Pharmaceutical composition containing AAK1 inhibitor

Abstract

A pharmaceutical composition of a compound of formula (I) or a stereoisomer, a pharmaceutically acceptable salt thereof, and a pharmaceutical preparation thereof; the invention further discloses a preparation method of the pharmaceutical composition and the pharmaceutical preparation and application of the pharmaceutical composition and the pharmaceutical preparation in preparation of drugs for treating, inhibiting or degrading AAK1 related diseases. # imgabs0 #

Description

A pharmaceutical composition containing an AAK1 inhibitor Technical Field

[0001] The present invention relates to a pharmaceutical composition and pharmaceutical preparation of a compound of formula (I) or its stereoisomers and pharmaceutically acceptable salts, and use thereof in preparing drugs for treating diseases related to inhibition of AAK1 inhibitors. Background Art

[0002] Neuropathic pain (NP) is a general term for a series of pains caused by damage and diseases of the somatic sensory nervous system. It is divided into peripheral neuropathic pain (pNP) and central neuropathic pain. Clinically, pNP is more common and can be divided into diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, and chronic postoperative neuralgia. Patients with pNP often experience symptoms such as spontaneous pain (pain without any external stimulation), allodynia (increased response to painful stimuli), hyperalgesia (feeling pain in response to stimuli that are normally painless), and paresthesia, which seriously affect the patient's quality of life.

[0003] AAK1 is a member of the Ark1 / Prk1 family of serine / threonine kinases and is widely expressed in the brain and spinal cord. Studies have shown that AAK1 knockout mice are endowed with responses to persistent pain or hypoalgesia, and that AAK1 knockout mice do not develop hyperalgesia in the spinal nerve ligation neuropathic pain model, confirming that AAK1 is a viable target for the treatment of pNP.

[0004] We provide an AAK1 inhibitor, but this compound has a low melting point and often sticks to the capsule punch or tablet punch when formulated into tablets or capsules. Based on this, we propose to provide a composition containing an AAK1 inhibitor that can be well used in the preparation of conventional solid dosage forms and exhibits good in vitro dissolution behavior and stability.

[0005] Summary of the Invention

[0006] The present invention provides a pharmaceutical composition and pharmaceutical preparation of a compound represented by formula (I) and its stereoisomers and pharmaceutically acceptable salts.

[0007] The pharmaceutical composition or pharmaceutical preparation of the present invention has good solubility, dissolution, bioavailability, oral performance, stable quality, good safety, low irritation, and meets the quality standards of pharmaceuticals.

[0008] In one aspect, the present invention provides a pharmaceutical composition comprising:

[0009] Active ingredient, the active ingredient is selected from the compound of formula (I) or its stereoisomers, pharmaceutically acceptable salts:

[0010] in,

[0011] Z is selected from NH or O;

[0012] R 1 、R 2 Each independently selected from H, deuterium, halogen, amino, -COOH, cyano, sulfonyl, aminoacyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, wherein the alkyl group is optionally further substituted by 1-3 R A Substituent substitution;

[0013] R 41 、R 42 Each independently selected from H, deuterium, amino, C 1-6 Alkyl, halogen, cyano, hydroxyl, halo C 1-6 Alkyl, deuterated C 1-6 alkyl;

[0014] R 51 、R 52 Each is independently selected from H, deuterium, amino, halogen;

[0015] R 61 、R6 2 、R 63 Each independently selected from H, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl;

[0016] Or, R 51 and R 61 , or R 61 and R 62 Together with the carbon atoms to which they are attached, they form double bonds;

[0017] R A Selected from deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy or hydroxy C 1-6 alkyl;

[0018] Provided that, when Z is selected from O, The following structure is not formed:

[0019] inactive ingredients;

[0020] The content of the active ingredient in the pharmaceutical composition is 5% to 90% w / w, preferably 5% to 80% w / w, more preferably 10% to 80% w / w;

[0021] In some embodiments, the content of the active ingredient (calculated as free base) in the pharmaceutical composition is 5% to 85% w / w, preferably 8% to 80% w / w, more preferably 10% to 80% w / w;

[0022] In some embodiments, the content of the active ingredient (calculated as free base) in the pharmaceutical composition is 8% to 85% w / w, preferably 10% to 85% w / w, more preferably 10% to 80% w / w;

[0023] In some embodiments, the content of the active ingredient (calculated as free base) in the pharmaceutical composition is 5-80% w / w, 5%-70% w / w, 5%-60% w / w, 5%-50% w / w, 5%-40% w / w, 5%-30% w / w, 5%-20% w / w, 10%-80% w / w, 10%-70% w / w, 10%-60% w / w, 10%-50% w / w, 10%-40% w / w, 10%-30% w / w, 10%-20% w / w.

[0024] In some embodiments, in the compound of formula (I), Z is O;

[0025] R 1 、R 2 Selected from halogenated C 1-2 alkyl;

[0026] R 51 、R 52 Each independently selected from H, deuterium;

[0027] R 41 、R 42 Each independently selected from amino, C 1-2 alkyl;

[0028] R 61 、R 62 、R 63 Each independently selected from H, deuterium, C 1-2 Alkyl, halogenated C 1-2 alkyl;

[0029] Or, R 51 and R 61 , or R 61 and R62 Together with the carbon atoms to which they are attached, they form double bonds;

[0030] In some embodiments, in the compound of formula (I),

[0031] R 1 、R 2 Each is independently selected from -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CHClCH2Cl, -CHClCHCl2, -CHClCCl3, -CCl2CH2Cl, -CCl2CHCl2, -CCl2CCl3;

[0032] R 51 、R 52 Each independently selected from H, deuterium;

[0033] R 41 、R 42 Each independently selected from amino, -CH3, -CH2CH3;

[0034] R 61 、R 62 、R 63 each independently selected from H, deuterium, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CHClCH2Cl, -CHClCHCl2, -CHClCCl3, -CCl2CH2Cl, -CCl2CHCl2, -CCl2CCl3;

[0035] Or, R 51 and R 61 , or R 61 and R 62 Together with the carbon atoms to which they are attached, they form double bonds;

[0036] In some embodiments, in the compound of formula (I),

[0037] Z is O;

[0038] R1 、R 2 Each independently selected from -CH2F, -CHF2, -CF3;

[0039] R 51 、R 52 Each independently selected from H, deuterium;

[0040] R 41 、R 42 Each is independently selected from amino, -CH3;

[0041] R 61 、R 62 、R 63 Each independently selected from H, deuterium, -CH3, CF3;

[0042] In some embodiments, in the compound of formula (I),

[0043] Z is O;

[0044] R 1 、R 2 Each independently selected from -CH2F, -CHF2, -CF3;

[0045] R 51 、R 52 Together with the carbon atoms to which they are attached, they form double bonds;

[0046] R 41 、R 42 Each is independently selected from amino, -CH3;

[0047] R 61 、R 62 、R 63 Each independently selected from H, deuterium, -CH3, CF3;

[0048] In some embodiments, in the compound of formula (I),

[0049] Z is O;

[0050] R 1 、R 2 Each independently selected from -CH2F, -CHF2, -CF3;

[0051] R 51 、R 52 Each independently selected from H, deuterium;

[0052] R 41 、R 42 Each is independently selected from amino, -CH3;

[0053] R 63 Each independently selected from H, deuterium, -CH3, CF3;

[0054] R 61 and R 62 Together with the carbon atoms to which they are attached, they form double bonds;

[0055] In some embodiments, the compound of formula (I) is selected from one of the following structures:

[0056] or

[0057] In some embodiments, the compound of formula (I) is selected from one of the following structures:

[0058] or

[0059] In some embodiments, the inactive ingredient comprises a wetting agent;

[0060] In some embodiments, the inactive ingredient comprises a disintegrant;

[0061] In some embodiments, the inactive ingredient comprises a diluent;

[0062] In some embodiments, the inactive ingredient comprises a lubricant;

[0063] In some embodiments, the wetting agent is selected from one or more silicates; preferably one or more of silicon dioxide, magnesium silicate, magnesium trisilicate, magnesium aluminum silicate and talc; more preferably one or more of fumed silica, precipitated silica, sol-gel silica, magnesium silicate, magnesium trisilicate, magnesium aluminum silicate and talc;

[0064] In some embodiments, the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, starch and its derivatives, low-substituted hydroxypropyl cellulose, low-substituted sodium hydroxymethyl cellulose, surfactants, alginic acid and sodium alginate, and clays; preferably one or more of cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, low-substituted sodium hydroxymethyl cellulose, cross-linked polyvinylpyrrolidone, starch, sodium carboxymethyl starch, hydroxypropyl starch, polysorbate 80, sodium lauryl sulfate, bentonite, and colloidal magnesium aluminum silicate; more preferably one or more of cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, low-substituted sodium hydroxymethyl cellulose, sodium carboxymethyl starch, and cross-linked polyvinylpyrrolidone;

[0065] In some embodiments, the diluent is selected from one or more of starch, pregelatinized starch, dextrin, lactose monohydrate, anhydrous lactose, sucrose, microcrystalline cellulose, inorganic salts, and sugar alcohols; preferably, it is one or more of pregelatinized starch, dextrin, lactose, sucrose, microcrystalline cellulose, calcium sulfate, dibasic calcium phosphate dihydrate, anhydrous dibasic calcium phosphate, calcium phosphate, calcium carbonate, calcium stearate, magnesium oxide, aluminum hydroxide, mannitol, xylitol, and sorbitol; more preferably, it is one or more of pregelatinized starch, lactose, sucrose, microcrystalline cellulose, dibasic calcium phosphate dihydrate, anhydrous dibasic calcium phosphate, calcium phosphate, mannitol, and dextrin;

[0066] In some embodiments, the lubricant is selected from one or more of talc, stearic acid, metal stearate, stearic acid ester, glyceryl behenate, sodium lauryl sulfate or colloidal silicon dioxide; in some embodiments, the lubricant is selected from one or more of talc, stearic acid, metal stearate, stearic acid ester, glyceryl behenate, sodium lauryl sulfate; preferably one or more of talc, calcium stearate, magnesium stearate and zinc stearate, polyoxyethylene stearate, glyceryl monostearate, glyceryl palmitostearate; more preferably one or more of talc, calcium stearate, magnesium stearate, glyceryl monostearate; more preferably one or more of magnesium stearate, talc or colloidal silicon dioxide;

[0067] In some embodiments, the weight ratio of the active ingredient to the wetting agent is 1:0.05 to 1:5, preferably 1:0.08 to 1:3, further preferably 1:0.12 to 1:2, more preferably 1:0.125, 1:0.2, 1:0.25, 1:0.375, 1:0.5, 1:0.5, 1:1, 1:1.5, 1:2;

[0068] In some embodiments, the weight ratio of the active ingredient to the diluent is 1:0.05 to 1:10, preferably 1:0.1 to 1:8.5, further preferably 1:0.18 to 1:8.5, more preferably 1:0.18125, 1:0.1875, 1:0.9875, 1:1, 1:1.1125, 1:1.125, 1:1.2375, 1:1.25, 1:1.3625, 1:1.375, 1:3.725, 1:3.75, 1:6.45, 1:6.95, 1:7.45, 1:7.95, 1:8.25, 1:8.45;

[0069] In some embodiments, the weight ratio of the active ingredient to the disintegrant is 1:0.01 to 1:3, preferably 1:0.03 to 1:1.5, further preferably 1:0.03 to 1:0.6, more preferably 1:0.0375, 1:0.0625, 1:0.075, 1:0.125, 1:0.15, 1:0.25, 1:0.5;

[0070] In some embodiments, the weight ratio of the active ingredient to the lubricant is 1:0.001 to 1:2, preferably 1:0.006 to 1:0.1, more preferably 1:0.00625, 1:0.0125, 1:0.025, 1:0.05, or 1:0.1. The present invention provides a pharmaceutical composition comprising an active ingredient and lactose, microcrystalline cellulose, low-substituted-hydroxypropyl cellulose, and magnesium stearate.

[0071] The invention provides a pharmaceutical composition, which contains active ingredients and silicon dioxide, lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and magnesium stearate.

[0072] The invention provides a pharmaceutical composition, which contains active ingredients and silicon dioxide, talcum powder, lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and magnesium stearate.

[0073] The invention provides a pharmaceutical composition, which contains active ingredients and microcrystalline cellulose, mannitol, cross-linked polyvinylpyrrolidone and magnesium stearate.

[0074] The invention provides a pharmaceutical composition, which contains active ingredients and silicon dioxide, magnesium silicate, microcrystalline cellulose, mannitol, cross-linked polyvinylpyrrolidone and magnesium stearate.

[0075] The invention provides a pharmaceutical composition, which contains active ingredients, pregelatinized starch, lactose, sodium carboxymethyl starch and talc.

[0076] The invention provides a pharmaceutical composition, which contains active ingredients and silicon dioxide, pregelatinized starch, lactose, sodium carboxymethyl starch and talc.

[0077] The invention provides a pharmaceutical composition, which contains active ingredients and microcrystalline cellulose, lactose, cross-linked sodium carboxymethyl cellulose and magnesium stearate.

[0078] The invention provides a pharmaceutical composition. The pharmaceutical composition contains active ingredients and silicon dioxide, microcrystalline cellulose, lactose, cross-linked sodium carboxymethyl cellulose and magnesium stearate.

[0079] The invention provides a pharmaceutical composition, which contains active ingredients and lactose, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and magnesium stearate.

[0080] The invention provides a pharmaceutical composition, which contains active ingredients, lactose, cross-linked sodium carboxymethyl cellulose and magnesium stearate.

[0081] The invention provides a pharmaceutical composition, which contains active ingredients, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and magnesium stearate.

[0082] The invention provides a pharmaceutical composition, which contains active ingredients, mannitol, low-substituted carboxymethyl cellulose sodium and talcum powder.

[0083] The invention provides a pharmaceutical composition, which contains active ingredients, microcrystalline cellulose, low-substituted carboxymethyl cellulose sodium and talc.

[0084] The invention provides a pharmaceutical composition, which contains active ingredients, mannitol, microcrystalline cellulose, low-substituted carboxymethyl cellulose sodium and talc.

[0085] The invention provides a pharmaceutical composition, which contains active ingredients, pregelatinized starch, sodium carboxymethyl starch and magnesium stearate.

[0086] The invention provides a pharmaceutical composition, which contains active ingredients, dextrin, sodium carboxymethyl starch and magnesium stearate.

[0087] The invention provides a pharmaceutical composition, which contains active ingredients, pregelatinized starch, dextrin, sodium carboxymethyl starch and magnesium stearate.

[0088] The invention provides a pharmaceutical composition, which contains active ingredients, calcium phosphate, cross-linked polyvinylpyrrolidone and talc.

[0089] The invention provides a pharmaceutical composition, which contains active ingredients, sucrose, cross-linked polyvinylpyrrolidone and talcum powder.

[0090] The present invention provides a pharmaceutical composition comprising an active ingredient and calcium phosphate, sucrose, cross-linked polyvinylpyrrolidone, and talc. The present invention provides a pharmaceutical composition comprising 10-80 w / w%, 10-60 w / w%, 10-45 w / w%, 10-40 w / w%, 5-35 w / w%, 5-20 w / w%, 10%, 20%, 40%, or 80% of the active ingredient.

[0091] The present invention provides a pharmaceutical composition, which contains 10-85w / w%, 10-80w / w%, 10-70w / w%, 10-60w / w%, 10-50w / w%, 10-40w / w%, 10-30w / w%, 14.5%, 15%, 39.5%, 40%, 44.5%, 45%, 49.5%, 50%, 54.5%, 55%, 64.5%, 69.5%, 74.5%, 75%, 79.5%, 80%, 82.5%, and 84.5% of a diluent.

[0092] The present invention provides a pharmaceutical composition comprising 1-8w / w%, 1-5w / w%, 1-3w / w%, 3-5w / w%, 5-8w / w%, 3w / w%, 5w / w%, or 8w / w% of a disintegrant.

[0093] The present invention provides a pharmaceutical composition, which contains 0.1-2w / w%, 0.1-1.5w / w%, 0.1-1w / w%, 0.1-0.5w / w%, 0.5-2w / w%, 0.5-1w / w%, 0.5w / w%, 1w / w%, and 2w / w% of a lubricant.

[0094] The present invention provides a pharmaceutical composition, which contains 2-35w / w%, 2-30w / w%, 2-25w / w%, 2-20w / w%, 2-15w / w%, 2-10w / w%, 2-5w / w%, 5-35w / w%, 5-30w / w%, 5-25w / w%, 5-20w / w%, 5-15w / w%, 5-10w / w%, 2w / w%, 5w / w%, 10w / w%, 15w / w%, and 20w / w% of a wetting agent.

[0095] The pharmaceutical composition according to any one of the present invention comprises the active ingredients and inactive ingredients according to any one of the aforementioned embodiments, including:

[0096] active ingredient;

[0097] a diluent selected from one or more of pregelatinized starch, lactose, microcrystalline cellulose, mannitol, dextrin, calcium phosphate, or sucrose;

[0098] a disintegrant, wherein the disintegrant is selected from one or more of cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, or low-substituted hydroxypropyl cellulose;

[0099] a lubricant selected from one or more of magnesium stearate, talc, or colloidal silicon dioxide;

[0100] Optionally, the pharmaceutical composition further comprises a wetting agent selected from silicon dioxide, talc, magnesium silicate,

[0101] One or more of.

[0102] The present invention provides a pharmaceutical composition, which contains 5-35w / w% active ingredient, 60-85w / w% diluent, 1-8w / w% disintegrant and 0.1-2w / w% lubricant.

[0103] The present invention provides a pharmaceutical composition, which contains 5-20 w / w% active ingredient, 70-85 w / w% diluent, 1-8 w / w% disintegrant, and 0.1-2 w / w% lubricant.

[0104] The present invention provides a pharmaceutical composition, which contains 10-80w / w% active ingredient, 2-35w / w% wetting agent, 15-85w / w% diluent, 1-10w / w% disintegrant and 0.1-5w / w% lubricant.

[0105] The present invention provides a pharmaceutical composition, which contains 10-60w / w% active ingredient, 2-35w / w% wetting agent, 25-80w / w% diluent, 1-10w / w% disintegrant and 0.1-5w / w% lubricant.

[0106] The present invention provides a pharmaceutical composition, which contains 10-45w / w% active ingredient, 2-25w / w% wetting agent, 30-70w / w% diluent, 1-10w / w% disintegrant and 0.1-5w / w% lubricant.

[0107] The present invention provides a pharmaceutical composition comprising 10-40 w / w% active ingredient, 5-20 w / w% wetting agent, 35-60 w / w% diluent, 1-10 w / w% disintegrant, and 0.1-5 w / w% lubricant. The present invention also provides a pharmaceutical composition comprising 10 w / w% active ingredient, 24.5 w / w% lactose, 60 w / w% microcrystalline cellulose, 5 w / w% low-substituted hydroxypropyl cellulose, and 0.5 w / w% magnesium stearate.

[0108] The present invention provides a pharmaceutical composition, which contains 10w / w% of active ingredients, 2w / w% of silicon dioxide, 24.5w / w% of lactose, 58w / w% of microcrystalline cellulose, 5w / w% of low-substituted hydroxypropyl cellulose, and 0.5w / w% of magnesium stearate.

[0109] The present invention provides a pharmaceutical composition, which contains 10w / w% of active ingredients, 5w / w% of silicon dioxide, 24.5w / w% of lactose, 55w / w% of microcrystalline cellulose, 5w / w% of low-substituted hydroxypropyl cellulose, and 0.5w / w% of magnesium stearate.

[0110] The present invention provides a pharmaceutical composition, which contains 10w / w% of active ingredients, 10w / w% of silicon dioxide, 24.5w / w% of lactose, 50w / w% of microcrystalline cellulose, 5w / w% of low-substituted hydroxypropyl cellulose, and 0.5w / w% of magnesium stearate.

[0111] The present invention provides a pharmaceutical composition, which contains 10w / w% of active ingredients, 10w / w% of silicon dioxide, 5w / w% of talc, 24.5w / w% of lactose, 45w / w% of microcrystalline cellulose, 5w / w% of low-substituted hydroxypropyl cellulose, and 0.5w / w% of magnesium stearate.

[0112] The present invention provides a pharmaceutical composition, which contains 10w / w% of active ingredients, 10w / w% of silicon dioxide, 10w / w% of talc, 24.5w / w% of lactose, 40w / w% of microcrystalline cellulose, 5w / w% of low-substituted hydroxypropyl cellulose, and 0.5w / w% of magnesium stearate.

[0113] The invention provides a pharmaceutical composition, which contains 20w / w% of active ingredients, 29.5w / w% of mannitol, 45w / w% of microcrystalline cellulose, 5w / w% of cross-linked polyvinylpyrrolidone, and 0.5w / w% of magnesium stearate.

[0114] The invention provides a pharmaceutical composition, which contains 40w / w% of active ingredients, 19.5w / w% of mannitol, 35w / w% of microcrystalline cellulose, 5w / w% of cross-linked polyvinylpyrrolidone, and 0.5w / w% of magnesium stearate.

[0115] The invention provides a pharmaceutical composition, which contains 80w / w% of active ingredients, 4.5w / w% of mannitol, 10w / w% of microcrystalline cellulose, 5w / w% of cross-linked polyvinylpyrrolidone, and 0.5w / w% of magnesium stearate.

[0116] The invention provides a pharmaceutical composition, which contains 40w / w% of active ingredients, 3w / w% of silicon dioxide, 2w / w% of magnesium silicate, 19.5w / w% of mannitol, 30w / w% of microcrystalline cellulose, 5w / w% of cross-linked polyvinylpyrrolidone, and 0.5w / w% of magnesium stearate.

[0117] The invention provides a pharmaceutical composition, which contains 40w / w% of active ingredients, 6w / w% of silicon dioxide, 4w / w% of magnesium silicate, 19.5w / w% of mannitol, 25w / w% of microcrystalline cellulose, 5w / w% of cross-linked polyvinylpyrrolidone, and 0.5w / w% of magnesium stearate.

[0118] The invention provides a pharmaceutical composition, which contains 40w / w% of active ingredients, 10w / w% of silicon dioxide, 5w / w% of magnesium silicate, 19.5w / w% of mannitol, 20w / w% of microcrystalline cellulose, 5w / w% of cross-linked polyvinylpyrrolidone, and 0.5w / w% of magnesium stearate.

[0119] The invention provides a pharmaceutical composition, which contains 20w / w% of active ingredients, 40w / w% of pregelatinized starch, 35w / w% of lactose, 3w / w% of sodium carboxymethyl starch and 2w / w% of talc.

[0120] The invention provides a pharmaceutical composition, which contains 40w / w% of active ingredients, 30w / w% of pregelatinized starch, 25w / w% of lactose, 3w / w% of sodium carboxymethyl starch and 2w / w% of talc.

[0121] The invention provides a pharmaceutical composition, which contains 80w / w% of active ingredients, 10w / w% of pregelatinized starch, 5w / w% of lactose, 3w / w% of sodium carboxymethyl starch, and 2w / w% of talc.

[0122] The present invention provides a pharmaceutical composition, which contains 40w / w% of active ingredients, 5w / w% of silicon dioxide, 30w / w% of pregelatinized starch, 20w / w% of lactose, 3w / w% of sodium carboxymethyl starch, and 2w / w% of talc.

[0123] The present invention provides a pharmaceutical composition, which contains 40w / w% of active ingredients, 10w / w% of silicon dioxide, 25w / w% of pregelatinized starch, 20w / w% of lactose, 3w / w% of sodium carboxymethyl starch, and 2w / w% of talc.

[0124] The invention provides a pharmaceutical composition, which contains 40w / w% of active ingredients, 15w / w% of silicon dioxide, 20w / w% of pregelatinized starch, 20w / w% of lactose, 3w / w% of sodium carboxymethyl starch, and 2w / w% of talc.

[0125] The invention provides a pharmaceutical composition, which contains 20w / w% of active ingredients, 45w / w% of microcrystalline cellulose, 29.5w / w% of lactose, 5w / w% of cross-linked sodium carboxymethyl cellulose, and 0.5w / w% of magnesium stearate.

[0126] The invention provides a pharmaceutical composition, which contains 40w / w% of active ingredients, 35w / w% of microcrystalline cellulose, 19.5w / w% of lactose, 5w / w% of cross-linked sodium carboxymethyl cellulose, and 0.5w / w% of magnesium stearate.

[0127] The invention provides a pharmaceutical composition, which contains 80w / w% of active ingredients, 10w / w% of microcrystalline cellulose, 4.5w / w% of lactose, 5w / w% of cross-linked sodium carboxymethyl cellulose, and 0.5w / w% of magnesium stearate.

[0128] The present invention provides a pharmaceutical composition, which contains 40w / w% of active ingredients, 5w / w% of silicon dioxide, 30w / w% of microcrystalline cellulose, 19.5w / w% of lactose, 5w / w% of cross-linked sodium carboxymethyl cellulose, and 0.5w / w% of magnesium stearate.

[0129] The present invention provides a pharmaceutical composition, which contains 40w / w% of active ingredients, 10w / w% of silicon dioxide, 25w / w% of microcrystalline cellulose, 19.5w / w% of lactose, 5w / w% of cross-linked sodium carboxymethyl cellulose, and 0.5w / w% of magnesium stearate.

[0130] The present invention provides a pharmaceutical composition, which contains 40w / w% of active ingredients, 15w / w% of silicon dioxide, 20w / w% of microcrystalline cellulose, 19.5w / w% of lactose, 5w / w% of cross-linked sodium carboxymethyl cellulose, and 0.5w / w% of magnesium stearate.

[0131] The invention provides a pharmaceutical composition, which contains 10 w / w% of active ingredients, 22 w / w% of lactose, 62 w / w% of microcrystalline cellulose, 5 w / w% of cross-linked sodium carboxymethyl cellulose, and 1 w / w% of magnesium stearate.

[0132] The invention provides a pharmaceutical composition, which contains 25w / w% of active ingredients, 30w / w% of mannitol, 40w / w% of microcrystalline cellulose, 3w / w% of low-substituted carboxymethyl cellulose sodium, and 2w / w% of talc.

[0133] The invention provides a pharmaceutical composition, which contains 25w / w% of active ingredients, 37.5w / w% of pregelatinized starch, 35w / w% of dextrin, 1.5w / w% of sodium carboxymethyl starch, and 1w / w% of magnesium stearate.

[0134] The present invention provides a pharmaceutical composition comprising 33 w / w% active ingredient, 27 w / w% calcium phosphate, 38.33 w / w% sucrose, 1 w / w% cross-linked polyvinylpyrrolidone, and 0.67 w / w% talc. In any of the above pharmaceutical compositions, the active ingredient is selected from a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0135] In one aspect, the present invention provides a pharmaceutical preparation comprising any one of the above-mentioned pharmaceutical compositions;

[0136] In some embodiments, the amount of active ingredient in a unit preparation of the pharmaceutical preparation is 1 mg to 100 mg; in some embodiments, the amount of active ingredient in a unit preparation of the pharmaceutical preparation is 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg.

[0137] In some embodiments, the pharmaceutical preparation is in the form of a tablet, granules, capsules, dry suspensions, oral solutions, soft capsules, and emulsions; in some embodiments, the pharmaceutical preparation is in the form of a tablet, granules, capsules, and soft capsules.

[0138] In one aspect, the present invention provides use of any of the above pharmaceutical compositions or any of the above pharmaceutical preparations in the preparation of a medicament for treating a disease associated with the inhibition or degradation of AAK1, wherein the disease is pain, preferably inflammatory pain, postoperative pain, trigeminal neuralgia, acute postherpetic neuralgia and postherpetic neuralgia, diabetic peripheral neuropathy, causalgia, occipital neuralgia, fibromyalgia, phantom limb pain, burn pain, and other forms of neuralgia, neuropathy, and spontaneous pain syndrome.

[0139] The preparation process of the pharmaceutical composition or pharmaceutical preparation of the present invention is one or more of direct mixing, wet granulation, dry granulation, fluidized bed granulation, spray drying, freeze drying, hot melt extrusion, and pellet coating, preferably direct mixing, wet granulation, fluidized bed granulation, dry granulation, and spray drying, and more preferably direct mixing and dry granulation.

[0140] In some embodiments, the preparation process is one or more of direct mixing, wet granulation, dry granulation, fluidized bed granulation, spray drying, freeze drying, hot melt extrusion, pellet coating, and extrusion spheronization, preferably spray drying and hot melt extrusion;

[0141] In some embodiments, the manufacturing process is dry granulation tableting, powder direct tableting, and powder direct capsule filling.

[0142] In some embodiments, the preparation process of the pharmaceutical composition further comprises pre-treating the active ingredient, wherein the pre-treatment method is selected from one or more of pulverization, solid dispersion, and nano-grinding.

[0143] Unless otherwise stated, the terms used in the specification and claims have the following meanings:

[0144] "Pharmaceutically acceptable salt" refers to salts that are safe, non-toxic, and neither biologically nor otherwise undesirable, and include salts thereof that are pharmaceutically acceptable for veterinary as well as human pharmaceutical use and possess the desired pharmacological activity.

[0145] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0146] "Optional" or "optionally" or "selectively" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclyl optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclyl group is substituted with an alkyl group and instances where the heterocyclyl group is not substituted with an alkyl group. BRIEF DESCRIPTION OF THE DRAWINGS

[0147] FIG1 is a time-MPT curve of the mechanical pain threshold (MPT) of mice in Example 5.

[0148] FIG2 is a dissolution curve of the tablet of Example 7.

[0149] FIG3 is a dissolution curve diagram of the capsule of Example 7. DETAILED DESCRIPTION

[0150] The following embodiments illustrate the technical problems, technical solutions and beneficial effects to be solved by the present invention. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0151] The compound of general formula (I) is prepared using the following synthesis scheme:

[0152] Example 1: Preparation of active ingredients

[0153] Intermediate 1:

[0154] first step:

[0155] The raw material 1A (10 g, 49 mmol) was dissolved in 200 mL of dichloromethane, cooled to -20°C, and DAST (11.7 mL, 88 mmol) was added. The temperature was slowly raised to room temperature and the reaction was allowed to react for 5 h. After the raw material disappeared, the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried and passed through a silica gel column (petroleum ether: ethyl acetate = 20:1) to obtain the target compound intermediate 1 (9.8 g, 89%).

[0156] 1 H NMR (400MHz, CDCl3) δ7.65-7.58 (m, 1H), 7.46-7.40 (m, 1H), 6.85-6.56 (m, 1H).

[0157] Intermediate 2:

[0158] first step:

[0159] 2A (5 g, 24 mmol), Xphos PdG2 (189 mg, 0.24 mmol, CAS: 1310584-14-5), Xphos (229 mg, 0.48 mmol, CAS 564483-18-7), bipyraclostrobin (9.14 g, 36 mmol), and KOAc (7.07 g, 72 mmol) were added to a flask. After nitrogen displacement, 200 mL of ethanol was added and the reaction was heated to 80°C for 5 h. After the disappearance of the starting material, water was added to quench the reaction. The ethanol in the system was evaporated and extracted with ethyl acetate. The organic phase was dried to obtain intermediate 2 (5.1 g).

[0160] LC-MS (ESI): m / z = 174.1 [M+H] + .

[0161] Intermediate 3:

[0162] first step:

[0163] Under a nitrogen atmosphere, 62 mL of chlorosulfonyl isocyanate was added to a three-necked round-bottom flask, followed by 200 mL of dichloromethane and the system was cooled to 0°C. 27 mL of formic acid was dissolved in 50 mL of dichloromethane and slowly added to the system while controlling the temperature at 0°C. After 30 minutes, the mixture was warmed to room temperature and stirred overnight. 36.3 mL of hydroxyacetone and 58 mL of pyridine were dissolved in 1000 mL of dichloromethane and slowly added to the system at 0°C. After the addition was complete, the system was warmed to room temperature and stirred overnight. The organic solvent in the system was dried and the mixture was passed through a silica gel column using dichloromethane as the eluent to obtain the title compound 3C (36 g, 56%).

[0164] 1H NMR (400MHz, CDCl3) δ5.06 (s, 2H), 2.42 (s, 3H).

[0165] Step 2:

[0166] Under nitrogen atmosphere, 3C (36 g, 267 mmol) was dissolved in 800 mL of methyl tert-butyl ether. The system was cooled to 0°C and 2-methylallylmagnesium chloride tetrahydrofuran solution (0.55 L, 0.5 M) was added dropwise. After the disappearance of the starting material by spot plate detection, saturated aqueous ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate, dried by spin drying, and passed through a silica gel column to obtain the title compound 3D (43 g, 84%).

[0167] 1 H NMR (400MHz, CDCl3) δ5.06-5.01 (m, 1H), 4.85-4.83 (m, 1H), 4.59 (s, 1H), 4.38 (d, 1H), 4.27(d, 1H), 2.57-2.50(m, 1H), 2.42-2.29(m, 1H), 1.84(s, 3H), 1.46(s, 3H).

[0168] Step 3:

[0169] Under nitrogen, 3D (1.91 g, 10 mmol) was dissolved in 50 mL of tetrahydrofuran, and 15 mL of a 1 M solution of potassium tert-butoxide in tetrahydrofuran was added, followed by the addition of CbzCl (2.1 mL, 15 mmol). After the disappearance of the starting material by plate detection, a saturated aqueous ammonium chloride solution was added to quench the reaction. The tetrahydrofuran in the system was dried up, and the mixture was extracted with ethyl acetate. The residue was passed through a silica gel column (petroleum ether: ethyl acetate = 10:1) to give the title compound 3E (2.6 g, 80%).

[0170] LC-MS(ESI): m / z=343.0[M+NH4] + .

[0171] 120g of 3E was subjected to chiral preparation to obtain 55g of the target compound 3F.

[0172] Preparation method: Instrument: Waters SFC 150Mgm, Column: DAICEL CHIRALPAK OJ (250 mm × 50 mm, 10 μm); Mobile phase: A for CO2 and B for MeOH (BASE); Gradient: 10% B; Flow rate: 130 mL / min, Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle time: 4.5 min; Sample preparation: Sample concentration: 157.5 mg / mL, ethanol solution; Injection: 0.8 mL per sample. After separation, the fraction was dried on a rotary evaporator at 40°C to yield Compound 3F (Retention time: 0.680 min).

[0173] Step 4:

[0174] Compound 3F (5 g, 15.4 mmol) was dissolved in 500 mL of methanol, and 50 mg of 10% palladium-carbon catalyst was added to replace the hydrogen atmosphere. After the fluorescence disappeared after spot plate detection, the palladium-carbon in the system was removed by filtration. The filtrate was spin-dried to obtain the crude title compound 3G, which was directly used in the next step.

[0175] Step 5:

[0176] Compound 3G was dissolved in 150 mL of tetrahydrofuran, and lithium aluminum tetrahydride (1.8 g, 47.4 mmol) was added portionwise at 0°C. The mixture was warmed to room temperature and stirred overnight. 1.8 mL of water, 3.6 mL of 10% aqueous sodium hydroxide solution, and 5.4 mL of water were added. After stirring for 1 hour, the solid was removed by filtration. The filtrate was spin-dried to dryness to obtain the crude product of intermediate 3, which was used directly in the next reaction.

[0177] LC-MS (ESI): m / z = 130.1 [M+H] + .

[0178] Intermediate 4:

[0179] first step:

[0180] Compound 4A (10 g, 57.8 mmol) was dissolved in 200 mL of acetone. Meta-chloroperbenzoic acid (11 g, 63.6 mmol) was dissolved in 200 mL of acetone at room temperature and added. The mixture was stirred for 5 min to generate a large amount of solid. The solid was filtered and washed with acetone. After drying, the crude product of compound 4B (10.7 g, 98%) was obtained.

[0181] LC-MS(ESI): m / z=189.0and 191.0[M+H] + .

[0182] Step 2:

[0183] 10.7 g of crude compound 4B was dissolved in 200 mL of trimethyl orthoformate, 1.25 mL of boron trifluoride etherate was added, and the system was heated to 105° C. for overnight reaction. The organic phase in the system was dried and separated by column chromatography to obtain compound 4C (9.1 g, 69%).

[0184] LC-MS(ESI): m / z=231.0and 233.0[M+H] + .

[0185] Step 3:

[0186] Compound 4C (3.5 g, 15.1 mmol), Xphos PdG2 (600 mg, 0.76 mmol, CAS: 1310584-14-5), Xphos (700 mg, 1.47 mmol, CAS 564483-18-7), potassium acetate (4.5 g, 45.8 mmol), and pinacol diboron (6 g, 23.6 mmol) were placed in a round-bottom flask and dissolved in 250 mL of ethanol. The atmosphere was purged with nitrogen, and the system was heated to 80°C and reacted overnight. The ethanol in the system was evaporated, and the product was extracted with ethyl acetate to obtain the title compound, Intermediate 4 (4 g).

[0187] LC-MS (ESI): m / z = 197.1 [M+H] + .

[0188] Intermediate 5:

[0189] first step:

[0190] The raw material 5A (5.00 g, 24.51 mmol) was dissolved in 100 mL of dichloromethane, cooled to -20°C, and DAST (6.5 mL, 49.02 mmol) was added. The temperature was slowly raised to room temperature and the reaction was allowed to react for 2 h. After the raw material disappeared after plate detection, the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was spin-dried and passed through a silica gel column (petroleum ether: ethyl acetate = 20:1) to obtain intermediate 5 (5.00 g, 90.27%).

[0191] 1 H NMR (400MHz, CDCl3) δ 8.40 (dd, 1H), 8.15 (dt, 1H), 6.95-6.67 (m, 1H).

[0192] 1.1 Preparation of Compound 1

[0193] first step:

[0194] 3D (8 g, 42 mmol) was dissolved in 500 mL of tetrahydrofuran, and the system was cooled to 0°C. Lithium aluminum tetrahydride (3.99 g, 105 mmol) was slowly added, and then the temperature was raised to room temperature for 6 h. 4 mL of water, 8 M NaOH aqueous solution, and 12 mL of water were added in sequence, and the mixture was stirred for 1 h. The solid was removed by filtration, and the filtrate was dried to give the crude product, target compound 1b (9 g), which was directly used in the next step without purification.

[0195] LC-MS (ESI): m / z = 130.2 [M+H] + .

[0196] Step 2:

[0197] The crude product 1b (2 g) was added to 27 mL of a tetrahydrofuran solution of potassium tert-butoxide, stirred at room temperature for 5 min, and then intermediate 1 (4 g, 18 mmol) was added. After nitrogen was replaced, the mixture was heated to 80°C and reacted overnight. The organic phase in the system was dried and separated and purified by silica gel column chromatography (dichloromethane). ∶ methanol = 10:1) to give the target compound 1c (1.1 g, 35%).

[0198] LC-MS (ESI): m / z = 335.1 and 337.1 [M+H] + .

[0199] Step 3:

[0200] Intermediate 2 (1.1 g, 3.3 mmol), 1c (880 mg, 5 mmol), potassium phosphate (9.2 g, 43 mmol), Xphos PdG2 (500 mg, 0.63 mmol, CAS: 1310584-14-5), and Xphos (650 mg, 1.36 mmol, CAS 564483-18-7) were added to a sealed tube. 30 mL of tetrahydrofuran was added, the atmosphere was replaced with nitrogen, and the temperature was raised to 80°C for 5 h. After the disappearance of the starting material by spot plate detection, the solid was removed by filtration and washed with methanol. The filtrate was spin-dried and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the title compound 1d (360 mg, 29%).

[0201] LC-MS (ESI): m / z = 384.2 [M+H] + .

[0202] 1HNMR (400MHz, DMSO-d6) δ8.80-8.76 (m, 1H), 8.42-8.36 (m, 1H), 8.32 (s, 1H), 8.24-8.18 (m, 1H), 7.84-7.79 (m, 1H), 7.42-6.88 (m, 2H), 4.87 (s, 1H), 4.72 (s, 1H), 3.88 (s, 2H), 2.22 (s, 2H), 1.78 (s, 3H), 1.15 (s, 3H).

[0203] Step 4:

[0204] Dissolve 1d (360 mg, 0.94 mmol) in 20 mL of dichloromethane, cool to -60°C, and introduce ozone. After the disappearance of the starting material by a spectrophotometer, add 1 g of triphenylphosphine and warm to room temperature, stirring for 15 minutes. The organic phase is then dried and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to afford the title compound 1e (300 mg, 83%).

[0205] LC-MS (ESI): m / z = 386.2 [M+H] + .

[0206] Step 5:

[0207] Under a nitrogen atmosphere, 1e (300 mg, 0.78 mmol) was dissolved in 20 mL of tetrahydrofuran and the system was cooled to 0°C. A solution of methylmagnesium bromide in THF (1 mL, 3 M) was added, and the mixture was slowly warmed to room temperature and then tested on a microplate. After the disappearance of the starting material, saturated aqueous ammonium chloride was added to quench the reaction. The mixture was extracted with dichloromethane, and the organic phase was dried to give the title compound 1f (240 mg, 0.6 mmol), which was directly used in the next step.

[0208] LC-MS (ESI): m / z = 402.2 [M+H] + .

[0209] Step 6:

[0210] Under nitrogen atmosphere, 1f (240 mg, 0.6 mmol) was dissolved in 15 mL of dichloromethane and cooled to -78 ° C. DAST (0.4 mL, 2.8 mmol) was added and the system was slowly warmed to room temperature. After the disappearance of the starting material by plate detection, saturated aqueous sodium bicarbonate solution was added to quench the reaction. The reaction was extracted with dichloromethane, and the organic phase was spin-dried and the resulting product was separated by HPLC and freeze-dried to obtain the title compound 1 (110 mg, 42%).

[0211] LC-MS (ESI): m / z = 404.2 [M+H] + .

[0212] 1H NMR (400MHz, DMSO-d6) δ8.82-8.76 (m, 1H), 8.42-8.36 (m, 1H), 8.32 (s, 1H), 8.23-8.18 (m, 1H), 7.8 1-7.75 (m, 1H), 7.41-6.89 (m, 2H), 3.95 (s, 2H), 1.94-1.86 (m, 2H), 1.49-1.36 (m, 6H), 1.23 (s, 3H).

[0213] 1.2 Preparation of compounds 2 and 3

[0214] 1d (80 mg) was subjected to chiral separation to give compound 2 (33.7 mg) and compound 3 (25.3 mg).

[0215] Preparation method:

[0216] Instrument: SHIMADZU LC-20AP, Column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); Mobile Phase: A: n-hexane, B: ethanol (0.1% NH3·H2O); Gradient: 8% B gradient elution; Flow Rate: 120 mL / min, Column Temperature: 25°C, Wavelength: 254 nm, Cycle Time: 16 min; Sample Preparation: Sample Concentration: 1.5 mg / mL, ethanol solution; Injection: 2 mL per sample. After separation, the fractions were dried on a rotary evaporator at a bath temperature of 40°C to yield P1 (retention time: 2.658 minutes, identified as compound 2) and P2 (retention time: 4.205 minutes, identified as compound 3).

[0217] 1.3 Preparation of compound 4

[0218] first step:

[0219] Intermediate 4 (500 mg, 1.8 mmol), intermediate 1 (500 mg, 2.2 mmol), Xphos PdG2 (200 mg, 0.25 mmol, CAS: 1310584-14-5), Xphos (250 mg, 0.52 mmol, CAS 564483-18-7), and potassium phosphate (4.5 g, 21.2 mmol) were added to a sealed tube. 20 mL of tetrahydrofuran was added and the nitrogen atmosphere was replaced. The temperature of the system was raised to 80° C. for 3 h. The sample was stirred with silica gel and separated by column chromatography to obtain compound 4a (197 mg, 37%).

[0220] LC-MS (ESI): m / z = 298.1 [M+H] + .

[0221] Step 2:

[0222] Compound 4a (197 mg, 0.66 mmol), intermediate 3 (90 mg, 0.7 mmol), and 1 mL of potassium tert-butoxide (1 M in THF) were added to a sealed tube. After nitrogen replacement, the system was heated to 80°C and reacted for 3 h. The reaction solution was concentrated to dryness and purified by preparative separation to obtain the title compound 4 (30 mg, 11%).

[0223] LC-MS (ESI): m / z = 407.1 [M+H] + .

[0224] 1 H NMR (400MHz, DMSO-d6) δ10.23 (s, 1H), 8.49 (s, 1H), 8.38-8.33 (m, 1H), 8.18-8.13 (m, 1H), 7.79-7.75 (m, 1H), 7.69-7.63 (m, 1H), 7.40-7.08 (m, 1H), 4.86 (s, 1H), 4.71 (s, 1H), 3.88 (s, 2H), 3.71 (s, 3H), 2.23 (s, 2H), 1.78 (s, 3H), 1.14 (s, 3H).

[0225] 1.4 Preparation of compound 5

[0226] first step:

[0227] 5a (1.5 g, 7.89 mmol), intermediate 4 (2.3 g, 11.84 mmol), potassium phosphate (21.8 g, 102.57 mmol), XphosPdG2 (1.24 g, 1.58 mmol, CAS: 1310584-14-5), and Xphos (1.5 g, 3.16 mmol, CAS 564483-18-7) were added to a sealed tube. 60 mL of tetrahydrofuran was added, and the atmosphere was replaced with nitrogen. The temperature was raised to 80°C and the reaction was allowed to react for 5 h. After the disappearance of the starting material by spot plate detection, the solid was removed by filtration and washed with methanol. The filtrate was dried and passed through a silica gel column (dichloromethane:methanol = 10:1) to obtain the title compound 5b (1.4 g, 68%).

[0228] LC-MS (ESI): m / z = 262.0 [M+H] + .

[0229] Step 2:

[0230] Intermediate 3 (495 mg, 3.83 mmol) was added to 15 mL of DMF solution. NaH (275 mg, 11.49 mmol) was added under ice-cooling and stirred for 10 min. Compound 5b (1 g, 3.83 mmol) was then added. After nitrogen was replaced, the reaction was incubated at 0°C for 1 h. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried and passed through a column (dichloromethane:methanol = 10:1) to afford compound 5 (110 mg).

[0231] LC-MS (ESI): m / z = 371.2 [M+H] + .

[0232] 1 HNMR (400MHz, DMSO-d6) δ10.16 (s, 1H), 8.47 (s, 1H), 8.29 (d, 1H), 7.80 (d, 1H), 7.62 (dd, 1H), 7.40 (d, 1H), 4.86 ( s, 1H), 4.70 (s, 1H), 3.75 (s, 2H), 3.70 (s, 3H), 2.50 (s, 3H), 2.23 (s, 2H), 1.78 (s, 3H), 1.58 (s, 2H), 1.14 (s, 3H).

[0233] 1.5 Preparation of compound 6

[0234] first step:

[0235] Intermediate 3 (1 g, 7.7 mmol), intermediate 1 (1.6 g, 7.1 mmol) and 12 mL of potassium tert-butoxide (1 M in THF) were added to a sealed tube. After nitrogen was replaced, the system was heated to 80°C and reacted for 3 h. The system was cooled to room temperature, mixed with silica gel, and separated by column chromatography (petroleum ether:ethyl acetate = 1:1 to ethyl acetate) to obtain the target compound 6a (500 mg, 21%).

[0236] LC-MS (ESI): m / z = 355.1 [M+H] + .

[0237] Step 2:

[0238] Compound 6a (500 mg, 1.5 mmol), intermediate 2 (620 mg, 3.6 mmol), Xphos PdG2 (200 mg, 0.25 mmol, CAS: 1310584-14-5), Xphos (250 mg, 0.52 mmol, CAS 564483-18-7), potassium phosphate (4.5 g, 21.2 mmol) were added to a sealed tube, 20 mL of tetrahydrofuran was added and nitrogen was replaced, the system was heated to 80 ° C for 3 h, the sample was mixed with silica gel, and the mixture was separated by column chromatography (petroleum ether).∶ Ethyl acetate = 1:1 to ethyl acetate) gave compound 6b (350 mg, 61%).

[0239] LC-MS (ESI): m / z = 384.2 [M+H] + .

[0240] Step 3:

[0241] Compound 6b (350 mg, 0.91 mmol) was dissolved in 20 mL of dichloromethane, and the system was cooled to -78 °C and introduced with ozone. After the raw material disappeared after the plate was detected, an excess of triphenylphosphine was added, and the temperature was slowly raised to room temperature. The sample was mixed with silica gel and separated by column chromatography (petroleum ether). ∶ Ethyl acetate = 1:1 to ethyl acetate) gave compound 6c (310 mg, 89%).

[0242] LC-MS (ESI): m / z = 386.1 [M+H] + .

[0243] Step 4:

[0244] Compound 6c (160 mg, 0.42 mmol) was dissolved in 10 mL of tetrahydrofuran and the atmosphere was replaced with nitrogen. 1.4 mL of methylmagnesium chloride (3 M in THF) was added at 0°C. The mixture was slowly warmed to room temperature and then saturated aqueous ammonium chloride was added to quench the reaction. The organic phase was dried and extracted with dichloromethane. The organic phase was dried and freeze-dried to obtain compound 6 (30 mg, 18%).

[0245] LC-MS (ESI): m / z = 402.2 [M+H] + .

[0246] 1 H NMR (400MHz, DMSO-d6) δ8.81-8.78(m, 1H), 8.42-8.37(m, 1H), 8.32(s, 1H), 8.23-8.19(m, 1H), 7.81-7.74(m, 1H), 7.41-6.88(m, 2H), 4.02-3.91(m, 2H), 1.71(d, 1H), 1.60(d, 1H), 1.27(s, 3H), 1.23(s, 3H), 1.16(s, 3H).

[0247] 1.6 Preparation of Compound 7

[0248] first step:

[0249] 7a (900 mg), intermediate 1 (633 mg, 2.8 mmol), Xphos PdG2 (250 mg, 0.32 mmol), Xphos (500 mg, 1.05 mmol), and potassium phosphate (6.0 g, 28.3 mmol) were added to a sealed tube. 30 mL of tetrahydrofuran was added and the nitrogen atmosphere was replaced. The temperature of the system was raised to 80° C. for 3 h. The sample was stirred with silica gel and separated by column chromatography to obtain compound 7b (428 mg, 54%).

[0250] LC-MS (ESI): m / z = 282.2 [M+H] + .

[0251] Step 2:

[0252] Compound 7b (200 mg, 0.71 mmol), intermediate 3 (100 mg, 0.77 mmol), and 2.5 mL of potassium tert-butoxide (1 M in THF) were added to a sealed tube. After nitrogen replacement, the system was heated to 80°C and reacted for 3 h. After preparative separation and purification, compound 7 (89 mg, 32%) was obtained.

[0253] LC-MS (ESI): m / z = 391.1 [M+H] + .

[0254] 1 H NMR (400MHz, DMSO-d6) δ10.54 (s, 1H), 8.68 (s, 1H), 8.41-8.37 (m, 1H), 8.16-8.10 (m, 1H), 7.81-7.75 (m, 1H), 7.72-7.67 (m, 1H), 7.38-7.07 (m, 1H), 4.86 (s, 1H), 4.71 (s, 1H), 3.88 (s, 2H), 2.23 (s, 2H), 2.12 (s, 3H), 1.78 (s, 3H), 1.14 (s, 3H).

[0255] 1.7 Preparation of Compound 8

[0256] first step:

[0257] Ferric nitrate nonahydrate (133 mg, 0.33 mmol) was dissolved in 3 mL of water, the atmosphere was replaced with nitrogen, and then cooled to 0°C. A selective fluorine reagent (117 mg, 0.33 mmol) and 3 mL of acetonitrile were added, and compound 7 (35 mg, 0.09 mmol) was dissolved in 3 mL of acetonitrile and added to the system. After stirring for 5 minutes, sodium borohydride (40 mg, 1.05 mmol) was added portionwise. The reaction was maintained at 0°C for 30 minutes, and 1 mL of ammonia was added to quench the reaction. The mixture was extracted with a mixed solvent of dichloromethane and methanol (10:1), and the mixture was spin-dried and purified by HPLC to obtain compound 8 (10 mg, 28%).

[0258] LC-MS (ESI): m / z = 411.3 [M+H] + .

[0259] 1 H NMR (400MHz, DMSO-d6) δ10.55 (s, 1H), 8.69 (s, 1H), 8.43-8.35 (m, 1H), 8.18-8.10 (m, 1H), 7.78-7.73 (m, 1H), 7.7 2-7.65 (m, 1H), 7.40-7.05 (m, 1H), 3.94 (s, 2H), 2.12 (s, 3H), 1.95-1.86 (m, 2H), 1.50-1.36 (m, 6H), 1.23 (s, 3H).

[0260] 1.8 Preparation of Compound 9

[0261] first step:

[0262] Ferric nitrate nonahydrate (324 mg, 0.8 mmol) was dissolved in 7 mL of water, the atmosphere was replaced with nitrogen, and then cooled to 0°C. A selective fluorine reagent (284 mg, 0.8 mmol) and 7 mL of acetonitrile were added, and compound 4 (81 mg, 0.2 mmol) was dissolved in 7 mL of acetonitrile and added to the system. After stirring for 5 minutes, sodium borohydride (100 mg, 2.6 mmol) was added portionwise. The reaction was maintained at 0°C for 30 minutes, and 2.5 mL of ammonia was added to quench the reaction. The mixture was extracted with a mixed solvent of dichloromethane: methanol (10:1), and the mixture was dried by spin drying and analyzed by HPLC to obtain compound 9 (9 mg, 11%).

[0263] LC-MS (ESI): m / z = 427.2 [M+H] + .

[0264] 1H NMR (400MHz, DMSO-d6) δ10.25 (s, 1H), 8.49 (s, 1H), 8.38-8.33 (m, 1H), 8.19-8.13 (m, 1H), 7.78-7.72 (m, 1H), 7.6 8-7.64 (m, 1H), 7.38-7.09 (m, 1H), 3.94 (s, 2H), 3.71 (s, 3H), 1.95-1.86 (m, 2H), 1.50-1.37 (m, 6H), 1.23 (s, 3H).

[0265] 1.9 Preparation of Compound 10

[0266] Ferric nitrate nonahydrate (88 mg, 0.22 mmol) was dissolved in water (2 mL), sonicated for 5 min, cooled to 0°C, and then a solution of a selective fluorine reagent (76 mg, 0.22 mmol) in 2 mL of acetonitrile was added, followed by a solution of compound 5 (20 mg, 0.05 mmol) in 2 mL of acetonitrile. Sodium borohydride (30 mg, 0.79 mmol) was added in batches and reacted for 1 h. LC-MS showed that the raw material had reacted completely. The product was diluted with water and extracted with dichloromethane. The organic phases were combined, dried, and concentrated to obtain a crude product, which was then purified by preparative separation to obtain compound 10 (10 mg, 47%).

[0267] LC-MS (ESI): m / z = 391.3 [M+H] + .

[0268] 1 H NMR (400MHz, CD3OD) δ8.42 (s, 1H), 8.27 (d, 1H), 7.76 (d, 1H), 7.61 (d, 1H), 7.40 (d, 1H), 3.98 (s, 2H), 3.80(s, 3H), 2.57(s, 3H), 2.09(s, 1H), 2.04(s, 1H), 1.50(d, 3H), 1.45(d, 3H), 1.40(s, 3H).

[0269] Example 2: In vitro AAK1 enzyme activity detection experiment

[0270] A 10 mM compound stock solution (dissolved in DMSO) was diluted to 0.2 mM with DMSO and then diluted 5-fold with DMSO to obtain 10 compound concentrations. Each compound concentration was then diluted 50-fold with 1× kinase reaction buffer (containing 40 mM Tris, 20 mM MgCl2, 0.1% BSA, and 0.5 mM DTT) for later use. AAK1 (Signalchem, Cat# A01-11G-10) was diluted to twice the final concentration (30 nM and 28 nM, respectively) with 1× kinase reaction buffer. 2 μL / well of AAK1 was added to a 384-well white plate, followed by 1 μL / well of compound. The plate was sealed with film and centrifuged at 1000 rpm for 30 seconds and allowed to stand at room temperature for 10 minutes. A mixture of ATP (Promega, Cat# V914B) and substrate Micro2 (GenScript, Cat# PE0890) was prepared at 4x the final concentration (the final ATP concentrations for AAK1 were 15 μM and 5 μM, respectively, and the final concentration of Micro2 was 0.1 mg / mL). 1 μL / well of the ATP and substrate mixture was added to the reaction plate. The plate was sealed with a sealing film and centrifuged at 1000 rpm for 30 seconds. The reaction was allowed to proceed at room temperature for 60 minutes (AAK1). Transfer 4 μL / well ADP-Glo ​​(Promega, Cat# V9102) to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes; transfer 8 μL / well Detection solution to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes; read the RLU (Relative luminescence unit) signal value using a Biotek multi-function microplate reader, and calculate the percentage inhibition rate according to the following formula: [1-(LUM 化合物 -LUM 阳性对照 ) / (LUM 阴性对照 -LUM 阳性对照 )] × 100. IC was calculated using a four-parameter nonlinear fitting equation in Graphpad 7.0 software. 50 The specific results are shown in Table 1.

[0271] Table 1 AAK1 inhibitory activity

[0272] Conclusion: The compounds of the present invention show high inhibitory activity against AAK1 receptor.

[0273] Example 3: Canine Pharmacokinetic Test

[0274] Experimental animals: Male beagle dogs, weighing about 8-11 kg, 6 per compound, purchased from Beijing Masi Biotechnology Co., Ltd.

[0275] Experimental Methods: On the day of the experiment, 12 beagle dogs were randomly divided into groups based on body weight. They were fasted but not watered for 12-14 hours prior to dosing and fed 4 hours after dosing. Dosing was performed according to Table 2.

[0276] Table 2. Dosing Information

[0277] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline Oral administration solvent: 0.5% MC

[0278] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose)

[0279] Before and after dosing, 1 ml of blood was collected from the jugular vein or limb vein into an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm at 4°C for 10 min, and plasma was collected. Blood was collected at the following time points: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, and 24 h for both the LX9211 intravenous and oral gavage groups; and at the following time points: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, and 48 h for both the compound 9 intravenous and oral gavage groups. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS. The results are shown in Table 3.

[0280] Table 3. Pharmacokinetic parameters of test compounds in beagle dog plasma -:not applicable.

[0281] Note: LX-9211 structure is

[0282] Conclusion: The compounds of the present invention have good pharmacokinetic characteristics.

[0283] Example 4: hERG potassium channel effect test

[0284] Experimental platform: electrophysiology manual patch clamp system

[0285] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0286] Experimental Methods: hERG potassium channel currents were recorded using the whole-cell patch-clamp technique at room temperature in CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. After perfusion with electrode solution, the tip resistance was approximately 2-5 MΩ. The microelectrodes were connected to the patch-clamp amplifier by inserting them into the amplifier headstage. Clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After whole-cell recordings were obtained, cells were clamped at -80 mV. To elicit hERG potassium currents (I hERG ), a 2-second depolarization step from -80 mV to +20 mV was applied, followed by repolarization to -50 mV, which was maintained for 1 second before returning to -80 mV. This voltage stimulus was applied every 10 seconds, and drug administration was initiated after confirming the stability of the hERG potassium current (at least 1 minute). Compounds were administered for at least 1 minute at each tested concentration, and at least two cells were tested at each concentration (n≥2).

[0287] Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5, and Excel. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1-(I / Io)] × 100%

[0288] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current before and after drug addition, respectively.

[0289] The IC50 of the compound was calculated using GraphPad Prism 5 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)×HillSlope))

[0290] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0291] Experimental results: The IC50 values ​​of the test compounds for the inhibition of hERG potassium channel current are shown in Table 4.

[0292] Table 4 Inhibition of hERG potassium channel current by test compounds

[0293] Example 5: Spinal Nerve Ligation (SNL)-induced Neuropathic Pain Model in Mice

[0294] Male C57BL / 6J mice (8 weeks old) purchased from Jinan Pengyue Experimental Animal Breeding Co., Ltd. were adaptively raised for one week before establishing the model. The specific establishment method is as follows:

[0295] 1) Sterilization of surgical instruments and ligatures;

[0296] 2) Anesthetize the mouse with isoflurane and place it in the prone position on the operating table;

[0297] 3) Prepare the skin near the hip bone of the mouse and make an incision approximately 2 cm along the spine;

[0298] 4) Separate the fascia along the spine, bluntly separate the muscles, and expose the L5 transverse process;

[0299] 5) Use forceps to carefully bite off the L5 transverse process to expose the L5 spinal nerve;

[0300] 6) Carefully separate the L5 nerve with a glass needle and ligate it with a 5-0 ligature.

[0301] 7) Suture the muscles and skin and disinfect with iodine;

[0302] The day after modeling, mice with unsuccessful modeling were eliminated (sign of successful modeling: the hind paw of the mouse curled up). After modeling, the mice were stroked for 3 to 5 minutes every day to ensure that the animals were familiar with the experimenter. Then, the mice were placed on a metal pain test frame to adapt for 40 to 60 minutes. After the third day, after environmental adaptation, the mice were placed on a metal pain test frame to adapt for 40 to 60 minutes. Pre-dose baseline values ​​(Ascending test) were obtained for test animals (0.16, 0.4, 0.6, 1.0, 1.4, and 2.0 g). Each animal was measured twice, with at least 5 minutes between measurements, and the average was calculated. The animals were then grouped according to baseline values ​​(10 animals per group). After grouping, LX-9211 (1 and 10 mg / kg), compound 2 (1 and 10 mg / kg), or vehicle (40% PEG-400 + 10% ethanol + 15% Tween 80 + 35% saline) was administered orally. The mechanical pain threshold (MPT) of the mice was measured 1, 3, and 6 hours after administration. Time-MPT curves were plotted and statistically analyzed using GraphPad 8.3.0.

[0303] Results and Conclusion: The results are shown in Figure 1. Both 10 mg / kg LX-9211 and Compound 2 effectively elevated the pain threshold of SNL-induced mice 1, 3, and 6 hours after a single dose. The analgesic efficacy of 10 mg / kg LX-9211 peaked 1 hour after administration and gradually declined thereafter. In contrast, the analgesic efficacy of 10 mg / kg Compound 2 peaked 3 hours after administration and remained stable from 1 to 6 hours, with superior efficacy to that of LX-9211 at 3 and 6 hours. These data demonstrate that Compound 2 exhibits superior analgesic activity to LX-9211.

[0304] Example 6: Mouse brain-to-blood ratio test

[0305] 6.1 Experimental Animals: Male ICR mice, 20-25 g, 9 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0306] 6.2 Experimental Design: On the day of the experiment, 18 ICR mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0307] Table 5. Dosing Information

[0308] Note: Oral administration solvent: 40% PEG-400 + 10% Ethanol + 15% Tween 80 + 35% Saline;

[0309] (Saline: physiological saline; Ethanol: ethanol; Tween 80: Tween 80)

[0310] Whole blood and brain tissue were collected 0.5, 4, and 24 hours after oral administration. The whole blood was centrifuged to separate the plasma. The brain tissue was rinsed with cold saline to remove any residual blood, blotted dry, and homogenized. All samples were stored at -80°C prior to analysis and quantitative analysis using LC-MS / MS.

[0311] The test results are shown in Table 6.

[0312] Table 6. Pharmacokinetic parameters of compounds in mouse plasma

[0313] -:not applicable.

[0314] Conclusion: The compounds of the present invention, especially compound 2, have high brain penetrance.

[0315] Example 7: Composition of Compound 3

[0316] 7.1 Prescriptions 1 to 6

[0317] Table 7. AAK1 inhibitor composition prescription (1)

[0318] Tablets containing a composition of Compound 3 were prepared according to the formulation in the table: Compound 3 and a wetting agent were first co-grinded and mixed for 15 minutes. A diluent and a disintegrant were then added and mixed in a mixer for 15 minutes. Finally, a lubricant was added and mixed for 3 minutes to obtain a composition containing Compound 3. The composition was compressed using a tablet press.

[0319] We observed whether the above formulations exhibited agglomeration or adhesion to the equipment due to softening or melting of compound 3 during the manufacturing process. Furthermore, we examined the content uniformity of the finished product.

[0320] Table 8. Test results

[0321] The results show that no matter whether a wetting agent is added to the formulation or not, there is no phenomenon of agglomeration or adhesion to the equipment caused by the softening or melting of compound 3.

[0322] 7.2 Prescription 7-12

[0323] Table 9. AAK1 inhibitor composition prescription (2)

[0324] Tablets containing a composition of compound 3 were prepared according to the formulation in the table: Compound 3 and a wetting agent were first sieved and mixed five times, followed by mixing in a mixer for 15 minutes. A diluent and a disintegrant were then added and mixed for 15 minutes. Finally, a lubricant was added and mixed for another 3 minutes to obtain a composition containing compound 3. The composition was compressed using a tablet press to obtain tablets.

[0325] We observed whether the above formulations exhibited agglomeration or adhesion to the equipment due to softening or melting of compound 3 during the manufacturing process. Furthermore, we examined the content uniformity of the finished product.

[0326] Table 10. Test results

[0327] Conclusion: Adding a certain amount of wetting agent to the formulation can significantly improve the softening / melting phenomenon of compound 3 during the preparation process, and the content uniformity of the tablets is better.

[0328] 7.3 Prescriptions 13-18

[0329] Table 11. AAK1 inhibitor composition prescription (3)

[0330] Preparation method: Compound 3 and a wetting agent are mixed in a mixer for 15 minutes, followed by the addition of a diluent and a disintegrant and mixing for 15 minutes, and finally, magnesium stearate is added and mixed for 3 minutes to obtain a composition containing Compound 3. The composition containing Compound 3 is then filled into capsules using a capsule filling machine.

[0331] We observed whether the above formulations exhibited agglomeration or adhesion to the equipment due to softening or melting of compound 3 during the manufacturing process. Furthermore, we examined the content uniformity of the finished product.

[0332] Table 12. Test results

[0333] Conclusion: The addition of wetting agent can significantly inhibit the softening / melting phenomenon of compound 3 during the preparation process.

[0334] 7.4 Prescriptions 19-24

[0335] Table 13. AAK1 inhibitor composition prescription (4)

[0336] Tablets containing the Compound 3 composition were prepared according to the formulation in the table: Compound 3 and the wetting agent were first sieved and mixed five times, followed by mixing in a blender for 15 minutes. A diluent and disintegrant were then added and mixed for 15 minutes. The premix was then loaded into a roller compactor and compacted at 0.6 kN / cm. The resulting ribbon was passed through a 0.8 mm vibrating mill. The milled granules were then mixed with a lubricant for 3 minutes before being compressed using a tablet press.

[0337] We investigated the dissolution behavior of the tablets prepared according to the above formulation and process in a pH 1.0 medium and the changes in their related substances after being placed at 40°C±2°C, 75%RH±5%RH for 6 months, as shown in Table 14.

[0338] As shown in Figure 2, for formulations 19 to 21, as the proportion of compound 3 increases, the softening / melting of compound 3 causes AAK1 aggregation, further reducing its solubility. For formulations 22 to 24, the addition of a wetting agent prevents the agglomeration caused by the softening / melting of compound 3, thereby improving their dissolution behavior.

[0339] Table 14. Stability results

[0340] It can be seen from the table that no matter whether the composition contains a wetting agent or not, the composition has good stability.

[0341] 7.5 Prescription 25~28

[0342] Table 15. AAK1 inhibitor composition prescription (5)

[0343] Preparation method: Compound 3 was mixed with lactose, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose in a mixer for 15 minutes, and then magnesium stearate was added and mixed for 3 minutes. The mixture was then compressed using a tablet press, and the tablet hardness was controlled at 50-100N.

[0344] Table 16. AAK1 inhibitor composition prescription (6)

[0345] Preparation: Compound 3 was mixed with mannitol, microcrystalline cellulose, and low-substituted carboxymethyl cellulose sodium in a premixer for 15 minutes. The premix was then loaded into a roller compactor and compacted at 0.6 kN / cm. The resulting ribbon was passed through a 0.8 mm vibrating mill. The milled particles were then mixed with talc for 3 minutes and compressed using a tablet press. The tablet hardness was controlled between 50 and 100 N.

[0346] Table 17. AAK1 inhibitor composition prescription (7)

[0347] Preparation method: Compound 3 was mixed with pregelatinized starch, sodium carboxymethyl starch and dextrin in a mixer for 15 minutes, and then magnesium stearate was added and mixed for 3 minutes. The mixture was then compressed using a tablet press, and the tablet hardness was controlled at 50-100N.

[0348] Table 18. AAK1 inhibitor composition prescription (8)

[0349] Preparation method: Compound 3 was mixed with calcium phosphate, sucrose, cross-linked polyvinylpyrrolidone and talc in a mixer for 15 minutes, and then the mixture was filled into capsules using a capsule filling machine.

[0350] The dissolution profiles of tablets prepared according to prescription 25 were investigated in water at pH 1.0, pH 4.5, and pH 6.8 using the second method (slurry method) in the dissolution and release assay section of Part 0931 of the 2015 edition of the Chinese Pharmacopoeia. The rotation speed was set at 50 rpm, and sampling was performed at 5, 10, 15, 20, 30, 45, and 60 minutes.

[0351] As shown in Figure 3, when pH = 1.0, the dissolution rate of the tablets prepared by prescription 25 can reach 90% in 5 minutes, and the dissolution is rapid. In 20 minutes, the dissolution rate of the tablets prepared by prescription 25 in water at pH 1.0, pH 4.5, and pH 6.8 can all reach 85%.

[0352] 7.6 Preparation Stability Study Methods and Results

[0353] The preparations prepared from Prescription 25, Prescription 26, Prescription 27 and Prescription 28 were packaged in aluminum-plastic blister packs, placed at 40°C ± 2°C, 75% RH ± 5% RH, and the changes in their related substances were observed.

[0354] Table 19. Stability test results

[0355] From the results in Table 19, it can be seen that the preparations prepared by prescriptions 25-28 are relatively stable and their stability is basically the same.

[0356] The pharmaceutical compositions of compound 2 were prepared by referring to the prescriptions 1-6, 10-13, 16-28 and process of the pharmaceutical composition of compound 3. There was no agglomeration or adhesion to the equipment, the content uniformity (A+2.2S) was 3-5.5, and the pharmaceutical compositions were relatively stable.

Claims

1. A pharmaceutical composition comprising: Active ingredient, the active ingredient is selected from the compound of formula (I) or its stereoisomers, pharmaceutically acceptable salts: in, Z is selected from NH or O; R 1 、R 2 Each independently selected from H, deuterium, halogen, amino, -COOH, cyano, sulfonyl, aminoacyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, wherein the alkyl group is optionally further substituted by 1-3 R A Substituent substitution; R 41 、R 42 Each independently selected from H, deuterium, amino, C 1-6 Alkyl, halogen, cyano, hydroxyl, halo C 1-6 Alkyl, deuterated C 1-6 alkyl; R 51 、R 52 Each is independently selected from H, deuterium, amino, halogen; R 61 、R 62 、R 63 Each independently selected from H, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl; Or, R 51 and R 61 , or R 61 and R 62 Together with the carbon atoms to which they are attached, they form double bonds; R A Selected from deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy or hydroxy C 1-6 alkyl; Provided that, when Z is selected from O, The following structure is not formed: b) inactive ingredients; The content of the active ingredient in the pharmaceutical composition is 5% to 90% w / w, preferably 5% to 80% w / w, and more preferably 10% to 80% w / w.

2. The pharmaceutical composition according to claim 1, wherein Z is O; R1 and R2 are selected from halogenated C1-2 alkyl groups; R51 and R52 are each independently selected from H and deuterium; R41 and R42 are each independently selected from amino and C1-2 alkyl; R61, R62, and R63 are each independently selected from H, deuterium, and C1-2 alkyl.

3. The pharmaceutical composition according to claim 1, wherein the compound of formula (I) is selected from one of the following structures: The pharmaceutical composition according to claim 1 , wherein the inactive ingredient is selected from diluents.

5. The pharmaceutical composition according to claim 4, wherein the diluent is selected from one or more of starch, pregelatinized starch, dextrin, lactose monohydrate, anhydrous lactose, sucrose, microcrystalline cellulose, inorganic salts, and sugar alcohols; preferably one or more of pregelatinized starch, dextrin, lactose, sucrose, microcrystalline cellulose, calcium sulfate, dibasic calcium phosphate dihydrate, anhydrous dibasic calcium phosphate, calcium phosphate, calcium carbonate, calcium stearate, magnesium oxide, aluminum hydroxide, mannitol, xylitol, and sorbitol; more preferably one or more of pregelatinized starch, lactose, sucrose, microcrystalline cellulose, dibasic calcium phosphate dihydrate, anhydrous dibasic calcium phosphate, calcium phosphate, mannitol, and dextrin.

6. The pharmaceutical composition according to claim 4, wherein the weight ratio of the active ingredient to the diluent is 1:0.05 to 1:10, preferably 1:0.1 to 1:8.5, and more preferably 1:0.18 to 1:8.

5.

7. The pharmaceutical composition according to claim 4, wherein the inactive ingredient further comprises one or more of a wetting agent, a disintegrant, and a lubricant; The wetting agent is selected from one or more silicates; preferably one or more of silicon dioxide, magnesium silicate, magnesium trisilicate, magnesium aluminum silicate and talc; more preferably one or more of fumed silica, precipitated silica, sol-gel silica, magnesium silicate, magnesium trisilicate, magnesium aluminum silicate and talc; The disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, starch and its derivatives, low-substituted hydroxypropyl cellulose, low-substituted sodium hydroxymethyl cellulose, surfactants, alginic acid and sodium alginate, and clays; preferably one or more of cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, low-substituted sodium hydroxymethyl cellulose, cross-linked polyvinylpyrrolidone, starch, sodium carboxymethyl starch, hydroxypropyl starch, polysorbate 80, sodium lauryl sulfate, bentonite, and colloidal magnesium aluminum silicate; more preferably one or more of cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, low-substituted sodium hydroxymethyl cellulose, sodium carboxymethyl starch, and cross-linked polyvinylpyrrolidone; The lubricant is selected from one or more of talc, stearic acid, metal stearate, stearic acid ester, glyceryl behenate, sodium lauryl sulfate or colloidal silicon dioxide; preferably one or more of talc, calcium stearate, magnesium stearate and zinc stearate, polyoxyethylene stearate, glyceryl monostearate and glyceryl palmitostearate; more preferably one or more of talc, calcium stearate, magnesium stearate and glyceryl monostearate.

8. The pharmaceutical composition according to claim 7, wherein the weight ratio of the active ingredient to the wetting agent is 1:0.05 to 1:

5. Preferably 1:0.08 to 1:3, more preferably 1:0.12 to 1:2; The weight ratio of the active ingredient to the disintegrant is 1:0.01 to 1:3, preferably 1:0.03 to 1:1.5, and more preferably 1:0.03 to 1:0.6; The weight ratio of the active ingredient to the lubricant is 1:0.001 to 1:2, preferably 1:0.006 to 1:0.

1.

9. A pharmaceutical preparation comprising the pharmaceutical composition according to any one of claims 1 to 8.

10. The pharmaceutical preparation according to claim 9, wherein the amount of the active ingredient in a unit preparation is 1 mg to 100 mg, preferably 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg. The pharmaceutical preparation according to claim 9 , wherein the pharmaceutical preparation is in the form of tablets, granules, capsules, and soft capsules.

12. Use of the pharmaceutical composition according to any one of claims 1 to 8 or the pharmaceutical preparation according to any one of claims 9 to 11 in the preparation of a drug for treating diseases related to the inhibition or degradation of AAK1.

13. The use according to claim 12, wherein the disease is selected from pain, including inflammatory pain, postoperative pain, trigeminal neuralgia, acute postherpetic neuralgia and postherpetic neuralgia, diabetic peripheral neuropathy, causalgia, occipital neuralgia, fibromyalgia, phantom limb pain, burn pain and other forms of neuralgia, neuropathy and spontaneous pain syndrome.

Images