a second aspect of the present invention, the above-mentioned compounds and pharmaceutically acceptable carriers form pharmaceutical compositions, and are formulated into usual pharmaceutical preparations, such as tablets, capsules, syrups, suspensions or injections, which may be formulated with usual pharmaceutical excipients such as perfumes, sweeteners, liquid/solid fillers, diluents and the like.
As a third aspect of the present invention, the above compound or a pharmaceutical composition thereof may be formulated as a CLK2 protein inhibitor drug, and may also be formulated as a DYRK1A protein inhibitor drug, particularly for use in the treatment of inflammation, including osteoarthritis, tendinosis or rheumatoid arthritis, with chondroprotective effect.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
(1) The compound and the pharmaceutical composition thereof can effectively inhibit the activities of CLK2 protein and DYRK1A protein, can obviously lower the expression level of protease related to cartilage degradation in an animal body of an inflammation model, and play a role in cartilage protection;
(2) The compound and the pharmaceutical composition thereof have wide application, can be prepared into medicines for treating osteoarthritis, can exert medicine effects at a molecular level and an animal level, have more excellent treatment effects, and can optimally reach a nanomolar concentration level;
(3) The preparation method of the compound is simple and convenient and is easy to operate.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
Example 1: synthesis of LBL-001
Synthesis of intermediate II:
in a 100ml single necked flask was added 5g of 5-bromoindazole (25.38 mmol,1 eq), which was dissolved with 10ml of LDMF followed by 12.88g of iodine (50.75 mmol,2 eq) and 4.27g of potassium hydroxide (76.14 mmol,3 eq), and after stirring at room temperature for 2 hours, TLC monitoring showed complete reaction. The reaction solution was quenched by adding a saturated sodium thiosulfate solution, extracted with ethyl acetate, and the organic layer was left and dried over anhydrous sodium sulfate, followed by spin-drying to obtain 7.6g of a yellowish white powder II in 93% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.94(t,J＝1.5Hz,1H),7.57(d,J＝1.6Hz,1H)ppm。HR-MS(ESI):Calculated for C 7 H 4 BrIN 2 [M+H] + ：321.8603，found 321.8605。
Synthesis of intermediate iii:
into a 100mL three-necked flask, 5g of intermediate II (15.5 mmol,1 eq) was charged, dissolved in 50mL of tetrahydrofuran, 2.6g of 3, 4-dihydro-2H-pyran (31.0 mmol,2 eq) was added dropwise, and after the completion of the addition, 0.59g of p-toluenesulfonic acid hydrate (3.1 mmol,0.2 eq) was added in portions, and the mixture was heated under reflux at 75℃after the completion of the addition. TLC monitoring after 5 hours showed complete reaction. Column chromatography after spin drying the reaction solution gave 5.4g of white powder III in 86.3% yield. 1 HNMR(300MHz，DMSO-d6)：δ＝7.77～7.74(m，1H)，7.76～7.61(m，2H)，5.88(dd，j1＝2.3Hz，j2＝2.0Hz，1H)，3.88(m，1H)，3.76(m，1H)，2.40(m，1H)，2.02(m，2H)，1.75(m，1H)，1.58(br，2H)ppm。HR-MS(ESI):Calculated for C 12 H 12 BrIN 2 O[M+H] + ：405.9178，found 405.9156。
Synthesis of intermediate v:
in a 50mL single necked flask were added 1.5g of intermediate III (3.69 mmol,1 eq), 0.44g of 3-ethynylpyridine (4.42 mmol,1.2 eq), 0.1g of bis triphenylphosphine palladium dichloride (0.18 mmol,0.05 eq), 70mg of cuprous iodide (0.37 mmol,0.1 eq) and 15mL of triethylamine, which was completely dissolved with 7.5mL of LDMF. After the addition, nitrogen is replaced, and the reaction is stirred at room temperature. TLC monitoring after 5h of reaction showed complete reaction. The reaction solution was suction-filtered, the filtrate was retained, and column chromatography was performed after spin-drying the filtrate to obtain 1.3g of yellow solid V with a yield of 88%. 1 H NMR(300MHz,DMSO-d 6 )δ8.79(dd,J＝2.2,1.6Hz,1H),8.69(ddd,J＝3.3,2.3,1.6Hz,1H),8.24(dd,J＝2.3,0.8Hz,1H),7.84(dt,J＝6.6,2.2Hz,1H),7.74–7.60(m,2H),7.40(dd,J＝6.6,3.2Hz,1H),5.92(t,J＝2.4Hz,1H),3.94–3.72(m,2H),2.30–2.06(m,2H),1.97–1.72(m,2H),1.78–1.58(m,2H)ppm。HR-MS(ESI):Calculated for C 19 H 16 BrN 3 O[M+H] + ：381.0477，found 381.0467。
Synthesis of intermediate vi:
in a 50mL single necked flask was charged 1.1g of intermediate V (2.76 mmol,1 eq), 0.54g of trimethylsilyyne (5.51 mmol,2 eq), 50mg of tetrakis triphenylphosphine palladium (0.14 mmol,0.05 eq), 10mg of cuprous iodide (0.06 mmol,0.02 eq) and 10mL of triethylamine, which was completely dissolved with 10mL of tetrahydrofuran. After the addition, nitrogen replacement was performed, and the mixture was heated to 70℃for reflux reaction. TLC monitoring after 10h reaction showed complete reaction. The reaction solution was suction-filtered, the filtrate was retained, and column chromatography was performed after spin-drying the filtrate to obtain 0.6g of yellow oily substance VI, with a yield of 45%. 1 H NMR(300MHz,DMSO-d 6 )δ8.79(dd,J＝2.3,1.6Hz,1H),8.69(ddd,J＝3.3,2.3,1.6Hz,1H),8.35–8.28(m,1H),7.89–7.74(m,2H),7.56(dd,J＝7.2,2.2Hz,1H),7.40(dd,J＝6.6,3.2Hz,1H),5.92(t,J＝2.4Hz,1H),3.94–3.72(m,2H),2.30–2.06(m,2H),1.97–1.72(m,2H),1.76–1.58(m,2H),0.25(s,8H)ppm。HR-MS(ESI):Calculated for C 24 H 25 N 3 OSi[M+H] + ：399.1767，found 399.1765。
Synthesis of intermediate vii:
in a 25mL single-necked flask, 0.4g of intermediate VI was added, and after complete dissolution thereof with 10mL of methanol, 0.4g of potassium carbonate was added thereto, and the mixture was stirred at room temperature. TLC monitoring after 30 minutes of reaction showed complete reaction. Extraction with dichloromethane and water left the organic layer and dried over anhydrous sodium sulfate, and after spin-drying 0.33g of white solid VII was obtained in 100% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.79(dd,J＝2.3,1.6Hz,1H),8.69(ddd,J＝3.3,2.3,1.6Hz,1H),8.40–8.29(m,1H),7.84(dt,J＝6.6,2.2Hz,1H),7.73–7.63(m,2H),7.40(dd,J＝6.6,3.2Hz,1H),5.92(t,J＝2.4Hz,1H),3.94–3.72(m,2H),2.30–2.06(m,2H),1.97–1.72(m,2H),1.78–1.58(m,2H)ppm。HR-MS(ESI):Calculated for C 21 H 17 N 3 O[M+H] + ：327.1372，found 327.1365。
Synthesis of intermediate ix:
in a 25mL single necked flask were added 0.26g of intermediate VII (0.75 mmol,1 eq) and 7mg of cuprous iodide (0.04 mmol,0.05 eq), which was completely dissolved with 4mL of LDMF and 0.5mL of methanol, and 130mg of azido trimethylsilane (1.13 mmol,1.5 eq) was added thereto, and the reaction was heated at 100℃after nitrogen substitution. TLC monitoring after 24h of reaction showed a small amount of starting material remaining. Column chromatography after spin drying gave 0.12g of white solid IX in 52% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.79(dd,J＝2.3,1.6Hz,1H),8.73–8.63(m,2H),8.45(d,J＝1.9Hz,1H),7.99(dd,J＝8.6,2.4Hz,1H),7.84(dt,J＝6.6,2.2Hz,1H),7.72(dd,J＝8.6,0.6Hz,1H),7.40(dd,J＝6.6,3.2Hz,1H),5.92(t,J＝2.4Hz,1H),3.94–3.72(m,2H),2.30–2.06(m,2H),1.97–1.72(m,2H),1.78–1.58(m,2H)ppm。HR-MS(ESI):Calculated for C 21 H 18 N 6 O[M+H] + ：370.1542，found 370.1544。
Synthesis of LBL-001:
the product obtained in the above step was put into a 25mL single-necked flask, and was completely dissolved with 8mL of methylene chloride, and then 100. Mu.l of triethylsilane was added thereto, the system was cloudy white, and after 10mL of trifluoroacetic acid was added thereto, the system became clear, and the reaction was stirred at room temperature. TLC monitoring after 1h of reaction showed complete reaction. The reaction solution was dried by spinning, extracted with ethyl acetate and sodium hydrogencarbonate solution, the organic layer was kept and dried over anhydrous sodium sulfate, and the organic phase was dried by spinning and then column chromatography to give 75mg of white solid LBL-001 in 100% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.79(dd,J＝2.3,1.6Hz,1H),8.73–8.62(m,2H),8.49(d,J＝1.9Hz,1H),8.04(dd,J＝9.7,2.4Hz,1H),7.84(dt,J＝6.6,2.2Hz,1H),7.59(dd,J＝9.8,0.6Hz,1H),7.40(dd,J＝6.6,3.2Hz,1H)ppm。HR-MS(ESI):Calculated for C 16 H 10 N 6 [M+H] + ：286.0967，found 286.0966。
By operating in a similar manner to example 1, the following compounds were prepared:
1 H NMR(300MHz,DMSO-d 6 )δ8.69–8.63(m,1H),8.55–8.45(m,2H),8.33(ddd,J＝7.7,1.9,1.3Hz,1H),8.04(dd,J＝9.7,2.4Hz,1H),7.76(ddd,J＝6.8,1.9,1.3Hz,1H),7.71–7.54(m,2H)ppm。Calculated for C 17 H 10 N 6 O 2 [M+H] + ：330.0865，found330.0854。
1 H NMR(300 MHz,DMSO-d 6 )δ8.66(d,J＝2.3 Hz,1H),8.49(d,J＝1.9 Hz,1H),8.04(dd,J＝9.7,2.4 Hz,1H),7.59(dd,J＝9.8,0.6 Hz,1H),7.46(td,J＝6.6,4.9 Hz,1H),7.38–7.27(m,2H),7.27–7.16(m,1H)ppm。Calculated for C 17 H 10 FN 5 [M+H] + ：303.0920，found 303.0913。
1 H NMR(300 MHz,DMSO-d 6 )δ8.69–8.63(m,1H),8.49(d,J＝1.9 Hz,1H),8.04(dd,J＝9.7,2.4 Hz,1H),7.96(t,J＝1.9 Hz,1H),7.68(ddd,J＝9.6,1.9,1.3 Hz,1H),7.59(dd,J＝9.8,0.6 Hz,1H),7.50(dd,J＝9.6,6.3 Hz,1H),7.40(ddd,J＝6.4,1.9,1.3 Hz,1H)ppm。Calculated for C 18 H 10 F 3 N 5 [M+H] + ：353.0888 found 353.0866。
1 H NMR(300 MHz,DMSO-d 6 )δ9.28(s,1H),8.69–8.62(m,1H),8.49(d,J＝1.9Hz,1H),8.04(dd,J＝9.7,2.4 Hz,1H),7.59(dd,J＝9.8,0.6 Hz,1H),7.26–7.12(m,2H),6.90(t,J＝1.7 Hz,1H),6.80(dt,J＝6.9,2.0 Hz,1H)ppm。Calculated forC 17 H 11 N 5 O[M+H] + ：301.0964 found 301.0962。
1 H NMR(300 MHz,DMSO-d 6 )δ8.69–8.62(m,2H),8.49(d,J＝1.9 Hz,2H),8.04(dd,J＝9.7,2.4 Hz,2H),7.59(dd,J＝9.8,0.6 Hz,2H),7.31(t,J＝6.8 Hz,2H),7.25(dt,J＝6.7,1.5 Hz,2H),7.17(t,J＝1.9 Hz,2H),7.05–6.96(m,2H)ppm。Calculated for C 18 H 13 N 5 O[M+H] + ：315.1120 found 315.1121。
1 H NMR(300 MHz,DMSO-d 6 )δ8.69–8.62(m,1H),8.49(d,J＝1.9 Hz,1H),8.04(dd,J＝9.7,2.4 Hz,1H),7.59(dd,J＝9.8,0.6 Hz,1H),7.25(t,J＝6.9 Hz,1H),7.10(ddd,J＝7.0,1.9,1.2 Hz,1H),6.99(t,J＝1.9 Hz,1H),6.65(ddd,J＝6.8,1.9,1.2 Hz,1H),4.97(s,2H)ppm。Calculated for C 17 H 12 N 6 [M+H] + ：300.1123 found300.1114。
1 H NMR(300 MHz,DMSO-d 6 )δ8.69–8.62(m,2H),8.49(d,J＝1.9 Hz,2H),8.04(dd,J＝9.7,2.4 Hz,2H),7.92(t,J＝1.7 Hz,2H),7.65(dd,J＝5.0,1.7 Hz,2H),7.59(dd,J＝9.8,0.6 Hz,2H),7.34(dd,J＝5.0,1.7 Hz,2H)ppm。Calculated for C 15 H 9 N 5 S[M+H] + ：291.0579 found 291.0578。
1 H NMR(300 MHz,DMSO-d 6 )δ8.68(dd,J＝2.4,0.5 Hz,1H),8.49(d,J＝1.9 Hz,1H),8.04(dd,J＝9.7,2.4 Hz,1H),7.59(dd,J＝9.8,0.6 Hz,1H),3.04(q,J＝6.2Hz,1H),1.37–1.13(m,5H).ppm。Calculated for C 14 H 11 N 5 [M+H] + ：249.1014 found 249.1011。
1 H NMR(300 MHz,DMSO-d 6 )δ8.68(d,J＝2.4 Hz,1H),8.49(d,J＝1.9 Hz,1H),8.04(dd,J＝9.7,2.4 Hz,1H),7.59(d,J＝9.8 Hz,1H),3.05–2.92(m,1H),1.70-1.55(m,J＝13.4,4.8,4.1,2.4,1.5 Hz,8H)ppm。Calculated for C1 6 H 15 N 5 [M+H] + ：277.1327found 277.1325。
1 H NMR(300 MHz,DMSO-d 6 )δ8.79(dd,J＝2.2,1.6 Hz,1H),8.73–8.63(m,2H),8.50(s,1H),8.05(dd,J＝9.7,2.4 Hz,1H),7.84(dt,J＝6.6,2.2 Hz,1H),7.59(dd,J＝9.8,0.5 Hz,1H),7.45–7.20(m,6H),5.37(t,J＝0.9 Hz,2H)ppm。Calculatedfor C 23 H 16 N 6 [M+H] + ：376.1436 found 376.1428。
1 H NMR(300 MHz,DMSO-d 6 )δ8.66(dd,J＝2.4,0.5 Hz,1H),8.51(t,J＝1.9 Hz,1H),8.50(s,1H),8.33(ddd,J＝7.7,1.9,1.3 Hz,1H),8.05(dd,J＝9.7,2.4 Hz,1H),7.76(ddd,J＝6.8,1.9,1.3 Hz,1H),7.71–7.54(m,2H),7.39–7.20(m,5H),5.37(t,J＝0.9 Hz,2H)ppm。Calculated for C 24 H 16 N 6 O 2 [M+H] + ：420.1335 found 420.1333。
1 H NMR(300 MHz,DMSO-d 6 )δ8.66(dd,J＝2.4,0.5 Hz,1H),8.50(s,1H),8.05(dd,J＝9.7,2.4 Hz,1H),7.59(dd,J＝9.8,0.5 Hz,1H),7.46(td,J＝6.6,5.0 Hz,1H),7.40–7.28(m,5H),7.33–7.21(m,3H),7.21-7.05(m,J＝6.8,2.0,1.1 Hz,1H),5.37(t,J＝0.9 Hz,2H)ppm。Calculated for C 24 H 16 FN 5 [M+H] + ：393.1390 found 393.1388。
1 H NMR(300 MHz,DMSO-d 6 )δ8.66(dd,J＝2.4,0.5 Hz,1H),8.50(s,1H),8.05(dd,J＝9.7,2.4 Hz,1H),7.96(t,J＝1.9 Hz,1H),7.68(ddd,J＝9.6,1.9,1.3 Hz,1H),7.63–7.20(m,8H),5.37(t,J＝0.9 Hz,2H)ppm。Calculated for C 25 H 16 F 3 N 5 [M+H] + ：443.1358 found 443.1344。
1 H NMR(300 MHz,DMSO-d 6 )δ9.28(s,1H),8.66(dd,J＝2.4,0.5 Hz,1H),8.50(s,1H),8.05(dd,J＝9.7,2.4 Hz,1H),7.59(dd,J＝9.8,0.6 Hz,1H),7.39–7.12(m,7H),6.90(t,J＝1.8 Hz,1H),6.80(dt,J＝6.9,1.9 Hz,1H),5.37(t,J＝0.9Hz,2H)ppm。Calculated for C 24 H 17 N 5 O[M+H] + ：391.1433 found 391.1430。
1 H NMR(300 MHz,DMSO-d 6 )δ8.66(dd,J＝2.4,0.5 Hz,1H),8.50(s,1H),8.05(dd,J＝9.7,2.4 Hz,1H),7.59(dd,J＝9.8,0.6 Hz,1H),7.39–7.20(m,8H),7.17(t,J＝1.9 Hz,1H),7.05–6.96(m,1H),5.37(t,J＝0.9 Hz,2H)ppm。Calculatedfor C 25 H 19 N 5 O[M+H] + ：405.1590 found 405.1588。
1 H NMR(300 MHz,DMSO-d 6 )δ8.66(dd,J＝2.4,0.5 Hz,1H),8.50(s,1H),8.05(dd,J＝9.7,2.4 Hz,1H),7.59(dd,J＝9.8,0.6 Hz,1H),7.39–7.20(m,7H),7.10(ddd,J＝7.0,1.9,1.2 Hz,1H),6.99(t,J＝1.9 Hz,1H),6.65(ddd,J＝6.8,1.9,1.2 Hz,1H),5.37(t,J＝0.9 Hz,2H),4.97(s,2H)ppm。Calculated for C 24 H 18 N 6 [M+H] + ：390.1593 found 390.1588。
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1 H NMR(300 MHz,DMSO-d 6 )δ8.66(dd,J＝2.4,0.5 Hz,1H),8.50(s,1H),8.05(dd,J＝9.7,2.4 Hz,1H),7.92(t,J＝1.7 Hz,1H),7.65(dd,J＝5.0,1.7 Hz,1H),7.59(dd,J＝9.8,0.6 Hz,1H),7.39–7.20(m,6H),5.37(t,J＝0.9 Hz,2H)ppm。Calculated for C 22 H 15 N 5 S[M+H] + ：381.1048 found 381.1047。
1 H NMR(300MHz,DMSO-d 6 )δ8.68(dd,J＝2.4,0.5Hz,1H),8.50(s,1H),8.05(dd,J＝9.7,2.4Hz,1H),7.59(dd,J＝9.8,0.5Hz,1H),7.39–7.20(m,6H),5.37(t,J＝0.9Hz,2H),3.04(q,J＝6.2Hz,1H),1.37–1.13(m,5H)ppm。Calculated for C 21 H 17 N 5 [M+H] + ：339.1484found 339.1479。
1 H NMR(300MHz,DMSO-d 6 )δ8.68(d,J＝2.4Hz,1H),8.50(s,1H),8.05(dd,J＝9.7,2.4Hz,1H),7.59(d,J＝9.8Hz,1H),7.39–7.20(m,5H),5.37(t,J＝0.9Hz,2H),3.05–2.92(m,1H),1.80–1.61(m,8H)ppm。Calculated for C 23 H 21 N 5 [M+H] + ：367.1797found 367.1793。
example 2: synthesis of LBL-021
Synthesis of intermediate IX-II:
in a 25mL single necked flask was added 0.2g of intermediate VII (0.58 mmol,1 eq), 83mg of ethyl azide acetate (1.1 mmol,1.1 eq), 15mg of copper sulfate pentahydrate (0.06 mmol,0.1 eq) and 23mg of sodium ascorbate (0.12 mmol,0.2 eq) and finally 5mL of LDMF was added and stirred at room temperature. TLC monitoring after 2h of reaction showed complete reaction. Extraction with ethyl acetate and water, the organic layer was retained and dried over anhydrous sodium sulfate, and column chromatography after spin-drying the organic phase gave 0.12g of white solid IX-II in 58% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.79(dd,J＝2.3,1.6Hz,1H),8.73–8.64(m,2H),8.39(s,1H),8.00(dd,J＝8.5,2.4Hz,1H),7.84(dt,J＝6.6,2.2Hz,1H),7.71(dd,J＝8.6,0.6Hz,1H),7.40(dd,J＝6.6,3.2Hz,1H),5.92(t,J＝2.4Hz,1H),5.16(d,J＝0.4Hz,2H),4.28–4.18(m,2H),3.94–3.72(m,2H),2.30–2.06(m,2H),1.97–1.72(m,2H),1.78–1.58(m,2H),1.24(t,J＝6.6Hz,3H)ppm。Calculated for C 25 H 24 N 6 O 3 [M+H] + ：456.1910found 456.1908。
The remaining procedure was as in example 1 to give compound LBL-021.
1 H NMR(300MHz,DMSO-d 6 )δ8.79(dd,J＝2.2,1.6Hz,1H),8.73–8.63(m,2H),8.39(s,1H),8.05(dd,J＝9.7,2.4Hz,1H),7.84(dt,J＝6.6,2.2Hz,1H),7.59(dd,J＝9.8,0.6Hz,1H),7.40(dd,J＝6.6,3.2Hz,1H),5.16(s,2H),4.28–4.18(m,2H),1.24(t,J＝6.6Hz,3H)ppm。Calculated for C 20 H 16 N 6 O 2 [M+H] + ：372.1335found372.1330。
By operating in a similar manner to example 2, the following compounds were prepared:
1 H NMR(300MHz,DMSO-d 6 )δ8.66(dd,J＝2.4,0.5Hz,1H),8.51(t,J＝1.9Hz,1H),8.42–8.28(m,2H),8.05(dd,J＝9.7,2.4Hz,1H),7.76(ddd,J＝6.8,1.9,1.3Hz,1H),7.71–7.54(m,2H),5.16(s,2H),4.28–4.18(m,2H),1.24(t,J＝6.6Hz,3H)ppm。Calculated for C 21 H 16 N 6 O 4 [M+H] + ：416.1233found 416.1238。
1 H NMR(300MHz,DMSO-d 6 )δ8.66(dd,J＝2.4,0.5Hz,1H),8.39(s,1H),8.05(dd,J＝9.7,2.4Hz,1H),7.59(dd,J＝9.8,0.6Hz,1H),7.46(td,J＝6.7,5.0Hz,1H),7.38–7.27(m,2H),7.27–7.16(m,1H),5.16(s,2H),4.28–4.18(m,2H),1.24(t,J＝6.6Hz,3H)ppm。Calculated for C 21 H 16 FN 5 O 2 [M+H] + ：389.1288found 389.1287。
1 H NMR(300 MHz,DMSO-d 6 )δ8.66(dd,J＝2.4,0.5 Hz,1H),8.39(s,1H),8.05(dd,J＝9.7,2.4 Hz,1H),7.96(t,J＝1.9 Hz,1H),7.68(ddd,J＝9.6,1.9,1.3 Hz,1H),7.59(dd,J＝9.8,0.6 Hz,1H),7.50(dd,J＝9.6,6.3 Hz,1H),7.40(ddd,J＝6.4,1.9,1.3 Hz,1H),5.16(s,2H),4.28–4.18(m,2H),1.24(t,J＝6.6 Hz,3H)ppm。Calculated for C 22 H 16 F 3 N 5 O 2 [M+H] + ：439.1256 found 439.1254。
1 H NMR(300 MHz,DMSO-d 6 )δ9.28(s,1H),8.66(dd,J＝2.4,0.5 Hz,1H),8.39(s,1H),8.05(dd,J＝9.7,2.4 Hz,1H),7.59(dd,J＝9.8,0.6 Hz,1H),7.26–7.12(m,2H),6.90(t,J＝1.8 Hz,1H),6.80(dt,J＝6.9,2.0 Hz,1H),5.16(s,2H),4.28–4.18(m,2H),1.24(t,J＝6.6 Hz,3H)ppm。Calculated for C 21 H 17 N 5 O 3 [M+H] + ：387.1331found 387.1330。
1 H NMR(300 MHz,DMSO-d 6 )δ8.66(dd,J＝2.4,0.5 Hz,1H),8.39(s,1H),8.05(dd,J＝9.7,2.4 Hz,1H),7.59(dd,J＝9.8,0.6 Hz,1H),7.36–7.20(m,2H),7.17(t,J＝1.9 Hz,1H),7.05–6.96(m,1H),5.16(s,2H),4.22(q,J＝6.6 Hz,2H),1.24(t,J＝6.6 Hz,3H)ppm。Calculated for C 22 H 19 N 5 O 3 [M+H] + ：401.1488 found 401.1485。
1 H NMR(300 MHz,DMSO-d 6 )δ8.66(dd,J＝2.4,0.5 Hz,1H),8.39(s,1H),8.05(dd,J＝9.7,2.4 Hz,1H),7.59(dd,J＝9.8,0.6 Hz,1H),7.25(t,J＝6.9 Hz,1H),7.10(ddd,J＝7.0,1.9,1.2 Hz,1H),6.99(t,J＝1.9 Hz,1H),6.65(ddd,J＝6.8,1.9,1.2 Hz,1H),5.16(s,2H),4.97(s,2H),4.28–4.18(m,2H),1.24(t,J＝6.6Hz,3H)ppm。Calculated for C 21 H 18 N 6 O 2 [M+H] + ：386.1491 found 386.1490。
1 H NMR(300 MHz,DMSO-d 6 )δ8.66(dd,J＝2.4,0.5 Hz,1H),8.39(s,1H),8.05(dd,J＝9.7,2.4 Hz,1H),7.92(t,J＝1.7 Hz,1H),7.65(dd,J＝5.0,1.7 Hz,1H),7.59(dd,J＝9.8,0.6 Hz,1H),7.34(dd,J＝5.0,1.7 Hz,1H),5.16(s,2H),4.28–4.18(m,2H),1.24(t,J＝6.6 Hz,3H)ppm。Calculated for C 19 H 15 N 5 O 2 S[M+H] + ：377.0946found 377.0944。
1 H NMR(300 MHz,DMSO-d 6 )δ8.68(dd,J＝2.4,0.5 Hz,1H),8.39(s,1H),8.05(dd,J＝9.7,2.4 Hz,1H),7.59(dd,J＝9.8,0.5 Hz,1H),5.16(s,2H),4.22(q,J＝6.6 Hz,2H),3.04(q,J＝6.2 Hz,1H),1.37–1.13(m,7H)ppm。Calculated for C 18 H 17 N 5 O 2 [M+H] + ：335.1382 found 335.1380。
1 H NMR(300 MHz,DMSO-d 6 )δ8.68(dd,J＝2.4,0.5 Hz,1H),8.39(s,1H),8.05(dd,J＝9.7,2.4 Hz,1H),7.59(dd,J＝9.8,0.6 Hz,1H),5.16(s,2H),4.22(q,J＝6.6 Hz,2H),3.05–2.92(m,1H),1.81–1.62(m,8H),1.24(t,J＝6.6 Hz,3H)ppm。Calculated for C 20 H 21 N 5 O 2 [M+H] + ：363.1695 found 363.1694。
1 H NMR(300 MHz,DMSO-d 6 )δ8.79(dd,J＝2.3,1.6 Hz,1H),8.69(ddd,J＝3.3,2.3,1.6 Hz,1H),8.64–8.57(m,1H),8.20(s,1H),8.04(dd,J＝9.8,2.4 Hz,1H),7.89–7.79(m,3H),7.59(dd,J＝9.8,0.6 Hz,1H),7.40(dd,J＝6.6,3.2 Hz,1H),7.34-7.20(m,J＝8.8,0.8 Hz,2H),2.39(d,J＝1.5 Hz,1H)ppm。Calculated for C 23 H 16 N 6 O 2 S[M+H] + ：440.1055 found 440.1050。
1 H NMR(300 MHz,DMSO-d 6 )δ8.64–8.57(m,1H),8.51(t,J＝1.9 Hz,1H),8.33(ddd,J＝7.7,1.9,1.3 Hz,1H),8.20(s,1H),8.04(dd,J＝9.8,2.4 Hz,1H),7.89–7.80(m,2H),7.76(ddd,J＝6.8,1.9,1.3 Hz,1H),7.66(dd,J＝7.7,6.8 Hz,1H),7.59(dd,J＝9.7,0.6 Hz,1H),7.40–7.29(m,2H),2.39(d,J＝1.4 Hz,1H)ppm。Calculated for C 24 H 16 N 6 O 4 S[M+H] + ：484.0954 found 484.0950。
1 H NMR(300 MHz,DMSO-d 6 )δ8.64–8.57(m,1H),8.20(s,1H),8.04(dd,J＝9.8,2.4 Hz,1H),7.89–7.79(m,2H),7.59(dd,J＝9.8,0.6 Hz,1H),7.46(td,J＝6.7,4.9 Hz,1H),7.39–7.16(m,5H),2.39(d,J＝1.4 Hz,1H)ppm。Calculated for C 24 H 16 FN 5 O 2 S[M+H] + ：457.1009 found 457.1007。
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1 H NMR(300 MHz,DMSO-d 6 )δ8.64–8.57(m,1H),8.20(s,1H),8.04(dd,J＝9.8,2.4 Hz,1H),7.96(t,J＝1.9 Hz,1H),7.89–7.79(m,2H),7.68(ddd,J＝9.6,1.9,1.3 Hz,1H),7.59(dd,J＝9.8,0.6 Hz,1H),7.50(dd,J＝9.6,6.4 Hz,1H),7.40(ddd,J＝6.4,1.9,1.3 Hz,1H),7.34-7.19(m,J＝8.8,0.7 Hz,2H),2.39(d,J＝1.4 Hz,1H)ppm。Calculated for C 25 H 16 F 3 N 5 O 2 S[M+H] + ：507.0977 found 507.0975。
1 H NMR(300 MHz,DMSO-d 6 )δ9.28(s,1H),8.64–8.57(m,1H),8.20(s,1H),8.04(dd,J＝9.8,2.4 Hz,1H),7.89–7.79(m,2H),7.59(dd,J＝9.8,0.6 Hz,1H),7.40–7.29(m,2H),7.26–7.12(m,2H),6.90(t,J＝1.8 Hz,1H),6.80(dt,J＝6.9,1.9 Hz,1H),2.39(d,J＝1.4 Hz,1H)ppm。Calculated for C 24 H 17 N 5 O 3 S[M+H] + ：455.1052found 455.1050。
1 H NMR(300 MHz,DMSO-d 6 )δ8.64–8.57(m,1H),8.20(s,1H),8.04(dd,J＝9.8,2.4 Hz,1H),7.89–7.79(m,2H),7.59(dd,J＝9.8,0.6 Hz,1H),7.40–7.26(m,3H),7.25(dt,J＝6.7,1.5 Hz,1H),7.17(t,J＝1.9 Hz,1H),7.05–6.96(m,1H),2.39(d,J＝1.3 Hz,1H)ppm。Calculated for C 25 H 19 N 5 O 3 S[M+H] + ：469.1209 found 469.1208。
1 H NMR(300 MHz,DMSO-d 6 )δ8.64–8.57(m,1H),8.20(s,1H),8.04(dd,J＝9.8,2.4 Hz,1H),7.89–7.79(m,2H),7.59(dd,J＝9.8,0.6 Hz,1H),7.34 -7.20(m,J＝8.8,0.7 Hz,2H),7.25(t,J＝6.9 Hz,1H),7.10(ddd,J＝7.0,1.9,1.2 Hz,1H),6.99(t,J＝1.9 Hz,1H),6.65(ddd,J＝6.8,1.9,1.2 Hz,1H),4.97(s,2H),2.39(d,J＝1.4 Hz,1H)ppm。Calculated for C 24 H 18 N 6 O 2 S[M+H] + ：454.1212 found 454.1210。
1 H NMR(300 MHz,DMSO-d 6 )δ8.64–8.57(m,1H),8.20(s,1H),8.04(dd,J＝9.8,2.4 Hz,1H),7.92(t,J＝1.7 Hz,1H),7.89–7.79(m,2H),7.65(dd,J＝5.0,1.7Hz,1H),7.59(dd,J＝9.8,0.6 Hz,1H),7.40–7.29(m,3H),2.39(d,J＝1.4 Hz,1H)ppm。Calculated for C 22 H 15 N 5 O 2 S 2 [M+H] + ：445.0667 found 445.0666。
1 H NMR(300MHz,DMSO-d 6 )δ8.66(dd,J＝2.4,0.5Hz,1H),8.20(s,1H),8.04(dd,J＝9.8,2.4Hz,1H),7.89–7.79(m,2H),7.59(dd,J＝9.8,0.6Hz,1H),7.34-7.19(m,J＝8.8,0.7Hz,2H),3.04(q,J＝6.2Hz,1H),2.39(d,J＝1.4Hz,1H),1.37–1.13(m,5H)ppm。Calculated for C 21 H 17 N 5 O 2 S[M+H] + ：403.1103found 403.1101。
1 H NMR(300MHz,DMSO-d 6 )δ8.66(dd,J＝2.4,0.5Hz,1H),8.20(s,1H),8.04(dd,J＝9.8,2.4Hz,1H),7.89–7.79(m,2H),7.59(dd,J＝9.8,0.5Hz,1H),7.34-7.19(m,J＝8.8,0.8Hz,2H),3.05–2.92(m,1H),2.42–2.36(m,2H),1.81–1.61(m,8H)ppm。Calculated for C 23 H 21 N 5 O 2 S[M+H] + ：431.1416found 431.1414。
example 3: in vitro inhibitory Activity of certain Compounds of the invention against CLK family and DYRK1A proteins
1. Experimental method
1. Preparation of 1X kinase reaction buffer
2. Enzyme activity test
(1) 2X kinase preparation:
(2) 4X substrate mixture preparation:
(1) The positive drug Lorecivint (SM-04690) was subjected to 4-fold gradient dilutions of compound in DMSO in dilution plates at final initial concentrations of 1, 0.02, 0.1. Mu.M.
(2) The compound was 50-fold diluted in 1X kinase reaction buffer and shaken on a shaker for 20 minutes.
(3) Preparation of 2X kinase with 1X enzyme reaction buffer.
(4) mu.L kinase was added to each well of the reaction plate.
(5) mu.L of the diluted compound in buffer was added to each well, and the plates were blocked with a plate membrane and centrifuged at 1000rpm for 60 seconds and incubated at 25℃for 10 minutes.
(6) A4X ATP mixed solution is prepared by using a 1X enzyme reaction buffer solution, and 1 mu L of the 4X ATP mixed solution is added into a reaction plate.
(7) Plates were sealed with a sealing plate membrane and centrifuged at 1000rpm for 60 seconds and incubated at 25℃for 60 minutes.
(8) Transfer 4. Mu.L of ADP-Glo to 384 reaction plates 1000rpm, centrifuge 1min, incubate at 25℃for 40min.
(9) Transfer 8. Mu.L of Detection solution to 384 reaction plates 1000rpm, centrifuge 1min, incubate at 25℃for 40min.
(10) The RLU (Relative luminescence unit) signal was read using a BMG multifunctional plate reader, and the signal intensity was used to characterize the extent of kinase activity.
2. Experimental results
TABLE 1 enzymatic Activity of some of the Compounds of the invention
Note that: a: < 10nM, B:10-50nM, C:50-100nM, D: > 100nM.
As can be seen from Table 1, the compounds of the present invention showed potent inhibitory activity against CLK2, DYRK 1A. At the same time, the compounds of the present invention, such as LBL-001, exhibit superior CLK2 inhibitory activity and CLK3 selectivity (IC for CLK2, CLK3, DYRK1A 50 4nM, 120nM, 3nM, respectively, and a selectivity index of 30 for CLK 3), which provides a basis for LBL-001 to exert its pharmacological activity and avoid possible side effects.

Claims (10)

1. A3-ethynyl-5- (1H-1, 2, 3-triazole-4-yl) -1H-indazole compound shown in a formula I, pharmaceutically acceptable salt or a mixture thereof is characterized in that,
wherein R1 is selected from the following groups: H.
r2 is selected from the following groups:
2. a 3-ethynyl-5- (1H-1, 2, 3-triazol-4-yl) -1H-indazole compound, pharmaceutically acceptable salt or mixtures thereof, according to formula I of claim 1, wherein:
R 1 selected from H,
R2 is selected from the following groups:
3. 3-ethynyl-5- (1H-1, 2, 3-triazol-4-yl) -1H-indazoles, pharmaceutically acceptable salts or mixtures thereof, according to formula I of claim 1, characterized in that they are selected from any of the following compounds:
4. 3-ethynyl-5- (1H-1, 2, 3-triazol-4-yl) -1H-indazoles of formula I according to claim 1, pharmaceutically acceptable salts or mixtures thereof, characterized in that said pharmaceutically acceptable salts are salts of said compounds with: hydrochloric acid, sulfuric acid, phosphoric acid, carbonic acid, nitric acid, hydrobromic acid, hydroiodic acid, maleic acid, fumaric acid, tartaric acid, citric acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, succinic acid, acetic acid, mandelic acid, isobutyric acid or malonic acid.
5. A pharmaceutical composition comprising a 3-ethynyl-5- (1H-1, 2, 3-triazol-4-yl) -1H-indazole compound of formula I according to any one of claims 1-4, a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
6. Use of a 3-ethynyl-5- (1H-1, 2, 3-triazol-4-yl) -1H-indazole compound of formula I, an isomer, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 1-4, in the preparation of a CLK2 protein inhibitor medicament.
7. Use of a 3-ethynyl-5- (1H-1, 2, 3-triazol-4-yl) -1H-indazole compound, a pharmaceutically acceptable salt according to any one of claims 1-4 or a pharmaceutical composition according to claim 5 in the preparation of a DYRK1A protein inhibitor medicament.
8. Use of a 3-ethynyl-5- (1H-1, 2, 3-triazol-4-yl) -1H-indazole compound, a pharmaceutically acceptable salt according to any one of claims 1-4 or a pharmaceutical composition according to claim 5 in the manufacture of a medicament for the treatment of inflammation.
9. The use according to claim 8, wherein the inflammation is osteoarthritis, tendinosis or rheumatoid arthritis.
10. The use according to claim 8, wherein the compound has a chondroprotective effect.
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CN115304583A (en) * 2022-09-07 2022-11-08 中国药科大学 5-pyridine-1H-indazole compound for targeted inhibition of CLK2 and application thereof

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