A class of pyridine biimidazole pyridine compounds and their preparation method and use

Abstract

The present invention discloses a class of pyridine biimidazole pyridine compounds, their preparation methods, and uses. The pyridine biimidazole pyridine compounds provided by the present invention have novel structures and exhibit excellent inhibitory effects on BET proteins. This inhibition is highly selective, specifically selectively inhibiting the BD1 domain of BET proteins. Those skilled in the art are aware that BET proteins are targets for tumor or inflammation treatment. Therefore, the pyridine biimidazole pyridine compounds provided by the present invention can be used to prepare anti-tumor or anti-inflammatory drugs.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a class of pyridine biimidazole pyridine compounds and a preparation method and use thereof. Background Art

[0002] The epigenetic target bromodomain and extra-terminal domain (BET) protein family is an extremely important target in the treatment of tumors and inflammation. The BET protein family includes four subtypes: BRD2, BRD3, BRD4, and BRDT, of which BRD4 is the most widely studied. BET family proteins all contain two highly conserved N-terminal tandem bromodomains, BD1 and BD2. Each bromodomain is composed of four antiparallel α-helices (αZ, αA, αB, and αC) and two hydrophobic loops (ZA loop and BC loop). Selective inhibition of one of the two bromodomains has become a focus of attention because it helps us understand the biological function of each bromodomain and thus rationally evaluate efficacy and toxicity.

[0003] Because BD1 and BD2 are two BDs linked in series on the same protein, it is difficult to investigate the biological function of a single BD using conventional biological methods. Non-selective inhibitors of BD1 and BD2 have already demonstrated certain limitations in basic research and clinical trials. Currently, there are more reports of BD2-selective inhibitors than BD1-selective inhibitors, and the activity and selectivity of reported BD1-selective inhibitors need to be further improved. The limited availability of BD1-selective inhibitors limits our understanding of the biological function and therapeutic value of selectively inhibiting BD1. Therefore, developing highly selective BD1 inhibitors and exploring their potential therapeutic effects are also urgent issues that need to be addressed. Summary of the Invention

[0004] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a class of pyridine biimidazole pyridine compounds and their preparation methods and uses.

[0005] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0006] A pyridine biimidazole pyridine compound is a compound represented by formula I or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in:

[0009] Ring A is selected from phenyl, 5-6 membered aromatic hetero groups; R a independently selected from hydrogen, C 1-5 Alkyl, -CF3, C 3-7 Cycloalkyl; n=1-5;

[0010] Ring B is a pyridine ring, and the pyridine nitrogen atom is located at any unsubstituted position on the ring.

[0011] Preferably, the pharmaceutically acceptable salt is an acid addition salt of the compound of formula I, wherein the acid used for salt formation includes hydrogen chloride, sulfuric acid, hydrogen bromide, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

[0012] The preparation method of the above-mentioned pyridine biimidazole pyridine compound, the compound structure is shown in Target 1 to Target 4, and the synthesis route is as follows:

[0013]

[0014] The preparation method of the above-mentioned pyridine biimidazole pyridine compound, the compound structure is shown in target 5 to target 14, and the synthesis route is as follows:

[0015]

[0016] The pyridine biimidazole pyridine compound is used for preparing BET inhibitor drugs.

[0017] Preferably, the inhibition is the selective inhibition of the BD1 domain of the BET protein.

[0018] The pyridine biimidazole pyridine compound is used for preparing anti-tumor drugs or anti-inflammatory drugs.

[0019] Beneficial effects:

[0020] The pyridine biimidazopyridine compounds provided by the present invention have novel structures and exhibit excellent inhibitory effects on BET proteins. This inhibition is highly selective, specifically inhibiting the BD1 domain of BET proteins. As known to those skilled in the art, BET proteins are targets for tumor or inflammation treatment. Therefore, the pyridine biimidazopyridine compounds provided by the present invention can be used to prepare anti-tumor or anti-inflammatory drugs. DETAILED DESCRIPTION

[0021] The following examples are used to describe the essential contents of the present invention, but the scope of protection of the present invention is not limited thereto. In the following examples, the experimental methods without specific conditions are carried out according to the existing methods and conditions in the industry.

[0022] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0023] MS was measured using a liquid chromatography-mass spectrometer (LC-MS / MS) (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS). HRMS used an Agilent 6230.

[0024] The thin layer chromatography silica gel plate used was Qingdao GF254 silica gel plate. The silica gel plate used for thin layer chromatography (TLC) was 0.15 mm to 0.2 mm in size, and the thin layer chromatography separation and purification product was 0.4 mm to 0.5 mm in size. Other starting materials disclosed in the present invention can be synthesized according to methods known in the art or obtained from commercially available products.

[0025] Unless otherwise specified in the examples, all reactions can be carried out under argon or nitrogen atmosphere.

[0026] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0027] Synthesis Route 1:

[0028] Examples 1 to 4 were synthesized according to Scheme 1.

[0029]

[0030] Scheme 1.Reagents and conditions: (a) Cs2CO3, Pd(dppf)Cl2·CH2Cl2, 1,4-Dioxane, H2O, 100℃, 3h; (b) AcOK, Pd(dppf)Cl2·CH2Cl2, dry 1,4-Dioxane, 100℃, 3h; (c) Cs2CO3, Pd(dppf)Cl2·CH2Cl2, 1,4-Dioxane, H2O, 100℃, 7h.

[0031] 4-(2-Bromopyridin-4-yl)-3,5-dimethylisoxazole (34b)

[0032] 4-(2-bromopyridin-4-yl)-3,5-dimethylisoxazole(34b)

[0033]

[0034] General Synthesis Route A: 33b (500 mg, 1.77 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole 19a (512.54 mg, 2.30 mmol), cesium carbonate (1.15 g, 3.53 mmol), and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (143.90 mg, 0.177 mmol) were added to a Shrek tube. Then, 9 mL of dioxane and 3 mL of water were added as the reaction solvent. The air in the Shrek tube was fully replaced with argon. The reaction was carried out at 100°C for 3 h, and the reaction was complete as monitored by TLC. After the reaction mixture was cooled to room temperature, equal volumes of ethyl acetate and water were added for three separate extractions. The organic layers were combined and concentrated under low pressure to remove the solvent. The residue was purified by column chromatography to obtain the target product 34b (446 mg, yield: 83.4%).

[0035] 4-(5-Bromopyridin-3-yl)-3,5-dimethylisoxazole (34c)

[0036] 4-(5-bromopyridin-3-yl)-3,5-dimethylisoxazole(34c)

[0037]

[0038] According to conventional route A, 33c (600 mg, 2.11 mmol) was used as the starting material to obtain the target product 34c (427 mg, yield: 79.8%).

[0039] 4-(4-Bromopyridin-2-yl)-3,5-dimethylisoxazole (34d)

[0040] 4-(4-bromopyridin-2-yl)-3,5-dimethylisoxazole(34d)

[0041]

[0042] According to conventional route A, 33d (600 mg, 2.11 mmol) was used as the starting material to obtain the target product 34d (363 mg, yield: 67.9%).

[0043] 4-(7-Bromo-2,3-dihydrobenzofuran-5-yl)-3,5-dimethylisoxazole (34e)

[0044] 4-(7-bromo-2,3-dihydrobenzofuran-5-yl)-3,5-dimethylisoxazole(34e)

[0045]

[0046] According to conventional route A, 33e (600 mg, 2.11 mmol) was used as the starting material to obtain the target product 34e (461 mg, yield: 84.9%).

[0047] 3,5-Dimethyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)isoxazole(35a)

[0048] 3,5-dimethyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)isoxazole(35a)

[0049]

[0050] Conventional Synthesis Route B: 34a (334 mg, 1.33 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) 21 (438.07 mg, 1.73 mmol), potassium acetate (260.47 mg, 2.65 mmol), and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (108.79 mg, 0.13 mmol) were added to a Shrek tube, followed by 10 mL of anhydrous dioxane as the reaction solvent. The atmosphere in the Shrek tube was fully replaced with argon. The reaction was carried out at 100°C for 3 h, and the reaction was complete after TLC monitoring. After cooling to room temperature, the reaction was extracted three times with equal volumes of ethyl acetate and water. The organic layers were combined and concentrated under low pressure to remove the solvent, yielding the residue 35a (297 mg, 50.0% yield). Without further purification, it was directly used for the next step.

[0051] 3,5-Dimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazole (35b)

[0052] 3,5-dimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazole(35b)

[0053]

[0054] According to conventional route B, 34b (500 mg, 1.98 mmol) was used as the starting material to obtain the target product 35b (421 mg, yield: 79.6%).

[0055] 3,5-Dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)isoxazole (35c)

[0056] 3,5-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)isoxazole(35c)

[0057]

[0058] According to conventional route B, 34c (500 mg, 1.98 mmol) was used as the starting material to obtain the target product 35c (439 mg, yield: 74.0%).

[0059] 3,5-Dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)isoxazole (35d)

[0060] 3,5-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)isoxazole(35d)

[0061]

[0062] According to conventional route B, 34d (500 mg, 1.98 mmol) was used as the starting material to obtain the target product 35d (412 mg, yield: 69.5%).

[0063] 5-(3,5-Dimethylisoxazol-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrofuro[2,3-c]pyridine (35e)

[0064] 5-(3,5-dimethylisoxazol-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrofuro[2,3-c]pyridine(35e)

[0065]

[0066] According to conventional route B, 34e (500 mg, 1.98 mmol) was used as the starting material to obtain the target product 35e (466 mg, yield: 80.1%).

[0067] Example 1:

[0068] 7-(6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)-1H-imidazo[4,5-b]pyridine (Example 1)

[0069] 7-(6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)-1H-imidazo[4,5-b]pyridine (Example 1)

[0070]

[0071] Conventional Synthesis Route C: 7-Bromo-1H-imidazo[4,5-b]pyridine 23 (258 mg, 1.3 mmol), 35a (400 mg, 1.28 mmol), cesium carbonate (848.66 mg, 2.60 mmol), and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (106.38 mg, 0.13 mmol) were added to a Shrek tube. 9 mL of dioxane and 3 mL of water were then added as the reaction solvent. The atmosphere in the Shrek tube was fully replaced with argon. The reaction was carried out at 100°C for 7 h, and TLC confirmed the complete reaction. After the reaction was cooled to room temperature, the reaction was extracted three times with equal volumes of ethyl acetate and water. The organic layers were combined and concentrated under low pressure to remove the solvent. The residue was purified by column chromatography to obtain Example 1 (102 mg, 34.1% yield). 1 H NMR (300MHz, DMSO-d6) δ13.41(s,1H),9.19(d,J=7.8Hz,1H),8.62(s,1H),8.52(d,J=5.0Hz,1H),8.16 (s,1H),8.14(d,J=2.0Hz,1H),7.69(d,J=7.7Hz,1H),2.71(s,3H),2.57(s,3H).HRMS(ESI):calcdfor C 16 H 13 N5O[M+H] + 292.11, found 292.1170 Purity: 92.26% by HPLC (MeOH / H2O=80:20, t R =5.222min).

[0072] Example 2:

[0073] 7-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)-1H-imidazo[4,5-b]pyridine (Example 2)

[0074] 7-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)-1H-imidazo[4,5-b]pyridine (Example 2)

[0075]

[0076] According to the conventional route C, 35b (400 mg, 1.28 mmol) was used as the reaction material to obtain Example 2 (98 mg, yield: 32.8%). 1 H NMR (300MHz, DMSO-d6) δ13.42(s,1H),8.88(d,J=5.1Hz,1H),8.52(d,J=5.2Hz,1H),8.18(d,J=5.1Hz,1H ),7.59(dd,J=4.9,2.0Hz,2H),7.27(dd,J=8.0,4.7Hz,1H),2.62(s,3H),2.44(s,3H).HRMS(ESI):calcd for C 16 H 13 N5O[M+H] + 292.11, found 292.1122. Purity: 98.23% by HPLC (MeOH / H2O=80:20, tR=2.578 min).

[0077] Example 3:

[0078] 7-(5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 3)

[0079] 7-(5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 3)

[0080]

[0081] According to the conventional route C, 35c (400 mg, 1.28 mmol) was used as the reaction material to obtain Example 3 (121 mg, yield: 40.5%). HRMS (ESI): calculated for C 16 H 13 N5O[M+H]+ 292.11, found 292.1138 Purity: 94.09% by HPLC (MeOH / H2O=80:20, t R =7.691min).

[0082] Example 4:

[0083] 7-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-4-yl)-1H-imidazo[4,5-b]pyridine (Example 4)

[0084] 7-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-4-yl)-1H-imidazo[4,5-b]pyridine (Example 4)

[0085]

[0086] According to the conventional route C, 35d (400 mg, 1.28 mmol) was used as the reaction material to obtain Example 4 (106 mg, yield: 35.5%). 1 HNMR(300MHz,DMSO-d6)δ13.45(s,1H),8.86(d,J=5.2Hz,1H),8.66–8.47(m,3H),8.23( d,J=5.1Hz,1H),7.79(d,J=5.1Hz,1H),2.69(s,3H),2.49(s,3H).HRMS(ESI):calcdfor C 16 H 13 N5O[M+H] + 292.11, found 292.1176 Purity: 93.56% by HPLC (MeOH / H2O=65:35, t R =10.303min).

[0087] Synthesis route 2:

[0088] Examples 5 to 14 were synthesized according to Scheme 2.

[0089]

[0090] Scheme 2.Reagents and conditions: (a) Cs2CO3, Pd(dppf)Cl2·CH2Cl2, 1,4-Dioxane, H2O, 100℃, 3h; (b) AcOK, Pd(dppf)Cl2·CH2Cl2, dry 1,4-Dioxane, 100℃, 3h; (c) Cs2CO3, Pd(dppf)Cl2·CH2Cl2, 1,4-Dioxane, H2O, 100℃, 7h, (d) Cs2CO3, DMF, rt, 5h.

[0091] 3-Bromo-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridine (37a)

[0092] 3-bromo-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridine(37a)

[0093]

[0094] According to conventional route A, 3-bromo-5-iodopyridine (500 mg, 1.76 mmol) and 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (540.62 mg, 2.29 mmol) were used as reaction raw materials to obtain the target product (410 mg, yield: 87.47%).

[0095] 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridine (38a)

[0096] 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridine(38a)

[0097]

[0098] According to conventional route B, 3-bromo-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridine 37a (410 mg, 1.54 mmol) was used as the reaction material to obtain the target product 38a (372 mg, yield: 77.1%).

[0099] 3-Bromo-5-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine (37b)

[0100] 3-bromo-5-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine(37b)

[0101]

[0102] According to conventional route A, 3-bromo-5-iodopyridine 33c (500 mg, 1.76 mmol) and 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 36a (508.5 mg, 2.29 mmol) were used as reaction raw materials to obtain the target product 37b (403 mg, yield: 90.7%).

[0103] 3-(1,3-Dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (38b)

[0104] 3-(1,3-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(38b)

[0105]

[0106] According to conventional route B, 3-bromo-5-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine 37b (410 mg, 1.63 mmol) was used as the starting material to obtain the target product 38b (385 mg, yield: 79.1%).

[0107] 3-Bromo-5-(1,5-dimethyl-1H-pyrazol-4-yl)pyridine (37c)

[0108] 3-bromo-5-(1,5-dimethyl-1H-pyrazol-4-yl)pyridine(37c)

[0109]

[0110] According to conventional route A, 3-bromo-5-iodopyridine 33c (500 mg, 1.76 mmol) and 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 36b (508.5 mg, 2.29 mmol) were used as reaction raw materials to obtain the target product 37c (403 mg, yield: 90.7%).

[0111] 3-(1,5-Dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (38c)

[0112] 3-(1,5-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(38c)

[0113]

[0114] Following conventional route B, 3-bromo-5-(1,5-dimethyl-1H-pyrazol-4-yl)pyridine 37c (410 mg, 1.63 mmol) was used as the starting material to obtain the target product 38c (378 mg, yield: 77.7%).

[0115] 3-Bromo-5-(1-methyl-1H-pyrazol-4-yl)pyridine (37d)

[0116] 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyridine(37d)

[0117]

[0118] According to conventional route A, 3-bromo-5-iodopyridine 33c (500 mg, 1.76 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 36c (476.5 mg, 2.29 mmol) were used as the reaction raw materials to obtain the target product 37d (379 mg, yield: 90.4%).

[0119] 3-(1-Methyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (38d)

[0120] 3-(1-methyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(38d)

[0121]

[0122] According to conventional route B, 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyridine 37d (410 mg, 1.72 mmol) was used as the starting material to obtain the target product 38d (362 mg, yield: 73.7%).

[0123] 3-Bromo-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyridine (37e)

[0124] 3-bromo-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyridine(37e)

[0125]

[0126] Following conventional route A, 3-bromo-5-iodopyridine 33c (500 mg, 1.76 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole 36d (632.1 mg, 2.29 mmol) were used as starting materials to give the target product 37e (435 mg, yield: 80.7%).

[0127] 3-(1-Methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (38e)

[0128] 3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(38e)

[0129]

[0130] Following conventional route B, 3-bromo-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyridine 37e (431.4 mg, 1.70 mmol) was used as the starting material to obtain the target product 38e (360 mg, yield: 78.1%).

[0131] 3-Bromo-5-(3,5-dimethyl-1H-pyrazol-4-yl)pyridine (37k)

[0132] 3-bromo-5-(3,5-dimethyl-1H-pyrazol-4-yl)pyridine(37k)

[0133]

[0134] According to conventional route A, 3-bromo-5-iodopyridine 33c (500 mg, 1.76 mmol) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1H-pyrazole 19f (513.1 mg, 2.29 mmol) were used as reaction raw materials to obtain the target product 37k (356 mg, yield: 80.1%).

[0135] 3-Bromo-5-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)pyridine (37f)

[0136] 3-bromo-5-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)pyridine(37f)

[0137]

[0138] General Synthesis Reaction D: 3-Bromo-5-(3,5-dimethyl-1H-pyrazol-4-yl)pyridine 38 (500 mg, 1.98 mmol), bromoethane 39a (324.16 mg, 2.97 mmol), and cesium carbonate (1.29 g, 3.97 mmol) were added to a round-bottom flask at room temperature, followed by the addition of 15 mL of DMF as the reaction solvent. After stirring at room temperature for 4 h, the reaction was confirmed to be complete by TLC. The mixture was extracted three times with equal volumes of ethyl acetate and water. The organic layers were combined and extracted again with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate for 1 h and then concentrated to remove the solvent. Column chromatography afforded 37f (490 mg, 88.2% yield) as a white oil.

[0139] 3-(1-Ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (38f)

[0140] 3-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(38f)

[0141]

[0142] Following conventional route B, 3-bromo-5-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)pyridine 37f (400 mg, 1.86 mmol) was used as the starting material to obtain the target product 38f (387 mg, yield: 82.8%).

[0143] 3-Bromo-5-(1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine (37 g)

[0144] 3-bromo-5-(1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine(37g)

[0145]

[0146] According to conventional route D, (bromomethyl)cyclopropane 24 (401.61 mg, 2.97 mmol) was used as the starting material to obtain the target product 37 g (490 mg, yield: 80.7%).

[0147] 3-Bromo-5-(1-(cyclobutylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine (37h)

[0148] 3-bromo-5-(1-(cyclobutylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine(37h)

[0149]

[0150] According to conventional route D, (bromomethyl)cyclobutane (443.34 mg, 2.97 mmol) was used as the reaction raw material to obtain the target product (493 mg, yield: 77.6%).

[0151] 3-Bromo-5-(1-(cyclopentylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine (37i)

[0152] 3-bromo-5-(1-(cyclopentylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine(37i)

[0153]

[0154] According to the conventional route D, (bromomethyl)cyclopentane 39c (485.07 mg, 2.97 mmol) was used as the starting material to obtain the target product 37i (467 mg, yield: 70.4%).

[0155] 3-Bromo-5-(1-(cyclohexylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine (37j)

[0156] 3-bromo-5-(1-(cyclohexylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine(37j)

[0157]

[0158] According to the conventional route D, (bromomethyl)cyclohexane 39d (526.8 mg, 2.97 mmol) was used as the starting material to obtain the target product 37j (493 mg, yield: 77.6%).

[0159] 3-(1-(Cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (38 g)

[0160] 3-(1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(38g)

[0161]

[0162] According to conventional route B, 37 g (400 mg, 1.31 mmol) of 3-bromo-5-(1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine was used as the reaction raw material to obtain 38 g (382 mg, yield: 82.8%) of the target product.

[0163] 3-(1-(Cyclobutylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (38h)

[0164] 3-(1-(cyclobutylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(38h)

[0165]

[0166] Following conventional route B, 3-bromo-5-(1-(cyclobutylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine 37h (400 mg, 1.25 mmol) was used as the starting material to obtain the target product 38h (389 mg, yield: 84.8%).

[0167] 3-(1-(Cyclopentylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (38i)

[0168] 3-(1-(cyclopentylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(38i)

[0169]

[0170] Following conventional route B, 3-bromo-5-(1-(cyclopentylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine 37i (400 mg, 1.20 mmol) was used as the starting material to obtain the target product 38i (383 mg, yield: 83.8%).

[0171] 3-(1-(Cyclohexylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (38j)

[0172] 3-(1-(cyclohexylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(38j)

[0173]

[0174] Following conventional route B, 3-bromo-5-(1-(cyclohexylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine 37j (400 mg, 1.15 mmol) was used as the starting material to obtain the target product 38j (363 mg, yield: 79.9%).

[0175] Example 5:

[0176] 7-(5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 5)

[0177] 7-(5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 5)

[0178]

[0179] Following the conventional route C, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridine 38a (345 mg, 1.10 mmol) was used as the starting material to obtain Example 5 (164 mg, yield: 63.6%). 1 HNMR(300MHz,Chloroform-d)δ9.28(s,1H),8.65(d,J=15.2Hz,2H),8.55(d,J=2.1Hz,1H) ,8.41(s,1H),7.58(d,J=5.0Hz,1H),3.87(s,3H),2.38(d,J=2.0Hz,6H).HRMS(ESI):calcd for C 17 H 16 N6[M+H] + 305.15, found 305.1506 Purity: 97.50% by HPLC (MeOH / H2O=80:20, t R =3.357min).

[0180] Example 6:

[0181] 7-(5-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 6)

[0182] 7-(5-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 6)

[0183]

[0184] Following the conventional route C, 3-(1,3-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 38b (329.24 mg, 1.10 mmol) was used as the starting material to obtain Example 6 (156 mg, yield: 66.7%). 1 H NMR(300MHz,DMSO-d6)δ9.33(s,1H),8.78(s,2H),8.57(s,1H),8.48(d,J=5.1Hz,1 H),8.15(s,1H),7.73(d,J=5.1Hz,1H),3.86(s,3H),2.42(s,3H).HRMS(ESI):calcd for C 16 H 14 N6[M+H] + 291.13, found 291.1357 Purity: 99.07% by HPLC (MeOH / H2O=80:20, t R =3.628min).

[0185] Example 7:

[0186] 7-(5-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 7)

[0187] 7-(5-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 7)

[0188]

[0189] According to the conventional route C, 3-(1,3-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 38c (329.24 mg, 1.10 mmol) was used as the reaction material to obtain Example 7 (156 mg, yield: 66.7%). 1 H NMR(300MHz,DMSO-d6)δ13.37(s,1H),9.30(s,1H),8.76(d,J=2.1Hz,1H),8.69(s,1H), 8.57(s,1H),8.48(d,J=5.0Hz,1H),7.81(s,1H),7.72(s,1H),3.86(s,3H),2.50(s,3H). 13C NMR (75MHz, DMSO-d6) δ149.37,149.07,146.89,144.82,144.68,140.44,136. 02,134.16,131.76,126.79,115.82,106.67,37.82,13.67.HRMS(ESI):calcd forC 16 H 14 N6[M+H] + 291.13, found 291.1353 purity: 99.22% by HPLC (MeOH / H2O=80:20, t R =4.330min).

[0190] Example 8:

[0191] 7-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 8)

[0192] 7-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 8)

[0193]

[0194] According to the conventional route C, 3-(1,5-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 38d (329.24 mg, 1.10 mmol) was used as the reaction raw material to obtain Example 8 (138 mg, yield: 56.2%). 1 H NMR(300MHz,DMSO-d6)δ13.37(s,1H),9.40(s,1H),8.96(s,1H),8.78(s,1H),8.59(s,1H),8.49( d,J=5.1Hz,1H),8.40(s,1H),8.10(s,1H),7.75(d,J=5.1Hz,1H),3.95(s,3H).HRMS(ESI):calcd for C 15 H 12 N6[M+H] + 277.12, found 277.1202 purity: 96.71% by HPLC (MeOH / H2O=80:20, t R =3.162min).

[0195] Example 9:

[0196] 7-(5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 9)

[0197] 7-(5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 9)

[0198]

[0199] Following conventional route C, 3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 38e (388.6 mg, 1.10 mmol) was used as the reaction raw material to obtain Example 9 (161 mg, yield: 55.2%). 1 H NMR(300MHz,DMSO-d6)δ13.39(s,1H),9.49(s,1H),8.75(d,J=13.3Hz,2H),8.58(s,1H), 8.49(d,J=5.1Hz,1H),8.41(s,1H),7.72(d,J=5.1Hz,1H),4.05(s,3H).HRMS(ESI):calcd for C 16 H 11 F3N6[M+H] + 345.10, found 345.1073 Purity: 96.12% by HPLC (MeOH / H2O=80:20, t R =3.149min).

[0200] Example 10:

[0201] 7-(5-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 10)

[0202] 7-(5-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 10)

[0203]

[0204] According to the conventional route C, 3-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 38f (132 mg, 1.10 mmol) was used as the reaction raw material to obtain Example 10 (127 mg, yield: 48.9%). 1 H NMR (300MHz, DMSO-d6) δ13.36(s,1H),9.37(s,1H),8.72–8.60(m,2H),8.56(s,1H),8.47(d,J=5.1Hz,1H),7. 73(d,J=5.1Hz,1H),4.11(q,J=7.2Hz,2H),2.36(s,3H),2.26(s,3H),1.37(t,J=7.2Hz,3H).HRMS(ESI):calcd for C 18 H 18 N6[M+H] + 319.16, found 319.1669 Purity: 97.31% by HPLC (MeOH / H2O=80:20, t R =3.224min).

[0205] Example 11:

[0206] 7-(5-(1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 11)

[0207] 7-(5-(1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine ((Example 11)

[0208]

[0209] According to conventional route C, 38 g (388.7 mg, 1.10 mmol) of 3-(1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was used as the reaction raw material to obtain Example 11 (145 mg, yield: 49.7%). 1HNMR(300MHz,Chloroform-d)δ9.26(s,1H),8.68(s,1H),8.61(d,J=5.0Hz,1H),8.54(s,1H),8.41(s,1H),7.57(d,J=4.5Hz,1H),4.01( d,J=6.8Hz,2H),2.40(s,3H),2.39(s,3H),1.30(d,J=4.3Hz,1H),0.66(dd,J=7.8,5.1Hz,2H),0.47(t,J=5.1Hz,2H).HRMS(ESI):calcd for C 20 H 20 N6[M+H] + 345.18, found 345.1828 Purity: 94.59% by HPLC (MeOH / H2O=80:20, t R =5.432min).

[0210] Example 12:

[0211] 7-(5-(1-(cyclobutylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 12)

[0212] 7-(5-(1-(cyclobutylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 12)

[0213]

[0214] Following conventional route C, 3-(1-(cyclobutylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 38h (404.21 mg, 1.10 mmol) was used as the reaction raw material to obtain Example 12 (145 mg, yield: 50.4%). 1HNMR(300MHz,DMSO-d6)δ13.35(s,1H),9.37(s,1H),8.70–8.60(m,2H),8.56(s,1H),8.47(d,J=5.1Hz,1H),7.73(d,J =5.2Hz,1H),4.09(d,J=7.2Hz,2H),2.35(s,3H),2.25(s,3H),2.06–1.98(m,2H),1.99–1.78(m,5H).HRMS(ESI):calcd forC 21 H 22 N6[M+H] + 359.19, found 359.1982 purity: 93.93% by HPLC (MeOH / H2O=80:20, t R =8.159min).

[0215] Example 13:

[0216] 7-(5-(1-(cyclopentylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyrrolidone (Example 13)

[0217] 7-(5-(1-(cyclopentylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 13)

[0218]

[0219] Following conventional route C, 3-(1-(cyclopentylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 38i (419.64 mg, 1.10 mmol) was used as the reaction raw material to obtain the target product Example 13 (149 mg, yield: 47.3%). 1H NMR (300MHz, DMSO-d6) δ13.35(s,1H),9.36(d,J=2.1Hz,1H),8.64(dq,J=5.9,3.7,3.0Hz,2H),8.56(s,1H),8.47(d,J=5.1Hz,1H),7.73(d,J=5.1Hz ,1H),3.96(d,J=6.9Hz,2H),2.36(d,J=3.5Hz,3H),2.26(s,3H),1.31(s,1 H),0.86(t,J=6.7Hz,4H),0.55(dt,J=8.1,2.9Hz,2H),0.45–0.37(m,2H). 13 C NMR(75MHz,DMSO-d6)δ149.83,149.24,147.26,144.78,144.57,144.51,136.68,136.54,134.91,132 .48,115.80,115.01,53.11,30.60,26.40,25.78,13.00,11.92,10.61,10.48,4.13.HRMS(ESI):calcd for C 22 H 24 N6[M+H] + 373.21, found 373.2135 purity: 93.10% by HPLC (MeOH / H2O=80:20, t R =11.745min).

[0220] Example 14:

[0221] 7-(5-(1-(cyclohexylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 14)

[0222] 7-(5-(1-(cyclohexylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyridine (Example 14)

[0223]

[0224] Following conventional route C, 3-(1-(cyclohexylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 38j (435.08 mg, 1.10 mmol) was used as the reaction raw material to obtain the target product Example 14 (143 mg, yield: 43.7%). 1 HNMR(300MHz,DMSO-d6)δ9.33(s,1H),8.63(s,2H),8.56(s,1H),8.48(d,J=5.1Hz,1H),7.71(d,J=5.1Hz,1H),3.90(d,J=7.1Hz,2H),2 .34(s,3H),2.26(s,3H),1.72–1.60(m,4H),1.29–1.18(m,4H),1.06(t,J=11.9Hz,2H),0.87(dd,J=7.3,2.0Hz,1H).HRMS(ESI):calcd for C 23 H 26 N6[M+H] + 387.22, found 387.2294 Purity: 95.99% by HPLC (MeOH / H2O=80:20, t R =11.127min).

[0225] Pharmacological activity evaluation

[0226] MST method to test the affinity of the examples for BRD4 (1) and BRD4 (2)

[0227] The protein buffer was replaced with the MonolithTM RED-NHS second-generation protein labeling kit (Nano Temper), and BRD4(1) and BRD4(2) proteins were fluorescently labeled. A solution without primary amino groups (such as Tris or glycine), imidazole (Leyan), or β-mercaptoethanol (Aladdin) was used as the analytical buffer. The fluorescently labeled protein was mixed with different concentrations of the compound at a ratio of 1:1. A microscopic temperature gradient field was set up by an infrared laser on the Monolith NT.115 (Nano Temper) analyzer. The movement of the molecules in the microscopic temperature gradient field was tracked using signals such as fluorescent dye labeling, tryptophan autofluorescence, and fluorescent fusion proteins. The affinity of the small molecules to BRD4(1) or BRD4(2) was analyzed using PR.ThermControl software.

[0228] Table 1. Binding affinity of the examples to BRD4(1) and BRD4(2)

[0229]

[0230]

[0231] In Table 1, a Selectivty refers to the K of the compound for BRD4(2) D Value / K of BRD4(1) D value.

[0232] The purpose of the above embodiments is to specifically introduce the essential content of the present invention, but those skilled in the art should know that the protection scope of the present invention should not be limited to this specific embodiment.

Claims

1. A pyridine biimidazopyridine compound, characterized in that: The compound represented by formula I or a pharmaceutically acceptable salt thereof: in: Ring A is selected from phenyl, 5-6 membered aromatic hetero groups; R a independently selected from hydrogen, C 1-5 Alkyl, -CF3, C 3-7 Cycloalkyl; n=1-5; Ring B is a pyridine ring, and the pyridine nitrogen atom is located at any unsubstituted position on the ring.

2. The pyridine biimidazopyridine compound according to claim 1, characterized in that: The pharmaceutically acceptable salt is an acid addition salt of the compound of formula I, wherein the acid used for salt formation is selected from one of hydrogen chloride, sulfuric acid, hydrogen bromide, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

3. Use of the pyridine biimidazole pyridine compound according to claim 1 for preparing BET inhibitor drugs. The use according to claim 3 , wherein the inhibition is the selective inhibition of the BD1 domain of the BET protein.

5. Use of the pyridine biimidazole pyridine compound according to claim 1 for preparing antitumor drugs or anti-inflammatory drugs.

Images