Nitrogen-containing heterocyclic compound as well as preparation method, pharmaceutical composition and application thereof

[0133] Preparation of compounds of formula I

[0134] In order to prepare the compound of the formula I, according to the structure of the formula I, the compound of the present invention can be obtained by the following method 1 or 2.

[0135] Method 1 includes the following steps:

[0136]

[0137] (a) Basic raw materials are based on a halogenate 1-1 and a suitable coupling agent 1-2 (like boric acid, borate, tin reagent or grace reagent), by palladium or copper catalyzed coupling reaction (like Suzuki, STILE or KUMADA coupled to the intermediate compound 1-3;

[0138] (b) The amide intermediate 1-5 is reacted with the carboxylic acid 1-4 under the action of the condensing agent (like Hatu, EDCI or HBTU);

[0139] (c) The protecting group (BOC) is removed from the intermediate body 1-5, and the protecting group (BOC) is removed, and the intermediate 1-6 is obtained;

[0140] (d) In the intermediate body 1-6 as the raw material, the nucleophilic reactive reaction is performed with the halogenated material under alkaline conditions, or the amination reaction is reduced to the aldehyde or ketone under the reducing agent to obtain a target compound I;

[0141]

[0142] Method 2 includes the following steps:

[0143] (c) The amine solution 2-3 is obtained by the amine acid catalysis by the carboxylate 2-1, and the amine 2-2 is performed, and the intermediate compound 2-3 is obtained.

[0144] (d) Basic raw materials by intermediate 2-3 and suitable coupling reagents 2-4 (like boric acid, borate, tin reagent or grace reagent), by palladium or copper catalyzed coupling reaction (like Suzuki, STILLE or KUMADA coupling) Get an intermediate compound 2-5;

[0145] (e) The protecting group (Boc) is removed in an intermediate body 2-5, and the protecting group (BOC) is subjected to the intermediate 2-6;

[0146] (f) The nucleation reactive reactive reaction is performed with the halogenated reaction under alkaline conditions, or reductant the amination reaction with the alkal or ketone under the action of the reducing agent to obtain a target compound I;

[0147]

[0148] Method 3 includes the following steps:

[0149] (i) BUCHWALD-HARTWIG coupling or ULLMAN coupling is carried out under palladium or copper catalysis with amine or copper catalysis to obtain an intermediate compound 3-3;

[0150] (j) is based on intermediate 3-3 and a suitable coupling agent 3-4 (like boric acid, borate, tin reagent or grace reagent), by palladium or copper catalyzed coupling reaction (like Suzuki, STILLE or KUMADA coupling) Get an intermediate compound 3-5;

[0151] (k) The protecting group (BOC) is removed in an intermediate body 3-5, and the protecting group (BOC) is subjected to the intermediate 3-6;

[0152] (L) The intermediate body 3-6 is a raw material, and the nucleophilic reactive reaction is performed with the halogenated material under alkaline conditions, or the amination reaction is reduced to the aldehyde or ketone under reductant to obtain a target compound I;

[0153] The CY is for Y 1 Y 2 ,Z 1 ,Z 2 ,Z 3 The definition of R is the same.

[0154] Further, the starting materials and intermediates in the above reaction are readily available, and each step can be easily synthesized according to the reported literature or to those skilled in the art. The compound of the formula I can be present in the form of a solvate or a non-solvent, and crystallization can be obtained by different solvents.

[0155] Pharmaceutical composition and method of administration

[0156] Since the compound of the present invention has an excellent inhibitory activity of the PD-1 / PD-L1 interaction, the compounds of the invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and contain A pharmaceutical composition of the compound of the present invention is used for the primary active ingredients can be used to prevent and / or treat (stabilize, alleviate or cure) PD-1 / PD-L1 interaction related diseases (eg, cancer, infectious diseases, autoimmune diseases) .

[0157] The pharmaceutical compositions of the present invention comprise the compounds of the invention and pharmaceutically acceptable excipients or vectors within the safe and effective amount range. Among them, "safe and effective amount" refers to: The amount of compound is sufficient to significantly improve the condition, not to produce severe side effects. Typically, the pharmaceutical composition contains from 1 to 200 mg of the compound / agent, more preferably, containing 10-200 mg of the compound / agent of the invention. Preferably, the "one agent" is a capsule or a pill.

[0158] "Pharmaceutically acceptable carrier" refers to: one or more compatible solids or liquid fillers or gel materials, which are suitable for use, and must have sufficient purity and low toxicity. "Compatibility" herein refers to the components of the composition and the compounds of the invention and the compounds thereof and the drug effects of the compounds are not significantly reduced. Pharmaceutically acceptable carrier parts include cellulose and derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricant (such as stearic acid) , Magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol, glycerol, mannitol, sorbitol, etc.), emulsifier (such as Tween ), Wetting agent (such as sodium sulfate sulfate), colorant, flavor, stabilizer, antioxidant, preservative, no hot producing water, and the like.

[0159] The method of administration of the compound or pharmaceutical composition of the invention is not particularly limited, and representative administration includes (but not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).

[0160] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. Among these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or vector) such as sodium citrate or calcium phosphate, or mixed with the following ingredient: (a) a filler or a compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol, silicic acid; (b) binder, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and Arabi gum; (C) moisturizer, For example, glycerol; (d) disintegrant, for example, agar, calcium carbonate, potato starch or cassava starch, alginate, certain composite silicate, and sodium carbonate; (e) slow solvent, such as paraffin; (f) Absorbing accelerator, for example, a quaternine compound; (g) wetting agent, such as cetyl alcohol and monohydrate, (H) adsorbent, such as kaolin; and (i) lubricant, for example, talc, hard Calcium acid, magnesium stearate, solid polyethylene glycol, dodecyl sodium sulfate, or mixtures thereof. Capsules, tablets and pills, the dosage form can also include a buffer.

[0161] Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared, such as casings and other materials well known in the art. They may comprise opaque agents, and the release of activated compounds or compounds in this composition can be released in a certain portion of the digestive tract in a manner. Examples of the embedded components that can be used are polymeric materials and wax substances. If necessary, the active compound can also form a microcapsule form in the form of a microcapsule in the above excipient.

[0162] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form can comprise an inert diluent, such as water or other solvents, solubilization and emulsifiers, ethanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, in the art. , 3-butanediol, dimethylformamide and oil, especially cottonseed oil, peanut oil, corn embryonic oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0163] In addition to these inert diluents, the composition may also comprise auxiliary agent such as a wetting agent, an emulsifier, and a suspending agent, sweetener, flavoring and spices.

[0164] In addition to the active compound, the suspension can comprise a suspending agent, such as an ethoxylated isobide, polyoxyethylene sorbitol, and dehydrated sorbitan, microcrystalline cellulose, methanol aluminum and agar or mixtures of these materials.

[0165] Compositions for parenteral injection may comprise physically acceptable sterile water or anhydrous solutions, dispersion, suspensions or emulsions, and sterile powders for reissolizing into sterile injectable solutions or dispersions. Suitable water and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyol, and suitable mixtures thereof.

[0166] The compounds of the invention may be administered separately or in combination with other pharmaceutically acceptable compounds such as other anticancer formulations.

[0167] When administered in combination, the pharmaceutical composition further comprises one or more (two, three, four, four, or more) other pharmaceutically acceptable compounds. One or more of the other pharmaceutically acceptable compounds (2, three, 4, or more) can be used to prevent and / or treat Pd simultaneously, separate or sequentially -1 / PD-L1 interaction related diseases.

[0168] When using the pharmaceutical composition, it is a mammal (such as a person) which is suitable for treatment, wherein the dose is a pharmaceutically acceptable effective administration of the drug when administered, and the time of 60 kg of weight is concerned. The dose is usually from 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dose should also consider the route of administration, the health of patients, etc., which are within the skilled physician skill.

[0169] The main advantages of the present invention include:

[0170] (1) The compound of the present invention has high inhibitory activity on the PD-1 / PD-L1 interaction, with the PD-L1 protein having a strong binding ability, and has the ability to release the PD-L1 inhibiting IFNγ.

[0171] (2) The compound of the present invention has better solubility; the toxicity of normal cells is very low, and thus it can be applied to the treatment target in a large dose range.

[0172] (3) Compared to the prior art compound, the compound of the present invention has better solubility, and thus has good episodeability, and compared to the existing compound, the compound of the invention exhibits good in the experiment. In addition to this, the compound of the present invention is pharmaceutically acceptable salts, thereby contributing to further formulation.

[0173] (4) In vivo pharmacological studies show that the compounds of the invention may significantly inhibit the growth of subcutaneous tumors, regardless of the tumor volume or by weight, and significantly increase the number of lymphocytes in mice in the blood, spleen.

[0185] Example 1 Synthesis of Compound LW1005-001

[0186]

[0187] Step 1-1:

[0188]

[0189] Compound 1 (51 g, Journal of Medicinal Chemistry, 2019, 62, 276-287), 2-methyl-3-bromobenzoic acid (95.56 g) were sequentially added to PPA (500 g), 140 ° C, mechanically stirred for 6 hours. After the reaction is complete, pour the ice water into the reaction bottle, and then pour out the gum 30min, filtrate. The solid was filtered to add 500 mL of water, and the sodium hydroxide solid was added under mechanically stirring, and the aqueous phase was adjusted to pH = 6-8, filtered. The filter cake solid was dried at 55 ° C to give a gray-white solid product 80G. MS-APCI: 305 [M + H] +.

[0190] Step 1-2:

[0191]

[0192] 3 (2.0 g), DMAP (805 mg) is added to DMF (30 mL), turbid, add BOC2O, solid dissolved, 40 degrees heating to react overnight. TLC displays a small amount of remaining. The reaction liquid is rotated with an oil pump. The solid was pulp with EA / Hep, filtered to give 1.6 g of white solid products. MS-APCI: 405.2 [M + H] +

[0193] Step 1-3:

[0194]

[0195] 4 (202 mg), 5 (230 mg, WO2018119286), Pd (DPPF) CL2 / DCM (19.5 mg) and NA were taken at room temperature. 2 CO 3 (21.2 mg) was placed in a reaction bottle, vacuum degassing, and the syringe was injected into Dioxane / H2O (5 mL / 1mL), and the reaction was heated at 100 degrees after degassing for 4 h. The reaction solution was poured into water, EA was extracted, dried, and the EA layer was pulp, filtered with EA / HEP (1: 1), filtered to obtain 100 mg of crude product, and purified from 50 mg to obtain 9.0 mg LW1005-001, yellow solid. MS-APCI: 559.2 [M + H] +

[0196] 1H NMR (400 MHz, DMSO-D6) δ11.85 (D, J = 6.1 Hz, 1H), 10.55-10.28 (m, 1H), 9.08 (S, 1H), 8.52 (S, 1H), 8.16 (S, 1H), 8.0-8.05 (m, 2H), 7.51 (Q, J = 7.1, 6.4 Hz, 2H), 7.46-7.32 (m, 2H), 7.25 (D, J = 6.1 Hz, 1H), 7.06 (S 1H), 6.87 (D, J = 7.1 Hz, 1H), 5.51 (S, 1H), 4.68 (D, J = 25.9 Hz, 2H), 4.47 (D, J = 27.3 Hz, 2H), 2.45 (S 3H), 2.34-2.29 (m, 1H), 2.02-2.01 (m, 1H), 1.90-1.86 (m, 1H), 1.52-1.46 (m, 1H).

[0197] Example 2 Synthesis of Compound LW1005-002

[0198]

[0199] Step 2-1:

[0200]

[0201] Compound 3 (10 g) was dissolved in DMF (150 mL), 6 (14.3 g; Macromolecules, 2015, 48, 1688-1702) and CS2CO3 (21.4 g) were added at room temperature overnight. The TLC detection reaction was completed. After filtration, the filtrate was given water EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc. MS-APCI: 587.1 [M + H] +

[0202] 1H NMR (400MHz, Chloroform-D) δ 8.05 (DD, J = 7.9, 1.3 Hz, 1H), 7.75 (DD, J = 8.0, 1.3 Hz, 1H), 7.54 (DT, J = 6.7, 1.5 Hz, 4h), 7.49 (D, J = 7.3Hz, 1H), 7.41-7.35 (M, 2H), 7.34-7.27 (M, 4H), 7.22 (T, J = 7.9 Hz, 1H), 6.58 (D, J = 7.3Hz, 1H), 4.26 (t, j = 4.7 Hz, 2H), 4.05 (DD, J = 5.5, 4.1 Hz, 2H), 2.92 (S, 3H), 1.05 (s, 9h).

[0203] Step 2-2:

[0204]

[0205] 7 (11 g) was dissolved in THF (110 mL) at room temperature, 1 nTBAF / THF (20.7 mL) was added, and the reaction was 2 hours. TLC shows that the feedstock reaction is complete. The reaction liquid was carried out, and the column (DCM: MeOH = 20: 1) obtained 4.5 g of a white solid product 8. MS-APCI: 349.1 [M + H] +

[0206] Step 2-3:

[0207]

[0208] 8 (350 mg), BPIN2 (304.8 mg), Pd (DPPF) CL2 (81.7 mg) and KOAC (196 mg) were placed at room temperature in the reaction bottle, vacuum degassing, syringe injection Dioxane (5ml), and 100 degrees after degassing again Heating and reacting overnight. TLC shows completely. The reaction mixture was added to EtOAc (EtOAc) EtOAc. EtOAc: 0000-00-00, gave 350 mg of Compound 9, gray solid. MS-APCI: 397.1 [M + H] +

[0209] Step 2-4:

[0210]

[0211] 9 (350 mg), 10 (364 mg, WO2018119286), PD (DPPF) CL2 / DCM (71.9 mg) and NA were taken at room temperature. 2 CO 3 (186.6 mg) was placed in a reaction bottle, vacuum degassing, syringe injection Dioxane / H2O (3.6 mL, 5: 1), and 100 degrees heated after 4 hours after degassing. TLC shows that the feedstock reaction is complete. The reaction solution was added to EtOAc (EtOAc) EtOAc.

[0212] MS-APCI: 603.2 [M + H] +

[0213] 1H NMR (400MHz, DMSO-D6) δ9.33 (S, 1H), 8.88 (D, J = 2.0 Hz, 1H), 8.47 (D, J = 8.2Hz, 1H), 8.19 (D, J = 1.6 Hz 1H), 8.13-8.00 (M, 2H), 7.77 (D, J = 7.3 Hz, 1H), 7.51 (T, J = 7.7 Hz, 1H), 7.37 (DD, J = 14.2, 7.4 Hz, 2H) , 7.19 (D, J = 5.8 Hz, 1H), 6.92 (DD, J = 7.2, 4.3Hz, 2H), 4.90 (T, J = 5.4 Hz, 1H), 4.72 (D, J = 4.5 Hz, 1H) 4.23 (S, 1H), 4.11 (t, j = 5.4 Hz, 2H), 3.82 (Q, J = 13.8 Hz, 2H), 3.68 (Q, J = 5.5 Hz, 2H), 2.80-2.72 (M, 1H), 2.67 (D, J = 8.0 Hz, 2H), 2.43 (S, 3H), 2.39-2.30 (m, 1H), 2.0 (S, 3H), 2.03 (DD, J = 13.4, 6.9 Hz, 1H ), 1.61-1.55 (m, 1h)