Pharmaceutical composition containing an AAK1 inhibitor

Abstract

The present invention relates to a pharmaceutical composition of the compound of formula (I) or its stereoisomer, a pharmaceutically acceptable salt thereof, a pharmaceutical formulation thereof, a method for preparing the pharmaceutical composition and pharmaceutical formulation thereof, and an application of the compound of formula (I) or its stereoisomer, a pharmaceutically acceptable salt thereof, a pharmaceutical composition and pharmaceutical formulation thereof, and a method for preparing the pharmaceutical composition and pharmaceutical formulation thereof, and an application of the compound of formula (I) or its stereoisomer in the manufacture of a drug for treating a disease associated with the inhibition or degradation of AAK1 [C1] TIFF2025538197000045.tif30156

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions of the compound of formula (I) or its stereoisomers, pharmaceutically acceptable salts and pharmaceutical formulations thereof, and their application in the manufacture of medicaments for treating diseases associated with inhibitors that inhibit AAK1. [Background technology]

[0002] Neuropathic pain (NP) is a general term for a range of pain caused by damage or disease of the somatosensory nervous system and can be divided into peripherally-induced neuropathic pain (pNP) and central neuropathic pain. Clinically, pNP is more common and can be specifically divided into diabetic peripheral neuralgia, postherpetic neuralgia, trigeminal neuralgia, and chronic postoperative neuralgia. Patients with pNP often experience symptoms such as spontaneous pain (pain without any external stimulus), allodynia (increased response to painful stimuli), hyperalgesia (pain in response to normally non-painful stimuli), and paresthesia, which significantly impact 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 gene knockout mice are endowed with persistent pain or hypoalgesia responses, and do not develop allodynia in a spinal nerve ligation neuropathic pain model, demonstrating that AAK1 is a viable target for the treatment of pNP.

[0004] The present inventors have provided an AAK1 inhibitor, but the compound has a low melting point and often adheres to capsule punch rods or tablet punches when made into tablets or capsules. Accordingly, the present inventors intend to provide a composition containing an AAK1 inhibitor, which can be easily used to prepare general solid preparations, and the preparations obtained by the preparation have good in vitro dissolution behavior and stability. Summary of the Invention [Means for solving the problem]

[0005] The present invention provides pharmaceutical compositions of the compounds of formula (I), their stereoisomers and pharmaceutically acceptable salts, and pharmaceutical formulations thereof.

[0006] The pharmaceutical composition or pharmaceutical preparation of the present invention has good solubility, dissolution rate, bioavailability and oral performance, and is of stable quality, good safety, low irritation and meets pharmaceutical quality standards.

[0007] In one aspect, the present invention provides a pharmaceutical composition, the pharmaceutical composition comprising: An active ingredient selected from a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, Z is selected from NH or O; R 1 , R 2 are each independently H, deuterium, halogen, amino group, -COOH, cyano group, sulfonyl group, aminoacyl group, C 1-6 Alkyl group, halo C 1-6 Alkyl groups, deuterated C 1-6 alkyl groups, wherein the alkyl group is optionally selected from 1 to 3 R A further substituted with a substituent, R 41 , R 42 are independently H, deuterium, amino group, C 1-6Alkyl group, halogen, cyano group, hydroxy group, haloC 1-6 Alkyl groups, deuterated C 1-6 alkyl groups, R 51 , R 52 are each independently selected from H, deuterium, an amino group, and a halogen; R 61 , R 62 , R 63 are each independently H, deuterium, halogen, amino group, cyano group, hydroxy group, C 1-6 Alkyl group, halo C 1-6 Alkyl groups, deuterated C 1-6 alkyl groups, Or R 51 and R 61 , or R 61 and R 62 form a double bond with the carbon atom to which they are attached, R A However, deuterium, halogen, amino group, cyano group, hydroxy group, C 1-6 Alkyl group, halo C 1-6 Alkyl groups, deuterated C 1-6 Alkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, deuterated C 1-6 Alkoxy or hydroxy C 1-6 alkyl groups, The proviso is that when Z is selected from O, [ka] but, [ka] An active ingredient that does not form a structure An inactive ingredient, 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, and the content of an inactive ingredient is In some embodiments, the content of the active ingredient (based on the free base) in the pharmaceutical composition is 5% to 85% w / w, preferably 8% to 80% w / w, and more preferably 10% to 80% w / w. In some embodiments, the content of the active ingredient (based on the free base) in the pharmaceutical composition is 8% to 85% w / w, preferably 10% to 85% w / w, and more preferably 10% to 80% w / w. In some embodiments, the content of the active ingredient (based on the free base) in the pharmaceutical composition is 5 to 80% w / w, 5% to 70% w / w, 5% to 60% w / w, 5% to 50% w / w, 5% to 40% w / w, 5% to 30% w / w, 5% to 20% w / w, 10% to 80% w / w, 10% to 70% w / w, 10% to 60% w / w, 10% to 50% w / w, 10% to 40% w / w, 10% to 30% w / w, or 10% to 20% w / w.

[0008] In some embodiments, in the compound of Formula (I), Z is O; R 1 , R 2 is Haro C 1-2 alkyl groups, R 51 , R 52 are each independently selected from H and deuterium; R 41 , R 42 are each independently an amino group, C 1-2 alkyl groups, R 61 , R 62 , R 63 are independently H, deuterium, and C 1-2 Alkyl group, halo C 1-2 alkyl groups, Or R 51 and R 61 , or R 61 and R 62 form a double bond with the carbon atom to which they are attached, In some embodiments, in the compound of Formula (I), R 1 , R 2 are each 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; R 51 , R 52 are each independently selected from H and deuterium; R 41 , R 42 are each independently selected from an amino group, —CH3, and —CH2CH3; R 61 , R 62 , R 63 are 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; Or R 51 and R 61 , or R 61 and R 62 form a double bond with the carbon atom to which they are attached, In some embodiments, in the compound of Formula (I), Z is O, R 1 , R 2 are each independently selected from —CHF, —CHF, and —CF; R51 , R 52 are each independently selected from H and deuterium; R 41 , R 42 are each independently selected from an amino group and —CH3; R 61 , R 62 , R 63 are each independently selected from H, deuterium, —CH3, and CF3; In some embodiments, in the compound of Formula (I), Z is O, R 1 , R 2 are each independently selected from —CHF, —CHF, and —CF; R 51 , R 52 form a double bond with the carbon atom to which they are attached, R 41 , R 42 are each independently selected from an amino group and —CH3; R 61 , R 62 , R 63 are each independently selected from H, deuterium, —CH3, and CF3; In some embodiments, in the compound of Formula (I), Z is O, R 1 , R 2 are each independently selected from —CHF, —CHF, and —CF; R 51 , R 52 are each independently selected from H and deuterium; R 41 , R 42 are each independently selected from an amino group and —CH3; R 63 are each independently selected from H, deuterium, —CH3, and CF3; R 61 and R 62 form a double bond with the carbon atom to which they are attached, In some embodiments, the compound of formula (I) is [ka] is selected from one of the structures In some embodiments, the compound of formula (I) is [ka] is selected from one of the structures In some embodiments, the inactive ingredients include a wetting agent; In some embodiments, the inactive ingredients include a disintegrant. In some embodiments, the inactive ingredients include a diluent; In some embodiments, the inactive ingredients include a lubricant; In some embodiments, the wetting agent is selected from one or more of silicates, preferably one or more of silica, 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; In some embodiments, the disintegrant is selected from one or more of crosscarboxymethylcellulose sodium, crospovidone, starch and its derivatives, low-substituted hydroxypropylcellulose, low-substituted hydroxymethylcellulose sodium, surfactants, alginic acid and sodium alginate, and clays, preferably one or more of crosscarboxymethylcellulose sodium, low-substituted hydroxypropylcellulose, low-substituted hydroxymethylcellulose sodium, crospovidone, starch, carboxymethylstarch sodium, hydroxypropyl starch, polysorbate 80, sodium dodecyl sulfate, bentonite, and colloidal magnesium aluminum silicate, more preferably one or more of crosscarboxymethylcellulose sodium, low-substituted hydroxypropylcellulose, low-substituted hydroxymethylcellulose sodium, carboxymethylstarch sodium, and crospovidone; 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 one or more of pregelatinized starch, dextrin, lactose, sucrose, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate dihydrate, anhydrous calcium hydrogen phosphate, calcium phosphate, calcium carbonate, calcium stearate, magnesium oxide, aluminum hydroxide, mannitol, xylitol, and sorbitol, and more preferably one or more of pregelatinized starch, lactose, sucrose, microcrystalline cellulose, calcium hydrogen phosphate dihydrate, anhydrous calcium hydrogen phosphate, calcium phosphate, mannitol, and dextrin; In some embodiments, the lubricant is selected from one or more of talc, stearic acid, metallic stearates, stearates, glyceryl behenate, sodium lauryl sulfate, or colloidal silica; in some embodiments, the lubricant is selected from one or more of talc, stearic acid, metallic stearates, stearates, glyceryl behenate, sodium lauryl sulfate, preferably one or more of talc, calcium stearate, magnesium stearate, and zinc stearate, polyoxyethylene stearate, glyceryl monostearate, glyceryl palmitate stearate; more preferably one or more of talc, calcium stearate, magnesium stearate, glyceryl monostearate, more preferably one or more of magnesium stearate, talc, or colloidal silica; 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, more preferably 1:0.12 to 1:2, and even 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, or 1:2; 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, more preferably 1:0.18 to 1:8.5, and even 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, or 1:8.45. 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, more preferably 1:0.03 to 1:0.6, and even more preferably 1:0.0375, 1:0.0625, 1:0.075, 1:0.125, 1:0.15, 1:0.25, or 1:0.5. 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, and 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, lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and magnesium stearate.

[0009] The present invention provides a pharmaceutical composition, which contains an active ingredient and silica, lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and magnesium stearate.

[0010] The present invention provides a pharmaceutical composition, which comprises an active ingredient and silica, talc, lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and magnesium stearate.

[0011] The present invention provides a pharmaceutical composition, which comprises an active ingredient and microcrystalline cellulose, mannitol, crospovidone, and magnesium stearate.

[0012] The present invention provides a pharmaceutical composition, which comprises an active ingredient and silica, magnesium silicate, microcrystalline cellulose, mannitol, crospovidone, and magnesium stearate.

[0013] The present invention provides a pharmaceutical composition, which comprises an active ingredient and pregelatinized starch, lactose, sodium carboxymethyl starch, and talc.

[0014] The present invention provides a pharmaceutical composition, which comprises an active ingredient and silica, pregelatinized starch, lactose, sodium carboxymethyl starch, and talc.

[0015] The present invention provides a pharmaceutical composition, which comprises an active ingredient and microcrystalline cellulose, lactose, cross-carboxymethylcellulose sodium, and magnesium stearate.

[0016] The present invention provides a pharmaceutical composition, which comprises an active ingredient and silica, microcrystalline cellulose, lactose, cross-carboxymethylcellulose sodium, and magnesium stearate.

[0017] The present invention provides a pharmaceutical composition, which comprises an active ingredient and lactose, microcrystalline cellulose, cross-carboxymethylcellulose sodium, and magnesium stearate.

[0018] The present invention provides a pharmaceutical composition, which comprises an active ingredient and lactose, cross-carboxymethylcellulose sodium, and magnesium stearate.

[0019] The present invention provides a pharmaceutical composition, which comprises an active ingredient and microcrystalline cellulose, cross-carboxymethylcellulose sodium, and magnesium stearate.

[0020] The present invention provides a pharmaceutical composition, which contains an active ingredient, mannitol, low-substituted sodium carboxymethylcellulose, and talc.

[0021] The present invention provides a pharmaceutical composition, which comprises an active ingredient, microcrystalline cellulose, low-substituted sodium carboxymethylcellulose, and talc.

[0022] The present invention provides a pharmaceutical composition, which contains an active ingredient and mannitol, microcrystalline cellulose, low-substituted sodium carboxymethylcellulose, and talc.

[0023] The present invention provides a pharmaceutical composition, which comprises an active ingredient and pregelatinized starch, sodium carboxymethyl starch, and magnesium stearate.

[0024] The present invention provides a pharmaceutical composition, which comprises an active ingredient and dextrin, sodium carboxymethyl starch, and magnesium stearate.

[0025] The present invention provides a pharmaceutical composition, which comprises an active ingredient and pregelatinized starch, dextrin, sodium carboxymethyl starch, and magnesium stearate.

[0026] The present invention provides a pharmaceutical composition, which contains an active ingredient, calcium phosphate, crospovidone, and talc.

[0027] The present invention provides a pharmaceutical composition, which comprises an active ingredient, sucrose, crospovidone, and talc.

[0028] The present invention provides a pharmaceutical composition containing an active ingredient, calcium phosphate, sucrose, crospovidone, and talc, and the active ingredient is present in an amount of 10 to 80 w / w%, 10 to 60 w / w%, 10 to 45 w / w%, 10 to 40 w / w%, 5 to 35 w / w%, 5 to 20 w / w%, 10%, 20%, 40%, or 80%.

[0029] The present invention provides pharmaceutical compositions, which contain 10 to 85 w / w%, 10 to 80 w / w%, 10 to 70 w / w%, 10 to 60 w / w%, 10 to 50 w / w%, 10 to 40 w / w%, 10 to 30 w / 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%, or 84.5% of a diluent.

[0030] The present invention provides pharmaceutical compositions, which contain 1-8 w / w%, 1-5 w / w%, 1-3 w / w%, 3-5 w / w%, 5-8 w / w%, 3 w / w%, 5 w / w%, or 8 w / w% of a disintegrant.

[0031] The present invention provides pharmaceutical compositions, which contain 0.1-2 w / w%, 0.1-1.5 w / w%, 0.1-1 w / w%, 0.1-0.5 w / w%, 0.5-2 w / w%, 0.5-1 w / w%, 0.5 w / w%, 1 w / w%, or 2 w / w% of a lubricant.

[0032] The present invention provides a pharmaceutical composition, which contains 2-35 w / w%, 2-30 w / w%, 2-25 w / w%, 2-20 w / w%, 2-15 w / w%, 2-10 w / w%, 2-5 w / w%, 5-35 w / w%, 5-30 w / w%, 5-25 w / w%, 5-20 w / w%, 5-15 w / w%, 5-10 w / w%, 2 w / w%, 5 w / w%, 10 w / w%, 15 w / w%, or 20 w / w% of a wetting agent.

[0033] The pharmaceutical composition according to any one of the preceding embodiments comprises the active ingredient and inactive ingredients, wherein: An active ingredient, a diluent selected from one or more of pregelatinized starch, lactose, microcrystalline cellulose, mannitol, dextrin, calcium phosphate, or sucrose; a disintegrant selected from one or more of croscarboxymethylcellulose sodium, carboxymethyl starch sodium, crospovidone, or low-substituted hydroxypropyl cellulose; a lubricant selected from one or more of magnesium stearate, talc, or colloidal silica; Optionally, the pharmaceutical composition further comprises a wetting agent, wherein the wetting agent is selected from one or more of silica, talc, magnesium silicate.

[0034] The present invention provides a pharmaceutical composition, which contains 5 to 35 w / w% of an active ingredient, 60 to 85 w / w% of a diluent, 1 to 8 w / w% of a disintegrant, and 0.1 to 2 w / w% of a lubricant.

[0035] The present invention provides a pharmaceutical composition, which contains 5 to 20 w / w% of an active ingredient, 70 to 85 w / w% of a diluent, 1 to 8 w / w% of a disintegrant, and 0.1 to 2 w / w% of a lubricant.

[0036] The present invention provides a pharmaceutical composition comprising 10-80 w / w% of an active ingredient, 2-35 w / w% of a wetting agent, 15-85 w / w% of a diluent, 1-10 w / w% of a disintegrant, and 0.1-5 w / w% of a lubricant.

[0037] The present invention provides a pharmaceutical composition, which contains 10-60 w / w% of an active ingredient, 2-35 w / w% of a wetting agent, 25-80 w / w% of a diluent, 1-10 w / w% of a disintegrant, and 0.1-5 w / w% of a lubricant.

[0038] The present invention provides a pharmaceutical composition, which contains 10-45 w / w% of an active ingredient, 2-25 w / w% of a wetting agent, 30-70 w / w% of a diluent, 1-10 w / w% of a disintegrant, and 0.1-5 w / w% of a lubricant.

[0039] The present invention provides a pharmaceutical composition containing 10-40 w / w% of an active ingredient, 5-20 w / w% of a wetting agent, 35-60 w / w% of a diluent, 1-10 w / w% of a disintegrant, and 0.1-5 w / w% of a lubricant.The present invention also provides a pharmaceutical composition containing 10 w / w% of the active ingredient, 24.5 w / w% of lactose, 60 w / w% of microcrystalline cellulose, 5 w / w% of low-substituted hydroxypropyl cellulose, and 0.5 w / w% of magnesium stearate.

[0040] The present invention provides a pharmaceutical composition comprising 10 w / w% of an active ingredient, 2 w / w% of silica, 24.5 w / w% of lactose, 58 w / w% of microcrystalline cellulose, 5 w / w% of low-substituted hydroxypropyl cellulose, and 0.5 w / w% of magnesium stearate.

[0041] The present invention provides a pharmaceutical composition comprising 10 w / w% of an active ingredient, 5 w / w% of silica, 24.5 w / w% of lactose, 55 w / w% of microcrystalline cellulose, 5 w / w% of low-substituted hydroxypropyl cellulose, and 0.5 w / w% of magnesium stearate.

[0042] The present invention provides a pharmaceutical composition comprising 10 w / w% of an active ingredient, 10 w / w% of silica, 24.5 w / w% of lactose, 50 w / w% of microcrystalline cellulose, 5 w / w% of low-substituted hydroxypropyl cellulose, and 0.5 w / w% of magnesium stearate.

[0043] The present invention provides a pharmaceutical composition comprising 10 w / w% of an active ingredient, 10 w / w% of silica, 5 w / w% of talc, 24.5 w / w% of lactose, 45 w / w% of microcrystalline cellulose, 5 w / w% of low-substituted hydroxypropyl cellulose, and 0.5 w / w% of magnesium stearate.

[0044] The present invention provides a pharmaceutical composition comprising 10 w / w% of an active ingredient, 10 w / w% silica, 10 w / w% talc, 24.5 w / w% lactose, 40 w / w% microcrystalline cellulose, 5 w / w% low-substituted hydroxypropyl cellulose, and 0.5 w / w% magnesium stearate.

[0045] The present invention provides a pharmaceutical composition comprising 20 w / w% of an active ingredient, 29.5 w / w% of mannitol, 45 w / w% of microcrystalline cellulose, 5 w / w% of crospovidone, and 0.5 w / w% of magnesium stearate.

[0046] The present invention provides a pharmaceutical composition comprising 40 w / w% of an active ingredient, 19.5 w / w% of mannitol, 35 w / w% of microcrystalline cellulose, 5 w / w% of crospovidone, and 0.5 w / w% of magnesium stearate.

[0047] The present invention provides a pharmaceutical composition comprising 80 w / w% of an active ingredient, 4.5 w / w% of mannitol, 10 w / w% of microcrystalline cellulose, 5 w / w% of crospovidone, and 0.5 w / w% of magnesium stearate.

[0048] The present invention provides a pharmaceutical composition comprising 40 w / w% of an active ingredient, 3 w / w% of silica, 2 w / w% of magnesium silicate, 19.5 w / w% of mannitol, 30 w / w% of microcrystalline cellulose, 5 w / w% of crospovidone, and 0.5 w / w% of magnesium stearate.

[0049] The present invention provides a pharmaceutical composition comprising 40 w / w% of an active ingredient, 6 w / w% of silica, 4 w / w% of magnesium silicate, 19.5 w / w% of mannitol, 25 w / w% of microcrystalline cellulose, 5 w / w% of crospovidone, and 0.5 w / w% of magnesium stearate.

[0050] The present invention provides a pharmaceutical composition comprising 40 w / w% of an active ingredient, 10 w / w% of silica, 5 w / w% of magnesium silicate, 19.5 w / w% of mannitol, 20 w / w% of microcrystalline cellulose, 5 w / w% of crospovidone, and 0.5 w / w% of magnesium stearate.

[0051] The present invention provides a pharmaceutical composition comprising 20 w / w% of an active ingredient, 40 w / w% of pregelatinized starch, 35 w / w% of lactose, 3 w / w% of sodium carboxymethyl starch, and 2 w / w% of talc.

[0052] The present invention provides a pharmaceutical composition comprising 40 wt% of an active ingredient, 30 wt% of pregelatinized starch, 25 wt% of lactose, 3 wt% of sodium carboxymethyl starch, and 2 wt% of talc.

[0053] The present invention provides a pharmaceutical composition comprising 80 w / w% of an active ingredient, 10 w / w% of pregelatinized starch, 5 w / w% of lactose, 3 w / w% of sodium carboxymethyl starch, and 2 w / w% of talc.

[0054] The present invention provides a pharmaceutical composition comprising 40 wt% of an active ingredient, 5 wt% of silica, 30 wt% of pregelatinized starch, 20 wt% of lactose, 3 wt% of sodium carboxymethyl starch, and 2 wt% of talc.

[0055] The present invention provides a pharmaceutical composition comprising 40 wt% of an active ingredient, 10 wt% of silica, 25 wt% of pregelatinized starch, 20 wt% of lactose, 3 wt% of sodium carboxymethyl starch, and 2 wt% of talc.

[0056] The present invention provides a pharmaceutical composition comprising 40 wt% of an active ingredient, 15 wt% of silica, 20 wt% of pregelatinized starch, 20 wt% of lactose, 3 wt% of sodium carboxymethyl starch, and 2 wt% of talc.

[0057] The present invention provides a pharmaceutical composition comprising 20 w / w% of an active ingredient, 45 w / w% of microcrystalline cellulose, 29.5 w / w% of lactose, 5 w / w% of sodium crosscarboxymethylcellulose, and 0.5 w / w% of magnesium stearate.

[0058] The present invention provides a pharmaceutical composition comprising 40 w / w% of an active ingredient, 35 w / w% of microcrystalline cellulose, 19.5 w / w% of lactose, 5 w / w% of sodium crosscarboxymethylcellulose, and 0.5 w / w% of magnesium stearate.

[0059] The present invention provides a pharmaceutical composition comprising 80 w / w% of an active ingredient, 10 w / w% of microcrystalline cellulose, 4.5 w / w% of lactose, 5 w / w% of cross-carboxymethylcellulose sodium, and 0.5 w / w% of magnesium stearate.

[0060] The present invention provides a pharmaceutical composition comprising 40 w / w% of an active ingredient, 5 w / w% of silica, 30 w / w% of microcrystalline cellulose, 19.5 w / w% of lactose, 5 w / w% of cross-carboxymethylcellulose sodium, and 0.5 w / w% of magnesium stearate.

[0061] The present invention provides a pharmaceutical composition comprising 40 w / w% of an active ingredient, 10 w / w% of silica, 25 w / w% of microcrystalline cellulose, 19.5 w / w% of lactose, 5 w / w% of sodium crosscarboxymethylcellulose, and 0.5 w / w% of magnesium stearate.

[0062] The present invention provides a pharmaceutical composition comprising 40 w / w% of an active ingredient, 15 w / w% of silica, 20 w / w% of microcrystalline cellulose, 19.5 w / w% of lactose, 5 w / w% of sodium crosscarboxymethylcellulose, and 0.5 w / w% of magnesium stearate.

[0063] The present invention provides a pharmaceutical composition comprising 10 w / w% of an active ingredient, 22 w / w% lactose, 62 w / w% microcrystalline cellulose, 5 w / w% crosscarboxymethylcellulose sodium, and 1 w / w% magnesium stearate.

[0064] The present invention provides a pharmaceutical composition comprising 25 w / w% of an active ingredient, 30 w / w% of mannitol, 40 w / w% of microcrystalline cellulose, 3 w / w% of low-substituted sodium carboxymethylcellulose, and 2 w / w% of talc.

[0065] The present invention provides a pharmaceutical composition comprising 25 w / w% of an active ingredient, 37.5 w / w% of pregelatinized starch, 35 w / w% of dextrin, 1.5 w / w% of sodium carboxymethyl starch, and 1 w / w% of magnesium stearate.

[0066] The present invention provides a pharmaceutical composition comprising 33 wt% of an active ingredient, 27 wt% of calcium phosphate, 38.33 wt% of sucrose, 1 wt% of crospovidone, and 0.67 wt% of talc, wherein the active ingredient is selected from the group consisting of a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0067] In one aspect, the present invention provides a pharmaceutical formulation comprising any one of the pharmaceutical compositions described above, In some embodiments, the amount of active ingredient in a unit dosage form is 1 mg to 100 mg, and in some embodiments, the amount of active ingredient in a unit dosage form 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.

[0068] In some embodiments, the dosage form of the pharmaceutical formulation is selected from tablets, granules, capsules, dry suspensions, oral solutions, soft capsules, and emulsions; in some embodiments, the dosage form of the pharmaceutical formulation is selected from tablets, granules, capsules, and soft capsules.

[0069] In one aspect, the present invention provides an application of any one of the above pharmaceutical compositions or any one of the above pharmaceutical preparations in the manufacture 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 neuralgia, causalgia, occipital neuralgia, fibromyalgia, phantom limb pain, burn pain and other forms of neuralgia, neuropathy and spontaneous pain syndromes.

[0070] The manufacturing process of the pharmaceutical composition or pharmaceutical formulation 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.

[0071] In some embodiments, the manufacturing process is one or more of direct blending, wet granulation, dry granulation, fluidized bed granulation, spray drying, freeze drying, hot melt extrusion, pellet coating, extrusion-spheronization, preferably spray drying and hot melt extrusion; In some embodiments, the manufacturing process is dry granulation tableting, direct powder tableting, and direct powder filling into capsules.

[0072] In some embodiments, the process for manufacturing the pharmaceutical composition further comprises pre-treating the active ingredient, wherein the pre-treatment method is selected from one or more of milling, solid dispersion, and nano-polishing.

[0073] Unless otherwise stated, terms used in the specification and claims have the following meanings:

[0074] "Pharmaceutically acceptable salts" includes salts that are safe, non-toxic, and not biologically or otherwise undesirable, and that are pharmaceutically acceptable for veterinary use and for use in human medicine, and that possess the desired pharmacological activity.

[0075] "Stereoisomer" refers to isomers that result from differences in the way atoms in molecules are arranged in space, and includes cis-trans isomers, enantiomers, and conformational isomers.

[0076] "Optionally," or "optionally," or "selective," or "optionally," means that the subsequently described event or circumstance may, but need not, occur, and the statement includes both instances where the event or circumstance occurs and instances where it does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the statement 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 explanation of the drawings]

[0077] [Figure 1] 1 shows the mechanical pain threshold (MPT) time-MPT curves of mice in Example 5. [Figure 2] FIG. 1 is a dissolution curve of the tablet of Example 7. [Figure 3] FIG. 1 is a dissolution curve of the capsules of Example 7. DETAILED DESCRIPTION OF THE INVENTION

[0078] The technical problems to be solved, technical solutions, and beneficial effects of the present invention will be described below in conjunction with examples. It should be understood that the specific examples described herein are only for the purpose of illustrating the present invention, and are not intended to limit the present invention.

[0079] The compounds of general formula (I) were prepared according to the following synthetic scheme.

[0080] Example 1: Preparation of the active ingredient Intermediate 1: [ka]

[0081] Step 1: The starting material 1A (10 g, 49 mmol) was dissolved in 200 mL of dichloromethane and cooled to -20°C. DAST (11.7 mL, 88 mmol) was added, and the mixture was allowed to warm slowly to room temperature and react for 5 h. After monitoring the disappearance of the starting material using a spot plate, the reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was spin-dried and then passed through a silica gel column (petroleum ether:ethyl acetate = 20:1) to obtain the target compound intermediate 1 (9.8 g, 89%).

[0082] 1 H NMR (400MHz, CDCl3) δ7.65 - 7.58 (m,1H),7.46 - 7.40 (m,1H),6.85 - 6.56 (m,1H). Intermediate 2: [ka]

[0083] Step 1: 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), bis(pinacolato)diboron (9.14 g, 36 mmol), and KOAc (7.07 g, 72 mmol) were added to a flask and purged with nitrogen. 200 mL of ethanol was added, heated to 80 °C, and reacted for 5 h. After monitoring with a spot plate until the starting material disappeared, water was added to quench the reaction. The ethanol in the system was spin-dried and extracted with ethyl acetate. The organic phase was spin-dried to give intermediate 2 (5.1 g).

[0084] LC-MS (ESI): m / z=174.1[M+H] + . Intermediate 3: [ka]

[0085] Step 1: Under a nitrogen gas atmosphere, 62 mL of chlorosulfonyl isocyanate was added to a three-necked round-bottom flask, 200 mL of dichloromethane was added, 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, controlling the temperature at 0°C. After 30 minutes, the system 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 dropwise addition was completed, the system was warmed to room temperature and stirred overnight. The organic solvent in the system was spin-dried, and the mixture was passed through a silica gel column using dichloromethane as an eluent to obtain the title compound 3C (36 g, 56%).

[0086] 1 H NMR (400MHz, CDCl3) δ 5.06 (s,2H),2.42 (s,3H).

[0087] Step 2: Under a nitrogen gas atmosphere, 3C (36 g, 267 mmol) was dissolved in 800 mL of methyl tert-butyl ether. After the system was cooled to 0°C, a solution of 2-methylallylmagnesium chloride in tetrahydrofuran (0.55 L, 0.5 M) was added dropwise. After the disappearance of the raw material was detected using a spot plate, a saturated aqueous ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate, spin-dried, and passed through a silica gel column to obtain the title compound 3D (43 g, 84%).

[0088] 1 H NMR (400MHz,CDCl3) δ 5.06 - 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).

[0089] Step 3: Under nitrogen gas, 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. Then, CbzCl (2.1 mL, 15 mmol) was added. After the disappearance of the raw material was detected by a spot plate, a saturated aqueous solution of ammonium chloride was added to quench the reaction. The tetrahydrofuran in the system was spin-dried, and the mixture was extracted with ethyl acetate, spin-dried, and passed through a silica gel column (petroleum ether:ethyl acetate=10:1) to obtain the title compound 3E (2.6 g, 80%).

[0090] LC-MS (ESI): m / z=343.0[M+NH4] + .

[0091] Chiral synthesis was carried out on 120 g of 3E to give 55 g of the target compound 3F.

[0092] Preparation method: Instrument: Waters SFC 150 Mgm, 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, Sample injection: 0.8 mL each time. After separation, the fraction was dried using a rotary evaporator at a bath temperature of 40°C to obtain compound 3F (retention time: 0.680 min).

[0093] Step 4: Compound 3F (5 g, 15.4 mmol) was dissolved in 500 mL of methanol, 50 mg of 10% palladium-carbon catalyst was added, and the atmosphere was replaced with hydrogen gas. After detecting the disappearance of fluorescence using a spot plate, the system was filtered by suction to remove the palladium-carbon. The resulting filtrate was spin-dried to obtain crude title compound 3G, which was directly used in the next step.

[0094] Step 5: Compound 3G was dissolved in 150 mL of tetrahydrofuran, and lithium aluminum hydride (1.8 g, 47.4 mmol) was added portionwise at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. 1.8 mL of water, 3.6 mL of 10% aqueous sodium hydroxide, and 5.4 mL of water were added, and the mixture was stirred for 1 hour. The solid was removed by suction filtration, and the resulting filtrate was spin-dried to obtain crude intermediate 3, which was used directly in the next step.

[0095] LC-MS (ESI): m / z=130.1[M+H] + . Intermediate 4: [ka]

[0096] Step 1: Compound 4A (10 g, 57.8 mmol) was dissolved in 200 mL of acetone, and metachloroperbenzoic acid (11 g, 63.6 mmol) dissolved in 200 mL of acetone was added at room temperature. The mixture was stirred for 5 min to produce a large amount of solid. The solid was collected by suction filtration, washed with acetone, and dried to give crude compound 4B (10.7 g, 98%).

[0097] LC-MS (ESI): m / z=189.0 and 191.0[M+H] + .

[0098] Step 2: 10.7 g of crude compound 4B was dissolved in 200 mL of trimethyl orthoformate, 1.25 mL of boron trifluoride diethyl etherate was added, the system was heated to 105°C, and the reaction was carried out overnight. The organic phase in the system was spin-dried and separated by column chromatography to obtain compound 4C (9.1 g, 69%).

[0099] LC-MS (ESI): m / z=231.0 and 233.0[M+H] + .

[0100] Step 3: 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 bis(pinacolato)diboron (6 g, 23.6 mmol) were added to a round-bottom flask and dissolved in 250 mL of ethanol. The mixture was purged with nitrogen gas, heated to 80 °C, and reacted overnight. The ethanol in the system was spin-dried, and the mixture was extracted with ethyl acetate to obtain the title compound intermediate 4 (4 g).

[0101] LC-MS (ESI): m / z=197.1[M+H] + . Intermediate 5: [ka]

[0102] Step 1: The starting material 5A (5.00 g, 24.51 mmol) was dissolved in 100 mL of dichloromethane and cooled to -20°C. DAST (6.5 mL, 49.02 mmol) was added, and the mixture was allowed to warm slowly to room temperature and react for 2 hours. After detecting the disappearance of the starting material using a spot plate, the reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was spin-dried and then passed through a silica gel column (petroleum ether: ethyl acetate = 20:1) to obtain intermediate 5 (5.00 g, 90.27%).

[0103] 1 H NMR (400MHz, CDCl3) δ 8.40 (dd, 1H), 8.15 (dt, 1H), 6.95 - 6.67 (m, 1H). 1.1 Preparation of Compound 1 [ka]

[0104] Step 1: 3D (8 g, 42 mmol) was dissolved in 500 mL of tetrahydrofuran, the system was cooled to 0 °C, lithium aluminum hydride (3.99 g, 105 mmol) was slowly added, and the mixture was then warmed to room temperature and reacted for 6 h. 4 mL of water, 8 M aqueous NaOH solution, and 12 mL of water were added sequentially, and the mixture was stirred for 1 h. The solid was removed by suction filtration, and the resulting filtrate was spin-dried to give crude target compound 1b (9 g), which was directly used for the next step without further purification.

[0105] LC-MS (ESI): m / z=130.2[M+H] + .

[0106] Step 2: Crude product 1b (2 g) was added to 27 mL of potassium tert-butoxide in tetrahydrofuran, and the mixture was stirred at room temperature for 5 min. Intermediate 1 (4 g, 18 mmol) was then added, and the mixture was purged with nitrogen gas. The mixture was then heated to 80°C and reacted overnight. The organic phase in the mixture was dried and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain target compound 1c (1.1 g, 35%).

[0107] LC-MS (ESI): m / z=335.1 and 337.1[M+H] + .

[0108] Step 3: 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, and the atmosphere was purged with nitrogen gas. The mixture was then heated to 80 °C and reacted for 5 h. After detecting the disappearance of the starting materials using a spot plate, the solids in the system were removed by suction filtration and washed with methanol. The filtrate was collected, spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title compound 1d (360 mg, 29%).

[0109] LC-MS (ESI): m / z=384.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.80 - 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).

[0110] Step 4: 1d (360 mg, 0.94 mmol) was dissolved in 20 mL of dichloromethane, cooled to -60 °C, ozone was added, and the disappearance of the raw material was detected using a spot plate. 1 g of triphenylphosphine was added, the mixture was warmed to room temperature, and stirred for 15 min. The organic phase was spin-dried and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the title compound 1e (300 mg, 83%).

[0111] LC-MS (ESI): m / z=386.2[M+H] + .

[0112] Step 5: 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 methyl magnesium bromide in THF (1 mL, 3 M) was added, and the mixture was slowly warmed to room temperature. After detecting the disappearance of the raw materials using a spot plate, the reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with dichloromethane, and the organic phase was spin-dried to obtain the title compound 1f (240 mg, 0.6 mmol), which was directly used in the next step.

[0113] LC-MS (ESI): m / z=402.2[M+H] + .

[0114] Step 6: Under a nitrogen gas 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 detecting the disappearance of the raw material using a spot plate, the reaction was quenched by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phase was spin-dried. The resulting product was separated by HPLC and freeze-dried to give the title compound 1 (110 mg, 42%).

[0115] LC-MS (ESI): m / z=404.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.82 - 8.76 (m,1H),8.42 - 8.36 (m,1H),8.32 (s,1H),8.23 - 8.18 (m,1H),7.81 - 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). 1.2 Preparation of Compounds 2 and 3 [ka]

[0116] 1d (80 mg) was subjected to chiral resolution to give compound 2 (33.7 mg) and compound 3 (25.3 mg).

[0117] Manufacturing method: 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: 1.5 mg / mL ethanol solution; Sample injection: 2 mL each time. After separation, the fractions were dried using a rotary evaporator at a bath temperature of 40°C to obtain P1 (retention time: 2.658 min, designated as compound 2) and P2 (retention time: 4.205 min, designated as compound 3). 1.3 Preparation of Compound 4 [ka]

[0118] Step 1: 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 mixture was purged with nitrogen gas. The mixture was heated to 80 °C and reacted for 3 h. The mixture was then mixed with silica gel and separated by column chromatography to give compound 4a (197 mg, 37%).

[0119] LC-MS (ESI): m / z=298.1[M+H] + .

[0120] Step 2: 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, and the mixture was purged with nitrogen gas. The system was then heated to 80 °C and reacted for 3 h. The reaction mixture was concentrated to dryness, separated, and purified to give the target compound 4 (30 mg, 11%).

[0121] LC-MS (ESI): m / z=407.1[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 10.23 (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). 1.4 Preparation of Compound 5 [ka]

[0122] Step 1: 5a (1.5 g, 7.89 mmol), intermediate 4 (2.3 g, 11.84 mmol), potassium phosphate (21.8 g, 102.57 mmol), Xphos PdG2 (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 purged with nitrogen gas. The mixture was then heated to 80 °C and reacted for 5 h. After detecting the disappearance of the starting materials using a spot plate, the solids in the system were removed by suction filtration and washed with methanol. The filtrate was collected, spin-dried, and passed through a silica gel column (dichloromethane:methanol = 10:1) to give the title compound 5b (1.4 g, 68%).

[0123] LC-MS (ESI): m / z=262.0[M+H] + .

[0124] Step 2: Intermediate 3 (495 mg, 3.83 mmol) was added to 15 mL of DMF solution, and NaH (275 mg, 11.49 mmol) was added in an ice bath. The mixture was stirred for 10 min, and then compound 5b (1 g, 3.83 mmol) was added. After purging with nitrogen gas, the mixture was reacted at 0 °C for 1 h. Water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was spin-dried and passed through a column (dichloromethane:methanol = 10:1) to give compound 5 (110 mg).

[0125] LC-MS (ESI): m / z=371.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 10.16 (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). 1.5 Preparation of Compound 6 [ka]

[0126] Step 1: 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, and the tube was purged with nitrogen gas. The mixture was then heated to 80°C and reacted for 3 h. The mixture was then cooled to room temperature, mixed with silica gel, and separated by column chromatography (petroleum ether:ethyl acetate=1:1, then ethyl acetate) to obtain the target compound 6a (500 mg, 21%).

[0127] LC-MS (ESI): m / z=355.1[M+H] + .

[0128] Step 2: 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), and potassium phosphate (4.5 g, 21.2 mmol) were added to a sealed tube, 20 mL of tetrahydrofuran was added, and the mixture was purged with nitrogen gas. The system was heated to 80 °C and reacted for 3 h. The mixture was then mixed with silica gel and separated by column chromatography (petroleum ether:ethyl acetate = 1:1 to ethyl acetate) to give compound 6b (350 mg, 61%).

[0129] LC-MS (ESI): m / z=384.2[M+H] + .

[0130] Step 3: Compound 6b (350 mg, 0.91 mmol) was dissolved in 20 mL of dichloromethane, the system was cooled to -78 °C, ozone was added, and the disappearance of the raw material was detected using a spot plate. After that, excess triphenylphosphine was added, the temperature was slowly raised to room temperature, the mixture was mixed with silica gel, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate = 1:1 to ethyl acetate) to obtain compound 6c (310 mg, 89%).

[0131] LC-MS (ESI): m / z=386.1[M+H] + .

[0132] Step 4: Compound 6c (160 mg, 0.42 mmol) was dissolved in 10 mL of tetrahydrofuran and purged with nitrogen gas. 1.4 mL of methylmagnesium chloride solution (3 M in THF) was added at 0°C, and the mixture was slowly warmed to room temperature. A saturated aqueous ammonium chloride solution was added to quench the reaction. The organic phase in the system was spin-dried, extracted with dichloromethane, spin-dried, separated, and freeze-dried to obtain compound 6 (30 mg, 18%). LC-MS (ESI): m / z=402.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.81 - 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). 1.6 Preparation of Compound 7 [ka]

[0133] Step 1: 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 mixture was purged with nitrogen gas. The mixture was heated to 80 °C and reacted for 3 h. The mixture was then mixed with silica gel and separated by column chromatography to give compound 7b (428 mg, 54%).

[0134] LC-MS (ESI): m / z=282.2[M+H] + .

[0135] Step 2: 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, and the mixture was purged with nitrogen gas. The mixture was then heated to 80 °C and reacted for 3 h. Compound 7 (89 mg, 32%) was obtained by fractionation, separation, and purification.

[0136] LC-MS (ESI): m / z=391.1[M+H] + . 1H NMR (400MHz,DMSO-d6) δ 10.54 (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). 1.7 Preparation of compound 8 [ka]

[0137] Step 1 Iron(III) nitrate nonahydrate (133 mg, 0.33 mmol) was dissolved in 3 mL of water, purged with nitrogen gas, and cooled to 0 °C. A selective fluorination 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 min, sodium borohydride (40 mg, 1.05 mmol) was added portionwise, and the mixture was maintained at 0 °C and reacted for 30 min. The reaction was quenched by adding 1 mL of aqueous ammonia. The mixture was extracted with a dichloromethane / methanol (10:1) mixed solvent, spin-dried, and then separated by HPLC to obtain compound 8 (10 mg, 28%).

[0138] LC-MS (ESI): m / z=411.3[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 10.55 (s,1H),8.69 (s,1H),8.43 - 8.35 (m,1H),8.18 - 8.10 (m,1H),7.78 - 7.73 (m,1H),7.72 - 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). 1.8 Preparation of Compound 9 [ka]

[0139] Step 1: Iron(III) nitrate nonahydrate (324 mg, 0.8 mmol) was dissolved in 7 mL of water, purged with nitrogen gas, and then cooled to 0 ° C. A selective fluorination reagent (284 mg, 0.8 mmol) and 7 mL of acetonitrile were added. Compound 4 (81 mg, 0.2 mmol) was dissolved in 7 mL of acetonitrile and added to the system. After stirring for 5 min, sodium borohydride (100 mg, 2.6 mmol) was added portionwise. The mixture was maintained at 0 ° C and reacted for 30 min. The reaction was quenched by adding 2.5 mL of aqueous ammonia. The mixture was extracted with a dichloromethane:methanol (10:1) mixed solvent, spin-dried, and then separated by HPLC to obtain compound 9 (9 mg, 11%).

[0140] LC-MS (ESI): m / z=427.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 10.25 (s,1H),8.49 (s,1H),8.38 - 8.33 (m,1H),8.19 - 8.13 (m,1H),7.78 - 7.72 (m,1H),7.68 - 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). 1.9 Preparation of Compound 10 [ka]

[0141] Iron(III) nitrate nonahydrate (88 mg, 0.22 mmol) was dissolved in water (2 mL), sonicated for 5 min, and cooled to 0 °C. 2 mL of a solution of a selective fluorination reagent (76 mg, 0.22 mmol) in acetonitrile was added, followed by 2 mL of a solution of compound 5 (20 mg, 0.05 mmol) in acetonitrile. Sodium borohydride (30 mg, 0.79 mmol) was then added portionwise and allowed to react for 1 h. LC-MS analysis showed the starting material had reacted completely. After dilution with water, the mixture was extracted with dichloromethane. The organic phases were combined, dried, and concentrated to give the crude product, which was separated, purified, and obtained compound 10 (10 mg, 47%).

[0142] LC-MS (ESI): m / z=391.3[M+H] + . 1 H NMR (400MHz,CD3OD) δ 8.42 (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).

[0143] Example 2: In vitro AAK1 enzyme activity detection experiment A 10 mM compound stock solution (dissolved in DMSO) was diluted to 0.2 mM with DMSO, followed by 5-fold dilutions with DMSO to obtain 10 compound concentrations. Each compound was then diluted 50-fold with 1x kinase reaction buffer (containing 40 mM Tris, 20 mM MgCl, 0.1% BSA, and 0.5 mM DTT). AAK1 (Signalchem, Cat# A01-11G-10) was diluted to twice the final concentration (30 nM and 28 nM, respectively) with 1x kinase reaction buffer. 2 μL of AAK1 was added to a 384-well white plate at 2 μL / well, followed by 1 μL of compound per well. The plate was sealed with sealing film, centrifuged at 1000 rpm for 30 seconds, and left at room temperature for 10 minutes. A mixture of 4x the final concentration of ATP (Promega, Cat# V914B) and the substrate Micro2 (GenScript, Cat# PE0890) was prepared (the final ATP concentrations corresponding to AAK1 were 15 μM and 5 μM, respectively, and the final Micro2 concentration was 0.1 mg / mL). 1 μL of the ATP and substrate mixture was added to the reaction plate at a rate of 1 μL / well. The plate was sealed with sealing film, centrifuged at 1000 rpm for 30 seconds, and reacted at room temperature for 60 minutes (AAK1). 4 μL / well of ADP-Glo ​​(Promega, Cat# V9102) was transferred to a 384-well plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 40 minutes. 8 μL / well of Detection Solution was transferred to a 384-well plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 40 minutes. RLU (Relative luminescence unit) signal values ​​were read using a Biotek multifunctional microplate reader and calculated using the following formula: [1-(LUM 化合物 -LUM 陽性対照 ) / (LUM 陰性対照 -LUM 陽性対照 Percent inhibition was calculated using the IC ) × 100. A four-parameter nonlinear fitting equation was used in Graphpad 7.0 software. 50 The values ​​were calculated, and the specific results are shown in Table 1.

[0144] [Table 1]

[0145] Conclusion: The compounds of the present invention exhibited high inhibitory activity against the AAK1 receptor.

[0146] Example 3: Pharmacokinetic study in dogs Test animals: male beagle dogs, approximately 8-11 kg, 6 dogs / compound, purchased from Beijing Masu Biotechnology Co., Ltd.

[0147] Test method: On the day of the test, 12 beagle dogs were randomly divided into groups based on weight. One day before administration, they were fasted for 12-14 hours without water prohibition, and fed 4 hours after administration. The doses were administered according to Table 2.

[0148] [Table 2] Note: Vehicle for intravenous administration: 5% DMA + 5% Solutol + 90% Saline. Vehicle for oral gavage administration: 0.5% MC. (DMA: dimethylacetamide, Solutol: polyethylene glycol-15-hydroxystearate, Saline: physiological saline, MC: methylcellulose)

[0149] Before and after administration, 1 ml of blood was collected from the jugular or limb vein and placed in an EDTAK2 centrifuge tube. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 minutes. Blood was collected at 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, and 24 h for both the LX9211 intravenous and gavage groups. Blood was collected at 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, and 48 h for both the Compound 9 intravenous and gavage groups. All samples were stored at -80°C before analysis and quantitative analysis was performed on the samples using LC-MS / MS. The test results are shown in Table 3.

[0150] [Table 3] -: Not applicable.

[0151] Note: LX-9211 structure is [ka] is.

[0152] Conclusion: The compounds of the present invention have good pharmacokinetic properties.

[0153] Example 4: hERG potassium ion channel activity test Experimental platform: electrophysiological manual patch clamp system Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium ion channel Experimental Method: hERG potassium channel currents were recorded at room temperature using the whole-cell patch clamp technique in CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel. Glass microelectrodes were fabricated by pulling glass electrode blanks with a BF150-86-10 Sutter puller. After filling the electrode with internal solution, the tip resistance was approximately 2-5 MΩ. The glass microelectrode was then inserted into the amplifier probe for connection to the patch clamp amplifier. Voltage clamping and data recording were computer-controlled using pClamp 10 software. The sampling frequency was 10 kHz and the filtering frequency was 2 kHz. After whole-cell recording, the cells were clamped to -80 mV, and a step voltage was applied to elicit the hERG potassium current (I hERG) by depolarizing from -80 mV for 2 s to +20 mV, repolarizing to -50 mV for 1 s, and then returning to -80 mV. The stimulation was repeated every 10 s, and the hERG potassium current was allowed to stabilize (for at least 1 min) before the administration process began. Compounds were administered for at least 1 min per test concentration, and at least two cells were tested for each concentration (n ≥ 2).

[0154] Data processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The inhibition of hERG potassium current (peak hERG tail current evoked at -50 mV) by different compound concentrations was calculated using the following formula:

[0155] Inhibition%=[1‐(I / Io)]×100% Here, Inhibition% represents the percentage of inhibition of the hERG potassium current by the compound, and I and Io represent the amplitude of the hERG potassium current after administration and before administration, respectively.

[0156] Compound IC50 was calculated by fitting the following equation using GraphPad Prism 5 software:

[0157] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)×HillSlope)) where X is the Log value of the sample detection concentration, Y is the percentage inhibition at the corresponding concentration, and Bottom and Top are the minimum and maximum percentage inhibition, respectively.

[0158] Experimental results: The IC50 values ​​of the test compounds for the inhibitory effect on the hERG potassium channel are shown in Table 4.

[0159] [Table 4]

[0160] Example 5: Spinal nerve ligation (SNL)-induced neuralgia model in mice Male C57BL / 6J mice (8 weeks old) purchased from Jinan Pengyue Experimental Animal Breeding Co., Ltd. were acclimatized and raised for one week before being used to create the model. The specific preparation method is as follows: 1) Disinfect surgical instruments and ligatures, 2) Anesthetize the mouse with isoflurane and place it in the prone position on the operating table. 3) Cut the mouse's hair near the hipbone, disinfect the skin, and make an incision approximately 2 cm long along the spine. 4) Separate the fascia along the spine and bluntly separate the muscles to expose the L5 transverse process. 5) Using forceps, carefully bite off the L5 transverse process to expose the L5 spinal nerve. 6) Carefully separate the L5 nerve using a glass separation needle and ligate the L5 nerve with a 5-0 ligature. 7) The muscles and skin are sutured and disinfected with iodophor. The day after model creation, mice that were not successfully created were removed (signs of successful model creation: the mouse's hind legs were curled). After model creation, mice were stroked for 3-5 minutes every day to allow the animals to become accustomed to the experimenter, and then placed on a metal pain measurement frame for 40-60 minutes of adaptation. After environmental adaptation was completed on the third day, Von Frey filaments (Aesthesio) were used. (R) The animals were tested for baseline values ​​(Ascending test) using 0.16, 0.4, 0.6, 1.0, 1.4, and 2.0 grams (0.16, 0.4, 0.6, 1.0, 1.4, and 2.0 grams). Each animal was measured twice, with at least 5 minutes between measurements, and the average was calculated. The animals were grouped according to their 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 by gavage, and the mechanical pain threshold (MPT) of the mice was tested 1, 3, and 6 hours after administration. Time-MPT curves were plotted and statistical analysis was performed using GraphPad 8.3.0.

[0161] Results and Conclusions: The results are shown in Figure 1. At 1, 3, and 6 hours after a single administration, both 10 mg / kg LX-9211 and Compound 2 effectively increased the pain threshold of SNL model mice. The analgesic effect of 10 mg / kg LX-9211 peaked at 1 hour after administration and gradually decreased thereafter. However, the analgesic effect of 10 mg / kg Compound 2 peaked at 3 hours after administration and remained stable from 1 to 6 hours, demonstrating superior efficacy at 3 and 6 hours after administration. These data suggest that the analgesic activity of Compound 2 is superior to that of LX-9211.

[0162] Example 6: Mouse brain / blood ratio test 6.1 Test animals: male ICR mice, 20-25g, 9 mice / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0163] 6.2 Experimental Design: On the day of the experiment, 18 ICR mice were randomly divided into groups according to their weight. One day before the experiment, they were fasted for 12-14 hours without water restriction, and fed 4 hours after the experiment.

[0164] [Table 5] NOTE: Vehicle for oral gavage: 40% PEG-400 + 10% Ethanol + 15% Tween 80 + 35% Saline; (Saline: physiological saline, Ethanol: ethanol, Tween 80: Tween 80)

[0165] After oral gavage, whole blood and brain tissue were collected at 0.5, 4, and 24 h. The whole blood was centrifuged to separate the plasma. The brain tissue was washed with cold saline to remove any remaining blood, then suction-dried and homogenized. All samples were stored at -80°C before analytical detection. Quantitative analysis of the samples was performed using LC-MS / MS.

[0166] The test results are shown in Table 6.

[0167] [Table 6] -: Not applicable.

[0168] Conclusion: The compounds of the present invention, especially compound 2, have high brain permeability.

[0169] Example 7: Composition of Compound 3 7.1 Prescriptions 1-6

[0170] [Table 7]

[0171] Tablets of the composition containing Compound 3 were prepared according to the formula in the table. First, Compound 3 was mixed with a wetting agent for a total of 15 minutes by grinding, then a diluent and a disintegrant were added and mixed in a mixer for 15 minutes, and finally a lubricant was added and mixed for 3 minutes to obtain a composition containing Compound 3. The composition was then compressed into tablets using a tablet press.

[0172] The present inventors have observed whether the above formulation causes the composition to aggregate or stick to equipment due to the softening or melting of Compound 3 during the process, and have also investigated the content uniformity of the finished product.

[0173] [Table 8]

[0174] As can be seen from the results, whether or not a wetting agent was added to the formulation, Compound 3 did not soften or melt, causing it to clump or stick to equipment. 7.2 Prescriptions 7-12

[0175] [Table 9]

[0176] Tablets of the composition containing Compound 3 were prepared according to the formula in the table. First, Compound 3 was mixed with a wetting agent by sieving five times, then mixed in a mixer for 15 minutes, then a diluent and a disintegrant were added and mixed for 15 minutes, and finally a lubricant was added and mixed for another 3 minutes to obtain a composition containing Compound 3. The composition was then compressed into tablets using a tablet press.

[0177] The present inventors have observed whether the above formulation causes the composition to aggregate or stick to equipment due to the softening or melting of Compound 3 during the process, and have also investigated the content uniformity of the finished product.

[0178] [Table 10]

[0179] Conclusion: Adding a certain amount of wetting agent in the formulation significantly improved the softening / melting phenomenon that occurred during the preparation of compound 3, and the content uniformity of the tablets was good. 7.3 Prescriptions 13-18

[0180] [Table 11]

[0181] Preparation method: Compound 3 and a wetting agent were mixed in a mixer for 15 minutes, then a diluent and a disintegrant were added and mixed for 15 minutes, and finally magnesium stearate was added and mixed for 3 minutes to obtain a composition containing Compound 3. The composition containing Compound 3 was filled into capsules using a capsule filling machine.

[0182] The present inventors have observed whether the above formulation causes the composition to aggregate or stick to equipment due to the softening or melting of Compound 3 during the process, and have also investigated the content uniformity of the finished product.

[0183] [Table 12]

[0184] Conclusion: The addition of wetting agent could significantly inhibit the softening / melting phenomenon of compound 3 during the preparation process. 7.4 Prescriptions 19-24

[0185] [Table 13]

[0186] Tablets containing Compound 3 were prepared according to the formula in the table. First, Compound 3 was mixed with a wetting agent by sieving five times, then mixed in a mixer for 15 minutes, and then a diluent and a disintegrant were added and mixed for 15 minutes. The premix was then placed in a roller compactor and compressed at 0.6 kN / cm. The resulting ribbons were passed through a 0.8 mm vibration grinder. Then, abrasive particles and a lubricant were mixed for 3 minutes, and finally, tablets were compressed using a tablet press.

[0187] The inventors investigated the dissolution behavior of tablets manufactured using the above formulation and process in a medium of pH 1.0 and the changes in related substances when left at 40°C ± 2°C and 75% RH ± 5% RH for 6 months. The results are shown in Table 14.

[0188] As can be seen from Figure 2, for formulations 19-21, as the ratio of compound 3 increased, the dissolution rate further decreased due to the aggregation of AAK1 caused by its softening / melting. For formulations 22-24, after a wetting agent was added to the formulation, the aggregation caused by the softening / melting of compound 3 could be avoided, and their dissolution behavior was further improved.

[0189] [Table 14]

[0190] As can be seen from the table, all compositions have good stability, whether or not they contain a wetting agent. 7.5 Prescription 25-28

[0191] [Table 15]

[0192] Preparation method: Compound 3 was mixed with lactose, microcrystalline cellulose, and sodium cross-carboxymethylcellulose in a mixer for 15 minutes, then magnesium stearate was added and mixed for 3 minutes, and then tableted using a tablet press to control the tablet hardness to 50-100N.

[0193] [Table 16]

[0194] Preparation method: Compound 3 was mixed with mannitol, microcrystalline cellulose, and low-substituted sodium carboxymethylcellulose in a premixer for 15 minutes, and then the premix was placed in a roller compactor and compressed at 0.6 kN / cm. The resulting ribbon-like material was passed through a 0.8 mm vibration grinder. Then, abrasive particles and talc were mixed for 3 minutes, and finally, tablets were compressed using a tablet press, and the tablet hardness was controlled to 50-100 N.

[0195] [Table 17]

[0196] Preparation method: Compound 3 was mixed with pregelatinized starch, sodium carboxymethyl starch, and dextrin in a mixer for 15 minutes, then magnesium stearate was added and mixed for 3 minutes, and then tableted using a tablet press, and the tablet hardness was controlled to 50-100N.

[0197] [Table 18]

[0198] Manufacturing method: Compound 3 was mixed with calcium phosphate, sucrose, crospovidone, and talc in a mixer for 15 minutes, and then filled into capsules using a capsule filling machine.

[0199] According to the second method (slurry method) of the Chinese Pharmacopoeia 2015 edition 0931 Dissolution and Release Determination Method, the dissolution curves of tablets manufactured by formulation 25 were investigated in water, pH 1.0, pH 4.5, and pH 6.8. The rotation speed was set at 50 rpm, and sampling time points were 5, 10, 15, 20, 30, 45, and 60 minutes.

[0200] As can be seen from the results in Figure 3, at pH = 1.0, the tablets prepared with formulation 25 had a dissolution rate of 90% in 5 minutes, demonstrating rapid dissolution. At 20 minutes, the dissolution rates of the tablets prepared with formulation 25 in water, pH 1.0, pH 4.5, and pH 6.8 all reached 85%.

[0201] 7.6 Formulation Stability Study Methods and Results The preparations manufactured using formulations 25, 26, 27, and 28 were packaged in aluminum blister packs and then left at 40°C ± 2°C and 75% RH ± 5% RH to examine changes in related substances.

[0202] [Table 19]

[0203] As can be seen from the results in Table 19, all of the preparations produced using formulations 25 to 28 were stable, and the stability was almost the same.

[0204] The pharmaceutical compositions of Compound 2 produced according to formulations 1-6, 10-13, 16-28 and processes of the pharmaceutical compositions of Compound 3 were all free from aggregation and adhesion to equipment, had content uniformity (A+2.2S) of 3-5.5, and were all stable.

Claims

1. 1. A pharmaceutical composition comprising: An active ingredient selected from the compounds of formula (I) or their stereoisomers or pharmaceutically acceptable salts, 【Chemistry 1】 During the ceremony, Z is selected from NH or O; R １ , R ２ are each independently H, deuterium, halogen, amino group, —COOH, cyano group, sulfonyl group, aminoacyl group, C １－６ Alkyl group, halo C １－６ Alkyl groups, deuterated C １－６ alkyl groups, wherein the alkyl groups are optionally selected from 1 to 3 R Ａ further substituted with a substituent, R ４１ , R ４２ are each independently H, deuterium, an amino group, or C １－６ Alkyl group, halogen, cyano group, hydroxy group, halo C １－６ Alkyl groups, deuterated C １－６ alkyl groups, R ５１ , R ５２ are each independently selected from H, deuterium, an amino group, and a halogen; R ６１ , R ６２ , R ６３ are each independently H, deuterium, halogen, amino group, cyano group, hydroxy group, C １－６ Alkyl group, halo C １－６ Alkyl groups, deuterated C １－６ alkyl groups, Or, R ５１ and R ６１ , or R ６１ and R ６２ form a double bond with the carbon atom to which they are attached, R Ａ Deuterium, halogen, amino group, cyano group, hydroxy group, C １－６ Alkyl group, halo C １－６ Alkyl groups, deuterated C １－６ Alkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, deuterated C １－６ Alkoxy group or hydroxy C １－６ alkyl groups, The proviso is that when Z is selected from O, 【Chemistry 2】 but, 【Transformation 3】 An active ingredient that does not form a structure b) an inactive ingredient, and an inactive ingredient, wherein 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. Z is O, R1 and R2 are selected from haloC1-2 alkyl groups; R51 and R52 are each independently selected from H and deuterium; R41 and R42 are each independently selected from an amino group and a C1-2 alkyl group; 2. The pharmaceutical composition of claim 1, wherein R61, R62, and R63 are each independently selected from H, deuterium, and a C1-2 alkyl group.

3. The compound of formula (I) 【Chemistry 4】 2. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of:

4. 10. The pharmaceutical composition of claim 1, wherein the inactive ingredient is selected from a diluent.

5. 5. The pharmaceutical composition of 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, sugar alcohols, preferably one or more of pregelatinized starch, dextrin, lactose, sucrose, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate dihydrate, anhydrous calcium hydrogen phosphate, calcium phosphate, calcium carbonate, calcium stearate, magnesium oxide, aluminum hydroxide, mannitol, xylitol, sorbitol, more preferably one or more of pregelatinized starch, lactose, sucrose, microcrystalline cellulose, calcium hydrogen phosphate dihydrate, anhydrous calcium hydrogen phosphate, calcium phosphate, mannitol, dextrin.

6. 5. 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 inactive ingredients further comprise one or more of a wetting agent, a disintegrant, a lubricant; the wetting agent is selected from one or more of silicates, preferably one or more of silica, magnesium silicate, magnesium trisilicate, magnesium aluminium silicate and talc, more preferably one or more of fumed silica, precipitated silica, sol-gel silica, magnesium silicate, magnesium trisilicate, magnesium aluminium silicate and talc; The disintegrant is selected from one or more of crosscarboxymethylcellulose sodium, crospovidone, starch and its derivatives, low-substituted hydroxypropylcellulose, low-substituted hydroxymethylcellulose sodium, surfactants, alginic acid and sodium alginate, and clays, preferably one or more of crosscarboxymethylcellulose sodium, low-substituted hydroxypropylcellulose, low-substituted hydroxymethylcellulose sodium, crospovidone, starch, carboxymethylstarch sodium, hydroxypropyl starch, polysorbate 80, sodium dodecyl sulfate, bentonite, and colloidal magnesium aluminum silicate, more preferably one or more of crosscarboxymethylcellulose sodium, low-substituted hydroxypropylcellulose, low-substituted hydroxymethylcellulose sodium, carboxymethylstarch sodium, and crospovidone; 5. The pharmaceutical composition of claim 4, wherein the lubricant is selected from one or more of talc, stearic acid, metallic stearates, stearates, glyceryl behenate, sodium lauryl sulfate or colloidal silica, preferably one or more of talc, calcium stearate, magnesium stearate and zinc stearate, polyoxyethylene stearate, glyceryl monostearate, glyceryl palmitate stearate, more preferably one or more of talc, calcium stearate, magnesium stearate, glyceryl monostearate.

8. The weight ratio of the active ingredient to the wetting agent is 1:0.05 to 1:5; Preferably, it is 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 pharmaceutical composition according to claim 7, wherein 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 formulation comprising the pharmaceutical composition of 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 dosage form 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.

11. The pharmaceutical preparation according to claim 9, wherein the pharmaceutical preparation is in the form of a tablet, a granule, a capsule, or a soft capsule.

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 manufacture of a medicament for treating a disease associated with the inhibition or degradation of AAK1.

13. 13. The application of claim 12, wherein the disease is selected from pain, including inflammatory pain, post-operative pain, trigeminal neuralgia, acute post-herpetic neuralgia and post-herpetic neuralgia, diabetic peripheral neuralgia, causalgia, occipital neuralgia, fibromyalgia, phantom limb pain, burn pain and other forms of neuralgia, neuropathic and spontaneous pain syndromes.

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