Pyridine amide compound-containing composition and pharmaceutical composition, preparation method therefor and use thereof

Abstract

A pyridine amide compound-containing composition and a pharmaceutical composition, a preparation method therefor and a use thereof. The composition comprises an active ingredient and at least one matrix material, wherein the active ingredient is a compound represented by formula I or a pharmaceutically acceptable salt, a stereoisomer, a solvate, an isotopically labeled compound, a polymorph, a metabolite or a prodrug thereof. The composition has a high drug loading capacity, improves drug solubility, and has good stability. The in vivo bioavailability of the composition can reach the same level of bioavailability as that of a clear drug solution.

Description

Compositions and pharmaceutical compositions containing pyridine amide compounds, their preparation methods and uses

[0001] Citation of relevant applications

[0002] This disclosure claims priority to Chinese Patent Application No. 202411479977.6, filed on October 22, 2024, entitled "Solid Dispersions and Pharmaceutical Compositions Containing Pyridine Amide Compounds and Preparation Methods and Uses Thereof", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure pertains to the field of pharmaceutical formulations and relates to a composition containing a pyridine amide compound, a pharmaceutical composition thereof, a method for its preparation, and its use. Background Technology

[0004] Pain is an unpleasant sensory and emotional experience, or a similar experience, associated with actual or potential tissue damage. Modern medicine classifies it as the fifth vital sign after respiration, pulse, blood pressure, and body temperature.

[0005] Middle-aged and elderly people are a high-risk group for various pain-related diseases. In today's aging society, the demand for pain treatment in my country is increasing year by year. Currently, the global incidence of pain is approximately 35% to 45%. According to the "China Pain Medicine Development Report (2020)," there are more than 300 million chronic pain patients in my country, and this number is increasing by 10-20 million per year.

[0006] Pain has a range of effects on a patient's physical and mental well-being. It can adversely affect the central nervous, circulatory, respiratory, endocrine, digestive, and autonomic nervous systems, leading to shallow and rapid breathing, increased heart rate, elevated blood pressure, promoting thrombosis, reducing gastrointestinal function, and causing restlessness, among other things. Untimely or inadequate treatment of acute pain is a risk factor for its transformation into chronic pain, delaying patient recovery. Chronic pain is often accompanied by anxiety, depression, and other mental and psychological problems, and is a significant cause of disability and death. The "China Pain Medicine Development Report (2020)" indicates that over 300 million people in my country are suffering from chronic pain, and this number is increasing by 10-20 million annually. Pain has now become the third leading health problem after cardiovascular and cerebrovascular diseases and tumors, seriously impacting people's health and quality of life.

[0007] The pathogenesis of pain is relatively complex, leading to unsatisfactory treatment effects from many approaches. Existing pain medications often suffer from low tolerability, poor long-term safety, and potential for abuse. Furthermore, moderate to severe pain can lead to opioid dependence. Commonly used analgesics are mainly nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. NSAIDs have weak analgesic effects and exhibit a ceiling effect. The core mechanism of action of opioids is to bind to opioid receptors, reducing the transmission and perception of pain signals, thus relieving pain in the central and peripheral nervous systems. However, opioid receptors also exist in the central nervous system in addition to pain transmission pathways. Therefore, the use of opioids can simultaneously stimulate opioid receptors in other parts of the body, resulting in various side effects and addiction, leading to tolerance problems. Consequently, opioid analgesics are generally addictive and suffer from serious abuse. In 2016, the U.S. Food and Drug Administration (FDA) issued a warning restricting the use of opioid analgesics.

[0008] Electrical signals are the foundation for controlling a series of physiological processes, including pain signal transmission, and sodium ion channels are the main factor in initiating these signals. Voltage-gated sodium channels are multi-subunit transmembrane glycoproteins expressed on the cell membrane, composed of α and β subunits. The α subunit is a functional unit, consisting of four homologous transmembrane domains, each containing six transmembrane hydrophobic α helices (S1-S6). S1-S4 constitute a voltage receptor, which can regulate the hydrophilicity of the sodium ion channel between S5 and S6, causing cell depolarization or hyperpolarization, thus completing the transmembrane signal transmission. In humans, there are nine different subtypes of the α subunit, named NaV1.1-1.9. Their abnormal inactivation or activation is associated with various neurological, cardiovascular, and muscular diseases, among which the subtypes mainly associated with pain are NaV1.3, NaV1.7, NaV1.8, and NaV1.9. NaV1.8 is a tetrodotoxin-insensitive sodium channel primarily expressed on nociceptive neurons. It plays a crucial role in pain signal transduction in the peripheral nervous system and is a major selective target for pain management. Because NaV1.8 is mainly distributed in pain-sensing neurons, the use of selective NaV1.8 inhibitors does not cause the adverse reactions commonly associated with non-selective NaV inhibitors. More importantly, NaV1.8 does not participate in central nervous system-related activities, so NaV1.8 inhibitors do not pose the addiction problems associated with opioids and do not affect motor function.

[0009] When drugs face low solubility, some formulation methods that can be tried include reducing particle size (micronization, nano-grinding, nanoforming), adjusting pH using surfactants, acidifiers, or alkalizers, complexing / inclusion complexes, preparing amorphous drugs, and preparing solid dispersions. However, it must be noted that because different drugs have different physicochemical properties and physiological characteristics, these solubilization methods are not universally applicable, and many methods are often unsuitable or fail to achieve the desired effect. Therefore, formulation method and composition have a significant impact on drug bioavailability. Summary of the Invention

[0010] The first aspect of this application provides a composition comprising an active ingredient and at least one matrix material, wherein the active ingredient is a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, polymorph, metabolite, or prodrug thereof.

[0011] in:

[0012] R a Selected from

[0013] Y 1 Y 2 Y 3 Y 4 Each is independently selected from O, S, N, NR. a1 and CR a2 ;

[0014] R a1 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -S(O)2R 1 ;

[0015] R a2 Each is independently selected from H, halogen, hydroxyl, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-6 cycloalkyl, -NR 2 R 3 -NHC(O)R 4 -C(O)OR 5 -C(O)NR 6 R 7 SR 8 -S(O)R 9 -S(O)2R 10 -S(O)2NR11 R 12 -S(O)(NR) 13 )R 14 -P(O)R 15 R 16 and The C mentioned 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally surrounded by one or more groups selected from hydroxyl and -NR. 19 R 20 The substituents are replaced;

[0016] Or adjacent R a1 and R a2 Or two Rs a2 The atoms bonded to it form 5-6 membered heteroaromatic rings;

[0017] R 1 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 19 R 20 Each is independently selected from H and C. 1-6 alkyl;

[0018] R 2 R 3 Each is independently selected from H and C. 1-6 C-substituted with alkyl and carbonyl groups 1-6 alkyl;

[0019] R 4 Each is independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 2-6 alkenyl;

[0020] R 17 R 18 Each is independently selected from H and C. 1-6 Alkyl, or R 17 R 18 Together with the linked boron and oxygen atoms, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally surrounded by one or more atoms selected from H, halogens, and C. 1-6 Substituents of alkyl groups;

[0021] Z 1 Z 2 Z 3 Z 4 Z 5 Each is independently selected from N, N + -O - and CR a3 ;

[0022] R a3 Each is independently selected from H, halogen, hydroxyl, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-6 cycloalkyl, -NR 21 R 22 -NHC(O)R 23 -C(O)OR 24 -C(O)NR 25 R 26 -SR 27 -S(O)R 28 -S(O)2R 29 -S(O)2NR 30 R 31 -S(O)(NR) 32 )R 33 -P(O)R 34 R 35 and The C mentioned 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally surrounded by one or more groups selected from hydroxyl and -NR. 38 R 39 The substituents are replaced;

[0023] Or two adjacent R a3 The carbon atom attached thereto forms a 5-6 membered heterocyclic group or a 5-6 membered heteroaromatic ring, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaromatic ring is optionally surrounded by one or more atoms selected from OH and C. 1-6 Substituents of alkyl groups;

[0024] R 24 R 25 R 26 R 27 R 28 R 29 R 30 R31 R 32 R 33 R 34 R 35 R 38 R 39 Each is independently selected from H and C. 1-6 alkyl;

[0025] R 21 R 22 Each is independently selected from H and C. 1-6 alkyl and carbonyl substituted C 1-6 Alkyl groups and -C(O)OC 1-6 alkyl;

[0026] R 23 Each is independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 2-6 alkenyl;

[0027] R 36 R 37 Each is independently selected from H and C. 1-6 Alkyl, or R 36 R 37 Together with the linked boron and oxygen atoms, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally surrounded by one or more atoms selected from H, halogens, and C. 1-6 Substituents of alkyl groups;

[0028] V is selected from N, N + -O - and CR a4 ;

[0029] R a4 Selected from H and C 1-6 alkyl;

[0030] R a5 Selected from H and C 1-6 alkyl;

[0031] R a6 Selected from H and C 1-6 alkyl;

[0032] R b1 and R b2 Each is independently selected from H and deuterium;

[0033] R b3 and R b4 Each is independently selected from H, deuterium, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl;

[0034] R b5 and R b6 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl, or R b5 R b6 Together with the bonded carbon atoms, they form C 3-5 Cycloalkyl or 4-6 membered heterocyclic groups;

[0035] R c Selected from H, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl and -OC 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 The cycloalkyl group is optionally surrounded by one or more groups selected from hydroxyl, carboxyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, -NR 40 R 41 C 3-6 The substituents are cycloalkyl, 3-6-membered heterocyclic, and 5-6-membered heteroaryl groups, wherein the 3-6-membered heterocyclic or 5-6-membered heteroaryl group is optionally replaced by one or more substituents selected from halogens and C. 1-6 Substituents of alkyl groups;

[0036] R 40 R 41 Each is independently selected from H and C. 1-6 alkyl;

[0037] X 1 X 2 X 3 X 4 Each is independently selected from N and CR c1 ;

[0038] R c1 Each is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups;

[0039] A second aspect of this application provides a method for preparing a composition, wherein the preparation method is a hot melt extrusion method or a solvent drying method.

[0040] A third aspect of this application is to provide a pharmaceutical composition comprising the composition described in the first aspect and at least one pharmaceutically acceptable carrier.

[0041] The fourth aspect of this application is to provide a method for preparing a pharmaceutical composition, the method comprising the steps of: mixing the composition of the first aspect of this disclosure with at least one pharmaceutically acceptable carrier, sieving, and tableting.

[0042] The fifth aspect of this application provides the use of the composition of the first aspect of this application or the pharmaceutical composition of the third aspect of this application in the preparation of a medicament for the prevention and / or treatment of NaV1.8-related diseases, preferably, said NaV1.8-related diseases being pain.

[0043] The sixth aspect of this application provides a composition of the first aspect of this application or a pharmaceutical composition of the third aspect of this application for the prevention and / or treatment of NaV1.8-related diseases, preferably, said NaV1.8-related diseases being pain.

[0044] The seventh aspect of this application provides a method for preventing and / or treating NaV1.8-related diseases, comprising administering to an individual a preventive and / or therapeutically effective amount of a composition of the first aspect of this application or a pharmaceutical composition of the third aspect of this application, preferably, the NaV1.8-related disease being pain.

[0045] Definitions and Explanations

[0046] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better interpret this disclosure.

[0047] As used herein, the terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0048] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this disclosure, chemical elements are defined according to the periodic table of elements, CAS edition, and the Handbook of Chemical Reagents, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0049] As used herein, the term "alkyl" refers to a 1-20 carbon atom saturated straight-chain or branched aliphatic hydrocarbon group, wherein the alkyl group may be independently and optionally substituted by one or more substituents described herein. As used herein, the term "C" refers to... 1-6 "Alkyl" refers to a straight-chain or branched group having 1 to 6 carbon atoms. The term "C"... 1-4"Alkyl" refers to a straight-chain or branched group having 1 to 4 carbon atoms, optionally substituted with one or more (such as 1 to 4) suitable substituents such as halogens. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (-Bu, -CH2CH2CH2CH3), 2-methylpropyl or isobutyl (i-Bu, -CH2CH(CH3)) 2), 1-Methylpropyl or sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH 2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2 -pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc. The term "alkyl" and its prefix "alkane" are used here, both encompassing straight-chain and branched saturated carbon chains.

[0050] The term "carbonyl-substituted C" 1-6 "alkyl" refers to C 1-6 In alkyl groups, hydrogen atoms are replaced by oxo groups (=O), the term "C" is used. 1-6 The definition of "alkyl" is as described above; it refers to "carbonyl-substituted C". 1-6 Examples of "alkyl" include, but are not limited to, those of the following: wait.

[0051] In this document, the term "alkoxy" refers to an alkyl group that is attached to the main carbon chain via an oxygen atom. The term "alkyl" is as defined above. For example, the term "C"...1-12 "Alkoxy" refers to "C 1-12 "alkyl-O-", the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms. In another embodiment, the alkoxy group contains 1-4 carbon atoms. In yet another embodiment, the alkoxy group contains 1-3 carbon atoms. Such embodiments include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, or n-hexoxy. In one embodiment, "C" 1-6 Alkyl groups are selected from one or more hydroxyl groups and C. 2-6 The case of "substituents of the alkenyl group" refers to the C... 1-6 In an alkoxy group, the hydrogen atom in the alkyl moiety is replaced by one or more substituents selected from hydroxyl and methylene (=CH2), the term "C" is used. 1-6 The definition of "alkoxy group" is as described above, "C 1-6 Alkyl groups are selected from one or more hydroxyl groups and C. 2-6 Examples of "substituents of alkenyl groups" include, but are not limited to, those of "substituents of alkenyl groups". And so on, and so on, without going into further detail.

[0052] In this document, the term "cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems, such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.), optionally substituted by one or more (such as 1 to 3) suitable substituents. For example, the term "C 3-10 "Cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (including fused, bridged, or spirocyclic structures) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) having 3 to 10 cyclic carbon atoms, optionally substituted with one or more (such as 1 to 3) suitable substituents, wherein the substituents may be, but are not limited to, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, -C (=O)-NH2, carboxyl, -S (=O). t OH, -OS (=O) t -H, -S (=O) t NH2, triazolyl, tetrazolyl, -(CR 3b R 3c ) n -NH2, alkyl, alkyl-S (=O) t-, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkoxythio, haloalkoxy, amino, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic, thiol, nitro, aryloxy, hydroxyalkoxy, alkanoyl, benzyl, cyclopropyl, phenyl, alkyl-C(=O)-, alkyl-C(=O)-NH-, formamido or alkoxyalkyl, etc., t is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. For example, C 3-8 cycloalkyl, C 3-6 Cycloalkyl.

[0053] Examples of cycloalkyl groups further include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl, etc.

[0054] As used herein, the term "halogen" group is defined as including fluorine, chlorine, bromine, or iodine.

[0055] As used in this article, the term "halogenation" refers to the substitution of one or more (such as 1 to 3) identical or different halogen atoms.

[0056] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms. For example, the term "C" 1-6 "Halogenated alkyl" refers to alkyl haloatoms having 1 to 6 carbon atoms, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0057] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more (such as 1 to 3) identical or different halogen atoms. For example, the term "C" 1-6 "Haloalkoxy" refers to haloalkoxy groups having 1 to 6 carbon atoms, such as -O-CF3, -O-C2F5, -O-CHF2, -O-CH2F, -O-CH2CF3, -O-CH2Cl, or -O-CH2CH2CF3, etc.

[0058] As used herein, the term "alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and in which one hydrogen atom is replaced by a bond. The alkenyl group can be straight-chain or branched and contains from about 2 to about 15 carbon atoms. In one embodiment, the alkenyl group contains from about 2 to about 12 carbon atoms. In another embodiment, the alkenyl group contains from about 2 to about 6 carbon atoms. Non-limiting examples of alkenyl groups include vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl, and decenyl. The alkenyl group can be unsubstituted or substituted with one or more identical or different substituents, each substituent being independently selected from halogens, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxyl, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH2, -NH(alkyl), -N(alkyl)2, -NH(cycloalkyl), -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-cycloalkyl, -C(O)OH, and -C(O)O-alkyl. The term "C..." 2-6 "Alkenyl" refers to an alkenyl group with 2 to 6 carbon atoms.

[0059] As used herein, the term "heterocyclic" or "heterocyclic group" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic group, for example, having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring and one or more (e.g., 1, 2, 3, or 4) independently selected from N, O, or S(O). t Heteroatoms (where t is 0, 1, or 2), such as 3-12 membered heterocyclic groups, 3-10 membered heterocyclic groups, 3-9 membered heterocyclic groups, 3-8 membered heterocyclic groups, 3-7 membered heterocyclic groups, 3-6 membered heterocyclic groups, 5-6 membered heterocyclic groups, etc. Representative examples of heterocyclic groups include, but are not limited to, ethylene oxide, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, hexahydro-1H-pyrrolline, pyrrolidone, imidazoalkyl, pyrazolyl, tetrahydropyranyl, tetrahydropyridinyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazine, etc.

[0060] As used herein, the term "aryl" or "aromatic ring" refers to a fully carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. For example, the term "C 6-10 "Aryl" or "C" 6-10 "Aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl (ring) or naphthyl (ring). The aryl or aromatic ring may optionally be substituented by one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C). 1-6 Alkyl groups, etc., are substituted.

[0061] In this document, the term "heteroaryl" refers to an aromatic cyclic group in which at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom, a boron atom, or a sulfur atom. Optionally, the ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxidized. Specific examples include, but are not limited to, 5-10-membered heteroaryl, 6-10-membered heteroaryl, 5-10-membered nitrogen-containing heteroaryl, 6-10-membered oxygen-containing heteroaryl, 6-8-membered nitrogen-containing heteroaryl, 5-8-membered oxygen-containing heteroaryl, etc., such as furanyl, thiophene, pyrrole, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazole, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-Oxadiazolyl, pyridyl, 2-pyridoneyl, 4-pyridoneyl, pyrimidinyl, 1,4-dioxazadienyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, pyridazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetraazinyl, aziridine-heptanetrienyl, 1,3-diazacycloheptanetrienyl, aziridine-octatetraenyl, etc.

[0062] The hydrogen in the groups involved in this disclosure can be replaced by isotopes such as protium, deuterium, and tritium.

[0063] The term "substitution" refers to the selective replacement of one or more (e.g., 1, 2, 3, or 4) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0064] If a substituent is described as “optionally substituted with…”, then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together with independently selected substituents or not substituted. If the nitrogen of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may be substituted individually with independently selected substituents or not substituted.

[0065] If a substituent is described as being "independently selected" from a group of groups, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0066] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, six, seven, eight, nine, or ten.

[0067] The text used This is represented as a connection key.

[0068] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0069] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0070] This disclosure also includes all pharmaceutically acceptable isotopically labeled compounds identical to those disclosed, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this disclosure include, but are not limited to, isotopes of hydrogen (e.g., 2 H, 3 H, deuterium (D), tritium (T); carbon isotopes (e.g., H, deuterium (D), tritium (T)); 11 C 13 C and 14 C); isotopes of chlorine (e.g. 37 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g., ... 35 S). Certain isotope-labeled compounds of this disclosure (e.g., those doped with radioisotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioisotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and monitoring. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of this disclosure can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by replacing previously used unlabeled reagents with appropriate isotopically labeled reagents. Pharmaceutically acceptable solvates of this disclosure include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0071] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of this disclosure can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0072] This disclosure covers all possible crystalline forms or polymorphs of the compounds disclosed herein, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0073] It should also be understood that certain compounds of this disclosure may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In this disclosure, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites, or prodrugs that, upon administration to a patient in need, can directly or indirectly provide the compounds of this disclosure or their metabolites or residues. Therefore, when referring herein to “compounds of this disclosure,” it is also intended to encompass the various derivative forms of the compounds described above.

[0074] Pharmaceutically acceptable salts of the compounds disclosed herein include their acid addition salts and base addition salts. Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed by bases that form pharmaceutically acceptable salts. A review of suitable salts can be found in Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds disclosed herein are known to those skilled in the art.

[0075] The compounds disclosed herein may exist as solvates (preferably hydrates), wherein the compounds of this disclosure contain a polar solvent as a structural element of the compound's crystal lattice. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0076] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized into oxides; those skilled in the art will identify nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp. 748-750; A.R. Katritzky and A.J. Boulton, Eds., Academic Press; and G.W. H. Heeseman and E.S. G. Wierstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp. 390-392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.

[0077] The scope of this disclosure also includes metabolites of the compounds of this disclosure, i.e., substances formed in the body upon administration of the compounds of this disclosure. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this disclosure includes metabolites of the compounds of this disclosure, including compounds prepared by methods that expose the compounds of this disclosure to mammals for a time sufficient to produce their metabolites.

[0078] This disclosure further includes, within its scope, prodrugs of the compounds of this disclosure, which are certain derivatives of the compounds of this disclosure that may themselves have little or no pharmacological activity, and which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of this disclosure having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987 (EB Roche, editor, American Pharmaceutical Association). Prodrugs of this disclosure can be prepared, for example, by replacing suitable functional groups present in the compounds of this disclosure with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0079] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0080] Unless otherwise specified, percentages in this application refer to weight percentages, and parts refer to weight parts.

[0081] As used herein, the term “particle size” refers to the size of a particle, and “average particle size” (Z-average Size) refers to the average particle size obtained by means of light scattering, which can be measured by conventional particle size measurement techniques and instruments well known to those skilled in the art, such as the Malvern nanoparticle size analyzer.

[0082] As used in this article, the term "ball mill" refers to the process of crushing and grinding materials by rotating a cylindrical body, which drives the movement of grinding balls inside the body.

[0083] As used in this article, the term "homogenization" refers to the process of micronizing and homogenizing the dispersions in a suspension system, which simultaneously reduces the size of the dispersions and improves the uniformity of their distribution.

[0084] This application is by no means limited to the methods and materials described herein. In the event that one or more of the referenced documents, patents and similar materials differ from or contradict this application (including but not limited to defined terms, application of terms, described techniques, etc.), the descriptions and accompanying structural formulas of this application shall prevail.

[0085] All technical features disclosed in this specification, or all steps in all disclosed methods or processes, may be combined in any way, except for mutually exclusive technical features and / or steps.

[0086] Composition (solid dispersion)

[0087] The first aspect of this disclosure provides a composition comprising an active ingredient and at least one matrix material; said active ingredient is a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, polymorph, metabolite, or prodrug thereof.

[0088] in:

[0089] R a Selected from

[0090] Y 1 Y 2 Y 3 Y 4 Each is independently selected from O, S, N, NR. a1 and CR a2 ;

[0091] R a1 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -S(O)2R 1 ;

[0092] R a2 Each is independently selected from H, halogen, hydroxyl, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-6 cycloalkyl, -NR 2 R 3 -NHC(O)R 4-C(O)OR 5 -C(O)NR 6 R 7 -SR 8 -S(O)R 9 -S(O)2R 10 -S(O)2NR 11 R 12 -S(O)(NR) 13 )R 14 -P(O)R 15 R 16 and The C mentioned 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally surrounded by one or more groups selected from hydroxyl and -NR. 19 R 20 The substituents are replaced;

[0093] Or adjacent R a1 and R a2 Or two Rs a2 The atoms bonded to it form 5-6 membered heteroaromatic rings;

[0094] R 1 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 19 R 20 Each is independently selected from H and C. 1-6 alkyl;

[0095] R 2 R 3 Each is independently selected from H and C. 1-6 C-substituted with alkyl and carbonyl groups 1-6 alkyl;

[0096] R 4 Each is independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 2-6 alkenyl;

[0097] R 17 R 18Each is independently selected from H and C. 1-6 Alkyl, or R 17 R 18 Together with the linked boron and oxygen atoms, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally surrounded by one or more atoms selected from H, halogens, and C. 1-6 Substituents of alkyl groups;

[0098] Z 1 Z 2 Z 3 Z 4 Z 5 Each is independently selected from N, N + -O - and CR a3 ;

[0099] R a3 Each is independently selected from H, halogen, hydroxyl, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-6 cycloalkyl, -NR 21 R 22 -NHC(O)R 23 -C(O)OR 24 -C(O)NR 25 R 26 -SR 27 -S(O)R 28 -S(O)2R 29 -S(O)2NR 30 R 31 -S(O)(NR) 32 )R 33 -P(O)R 34 R 35 and The C mentioned 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally surrounded by one or more groups selected from hydroxyl and -NR. 38 R 39 The substituents are replaced;

[0100] Or two adjacent R a3 The carbon atom attached thereto forms a 5-6 membered heterocyclic group or a 5-6 membered heteroaromatic ring, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaromatic ring is optionally surrounded by one or more atoms selected from OH and C. 1-6 Substituents of alkyl groups;

[0101] R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 R 38 R 39 Each is independently selected from H and C. 1-6 alkyl;

[0102] R 21 R 22 Each is independently selected from H and C. 1-6 alkyl and carbonyl substituted C 1-6 Alkyl groups and -C(O)OC 1-6 alkyl;

[0103] R 23 Each is independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 2-6 alkenyl;

[0104] R 36 R 37 Each is independently selected from H and C. 1-6 Alkyl, or R 36 R 37 Together with the linked boron and oxygen atoms, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally surrounded by one or more atoms selected from H, halogens, and C. 1-6 Substituents of alkyl groups;

[0105] V is selected from N, N + -O - and CR a4 ;

[0106] R a4 Selected from H and C 1-6 alkyl;

[0107] R a5 Selected from H and C 1-6 alkyl;

[0108] R a6 Selected from H and C 1-6 alkyl;

[0109] R b1 and R b2 Each is independently selected from H and deuterium;

[0110] R b3 and R b4 Each is independently selected from H, deuterium, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl;

[0111] R b5 and R b6 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl, or R b5 R b6 Together with the bonded carbon atoms, they form C 3-5 Cycloalkyl or 4-6 membered heterocyclic groups;

[0112] R c Selected from H, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl and -OC 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 The cycloalkyl group is optionally surrounded by one or more groups selected from hydroxyl, carboxyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 alkenyl, -NR 40 R 41 C 3-6 The substituents are cycloalkyl, 3-6-membered heterocyclic, and 5-6-membered heteroaryl groups, wherein the 3-6-membered heterocyclic or 5-6-membered heteroaryl group is optionally replaced by one or more substituents selected from halogens and C. 1-6 Substituents of alkyl groups;

[0113] R 40 R 41 Each is independently selected from H and C. 1-6 alkyl;

[0114] X 1 X 2 X 3 X 4 Each is independently selected from N and CR c1 ;

[0115] R c1 Each is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0116] In some embodiments, in the compound of formula I of this application, wherein:

[0117] R a Selected from

[0118] Y 1 Y 2 Y 3 Y 4 Each is independently selected from O, S, N, NR. a1 and CR a2 ;

[0119] R a1 Each is independently selected from H and C. 1-4 Alkyl (e.g., methyl, ethyl, propyl, butyl), C 1-4 Halogenated alkyl groups (e.g., CF3, CHF2, CH2F) and -S(O)2R 1 (e.g., -S(O)2CH3);

[0120] R a2 Each is independently selected from H, halogens (e.g., fluorine, chlorine, bromine, iodine), hydroxyl groups, -CN, C. 1-4 Alkyl (e.g., methyl, ethyl, propyl, butyl), C 1-4 Haloalkyl (e.g., CF3, CHF2, CH2F), C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-4 cycloalkyl, -NR 2 R 3 -NHC(O)R 4 -C(O)OR 5 -C(O)NR 6 R 7 SR 8 -S(O)R 9 -S(O)2R 10 -S(O)2NR 11 R 12 -S(O)(NR) 13 )R 14 -P(O)R 15 R 16 and The C mentioned 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 The haloalkoxy group is optionally surrounded by one or more groups selected from hydroxyl and -NR. 19 R 20 The substituents are replaced;

[0121] Or adjacent R a1 and R a2 Or two Rs a2 The atoms bonded to it form 5-6 membered heteroaromatic rings;

[0122] R 1 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 19 R 20 Each is independently selected from H and C. 1-4 alkyl;

[0123] R 2 R 3 Each is independently selected from H and C. 1-4 C-substituted with alkyl and carbonyl groups 1-4 alkyl;

[0124] R 4 Each is independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl and C 2-6 alkenyl;

[0125] R 17 R 18 Each is independently selected from H and C. 1-4 Alkyl, or R 17 R 18 Together with the linked boron and oxygen atoms, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally surrounded by one or more atoms selected from H, halogens, and C. 1-4 Substituents of alkyl groups;

[0126] Z 1 Z 2 Z 3 Z 4 Z 5 Each is independently selected from N, N+ -O - and CR a3 ;

[0127] R a3 Each is independently selected from H, halogens (e.g., fluorine, chlorine, bromine, iodine), hydroxyl groups, -CN, C. 1-4 Alkyl (e.g., methyl, ethyl, propyl, butyl), C 1-4 Haloalkyl (e.g., CF3, CHF2, CH2F), C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-4 cycloalkyl, -NR 21 R 22 -NHC(O)R 23 -C(O)OR 24 -C(O)NR 25 R 26 -SR 27 -S(O)R 28 -S(O)2R 29 -S(O)2NR 30 R 31 -S(O)(NR) 32 )R 33 -P(O)R 34 R 35 and The C mentioned 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 The haloalkoxy group is optionally surrounded by one or more groups selected from hydroxyl and -NR. 38 R 39 The substituents are replaced;

[0128] Or two adjacent R a3 The carbon atom attached thereto forms a 5-6 membered heterocyclic group or a 5-6 membered heteroaromatic ring, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaromatic ring is optionally surrounded by one or more atoms selected from OH and C. 1-6 Substituents of alkyl groups;

[0129] R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R35 R 38 R 39 Each is independently selected from H and C. 1-4 alkyl;

[0130] R 21 R 22 Each is independently selected from H and C. 1-4 alkyl and carbonyl substituted C 1-4 Alkyl groups and -C(O)OC 1-4 alkyl;

[0131] R 23 Each is independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl and C 2-6 alkenyl;

[0132] R 36 R 37 Each is independently selected from H and C. 1-4 Alkyl, or R 36 R 37 Together with the linked boron and oxygen atoms, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally surrounded by one or more atoms selected from H, halogens, and C. 1-4 Substituents of alkyl groups;

[0133] V is selected from N, N + -O - and CR a4 ;

[0134] R a4 Selected from H and C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, butyl);

[0135] R a5 Selected from H and C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, butyl);

[0136] R a6 Selected from H and C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, butyl).

[0137] In some embodiments, in the compound of formula I of this application, wherein:

[0138] R a Selected from

[0139] Y 1 Y 2 Y 3 Y 4 Each is independently selected from O, S, N, NR. a1and CR a2 ;

[0140] R a1 Each is independently selected from H, methyl, CF3, CHF2 and -S(O)2CH3;

[0141] R a2 Each is independently selected from H, fluorine, chlorine, methyl, CF3, CHF2, -C(O)NH2, -NH2 and

[0142] Or adjacent R a1 and R a2 Or two Rs a2 The atoms bonded to it form 5-6 membered heteroaromatic rings;

[0143] R 17 R 18 Each is independently selected from H and C. 1-4 Alkyl, or R 17 R 18 Together with the linked boron and oxygen atoms, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally surrounded by one or more atoms selected from H, halogens, and C. 1-4 Substituents of alkyl groups;

[0144] Z 1 Z 2 Z 3 Z 4 Z 5 Each is independently selected from N, N + -O - and CR a3 ;

[0145] R a3 Each is independently selected from H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, vinyl, cyclopropyl, -CH2OH, -C(CH3)2OH, -CH(OH)CH2(OH), -CH(OH)CH2F, -CH(NH2)CH2(OH), -CH(NH-CH3)CH2(OH), -OCH2CH(OH)CH2(OH), -NR 21 R 22 -NHC(O)R 23 -C(O)OR 24 -C(O)NR 25 R 26 -SR 27 -S(O)R 28 -S(O)2R 29 -S(O)2NR 30 R31 -S(O)(NR) 32 )R 33 -P(O)R 34 R 35 and Preferably, R a3 Each is independently selected from H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, vinyl, cyclopropyl, -CH2OH, -C(CH3)2OH, -CH(OH)CH2(OH), -CH(OH)CH2F, -CH(NH2)CH2(OH), -NR 21 R 22 -NHC(O)R 23 -C(O)OR 24 -C(O)NR 25 R 26 -SR 27 -S(O)R 28 -S(O)2R 29 -S(O)2NR 30 R 31 -S(O)(NR) 32 )R 33 -P(O)R 34 R 35 and

[0146] Or two adjacent R a3 The carbon atom attached thereto forms a 5-6 membered heterocyclic group or a 5-6 membered heteroaromatic ring, wherein the heterocyclic group is optionally substituted by one or more hydroxyl or methyl groups;

[0147] R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 Each is independently selected from H and C. 1-4 alkyl;

[0148] R 21 R 22 Each is independently selected from H and C. 1-4 alkyl and carbonyl substituted C 1-4 alkyl and carbonyl substituted C 2-4 alkenyl and -C(O)OC 1-4 Alkyl; preferably, R21 R 22 Each is independently selected from H and C. 1-4 C-substituted with alkyl and carbonyl groups 1-4 alkyl;

[0149] R 23 Each is independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl and C 2-6 alkenyl;

[0150] R 36 R 37 Each is independently selected from H and C. 1-4 Alkyl, or R 36 R 37 Together with the linked boron and oxygen atoms, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally surrounded by one or more atoms selected from H, halogens, and C. 1-4 Substituents of alkyl groups;

[0151] V is selected from N, N + -O - and CR a4 ;

[0152] R a4 Selected from H and methyl;

[0153] R a5 Selected from H and methyl;

[0154] R a6 Selected from H and methyl.

[0155] In some embodiments, in the compound of formula I of this application, Z 1 Z 2 Z 3 Z 4 Z 5 Each is independently selected from N and CR a3 .

[0156] In some embodiments, in the compound of formula I of this application, wherein:

[0157] R a3 Each is independently selected from H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, vinyl, cyclopropyl, -CH2OH, -C(CH3)2OH, -CH(OH)CH2(OH), -CH(OH)CH2F, -CH(NH2)CH2(OH), -NR 21 R 22 -NHC(O)R 23 -C(O)OR 24-C(O)NR 25 R 26 -SR 27 -S(O)R 28 -S(O)2R 29 -S(O)2NR 30 R 31 -S(O)(NR) 32 )R 33 -P(O)R 34 R 35 and

[0158] Or two adjacent R a3 The carbon atoms connected to it form

[0159] R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 Each is independently selected from H and C. 1-4 alkyl;

[0160] R 21 R 22 Each is independently selected from H and C. 1-4 C-substituted with alkyl and carbonyl groups 1-4 alkyl;

[0161] R 23 Each is independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl and C 2-6 Alkenyl group.

[0162] In some embodiments, in the compound of formula I of this application, R a3Each is independently selected from H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, vinyl, cyclopropyl, -CH2OH, -C(CH3)2OH, -CH(OH)CH2(OH), -CH(OH)CH2F, -CH(NH2)CH2(OH), -CH(NH-CH3)CH2(OH), -OCH2CH(OH)CH2(OH), -N(CH3)-Boc, -NH(CH3), -N(CH3)2, -NH-CH2-C(O)CH3, -NH-C(O)CH2-CH3, -NH-C(O)CH2=CH2, -C(O)OCH3, -C(O)N H2, -SH, -SCH3, -S(O)CH3, -S(O)2CH3, -S(O)2NH2, -S(O)(NH)CH3, -S(O)(NCH3)CH3, -P(O)(CH3)2 and Preferably, R a3 Each is independently selected from H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, vinyl, cyclopropyl, -CH2OH, -C(CH3)2OH, -CH(OH)CH2(OH), -CH(OH)CH2F, -CH(NH2)CH2(OH), -N(CH3)-Boc, -NH(CH3), -N(CH3)2, -C(O)OCH3, -C(O)NH2, -SH, -S(O)CH3, -S(O)2CH3, -S(O)2NH2, -S(O)(NH)CH3, -S(O)(NCH3)CH3, -P(O)(CH3)2 and

[0163] Or two adjacent R a3 The carbon atoms connected to it form

[0164] More preferably, R a3 Each is independently selected from H, fluorine, chlorine, bromine, -C(O)NH2 and

[0165] More preferably, R a3 They are each independently selected from H and -C(O)NH2.

[0166] In some embodiments, in the compound of formula I of this application, R b3 and R b4 Each is independently selected from H, deuterium, and C. 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, and butyl), C 1-4 Halogenated alkyl and C 3-6 Cycloalkyl.

[0167] In some embodiments, in the compound of formula I of this application, R b3 and R b4 Each is independently selected from H, deuterium, and methyl.

[0168] In some embodiments, in the compound of formula I of this application, R b3 and R b4 Each is independently selected from H and deuterium.

[0169] In some embodiments, in the compound of formula I of this application, R b3 and R b4 For H.

[0170] In some embodiments, in the compound of formula I of this application, R b5 and R b6 Each is independently selected from H and C. 1-4 Alkyl, C 1-4 Halogenated alkyl and C 3-6 cycloalkyl, or R b5 R b6 Together with the bonded carbon atoms, they form C 3-5 Cycloalkyl or 4-6 membered heterocyclic groups (e.g., 4-6 membered oxygen-containing heterocyclic groups).

[0171] In some embodiments, in the compound of formula I of this application, R b5 and R b6 Each is independently selected from H, methyl, cyclopropyl, and trifluoromethyl, or R b5 R b6 The carbon atoms attached to it form cyclobutyl, cyclopentyl, or 4-6 member oxygen-containing heterocyclic groups.

[0172] In some embodiments, in the compound of formula I of this application, R b5 and R b6 Each is independently selected from H, methyl, cyclopropyl, and trifluoromethyl, or R b5 R b6 The carbon atoms attached to it form cyclobutyl or

[0173] In some embodiments, in the compound of formula I of this application, R b5 and R b6 Each is independently selected from methyl and trifluoromethyl.

[0174] In some embodiments, in the compound of formula I of this application, R c Selected from H, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkenyl and -OC 3-6 cycloalkyl, the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 3-6 The cycloalkyl group is optionally surrounded by one or more groups selected from hydroxyl, carboxyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkenyl, -NR 40 R 41 C 3-6 The substituents are cycloalkyl, 3-6-membered heterocyclic, and 5-6-membered heteroaryl groups, wherein the 3-6-membered heterocyclic or 5-6-membered heteroaryl group is optionally replaced by one or more substituents selected from halogens and C. 1-4 Alkyl substituents; R 40 R 41 Each is independently selected from H and C. 1-4 alkyl.

[0175] In some embodiments, in the compound of formula I of this application, X 1 X 2 X 3 X 4 Each independently selected from CR c1 .

[0176] In some embodiments, in the compound of formula I of this application, R c1 Each is independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups.

[0177] In some embodiments, in the compound of formula I of this application, R c1 Each is independently selected from H, F, Cl, methyl, ethyl, propyl, butyl, fluoromethyl, fluoroethyl, fluoropropyl, methoxy, ethoxy, propoxy, butoxy, fluoromethoxy, fluoroethoxy, and fluoropropoxy.

[0178] In some embodiments, in the compound of formula I of this application, R c1 Each is independently selected from H, F, methyl, difluoromethyl, trifluoromethyl, difluoromethoxy, methoxy, and difluoromethoxy.

[0179] In some embodiments, in the compound of formula I of this application, R c1Each is independently selected from H and F.

[0180] In some embodiments, in the compound of formula I of this application, wherein R a Selected from:

[0181] In some embodiments, in the compound of formula I of this application, wherein R a Selected from:

[0182] In some embodiments, in the compound of formula I of this application, wherein R a Selected from:

[0183] In some embodiments, in the compound of formula I of this application, wherein R a Selected from:

[0184] In some embodiments, in the compound of formula I of this application, wherein R a Selected from:

[0185] In some embodiments, in the compound of formula I of this application, wherein R c Selected from H, -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -OCH2CF3, -OCH2CF2CH3, -OCH2CHF2, -OCHF2、

[0186] In some embodiments, in the compound of formula I of this application, wherein R c Selected from -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -OCH2CF3, -OCH2CF2CH3, -OCH2CHF2 and -OCHF2.

[0187] In some embodiments, in the compound of formula I of this application, wherein R c It is -OCH3.

[0188] In some embodiments, in the compound of formula I of this application, for

[0189] In some embodiments, in the compound of formula I of this application, wherein:

[0190] R a Selected from in:

[0191] Y 1 Y 2 Y 3 Y 4 Each was independently selected from S and CR a2 ;

[0192] R a2 Each is independently selected from H and

[0193] Z 1 Z 2 Z 3 Z 4 Z 5 Each is independently selected from N and CR a3 ;

[0194] R a3 Each is independently selected from H, fluorine, chlorine, bromine, -C(O)NH2 and

[0195] V is selected from CR a4 ;

[0196] R a4 Selected from H and methyl;

[0197] R a5 Selected from H and methyl;

[0198] R a6 Selected from H and methyl;

[0199] R b1 and R b2 Each is independently selected from H and deuterium;

[0200] R b3 and R b4 Each is independently selected from H and deuterium;

[0201] R b5 and R b6 Each is independently selected from methyl and trifluoromethyl;

[0202] R c Selected from -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -OCH2CF3, -OCH2CF2CH3, -OCH2CHF2, and -OCHF2; preferably, R c It is -OCH3;

[0203] X 1 X 2 X 3 X4 Each independently selected from CR c1 ;

[0204] R c1 Each is independently selected from H and F.

[0205] In some embodiments, the compound of formula I is selected from:

[0206] In some embodiments, the active ingredient is a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, or polymorph thereof.

[0207] In some embodiments, the active ingredient is a compound of formula II or a pharmaceutically acceptable salt or polymorph thereof:

[0208] The aforementioned active ingredients, their preparation, and uses are described in Chinese Patent Application No. 202311551257.1 filed by the applicant. The aforementioned Chinese Patent Application is incorporated herein by reference in its entirety.

[0209] In some embodiments, the composition comprises an active ingredient and at least one matrix material, wherein the active ingredient is a compound of Formula II or a pharmaceutically acceptable salt or polymorph thereof.

[0210] In some embodiments, the composition comprises an active ingredient and at least one matrix material, wherein the active ingredient is an amorphous or polymorphic form (e.g., crystal form I) of a compound represented by Formula II or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments, the composition comprises an active ingredient and at least one matrix material, wherein the active ingredient is an amorphous form of a compound represented by Formula II.

[0212] In some embodiments, the composition comprises an active ingredient and at least one matrix material, wherein the active ingredient is a compound of formula II containing at least 95% amorphous form.

[0213] In some embodiments, the composition is a solid dispersion.

[0214] In some embodiments, the solid dispersion comprises an active ingredient and at least one matrix material, wherein the active ingredient is a compound of Formula II or a pharmaceutically acceptable salt or polymorph thereof.

[0215] In some embodiments, the solid dispersion comprises an active ingredient and at least one matrix material, wherein the active ingredient is an amorphous or polymorphic form (e.g., crystal form I) of a compound represented by Formula II or a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, the solid dispersion comprises an active ingredient and at least one matrix material, wherein the active ingredient is an amorphous form of a compound represented by Formula II.

[0217] In some embodiments, the solid dispersion comprises an active ingredient and at least one matrix material, wherein the active ingredient is a compound of formula II containing at least 95% amorphous form.

[0218] In some embodiments, the matrix material is one or more of povidone, copovidone, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus).

[0219] In some embodiments, the matrix material is one or more of hydroxypropyl methylcellulose acetate succinate, copovidone, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0220] In some embodiments, the matrix material is hydroxypropyl methylcellulose succinate.

[0221] In some embodiments, the matrix material is one or more of the following: povidone K25, copovidone VA64, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate L-type, hydroxypropyl methylcellulose acetate succinate H-type, hydroxypropyl methylcellulose acetate succinate M-type, hydroxypropyl cellulose EF, hydroxypropyl methylcellulose E5, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0222] In some embodiments, the matrix material is one or more of copovidone VA64, hydroxypropyl methylcellulose acetate succinate L-type, hydroxypropyl methylcellulose acetate succinate H-type, hydroxypropyl methylcellulose acetate succinate M-type, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0223] In some embodiments, the mass ratio of the active ingredient to the matrix material is 1:1 to 1:5.

[0224] In some embodiments, the mass ratio of the active ingredient to the matrix material is 1:2 to 1:4.

[0225] In some embodiments, the mass ratio of the active ingredient to the matrix material is 1:1.

[0226] In some embodiments, the mass ratio of the active ingredient to the matrix material is 1:2.

[0227] In some embodiments, the mass ratio of the active ingredient to the matrix material is 1:3.

[0228] In some embodiments, the mass ratio of the active ingredient to the matrix material is 1:4.

[0229] In some embodiments, the mass ratio of the active ingredient to the matrix material is 1:5.

[0230] In some embodiments, the composition may also optionally include one or more of surfactants, plasticizers, and flow aids (anti-sticking agents).

[0231] In some embodiments, the solid dispersion may optionally include one or more of surfactants, plasticizers, and flow aids (anti-sticking agents).

[0232] In some embodiments, the surfactant is one or more of anionic surfactants (such as sodium lauryl sulfate), cationic surfactants (such as dodecyltrimethylammonium bromide, hexadecyltrimethylammonium chloride, bromobrowntrimethylammonium, and lauric acid), and nonionic surfactants (such as polysorbates 20, 40, 60, 80, sorbitan fatty acid esters 20, 40, 60, 80, and poloxamer).

[0233] In some embodiments, if present, the surfactant comprises 0.1-5% by weight of the composition (e.g., solid dispersion), preferably 0.5-2%.

[0234] In some embodiments, the plasticizer is one or more selected from polyethylene glycol, triethyl citrate, triacetin, glycerol, glyceryl monostearate, polyvinyl phthalate, and propylene glycol.

[0235] In some embodiments, if present, the plasticizer comprises 0.1-5% by weight of the composition (e.g., solid dispersion), preferably 0.5-2%.

[0236] Flow aids (anti-sticking agents) can appropriately reduce the viscosity of a composition (e.g., a solid dispersion) and improve its processability, for example, by improving material flowability and ensuring smooth feeding when using hot melt extrusion. In some embodiments, the flow aid (anti-sticking agent) is one or more of silica and colloidal silica.

[0237] In some embodiments, if present, the flow aid (anti-adhesion agent) comprises 0.1-5% by weight of the composition (e.g., solid dispersion), preferably 0.5-2%.

[0238] In some embodiments, the composition (e.g., a solid dispersion) is particles or powder with a D90 particle size ≤ 100 μm, preferably particles or powder with a D90 particle size ≤ 70 μm.

[0239] The compositions disclosed herein (e.g., solid dispersions) have high drug loading capacity, significantly improved drug solubility, good stability, and in vivo bioavailability that can reach the same level as that of clear drug solutions. This makes it possible to prepare oral solid dosage forms containing compounds of formula I, especially compounds of formula II.

[0240] Method for preparing a composition (e.g., a solid dispersion)

[0241] A second aspect of this disclosure provides a method for preparing a composition (e.g., a solid dispersion), wherein the method is a hot melt extrusion method or a solvent drying method.

[0242] In some embodiments, the composition (e.g., solid dispersion) is prepared by hot melt extrusion.

[0243] In some embodiments, the composition (e.g., a solid dispersion) is prepared by hot melt extrusion, and the method includes the following steps:

[0244] Step 1: Mix the active ingredients with the matrix material evenly, and optionally add surfactants, plasticizers or flow aids (anti-sticking agents);

[0245] Step 2: Heat the mixture obtained in Step 1 to a certain temperature, and then use a screw to shear and mix the mixture at high speed and extrude it into shape;

[0246] Step 3: Crush the extrudate from Step 2 to obtain the composition (e.g., solid dispersion).

[0247] In some implementations, in step two, the mixture obtained in step one is heated to 140°C-200°C, and then sheared and mixed by a screw at high speed and extruded into shape.

[0248] In some implementations, in step two, the mixture obtained in step one is heated to 160°C-180°C, and then sheared and mixed by a screw at high speed and extruded into shape.

[0249] In some embodiments, in step three, the extrudate from step two is pulverized by a hammer mill and then by a needle mill to obtain the composition (e.g., a solid dispersion).

[0250] In some embodiments, the composition (e.g., a solid dispersion) is prepared by solvent drying, and the method includes the following steps:

[0251] The active ingredient is mixed uniformly with the matrix material, and optionally a surfactant, plasticizer or flow aid (anti-sticking agent) is also added. Then a solvent (e.g. ethanol, acetone) is added, stirred to dissolve, and dried (e.g., rotary drying and / or vacuum drying) to remove the solvent, thereby obtaining the composition (e.g., solid dispersion).

[0252] The method for preparing solid dispersions provided in this application has a stable process and can obtain solid dispersions with stable performance; the use of hot melt extrusion method can also avoid the use of solvents.

[0253] Pharmaceutical compositions containing solid dispersions

[0254] A third aspect of this disclosure provides a pharmaceutical composition comprising the composition of the first aspect (e.g., a solid dispersion) and at least one pharmaceutically acceptable carrier.

[0255] In some embodiments, the pharmaceutical composition contains 1-1000 mg of active ingredient per unit dosage form.

[0256] In some embodiments, the pharmaceutical composition contains 10-200 mg of active ingredient per unit dosage form.

[0257] In some embodiments, the pharmaceutical composition contains 1-1000 mg of a compound of formula II per unit dosage.

[0258] In some embodiments, the pharmaceutical composition contains 10-200 mg of a compound of formula II per unit dosage.

[0259] In some embodiments, the pharmaceutical composition comprises, in unit dosage form, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg of active ingredient.

[0260] In some embodiments, the unit dosage form of the pharmaceutical composition comprises 12.5 mg, 25 mg, 50 mg, 75 mg, or 100 mg of the active ingredient.

[0261] In some embodiments, the pharmaceutical composition comprises, in unit dosage form, a compound of formula II in the amounts of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg.

[0262] In some embodiments, the pharmaceutical composition comprises, in unit dosage form, 12.5 mg, 25 mg, 50 mg, 75 mg, or 100 mg of a compound of formula II.

[0263] In some embodiments, the pharmaceutical composition is in the form of tablets, capsules, granules, or other oral dosage forms.

[0264] In some implementations, the pharmaceutically acceptable carrier is one or more of fillers, disintegrants, binders, flow aids, and lubricants.

[0265] In some embodiments, the filler is one or more of mannitol, mannitol complex, sorbitol, lactose, sucrose, lactose complex, microcrystalline cellulose, microcrystalline cellulose derivatives (such as silicified microcrystalline cellulose), starch, pregelatinized starch, modified starch, calcium phosphate, calcium carbonate, and calcium hydrogen phosphate.

[0266] In some embodiments, the filler is one or more of mannitol, mannitol complex, microcrystalline cellulose, microcrystalline cellulose derivatives (such as silicified microcrystalline cellulose), and dicalcium phosphate.

[0267] In some implementations, the disintegrant is one or more of croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch.

[0268] In some implementations, the disintegrant is croscarmellose sodium.

[0269] In some embodiments, the adhesive is one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, methylcellulose, and polyvinyl alcohol.

[0270] In some embodiments, the adhesive is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, and copovidone.

[0271] In some embodiments, the flow aid is one or more of colloidal silica, silica, fumed silica, and talc.

[0272] In some implementations, the flow aid is one or both of colloidal silica and silica.

[0273] In some implementations, the lubricant is one or more of magnesium stearate, calcium stearate, magnesium lauryl stearate, stearic acid, sodium stearate fumarate, glyceryl sorbate, and hydrogenated castor oil.

[0274] In some implementations, the lubricant is one or both of magnesium stearate and sodium stearate fumarate.

[0275] In some embodiments, when the pharmaceutical composition is a tablet, a coating may be applied to the outside of the tablet core. The coating material may be a stomach-soluble coating powder such as Opadry or a product with a similar composition. In some embodiments, the coating material is Opadry Type I film-coating premix. The weight of the coating material is 1%-6% of the weight of the tablet core, preferably 2%-4%.

[0276] In some embodiments, the pharmaceutical composition comprises the following components by weight percentage: 25%-85.7% composition (e.g., solid dispersion), 5%-73.8% filler, 1%-10% disintegrant, 0%-5% binder, 0.1%-2% flow aid, and 0.1%-2% lubricant.

[0277] In some embodiments, the pharmaceutical composition comprises the following components by weight percentage: 42.9%-83.3% composition (e.g., solid dispersion), 10%-53.1% filler, 3%-7% disintegrant, 0%-3% binder, 0.5%-1.5% flow aid, and 0.5%-1.5% lubricant.

[0278] In some embodiments, the pharmaceutical composition comprises the following components by weight percentage: 57.1%-80% composition (e.g., solid dispersion), 13%-38.9% filler, 3%-5% disintegrant, 0.5%-1% flow aid, and 0.5%-1% lubricant.

[0279] The disclosed pharmaceutical composition comprises a solid dispersion and suitable excipients, exhibiting stable dissolution and disintegration behavior. The composition is available in dosage forms including, but not limited to, tablets and capsules. This formulation features stable dissolution behavior, significantly improved bioavailability, high chemical stability, and ease of commercial production. Furthermore, the formulation has a suitable weight and size, allowing for dosage control to be within two tablets or capsules per administration, thus minimizing the patient's medication burden.

[0280] Method for preparing pharmaceutical compositions containing solid dispersions

[0281] The fourth aspect of this disclosure provides a method for preparing a pharmaceutical composition, wherein the pharmaceutical composition is a solid dispersion tablet, and the preparation method includes the following steps:

[0282] (1) Premixing; The composition (e.g., a solid dispersion) of the first aspect of this disclosure is mixed uniformly with optional fillers, disintegrants, binders, and flow aids;

[0283] (2) Sieving: Pass the premix through a sieve with a mesh size of 20-60 mesh;

[0284] (3) Final mixing: Add the sieved premix to the lubricant and mix thoroughly;

[0285] (4) Tableting: The mixture is compressed into tablets with a hardness controlled at 50-180N;

[0286] (5) Coating: Coating the tablet core, with the weight gain controlled at 1%-6%.

[0287] Treatment methods and uses

[0288] This application also provides the use of the composition (e.g., a solid dispersion) of the first aspect of this application or the pharmaceutical composition of the third aspect in the preparation of a medicament for the prevention and / or treatment of NaV1.8-related diseases, preferably, said NaV1.8-related diseases being pain.

[0289] This application also provides compositions (e.g., solid dispersions) from the first aspect of this application or pharmaceutical compositions from the third aspect for the prevention and / or treatment of NaV1.8-related diseases, preferably, said NaV1.8-related diseases being pain.

[0290] This application also provides methods for preventing and / or treating NaV1.8-related diseases, including administering to an individual a preventive and / or therapeutically effective amount of a composition (e.g., a solid dispersion) from the first aspect of this application or a pharmaceutical composition from the third aspect, preferably wherein the NaV1.8-related disease is pain.

[0291] In some implementations, the NaV1.8-related diseases are selected from, but not limited to, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from bunion removal, hernia repair, or abdominoplasty), and visceral pain, particularly postoperative pain.

[0292] In some embodiments, the pharmaceutical composition of this application is used simultaneously, alone, or sequentially in combination with other therapeutic or preventative agents.

[0293] In some implementations, the additional therapeutic or preventative agent is an analgesic.

[0294] As used in this article, the term "effective amount" refers to an amount sufficient to achieve the desired preventive or therapeutic effect, such as an amount that reduces one or more symptoms associated with the disease to be treated.

[0295] The dosing regimen can be adjusted to provide the optimal required response. For example, it can be administered as a single dose, as several fractions administered over time, or as the urgency of the treatment condition indicates, the dose can be reduced or increased proportionally. It should be noted that the dosage value can vary depending on the type and severity of the condition to be alleviated, and can include single or multiple doses. To further understand, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the pharmaceutical composition of this disclosure.

[0296] The amount of the pharmaceutical composition of this disclosure administered will depend on the individual being treated, the severity of the condition or illness, the rate of administration, the disposal of the compound, and the judgment of the prescribing physician. In some cases, a dose level not exceeding the lower limit of the foregoing range may be sufficient, while in other cases, a larger dose may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.

[0297] Unless otherwise stated, as used herein, the term “treatment” means to reverse, alleviate, or improve the condition or illness to which such term applies, or the progression of one or more symptoms of such condition or illness.

[0298] The term "prevention" refers to suppressing and delaying the onset of disease, including not only prevention before the disease develops, but also prevention of recurrence after treatment.

[0299] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this disclosure, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.). Attached Figure Description

[0300] Figure 1 shows the XRPD pattern of crystal form I of compound II. Detailed Implementation

[0301] To make the objectives and technical solutions of this disclosure clearer, the embodiments of this disclosure are described in detail below. However, those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of this disclosure. Unless otherwise specified, specific conditions in the embodiments are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0302] The following table has the meanings in this disclosure:

[0303] The crystal forms in the example samples were characterized by X-ray powder diffraction (XRPD).

[0304] XRPD patterns of the crystal form were acquired using an X'Pert3 Powder Diffractometer, which employs Cu-palladium irradiation and absolute scan detection at room temperature. The detector was a PIXcel1D; the detection range was 3.5° to 40°, with a step size of 0.013°, a dwell time of 50 s, and one scan. for The voltage is 40kV; the current is 40mA.

[0305] Preparation Example 1: Preparation of (3-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carbamate)phenyl)boronic acid (compound 9)

[0306] Compounds 1-7 (30 mg, 0.08 mmol) were dissolved in anhydrous DMF (5 mL), and 3-aminophenylboronic acid (33 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath conditions. After allowing the mixture to return to room temperature, stirring was continued for 1 h. The reaction was monitored by LC-MS to ensure complete reaction of the starting material. The target compound (79 mg, 0.04 mmol, yield 50%) was obtained by Pre-HPLC separation. MS: m / z = 476.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.17(s,1H),8.00(s,2H),7.76(s,1H),7.59(d,J=8.1Hz,1H),7.46(d,J=7.3Hz,1H),7.23(t,J=7.7Hz,1H),7.20– 7.11(m,2H),4.62(d,J=10.7Hz,1H),4.31-4.19(m,1H),3.96(d,J=1.6Hz,3H),2.39(t,J=12.9Hz,1H),2.35–2.25(m,1H),1.73(s,3H).

[0307] Preparation Example 2: Preparation of (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carbamate)-2-methylphenyl)boronic acid (compound 13)

[0308] Compounds 1-7 (30 mg, 0.08 mmol) were dissolved in anhydrous DMF (5 mL), and 3-amino-4-methylphenylboronic acid (36 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath conditions. After allowing the mixture to return to room temperature, stirring was continued for 1 h. The reaction was monitored by LC-MS to ensure complete reaction of the starting material. The target compound (24.5 mg, 0.05 mmol, yield 62.50%) was obtained by Pre-HPLC separation. MS: m / z = 490.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.07(s,1H),7.96(s,2H),7.45–7.40(m,2H),7.19–7.12(m,2H),7.00(d,J=8.0Hz ,1H),4.59(d,J=10.8Hz,1H),4.34-4.22(m,1H),3.96(d,J=1.6Hz,3H),2.42-2.27(m,1H),1.72(s,3H).

[0309] Preparation Example 3: Preparation of (3-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carbamate)-5-fluorophenyl)boronic acid (compound 17)

[0310] Compounds 1-7 (30 mg, 0.08 mmol) were dissolved in anhydrous DMF (5 mL), and 3-amino-5-fluorophenylboronic acid (70 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath conditions. After allowing the mixture to return to room temperature, stirring was continued for 1 h. The reaction was monitored by LC-MS to ensure complete reaction of the starting material. The target compound (20.0 mg, 0.04 mmol, yield 60.40%) was obtained by Pre-HPLC separation. MS: m / z = 494.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.41(s,1H),8.19(s,2H),7.61–7.50(m,2H),7.24–7.13(m,3H),4.60(d,J=10.8 Hz,1H),4.30-4.23(m,1H),3.96(d,J=1.6Hz,3H),2.45-2.41(m,1H),2.32-2.28(m,1H),1.73(s,3H).

[0311] Preparation Example 4: Preparation of (3-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carbamate)-4-fluorophenyl)boronic acid (compound 18)

[0312] Compounds 1-7 (30 mg, 0.08 mmol) were dissolved in anhydrous DMF (5 mL), and 3-amino-4-fluorophenylboronic acid (70 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath conditions. After allowing the mixture to return to room temperature, stirring was continued for 1 h. The reaction was monitored by LC-MS to ensure complete reaction of the starting material. The target compound (16 mg, 0.03 mmol, yield 40.50%) was obtained by Pre-HPLC separation. MS: m / z = 494.2, [M+H] + , 1H NMR(400MHz,DMSO)δ9.92(s,1H),8.03(s,2H),7.57-7.56(m,2H),7.30-7.29(m,1H),6. 88-6.86(m,2H),4.53(s,1H),4.23(s,1H),3.83(s,3H),2.17–1.96(m,2H),1.38(s,3H).

[0313] Preparation Example 5: Preparation of (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-fluorophenyl)boronic acid (compound 19)

[0314] Compounds 1-7 (301 mg, 0.8 mmol) were dissolved in anhydrous DMF (5 mL), and 5-amino-2-fluorophenylboronic acid (703 mg, 2.4 mmol) was added. TCFH (1.19 g, 4.1 mmol) and NMI (556 mg, 6.4 mmol) were added under ice bath conditions. After allowing the mixture to return to room temperature, stirring was continued for 1 h. The reaction was monitored by LC-MS to ensure complete reaction of the starting material. The target compound (209 mg, 0.43 mmol, yield 53.7%) was obtained by Pre-HPLC separation. MS: m / z = 494.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.22(s,1H),8.17(s,2H),7.59-7.51(m,2H),7.22-7.14(m,2H),7.09-6.89(m,1H),4.58( d,J=10.7Hz,1H),4.33-4.24(m,1H),3.96(d,J=1.5Hz,3H),2.45-2.35(m,1H),2.32-2.25(m,1H),1.73(s,3H).

[0315] Preparation Example 6: Preparation of (3-cyano-5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carbamoyl)phenyl)boronic acid (compound 26)

[0316] Compounds 1-7 (30 mg, 0.08 mmol) were dissolved in anhydrous DMF (5 mL), and 3-amino-5-cyanobenzonic acid (62 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath conditions. After allowing the mixture to return to room temperature, stirring was continued for 1 h. The reaction was monitored by LC-MS to ensure complete reaction of the starting material. The target compound (18.41 mg, 0.03 mmol, yield 46%) was obtained by Pre-HPLC separation. MS: m / z = 501.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.59(s,1H),8.41(s,2H),8.10(s,1H),8.02(s,1H),7.86(s,1H),7.26-7.14(m, 2H),4.64(d,J=10.8Hz,1H),4.36-4.25(m,1H),4.00(d,J=1.6Hz,3H),2.54-2.32(m,2H),1.76(s,3H).

[0317] Preparation Example 7: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoboro-6-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (compound 31)

[0318] Compounds 1-7 (30.0 mg, 0.084 mmol) were dissolved in DMF (1.5 mL), and 6-aminobenzo[c][1,2]oxoboron-1(3H)-ol (19.0 mg, 0.126 mmol) and NMI (55.3 mg, 0.673 mmol) were added. TCHF (94.0 mg, 0.337 mmol) was added under ice bath conditions, and the mixture was allowed to warm naturally to room temperature and reacted for another 4 hours. The reaction was monitored by LC-MS. After the reaction was complete, the target compound (23.5 mg, 0.048 mmol, yield 57.4%) was obtained by Pre-HPLC. MS: m / z = 488.1, [M+H] + , 1H NMR (400MHz, DMSO) δ10.28(s,1H),9.20(s,1H),7.92(d,J=1.7Hz,1H),7.50(dd,J=8.3,2.0Hz,1H),7.30(d,J=8.3Hz,1H),7.2 3–7.11(m,2H),4.90(s,2H),4.62(d,J=10.7Hz,1H),4.34–4.23(m,1H),3.97(d,J=1.7Hz,3H),2.47-2.15(m,2H),1.73(s,3H).

[0319] Preparation Example 8: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carbamate)thiophene-2-yl)boronic acid (compound 48)

[0320] Intermediate 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and 4-aminothiophene-2-boric acid (36 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath conditions. After allowing the mixture to return to room temperature, stirring was continued for 1 h. LC-MS was used to monitor the reaction until complete. The target compound (18 mg, 0.04 mmol, yield 46.25%) was obtained by pre-HPLC separation. MS: m / z = 482.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.64(s,1H),8.27(s,2H),7.67(d,J=0.6Hz,1H),7.53(d,J=0.8Hz,1H),7.20-7.16( m,1H),4.62(d,J=10.8Hz,1H),4.34–4.26(m,1H),3.99(d,J=1.6Hz,3H),2.43-2.33(m,1H),1.75(s,3H).

[0321] Preparation Example 9: Preparation of (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carbamoyl)thiophene-3-yl)boronic acid (compound 49)

[0322] Compounds 1-7 (30 mg, 0.08 mmol) were dissolved in anhydrous DMF (5 mL), and 5-aminothiophene-3-boronic acid (36 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath conditions. After allowing the mixture to return to room temperature, stirring was continued for 1 h. The reaction was monitored by LC-MS to ensure complete reaction of the starting material. The target compound (16 mg, 0.03 mmol, yield 41.25%) was obtained by Pre-HPLC separation. MS: m / z = 482.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.64(s,1H),8.27(s,2H),7.67(d,J=0.6Hz,1H),7.53(d,J=0.8Hz,1H),7.20-7.16( m,1H),4.62(d,J=10.8Hz,1H),4.34–4.26(m,1H),3.99(d,J=1.6Hz,3H),2.43-2.33(m,1H),1.75(s,3H).

[0323] Preparation Example 10: Preparation of (6-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carbamate)-1H-indole-4-yl)boronic acid (compound 53)

[0324] Compounds 1-7 (30 mg, 0.08 mmol) were dissolved in anhydrous DMF (5 mL), and 6-amino-1H-indole-4-boronic acid (43 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath conditions. After allowing the mixture to return to room temperature, stirring was continued for 1 h. The reaction was monitored by LC-MS to ensure complete reaction of the starting material. The target compound (15.4 mg, 0.03 mmol, yield 40.50%) was obtained by Pre-HPLC separation. MS: m / z = 515.2, [M+H] + , 1 H NMR(400MHz,DMSO)δ10.85(s,1H),10.09(s,1H),7.91(s,1H),7.76(s,2H),7.23-7.11(m,4H),6.6 6(s,1H),4.67(d,J=10.8Hz,1H),4.35–4.26(m,1H),3.97(s,3H),2.42–2.28(m,2H),1.74(s,3H).

[0325] Preparation Example 11: Preparation of (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carbamoyl)-1H-indazol-7-yl)boronic acid (compound 54)

[0326] Compounds 1-7 (50 mg, 0.14 mmol) were dissolved in anhydrous DMF (5 mL), and 5-amino-1H-indazole-7-boric acid (75 mg, 0.42 mmol) was added. TCFH (196 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath conditions. After allowing the mixture to return to room temperature, stirring was continued for 1 h. The reaction was monitored by LC-MS to ensure complete reaction of the starting material. The target compound (5.39 mg, 0.03 mmol, yield 7.47%) was obtained by Pre-HPLC separation. MS: m / z = 516.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ12.32(s,1H),10.22(s,1H),8.36(s,2H),8.09(s,1H),7.99(s,1H),7.65(d,J=1.6Hz,1H),7. 27–7.15(m,2H),4.69(d,J=10.8Hz,1H),4.37–4.29(m,1H),4.00(d,J=1.6Hz,3H),2.46-2.33(m,2H),1.77(s,3H).

[0327] Preparation Example 12: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carbamate)phenyl)boronic acid (compound 82)

[0328] Compounds 1-7 (30 mg, 0.08 mmol) were dissolved in anhydrous DMF (5 mL), and 4-aminophenylboronic acid (33 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath conditions. After allowing the mixture to return to room temperature, stirring was continued for 1 h. The reaction was monitored by LC-MS to ensure complete reaction. The target compound (21 mg, 0.04 mmol, yield 55%) was obtained by Pre-HPLC separation. MS: m / z = 476.2, [M+H] + , 1H NMR (400MHz, DMSO) δ10.24(s,1H),7.89(s,2H),7.68(d,J=8.3Hz,2H),7.45(d,J=8.3Hz,2H),7.22–7.09( m,2H),4.61(d,J=10.7Hz,1H),4.35–4.23(m,1H),3.97(d,J=1.4Hz,3H),2.47-2.25(m,2H),1.73(s,3H).

[0329] Preparation Example 13: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-3-fluorophenyl)boronic acid (compound 87)

[0330] Compounds 1-7 (30 mg, 0.08 mmol) were dissolved in anhydrous DMF (5 mL), and 4-amino-3-fluorophenylboronic acid (70 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath conditions. After allowing the mixture to return to room temperature, stirring was continued for 1 h. The reaction was monitored by LC-MS to ensure complete reaction of the starting material. The target compound (19.7 mg, 0.04 mmol, yield 50.01%) was obtained by Pre-HPLC separation. MS: m / z = 494.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.04(s,1H),8.12(s,2H),7.79(t,J=7.8Hz,1H),7.53–7.49(m,2H),7.19-7.15(m ,2H),4.84(d,J=10.8Hz,1H),4.30-4.23(m,1H),3.95(d,J=1.2Hz,3H),2.37-2.31(m,2H),1.73(s,3H).

[0331] Preparation Example 14: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carbamate)-3-methoxyphenyl)boronic acid (compound 94)

[0332] Compounds 1-7 (30 mg, 0.08 mmol) were dissolved in anhydrous DMF (5 mL), and 4-amino-3-methoxyphenylboronic acid (63 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath conditions. After allowing the mixture to return to room temperature, stirring was continued for 1 h. The reaction was monitored by LC-MS to ensure complete reaction of the starting material. The target compound (17 mg, 0.03 mmol, yield 42.10%) was obtained by Pre-HPLC separation. MS: m / z = 506.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ9.42(s,1H),8.01(s,2H),7.88(d,J=8.0Hz,1H),7.42(s,1H),7.33(d,J=8.0Hz,1H),7.28–7.15(m, 2H), 5.00 (d, J = 10.7Hz, 1H), 4.29 (d, J = 8.0Hz, 1H), 3.96 (d, J = 1.2Hz, 3H), 3.81 (s, 3H), 2.36–2.31 (m, 2H), 1.75 (s, 3H).

[0333] Preparation Example 15: Preparation of (2-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carbamoyl)pyrimidin-5-yl)boronic acid (compound 111)

[0334] Compounds 1-7 (30 mg, 0.08 mmol) were dissolved in anhydrous DMF (5 mL), and 2-aminopyrimidine-5-boric acid (34 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath conditions. After allowing the mixture to return to room temperature, stirring was continued for 1 h. The reaction was monitored by LC-MS to ensure complete reaction of the starting material. The target compound (23.9 mg, 0.05 mmol, yield 62.50%) was obtained by Pre-HPLC separation. MS: m / z = 478.2, [M+H] + , 1 H NMR(400MHz,DMSO)δ10.90(s,1H),8.83(s,2H),8.46(s,2H),7.19–7.14(m,2H),4.92(d, J=10.2Hz,1H),4.36–4.28(m,1H),3.95(d,J=1.6Hz,3H),2.40–2.28(m,2H),1.72(s,3H).

[0335] Preparation Example 16: Preparation of 4-(3-(3,4-difluoro-2-methoxyphenyl)-5,5-dimethyltetrahydrothiophene-2-carbamoyl)pyridine amide (compound 134)

[0336] Step 1: Synthesis of methyl 4-(3-(3,4-difluoro-2-methoxyphenyl)-5,5-dimethyltetrahydrothiophene-2-carboxamide)pyridinecarboxylate

[0337] Add 2-7 (500 mg, 1.65 mmol), acetonitrile (10 mL), NMI (583 mg, 5.7 mmol), and methyl 4-aminopyridinecarboxylate (275 mg, 1.82 mmol) to a dry round-bottom flask. Stir until homogeneous, then add TCFH (693 mg, 2.4 mmol) and continue stirring at room temperature for 1 h. Quench the reaction with water, concentrate under reduced pressure, add water to the residue, extract three times with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by Pre-HPLC to obtain the target compound (523 mg, 1.2 mmol, yield 78.1%). MS: m / z = 437.1, [M+H] + .

[0338] Step 2: Synthesis of 4-(3-(3,4-difluoro-2-methoxyphenyl)-5,5-dimethyltetrahydrothiophene-2-carboxamide)pyridine amide

[0339] The product from step one (523 mg, 1.2 mmol) and a 2M ammonia solution in methanol (10 mL) were added to a hydrothermal reactor. The reaction was heated to 60 °C and stirred overnight. The system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated by Pre-HPLC to obtain the target compound (283 mg, 0.67 mmol, yield 56.1%). MS: m / z = 422.1, [M+H] + . 1 H NMR (400MHz, DMSO) δ10.60(s,1H),8.45(d,J=5.2Hz,1H),8.18(s,1H),8.06(s,1H),7.74–7.57(m ,2H),7.29-7.12(m,2H),4.40(s,2H),3.90(s,3H),2.30-2.12(m,2H),1.60(s,3H),1.48(s,3H).

[0340] Chiral separation method: OJ-H column, column temperature 30℃, mobile phase (n-hexane-anhydrous ethanol-isopropanol-diethylamine = 80:16:4:0.05), flow rate 0.6 mL / min. Compound 134-A (retention time 14.689 min), compound 134-B (retention time 17.899 min).

[0341] Preparation Example 17: Preparation of 4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carbamoyl)pyridine amide (compound 139)

[0342] Step 1: Synthesis of methyl 4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)pyridinecarboxylate (139-1)

[0343] Intermediate 1-7 (837 mg, 2.35 mmol), DMF (30 mL), NMI (1.17 g, 11.4 mmol), and methyl 4-aminopyridinecarboxylate (550 mg, 3.64 mmol) were added to a dry round-bottom flask. TCFH (2.08 mg, 7.2 mmol) was added under ice bath conditions. After allowing the mixture to return to room temperature, stirring was continued for 1 h. The reaction was quenched with water (20 mL), and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed three times with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by Pre-HPLC to obtain the target compound (910 mg, 1.86 mmol, yield 78.99%). MS: m / z = 491.1, [M+H] + .

[0344] Step 2: Synthesis of 4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carbamoyl)pyridine amide (compound 139)

[0345] The product from step one (910 mg, 1.86 mmol) and a 2M ammonia methanol solution (15 mL) were added to a hydrothermal reactor. The system was heated to 60 °C and stirred overnight. The system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated by Pre-HPLC to obtain the target compound (711 mg, 1.5 mmol, yield 80.6%), MS: m / z = 476.3, [M+H]. + , 1H NMR (400MHz, DMSO) δ10.81(s,1H),8.46(d,J=5.5Hz,1H),8.15(d,J=1.7Hz,1H),8.03(s,1H),7.67(dd,J=5.5,2.0Hz,1H),7.6 0(s,1H),7.28–7.09(m,2H),4.61(d,J=10.6Hz,1H),4.39-7.18(m,1H),3.97(d,J=1.5Hz,3H),2.47-2.13(m,2H),1.74(s,3H).

[0346] The product from step two was separated using the following chiral separation method: AD-H column, column temperature 30℃, mobile phase (n-hexane-anhydrous ethanol-isopropanol-diethylamine = 80:16:4:0.05), flow rate 1 mL / min, and the fraction with a retention time of approximately 5.3 min was dried to obtain compound II.

[0347] Preparation Example 18: Preparation of N-(3-carbamoyl-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (compound 146).

[0348] Step 1: Synthesis of methyl 5-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carbamate-2-fluorobenzoate (compound 146-1).

[0349] Compounds 1-7 (50.7 mg, 0.1 mmol) were completely dissolved in 3 mL of dry DMF. Methyl 5-amino-2-fluorobenzoate (169.1 mg, 0.1 mmol), NMI (240.2 mg, 3.0 mmol), and TCFH (420 mg, 0.15 mmol) were added sequentially under ice bath conditions. After the additions were complete, the mixture was allowed to return to room temperature and reacted for another 4 hours. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was washed three times with water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by Pre-HPLC to obtain the target compound (22.3 mg, 0.044 mmol, yield 44.0%). MS: m / z = 508.2, [M+H] + .

[0350] Step 2: Synthesis of N-(3-carbamoyl-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (compound 146)

[0351] The product from step one (22.3 mg, 0.044 mmol) was added to 2 mL of 7 M NH3 MeOH solution and stirred overnight at room temperature. After the reaction was complete, the product was concentrated to obtain the crude product. Pre-HPLC separation yielded the target compound (17 mg, 0.034 mmol, yield 77.2%). MS: m / z = 493.2, [M+H] + . 1 H NMR (400MHz, DMSO) δ10.42(s,1H),7.80(dd,J=6.4,2.8Hz,1H),7.71–7.56(m,3H),7.18(dt,J=10.8,8.5H z,3H),4.57(d,J=10.7Hz,1H),4.32–4.20(m,1H),3.96(d,J=1.8Hz,3H),2.43–2.29(m,2H),1.73(s,3H).

[0352] Preparation Example 19: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (compound 170)

[0353] Compounds 1-7 (30.0 mg, 0.084 mmol) were dissolved in 1.0 mL of dry MeCN, and T3P (267.8 mg, 0.842 mmol) and Et3N (68.16 mg, 0.673 mmol) were added sequentially. The reaction was carried out at 60 °C for 0.5 h, followed by the addition of 4-aminopyridin-2(1H)-one (13.9 mg, 0.126 mmol). The reaction was continued at 60 °C for 3.0 h. The target compound (13.0 mg, 0.289 mmol, yield 34.43%) was obtained by pre-HPLC. MS: m / z = 449.2, [M+H] + . 1 H NMR (400MHz, DMSO) δ11.23(s,1H),10.31(s,1H),7.24(d,J=7.2Hz,1H),7.20–7.14(m,2H),6.60(d,J=2.0Hz,1H),6.18(dd,J=7.2 ,1.9Hz,1H),4.55(d,J=10.6Hz,1H),4.29–4.18(m,1H),3.96(d,J=1.9Hz,3H),2.44–2.37(m,1H),2.33–2.26(m,1H),1.71(s,3H).

[0354] Preparation Example 20: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (compound 172)

[0355] Compounds 1-7 (30 mg, 0.084 mmol) were dissolved in anhydrous DMF (2 mL), and 4-amino-1-methylpyridin-2(1H)-one (16 mg, 0.13 mmol) and NMI (33 mg, 0.4 mmol) were added. The mixture was stirred in an ice bath. TCFH (56 mg, 0.2 mmol) was added to the reaction flask in one go, and the mixture was stirred at room temperature for 2 hours. 10 mL of water was added during the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by Pre-HPLC to obtain the target compound (13 mg, 0.028 mmol, yield 33%). MS: m / z = 463.1, [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.76(s,1H),7.23(d,J=7.4Hz,1H),7.02(d,J=6.2Hz,1H),6.95–6.78(m,2H),6.54(s,1H) ,4.49(d,J=10.7Hz,1H),4.29–4.11(m,1H),4.00(d,J=2.0Hz,3H),3.52(s,3H),2.47–2.16(m,2H),1.75(s,3H).

[0356] Preparation Example 21: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (compound 176)

[0357] Compounds 1-7 (30.0 mg, 0.084 mmol) were dissolved in DMF (1.5 mL), and 5-aminopyridin-2(1H)-one (15.0 mg, 0.126 mmol) and HOBt (24.0 mg, 0.168 mmol) were added. The reaction flask was placed in an ice-water bath, and DIC (33.0 mg, 0.252 mmol) was added. The mixture was allowed to warm naturally to room temperature and the reaction was continued for 4 hours. The reaction solution was separated by Pre-HPLC to obtain the target compound (20.8 mg, 0.046 mmol, yield 55.2%). MS: m / z = 449.2, [M+H] + , 1H NMR (400MHz, DMSO) δ11.25(s,1H),10.06(s,1H),7.77(d,J=2.8Hz,1H),7.30(dd,J=9.7,2.9Hz,1H),7.20–7.10(m,2H),6 .30(d,J=9.7Hz,1H),4.50(d,J=10.8Hz,1H),4.29–4.16(m,1H),,3.95(d,J=1.8Hz,3H),2.45–2.23(m,2H),1.71(s,3H).

[0358] Preparation Example 22: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-deuterium-2-carboxamide (compound 177)

[0359] Compounds 1-8 (40.0 mg, 0.112 mmol) were dissolved in DMF (2.0 mL), and 5-aminopyridin-2(1H)-one (18.0 mg, 0.168 mmol) and HOBt (30.0 mg, 0.224 mmol) were added. DIC (42.0 mg, 0.336 mmol) was added at 0 °C, and the mixture was allowed to warm naturally to room temperature and reacted for another 4 hours. The reaction solution was separated by Pre-HPLC to obtain the target compound (27.6 mg, 0.061 mmol, yield 54.8%). MS: m / z = 450.1, [M+H] + . 1 H NMR (400MHz, DMSO) δ11.31 (s, 1H), 10.05 (s, 1H), 7.77 (d, J = 2.8Hz, 1H), 7.36-7.25 (m, 1H), 7.22-7.01 (m,2H),6.33–6.28(m,1H),4.31-4.17(m,1H),3.95(d,J=1.9Hz,3H),2.46–2.23(m,2H),1.71(s,3H).

[0360] Preparation Example 23: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (compound 178)

[0361] Compounds 1-7 (30.0 mg, 0.084 mmol) were dissolved in 1.0 mL of dry MeCN. T3P (267.8 mg, 0.842 mmol) and Et3N (68.16 mg, 0.673 mmol) were added sequentially, and the mixture was stirred at 60 °C for 0.5 h. Then, 5-amino-1-methylpyridin-2(1H)-one (15.6 mg, 0.126 mmol) was added, and the mixture was stirred at 60 °C for another 3.0 h. The reaction solution was separated by Pre-HPLC to obtain the target compound (13.0 mg, 0.028 mmol, yield 33.45%), MS: m / z = 463.2, [M+H]. + . 1 H NMR (400MHz, DMSO) δ10.42(s,1H),7.80(dd,J=6.4,2.8Hz,1H),7.71–7.56(m,3H),7.24–7.11(m,3H ),4.57(d,J=10.7Hz,1H),4.32–4.20(m,1H),3.96(d,J=1.8Hz,3H),2.43–2.31(m,2H),1.73(s,3H).

[0362] Preparation Example 24: Synthesis of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-deuter-2-carboxamide (compound 179)

[0363] Compounds 1-8 (35 mg, 0.098 mmol) were dissolved in anhydrous DMF (2 mL), and 5-amino-1-methylpyridin-2(1H)-one (18 mg, 0.14 mmol) and NMI (33 mg, 0.4 mmol) were added. The mixture was stirred at 0 °C. TCFH (56 mg, 0.2 mmol) was added to the reaction flask in one go, and the mixture was stirred at room temperature for 2 hours. The reaction solution was separated by Pre-HPLC to obtain the target compound (15 mg, 0.032 mmol, yield 32%). MS: m / z = 464.2, [M+H] + . 1 H NMR (400MHz, DMSO) δ10.05(s,1H),8.07(d,J=2.8Hz,1H),7.30–7.21(m,1H),7.20–7.14(m,2H),6.35(d ,J=9.7Hz,1H),4.27–4.17(m,1H),3.96(d,J=1.8Hz,3H),3.36(s,3H),2.44–2.25(m,2H),1.71(s,3H).

[0364] Preparation Example 25: Preparation of Crystal Form I of Compound II

[0365] Add 25 mL of acetone to 5 g of compound II, heat and stir to 50 °C until dissolved, then cool to 20 °C and add 125 mL of purified water dropwise to the dissolved solution at a constant temperature. After the addition is complete, cool to 20 °C, allow crystals to grow for 30 min, filter, and dry under vacuum at 55 °C and -0.07 MPa for 16 h to obtain 4.85 g of compound II, crystal form I. The XRPD pattern of the obtained compound II, crystal form I, is shown in Figure 1.

[0366] Example 1

[0367] Using a Process11 hot melt extruder, the compound of Formula II was mixed with different matrix materials and then a solid dispersion was prepared according to the hot melt extrusion process in Table 1.

[0368] Table 1: Process conditions for preparing solid dispersions of Formula II compounds with different matrix materials

[0369] Example 2

[0370] The formulation and preparation method of solid dispersion tablets containing compound II are as follows:

[0371] (1) Solid dispersion particles: The solid dispersions of Examples 1-3 were pulverized to obtain solid dispersion particles with a D90 of 65 μm;

[0372] (2) Mixing: Place the solid dispersion particles, microcrystalline cellulose 301, cross-linked sodium carboxymethyl cellulose and colloidal silica in a mixer and mix for 10 min. Pass the mixture through a 50-mesh sieve and add magnesium stearate and continue mixing for 5 min.

[0373] (3) Tableting: tablets are made using an elliptical die with a diameter of 14.7*7.4mm, with a hardness of 60-100N and a tablet weight of 500mg.

[0374] (4) Coating: Prepare a 10% solution of type I film coating premix of Opadry and coat the tablet core. The weight gain of the coating is controlled at 2-4%, thus obtaining a solid dispersion tablet containing compound II.

[0375] Example 3

[0376] The formulation and preparation method of solid dispersion tablets containing compound II are as follows:

[0377] (1) Solid dispersion particles: Compound II, Soluplus and colloidal silica were mixed in a mass ratio of 20:60:1 and then a solid dispersion was prepared according to the hot melt extrusion process of Examples 1-8. The solid dispersion particles with D90 of 79 μm were then pulverized.

[0378] (2) Mixing: Place the solid dispersion particles, microcrystalline cellulose 301, cross-linked sodium carboxymethyl cellulose and colloidal silica in a mixer and mix for 10 min. Pass the mixture through a 50-mesh sieve and add sodium stearate fumarate and continue mixing for 5 min.

[0379] (3) Tableting: tablets are made using an elliptical die with a diameter of 14.7*7.4mm, with a hardness of 60-100N and a tablet weight of 500mg.

[0380] (4) Coating: Prepare a 10% solution of type I film coating premix of Opadry and coat the tablet core. The weight gain of the coating is controlled at 2-4%, thus obtaining a solid dispersion tablet containing compound II.

[0381] Example 4

[0382] The formulation and preparation method of solid dispersion tablets containing compound II are as follows:

[0383] (1) Solid dispersion particles: Compound of Formula II, copovidone VA64 and colloidal silica are mixed in a mass ratio of 20:60:1 and then a solid dispersion is prepared according to the hot melt extrusion process of Examples 1-6. The solid dispersion particles with D90 of 75 μm are then pulverized.

[0384] (2) Mixing: Place the solid dispersion particles, mannitol, cross-linked sodium carboxymethyl cellulose and colloidal silica in a mixer and mix for 10 min. Pass the mixture through a 50-mesh sieve, add sodium stearate fumarate and continue mixing for 5 min.

[0385] (3) Tableting: tablets are made using an elliptical die with a diameter of 14.7*7.4mm, with a hardness of 60-100N and a tablet weight of 500mg.

[0386] (4) Coating: Prepare a 10% solution of type I film coating premix of Opadry and coat the tablet core. The weight gain of the coating is controlled at 2-4%, thus obtaining a solid dispersion tablet containing compound II.

[0387] Example 5

[0388] The formulation is the same as in Example 2. The only difference between the preparation method and Example 2 is that the solid dispersions of Examples 1-3 are pulverized into solid dispersion particles with the particle size shown in the table below to obtain solid dispersion tablets containing compound II.

[0389] Example 6

[0390] After mixing compound I of formula II with matrix material, solid dispersions were prepared by hot melt extrusion process while maintaining the screw speed at 200 rpm according to the melt temperature in Table 2 below. The crystal form and degradation products of the solid dispersions prepared at various melt temperatures were tested, as shown in Table 2.

[0391] Table 2: Crystal forms and degradation products of solid dispersions at different melt temperatures

[0392] As shown in Table 2, when the temperature is approximately 120°C, both crystal form I of compound II and the solid dispersion prepared from the matrix material were found to contain crystal form I, indicating that during hot melt extrusion at approximately 120°C, crystal form I of compound II did not completely melt and transform into an amorphous form. When the temperature rises to approximately 140°C, 160°C, 180°C, and 200°C, no crystal form was detected, indicating that during hot melt extrusion at 140-200°C, crystal form I of compound II completely transformed into an amorphous form. However, when the temperature rises to approximately 200°C, the degradation products show a significant increasing trend. Preferably, the solid dispersion described in this disclosure can be hot melt extruded at a temperature of approximately 140°C-200°C. Preparation at higher temperatures may be riskier, as the degradation products of the compound will further increase at higher temperatures, and the polymer matrix used may also degrade. More preferably, the solid dispersion described in this disclosure is hot-melt extruded at a temperature of approximately 160°C-180°C, within which the crystal transformation of the compound and the control of degradation products are within a relatively ideal and safe range.

[0393] Comparative Example 1

[0394] The formulation and preparation method of tablets containing compound II are as follows:

[0395] (1) Pulverization: The crystal form I of compound II is pulverized into micro powder with D90≤10μm using an air jet mill;

[0396] (2) Granulation: Prepare a 4% concentration of polyvinyl chloride K30 solution; mix the pulverized form II compound crystal I with mannitol, microcrystalline cellulose PH101, cross-linked sodium carboxymethyl cellulose and sodium dodecyl sulfate, add the polyvinyl chloride K30 solution, and make soft material by stirring and shearing in a wet granulator, and granulate with a 20-mesh sieve.

[0397] (3) Drying and granulation: After the wet granules are dried at 60℃, they are granulated through a 20-mesh sieve.

[0398] (4) Mixing: The prepared granules are mixed evenly with cross-linked sodium carboxymethyl cellulose and magnesium stearate, and the tablet weight is 360g.

[0399] (5) Tableting: 10mm die is used to press tablets into tablets with a hardness of 50-90N.

[0400] (6) Coating: Prepare a 10% solution of type I film coating premix of Opadry and coat the tablet core. The weight gain of the coating is controlled at 2-4%, thus obtaining a tablet containing compound II.

[0401] Comparative Example 2

[0402] The formulation and preparation method of the suspension capsules containing compound II are as follows:

[0403] (1) Pulverization: The crystal form I of compound II is pulverized into micro powder with D90≤10μm using an air jet mill;

[0404] (2) Preparation of contents: Add the mixed fatty acid glycerides (stearin) and medium- and long-chain triglycerides to the mixing tank and stir continuously at 45°C for 10 min; add soybean lecithin to the mixing tank and stir continuously at 45°C for 10 min; add the pulverized form II compound crystal form I to the mixing tank and stir continuously at 45°C for 30 min, and keep warm for later use.

[0405] (3) Capsule filling: The contents (suspension) of the above unit dose (336g per tablet) are filled into gelatin capsules to obtain suspension capsules containing compound II.

[0406] Experimental Example 1: Monitoring the effect of the test substance on the stable overexpression of Nav1.8 channel current using manual patch-clamp technique

[0407] Experimental methods:

[0408] 1. Reagent Preparation

[0409] The test compound is soluble in dimethyl sulfoxide (DMSO).

[0410] The extracellular fluid consisted of 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl₂·6H₂O, 2 mM CaCl₂·2H₂O, 10 mM D-Glucose, 10 mM HEPES, and 1.25 mM NaH₂PO₄·2H₂O, with pH adjusted to 7.4 using NaOH. The intracellular fluid consisted of 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, and 20 mM EGTA, with pH adjusted to 7.2 using CsOH.

[0411] 2. Experimental Materials and Instruments

[0412] 1) Patch clamp amplifier: EPC 10 (HEKA)

[0413] 2) Micromanipulator: MP225 (Sutter Instrument)

[0414] 3) Inverted microscope: MF53 (Mshot)

[0415] 4) Microelectrode pulling instrument: P97 (Sutter Instrument)

[0416] 5) Capillary glass tube: BF150-86-10 (Sutter Instrument)

[0417] 3 Experimental Steps

[0418] 1) After the compound is prepared into a solution of a specified concentration, it is added to the drug delivery system tubing in sequence and labeled.

[0419] 2) Place the cell slide in the recording chamber, select suitable cells under an inverted microscope, and adjust the position of the drug delivery head.

[0420] 3) The capillary glass tube is drawn into a suitable recording electrode using a microelectrode drawing device. The electrode, filled with intracellular fluid, is then inserted into the microelectrode holder. Under an inverted microscope, the micromanipulator is adjusted to bring the recording electrode into contact with the cell. Negative pressure is applied to the electrode to create a high-resistance seal. Fast capacitance compensation is then performed, followed by continued application of negative pressure to rupture the cell membrane, establishing a whole-cell recording mode. Finally, slow capacitance compensation is performed, and relevant parameters are recorded.

[0421] 4) Once the cell current has stabilized, begin drug administration. Each drug concentration is administered for five minutes or until the current stabilizes, then monitor the next concentration. The drug solution is administered to the cells sequentially from low to high concentration through the recording bath by gravity, and a peristaltic pump is used for fluid replacement during the recording process.

[0422] 4. Test voltage procedure (resting state) and results

[0423] After whole-cell sealing was achieved, the cell voltage was clamped at -120 mV, then depolarized to 0 mV using a 50 ms square wave pulse to obtain the Nav1.8 current. This procedure was repeated every 20 s, monitoring the maximum current induced by the square wave, and the test compound was introduced after it stabilized. The strength of the current blocking was calculated after the reaction stabilized.

[0424] 5. The experimental results are shown in Tables 3 and 4 below:

[0425] Table 3: Inhibition rate determination results of the compound disclosed herein at a concentration of 10 nM

[0426] As can be seen from the data in Table 3, compounds 9, 19, 31, 48, 82, 134, 134-A, 139, II, 170, 172 and 178 of this disclosure all have good inhibitory effects at a concentration of 10 nM.

[0427] Table 4: Inhibition rate IC50 of some compounds disclosed herein 50 Measurement results

[0428] As can be seen from the data in Table 4, compound 139 of this disclosure has superior activity, being 8 times that of VX-548, while compound 134 and VX-548 have comparable activity.

[0429] Experimental Example 2: Pharmacokinetic Study of Compounds in SD Rats

[0430] Experimental animals: SD rats, male, 6-8 weeks old.

[0431] Compound preparation: First, add 5% DMSO to dissolve the compound to be tested, then add 10% Cremophor EL and 85% Saline to the final volume of the solution.

[0432] Experimental Design: SD rats were administered the test compound (2 mg / kg by injection, 10 mg / kg by oral administration; n=3) via intravenous or oral administration. The injection group was allowed unrestricted food and water. The oral administration group was fasted overnight (>12 h), but allowed unrestricted water; food was introduced 4 h after administration. Blood samples were collected from the jugular vein of SD rats at 5 min, 15 min, 0.5, 1, 2, 4, 8, and 24 h after injection, and at 15 min, 0.5, 1, 2, 4, 6, 8, and 24 h after oral administration. After anticoagulation (blood samples were placed in an ice bath after collection), the samples were centrifuged at 6000g for 5 min to separate plasma, which was stored at -70℃ for later analysis.

[0433] Sample monitoring: The concentration of the specified drug compound in plasma was determined by LC-MS / MS; the main pharmacokinetic parameters were calculated using the Winnolin 8.3 non-compartmental model.

[0434] The experimental results are shown in Table 5 below:

[0435] Table 5: Pharmacokinetic Test Results of Some Compounds in this Disclosure

[0436] As shown in Table 5, compound 139 of this disclosure exhibits superior pharmacokinetic properties in rats, with oral administration resulting in twice the exposure of VX-548. 1 / 2 It is also twice that of VX-548, indicating that compound 139 has stronger efficacy and longer analgesic duration.

[0437] Experimental Example 3: Solubility and Permeability of Compound II

[0438] The equilibrium solubility of compound II crystal form I in water, a series of pH buffer solutions within the physiological pH range, and simulated gastrointestinal media was determined. The results are detailed in Tables 6 and 7.

[0439] Table 6: Equilibrium solubility of compound I of formula II in a series of pH buffer solutions in water and physiological pH range

[0440] Table 7: Equilibrium solubility of the crystal form of compound II in simulated gastrointestinal media

[0441] Tables 6 and 7 show that even in its crystalline form, the compound of formula II exhibits low solubility at different human physiological pH levels.

[0442] In vitro Caco-2 cell experiments: The apparent permeability coefficient of compound II was higher than that of the medium-permeability drug atenol and close to that of the hyper-permeability drug minoxidil. Therefore, compound II is a medium-to-high permeability drug.

[0443] Based on data on solubility and permeability, compound II is a poorly soluble drug with medium to high permeability. It has extremely low solubility at different human physiological pH levels, and the drug's solubility greatly limits its absorption in vivo.

[0444] Experimental Example 4: Determination of Equilibrium Solubility of Solid Dispersions

[0445] The solubility of the solid dispersion prepared in Example 1 was evaluated using simulated fasting intestinal fluid (FASSIF). Specifically, the solid dispersion particles were added in excess to the simulated fasting intestinal fluid (FASSIF), and the mixture was shaken in a water bath at 37°C at a shaking frequency of 70 r / min. After shaking for 24 h, the concentration of compound II was measured. The specific results are shown in Table 8.

[0446] Table 8: Determination of equilibrium solubility of compound I of formula II and solid dispersion

[0447] Table 8 shows that the solid dispersion particles prepared with povidone, copovidone, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or hydroxypropyl cellulose and compound II exhibit more than 5 times higher equilibrium solubility in simulated fasting intestinal fluid (FASSIF) compared to crystal form I of compound II, and can continuously and stably suppress the formation of the crystal form of compound II. In particular, the solid dispersion particles prepared with hydroxypropyl methylcellulose acetate succinate, copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and compound II exhibit more than 7 times higher equilibrium solubility in simulated fasting intestinal fluid (FASSIF) compared to crystal form I of compound II. More specifically, the solid dispersion particles prepared from hydroxypropyl methylcellulose succinate of Formula II have a more than 10-fold increased equilibrium solubility in simulated fasting intestinal fluid (FASSIF) compared to the crystal form of Formula II compound I.

[0448] Experimental Example 5: Investigation of the Crystal Form Stability of Solid Dispersions

[0449] The solid dispersions prepared in Example 1 were stored at 30°C and 60% RH for one month, and their crystal stability was evaluated using XRPD. In the solid dispersions obtained in Examples 1-1 to 1-21, the compound of Formula II existed in an amorphous form. After one month of storage under the above conditions, the compound of Formula II in the solid dispersions prepared in Examples 1-1 to 1-17 still existed in an amorphous form, while crystalline forms were detected in Examples 1-18 to 1-21. The results indicate that solid dispersions prepared with compounds of Formula II using povidone, copovidone, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or hydroxypropyl cellulose as matrix materials do not exhibit crystallization after storage at 30°C and 60% RH.

[0450] Experimental Example 6: Determination of Dissolution

[0451] The dissolution rate of the pharmaceutical composition was determined according to the Dissolution and Release Determination Method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). The specific method is as follows: 900 ml of pH 1.0 hydrochloric acid solution containing 0.2% SDS was used as the dissolution medium. The rotation speed was 75 rpm. 2 ml of the filtrate was collected at 5 min, 10 min, 15 min, 30 min, 45 min, and 60 min, and the content was detected by HPLC. The HPLC detection parameters were as follows: octadecylsilane-bonded silica gel was used as the packing material (Waters XBridge C18, 4.6 mm × 150 mm, 5 μm or equivalent column); 0.1% acetic acid aqueous solution-acetonitrile (40:60) was used as the mobile phase; the flow rate was 1.0 mL per minute; the column temperature was 35℃; the detection wavelength was 254 nm; and the injection volume was 10 μL.

[0452] The dissolution rates of Examples 2-3 and Comparative Examples 1-2 are shown in Table 9 below.

[0453] Table 9: Dissolution rates of Examples 2-3 and Comparative Examples 1-2

[0454] As can be seen from the dissolution data in the table above, although Comparative Example 1 reduced the raw material particle size to D90≤10μm (the limit of general micronization) through micronization and added surfactants, the tablets prepared using a wet granulation process did not show significant improvement in solubility; only a small amount of drug dissolved. Similarly, in Comparative Example 2, although the raw material particle size was reduced to D90≤10μm through micronization and various oils were added, and a self-emulsification process was used to prepare suspension capsules, the solubility did not show significant improvement; only a small amount of drug dissolved. In contrast, the solid dispersion tablets of Examples 2 and 3 of this disclosure both achieved complete dissolution and maintained saturation within 30 minutes.

[0455] Table 10: Dissolution rates of Examples 5-1 to 5-5

[0456] As shown in Table 10, the particle size of the solid dispersion affects its dissolution rate. Solid dispersion particles with D90≤100μm, preferably D90≤70μm, exhibit rapid dissolution behavior (dissolution rate ≥85% within 30min).

[0457] Experiment Example 7: Evaluation of the bioavailability of solid dispersion particles in rats

[0458] SD rats were administered the drug via gavage at a dose of 50 mg / kg. Blood samples were collected at 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The concentration of compound II in the collected blood samples was determined by LC-MS / MS. The specific administration method was as follows:

[0459] Solid dispersion particles of Example 2: The solid dispersion particles prepared in Example 2 were diluted with physiological saline to form a suspension containing 5 mg / ml of compound II before administration, with a volume of 10 ml / kg, and were administered to 3 male SD rats by gavage.

[0460] Solid dispersion particles of Example 3: The solid dispersion particles prepared in Example 3 were diluted with physiological saline to form a suspension containing 5 mg / ml of compound II before administration, with a volume of 10 ml / kg, and were administered to 3 male SD rats by gavage.

[0461] Clarifying solution containing compound II: 0.352 mL of DMSO was added to a glass bottle containing 36.03 mg of compound II and mixed thoroughly. After the compound dissolved, 0.703 mL of Cremophor EL was added and vortexed. Finally, 5.979 mL of physiological saline was added and sonicated to vortex, yielding a clear, transparent solution with a concentration of 5.0 mg / mL. The solution was administered to three male SD rats via gavage at a volume of 10 mL / kg.

[0462] Suspension of Compound I of Formula II: A suspension of Compound I of Formula II was prepared directly with physiological saline to a concentration of 5.0 mg / mL. The suspension was administered immediately to three male SD rats via gavage at a volume of 10 ml / kg.

[0463] Table 11: Pharmacokinetic parameters of solid dispersions in rats

[0464] The above data indicate that the solid dispersion particles of Examples 2 and 3, at the same dosage, have a C0 ratio of 1.5%. max and AUC 0-t Compared to compound I of formula II, the results show significant improvements. In Example 2, the in vivo exposure (AUC) of the solid dispersion particles reached the equivalent exposure of a clear solution containing compound II. Generally, for poorly soluble compounds, it is difficult for compounds in solid form to achieve the same exposure as compounds in solution, because highly permeable drugs in solution can be directly absorbed in the gastrointestinal tract, while solid drugs must undergo a dissolution process.

[0465] Experiment Example 8: Evaluation of the bioavailability of solid dispersion tablets in standard monkeys

[0466] The standard monkey drug was administered orally at a dose of 25 mg / kg. Blood samples were collected at 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, and 72 h after administration. The concentration of compound II in the collected blood samples was determined by LC-MS / MS. The specific dosing regimen is as follows:

[0467] Solid dispersion tablets of Example 2: administered orally to standard monkeys at a dose of 25 mg / kg.

[0468] Solid dispersion tablets of Example 3: administered orally to standard monkeys at a dose of 25 mg / kg.

[0469] Clarifying solution containing compound II: 368.86 mg of compound II was dissolved in 3.659 mL of DMSO, vortexed and sonicated, then 7.319 mL of Cremophor EL was added, vortexed and sonicated again, and finally 62.209 mL of physiological saline was added to obtain a clear solution with a concentration of 5 mg / mL. This solution was administered orally to standard monkeys at a volume of 5 mL / kg.

[0470] Formula II compound crystal form I suspension: Formula II compound crystal form I was directly prepared into a suspension with a concentration of 5 mg / mL using physiological saline. It was administered orally to standard monkeys at a volume of 5 ml / kg.

[0471] Table 12: Pharmacokinetic parameters of solid dispersion tablets in standard monkeys

[0472] Data show that the solid dispersion tablets of Examples 2 and 3, at the same dosage, have the maximum plasma concentration (C0). max Both the concentration and in vivo exposure (AUC) of the solid dispersion tablets in Example 2 were significantly increased (at least 4 times) compared to crystal form I of Formula II. max The in vivo exposure (AUC) was equivalent to that of a clear solution containing compound II. This finding allows for a significant reduction in the daily dosage to achieve the desired in vivo exposure for compounds of formula II, which have extremely low solubility.

[0473] The above embodiments do not limit the scope of this application in any way. In addition to those described herein, various modifications to this disclosure will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

A composition comprising an active ingredient and at least one matrix material, wherein the active ingredient is a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, polymorph, metabolite, or prodrug thereof. in: R a Selected from Y 1 Y 2 Y 3 Y 4 Each is independently selected from O, S, N, NR. a1 and CR a2 ; R a1 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -S(O)2R 1 ; R a2 Each is independently selected from H, halogen, hydroxyl, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-6 cycloalkyl, -NR 2 R 3 -NHC(O)R 4 -C(O)OR 5 -C(O)NR 6 R 7 -SR 8 -S(O)R 9 -S(O)2R 10 -S(O)2NR 11 R 12 -S(O)(NR) 13 )R 14 -P(O)R 15 R 16 and The C mentioned 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally surrounded by one or more groups selected from hydroxyl and -NR. 19 R 20 The substituents are replaced; Or adjacent R a1 and R a2 Or two Rs a2 The atoms bonded to it form 5-6 membered heteroaromatic rings; R 1 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 19 R 20 Each is independently selected from H and C. 1-6 alkyl; R 2 R 3 Each is independently selected from H and C. 1-6 C-substituted with alkyl and carbonyl groups 1-6 alkyl; R 4 Each is independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 2-6 alkenyl; R 17 R 18 Each is independently selected from H and C. 1-6 Alkyl, or R 17 R 18 Together with the linked boron and oxygen atoms, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally surrounded by one or more atoms selected from H, halogens, and C. 1-6 Substituents of alkyl groups; Z 1 Z 2 Z 3 Z 4 Z 5 Each is independently selected from N, N + -O - and CR a3 ; R a3 Each is independently selected from H, halogen, hydroxyl, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-6 cycloalkyl, -NR 21 R 22 -NHC(O)R 23 -C(O)OR 24 -C(O)NR 25 R 26 -SR 27 -S(O)R 28 -S(O)2R 29 -S(O)2NR 30 R 31 -S(O)(NR) 32 )R 33 -P(O)R 34 R 35 and The C mentioned 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally surrounded by one or more groups selected from hydroxyl and -NR. 38 R 39 The substituents are replaced; Or two adjacent R a3 The carbon atom attached thereto forms a 5-6 membered heterocyclic group or a 5-6 membered heteroaromatic ring, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaromatic ring is optionally surrounded by one or more atoms selected from OH and C. 1-6 Substituents of alkyl groups; R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 R 38 R 39 Each is independently selected from H and C. 1-6 alkyl; R 21 R 22 Each is independently selected from H and C. 1-6 alkyl and carbonyl substituted C 1-6 Alkyl groups and -C(O)OC 1-6 alkyl; R 23 Each is independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 2-6 alkenyl; R 36 R 37 Each is independently selected from H and C. 1-6 Alkyl, or R 36 R 37 Together with the linked boron and oxygen atoms, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally surrounded by one or more atoms selected from H, halogens, and C. 1-6 Substituents of alkyl groups; V is selected from N, N + -O - and CR a4 ; R a4 Selected from H and C 1-6 alkyl; R a5 Selected from H and C 1-6 alkyl; R a6 Selected from H and C 1-6 alkyl; R b1 and R b2 Each is independently selected from H and deuterium; R b3 and R b4 Each is independently selected from H, deuterium, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl; R b5 and R b6 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl, or R b5 R b6 Together with the bonded carbon atoms, they form C 3-5 Cycloalkyl or 4-6 membered heterocyclic groups; R c Selected from H, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl and -OC 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 The cycloalkyl group is optionally surrounded by one or more groups selected from hydroxyl, carboxyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, -NR 40 R 41 C 3-6 The substituents are cycloalkyl, 3-6-membered heterocyclic, and 5-6-membered heteroaryl groups, wherein the 3-6-membered heterocyclic or 5-6-membered heteroaryl group is optionally replaced by one or more substituents selected from halogens and C. 1-6 Substituents of alkyl groups; R 40 R 41 Each is independently selected from H and C. 1-6 alkyl; X 1 X 2 X 3 X 4 Each is independently selected from N and CR c1 ; R c1 Each is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups. The composition according to claim 1, characterized in that, The compound of formula I satisfies one or more of the following conditions: 1)R a Selected from Y 1 Y 2 Y 3 Y 4 Each is independently selected from O, S, N, NR. a1 and CR a2 ; R a1 Each is independently selected from H and C. 1-4 Alkyl (e.g., methyl, ethyl, propyl, butyl), C 1-4 Halogenated alkyl groups (e.g., CF3, CHF2, CH2F) and -S(O)2R 1 (e.g., -S(O)2CH3); R a2 Each is independently selected from H, halogens (e.g., fluorine, chlorine, bromine, iodine), hydroxyl groups, -CN, C. 1-4 Alkyl (e.g., methyl, ethyl, propyl, butyl), C 1-4 Haloalkyl (e.g., CF3, CHF2, CH2F), C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-4 cycloalkyl, -NR 2 R 3 -NHC(O)R 4 -C(O)OR 5 -C(O)NR 6 R 7 SR 8 -S(O)R 9 -S(O)2R 10 -S(O)2NR 11 R 12 -S(O)(NR) 13 )R 14 -P(O)R 15 R 16 and The C mentioned 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 The haloalkoxy group is optionally surrounded by one or more groups selected from hydroxyl and -NR. 19 R 20 The substituents are replaced; Or adjacent R a1 and R a2 Or two Rs a2 The atoms bonded to it form 5-6 membered heteroaromatic rings; R 1 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 19 R 20 Each is independently selected from H and C. 1-4 alkyl; R 2 R 3 Each is independently selected from H and C. 1-4 C-substituted with alkyl and carbonyl groups 1-4 alkyl; R 4 Each is independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl and C 2-6 alkenyl; R 17 R 18 Each is independently selected from H and C. 1-4 Alkyl, or R 17 R 18 Together with the linked boron and oxygen atoms, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally surrounded by one or more atoms selected from H, halogens, and C. 1-4 Substituents of alkyl groups; Z 1 Z 2 Z 3 Z 4 Z 5 Each is independently selected from N, N + -O - and CR a3 ; R a3 Each is independently selected from H, halogens (e.g., fluorine, chlorine, bromine, iodine), hydroxyl groups, -CN, C. 1-4 Alkyl (e.g., methyl, ethyl, propyl, butyl), C 1-4 Haloalkyl (e.g., CF3, CHF2, CH2F), C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-4 cycloalkyl, -NR 21 R 22 -NHC(O)R 23 -C(O)OR 24 -C(O)NR 25 R 26 -SR 27 -S(O)R 28 -S(O)2R 29 -S(O)2NR 30 R 31 -S(O)(NR) 32 )R 33 -P(O)R 34 R 35 and The C mentioned 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 The haloalkoxy group is optionally surrounded by one or more groups selected from hydroxyl and -NR. 38 R 39 The substituents are replaced; Or two adjacent R a3 The carbon atom attached thereto forms a 5-6 membered heterocyclic group or a 5-6 membered heteroaromatic ring, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaromatic ring is optionally surrounded by one or more atoms selected from OH and C. 1-6 Substituents of alkyl groups; R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 R 38 R 39 Each is independently selected from H and C. 1-4 alkyl; R 21 R 22 Each is independently selected from H and C. 1-4 alkyl and carbonyl substituted C 1-4 Alkyl groups and -C(O)OC 1-4 alkyl; R 23 Each is independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl and C 2-6 alkenyl; R 36 R 37 Each is independently selected from H and C. 1-4 Alkyl, or R 36 R 37 Together with the linked boron and oxygen atoms, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally surrounded by one or more atoms selected from H, halogens, and C. 1-4 Substituents of alkyl groups; V is selected from N, N + -O - and CR a4 ; R a4 Selected from H and C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, butyl); R a5 Selected from H and C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, butyl); R a6 Selected from H and C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, butyl); 2)R b3 and R b4 Each is independently selected from H, deuterium, and C. 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, and butyl), C 1-4 Halogenated alkyl and C 3-6 cycloalkyl; 3)R b5 and R b6 Each is independently selected from H and C. 1-4 Alkyl, C 1-4 Halogenated alkyl and C 3-6 cycloalkyl, or R b5 R b6 Together with the bonded carbon atoms, they form C 3-5 Cycloalkyl or 4-6 membered heterocyclic groups (e.g., 4-6 membered oxygen-containing heterocyclic groups); 4)R c Selected from H, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkenyl and -OC 3-6 cycloalkyl, the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 3-6 The cycloalkyl group is optionally surrounded by one or more groups selected from hydroxyl, carboxyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-6 alkenyl, -NR 40 R 41 C 3-6 The substituents are cycloalkyl, 3-6-membered heterocyclic, and 5-6-membered heteroaryl groups, wherein the 3-6-membered heterocyclic or 5-6-membered heteroaryl group is optionally replaced by one or more substituents selected from halogens and C. 1-4 Alkyl substituents; R 40 R 41 Each is independently selected from H and C. 1-4 alkyl; 5)X 1 X 2 X 3 X 4 Each is independently selected from N and CR c1 ; R c1 Each is independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups; 6)R a Selected from Y 1 Y 2 Y 3 Y 4 Each is independently selected from O, S, N, NR. a1 and CR a2 ; R a1 Each is independently selected from H, methyl, CF3, CHF2 and -S(O)2CH3; R a2 Each is independently selected from H, fluorine, chlorine, methyl, CF3, CHF2, -C(O)NH2, -NH2 and Or adjacent R a1 and R a2 Or two Rs a2 The atoms bonded to it form 5-6 membered heteroaromatic rings; R 17 R 18 Each is independently selected from H and C. 1-4 Alkyl, or R 17 R 18 Together with the linked boron and oxygen atoms, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally surrounded by one or more atoms selected from H, halogens, and C. 1-4 Substituents of alkyl groups; Z 1 Z 2 Z 3 Z 4 Z 5 Each is independently selected from N, N + -O - and CR a3 ; R a3 Each is independently selected from H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, vinyl, cyclopropyl, -CH2OH, -C(CH3)2OH, -CH(OH)CH2(OH), -CH(OH)CH2F, -CH(NH2)CH2(OH), -CH(NH-CH3)CH2(OH), -OCH2CH(OH)CH2(OH), -NR 21 R 22 -NHC(O)R 23 -C(O)OR 24 -C(O)NR 25 R 26 -SR 27 -S(O)R 28 -S(O)2R 29 -S(O)2NR 30 R 31 -S(O)(NR) 32 )R 33 -P(O)R 34 R 35 and Preferably, R a3 Each is independently selected from H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, vinyl, cyclopropyl, -CH2OH, -C(CH3)2OH, -CH(OH)CH2(OH), -CH(OH)CH2F, -CH(NH2)CH2(OH), -NR 21 R 22 -NHC(O)R 23 -C(O)OR 24 -C(O)NR 25 R 26 -SR 27 -S(O)R 28 -S(O)2R 29 -S(O)2NR 30 R 31 -S(O)(NR) 32 )R 33 -P(O)R 34 R 35 and Or two adjacent R a3 The carbon atom attached thereto forms a 5-6 membered heterocyclic group or a 5-6 membered heteroaromatic ring, wherein the heterocyclic group is optionally substituted by one or more hydroxyl or methyl groups; R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 Each is independently selected from H and C. 1-4 alkyl; R 21 R 22 Each is independently selected from H and C. 1-4 alkyl and carbonyl substituted C 1-4 alkyl and carbonyl substituted C 2-4 alkenyl and -C(O)OC 1-4 Alkyl; preferably, R 21 R 22 Each is independently selected from H and C. 1-4 C-substituted with alkyl and carbonyl groups 1-4 alkyl; R 23 Each is independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl and C 2-6 alkenyl; R 36 R 37 Each is independently selected from H and C. 1-4 Alkyl, or R 36 R 37 Together with the linked boron and oxygen atoms, a 5-6 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally surrounded by one or more atoms selected from H, halogens, and C. 1-4 Substituents of alkyl groups; V is selected from N, N + -O - and CR a4 ; R a4 Selected from H and methyl; R a5 Selected from H and methyl; R a6 Selected from H and methyl; 7)R a3 Each is independently selected from H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, vinyl, cyclopropyl, -CH2OH, -C(CH3)2OH, -CH(OH)CH2(OH), -CH(OH)CH2F, -CH(NH2)CH2(OH), -CH(NH-CH3)CH2(OH), -OCH2CH(OH)CH2(OH), -N(CH3)-Boc, -NH(CH3), -N(CH3)2, -NH-CH2-C(O)CH3, -NH-C(O)CH2-CH3, -NH-C(O)CH2=CH2, -C(O)OCH3, -C(O)N H2, -SH, -SCH3, -S(O)CH3, -S(O)2CH3, -S(O)2NH2, -S(O)(NH)CH3, -S(O)(NCH3)CH3, -P(O)(CH3)2 and Preferably, R a3 Each is independently selected from H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, vinyl, cyclopropyl, -CH2OH, -C(CH3)2OH, -CH(OH)CH2(OH), -CH(OH)CH2F, -CH(NH2)CH2(OH), -N(CH3)-Boc, -NH(CH3), -N(CH3)2, -C(O)OCH3, -C(O)NH2, -SH, -S(O)CH3, -S(O)2CH3, -S(O)2NH2, -S(O)(NH)CH3, -S(O)(NCH3)CH3, -P(O)(CH3)2 and Or two adjacent R a3 The carbon atoms connected to it form More preferably, R a3 Each is independently selected from H, fluorine, chlorine, bromine, -C(O)NH2 and 8)R a Selected from: Preferably, R a Selected from: More preferably, R a Selected from: 9)R c Select from H, -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -OCH2CF3, -OCH2CF2CH3, -OCH2CHF2, -OCHF2、 Preferably, R c Selected from -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -OCH2CF3, -OCH2CF2CH3, -OCH2CHF2 and -OCHF2; More preferably, R c It is -OCH3. The composition according to claim 1 or 2 is characterized in that, The compound of formula I is selected from: The composition according to any one of claims 1-3 is characterized in that, The composition comprises an active ingredient and at least one matrix material, wherein the active ingredient is a compound of formula II or a pharmaceutically acceptable salt or polymorph thereof. Preferably, the active ingredient is an amorphous or polymorphic form of the compound represented by Formula II or a pharmaceutically acceptable salt thereof; More preferably, the active ingredient is an amorphous form of the compound shown in Formula II. The composition according to any one of claims 1-4 is characterized in that, The matrix material is one or more of the following: povidone, copovidone, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus); Preferably, the matrix material is one or more of hydroxypropyl methylcellulose acetate succinate, copovidone, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; More preferably, the matrix material is hydroxypropyl methylcellulose succinate. The composition according to any one of claims 1-5 is characterized in that, The mass ratio of the active ingredient to the matrix material is 1:1 to 1:5; preferably, the mass ratio of the active ingredient to the matrix material is 1:2 to 1:

4. The composition according to any one of claims 1-6 is characterized in that, The composition is particles or powder with a D90 particle size ≤ 100 μm, preferably particles or powder with a D90 particle size ≤ 70 μm. The method for preparing the composition according to any one of claims 1-7 is a hot melt extrusion method or a solvent drying method; Preferably, the preparation method is a hot melt extrusion method, which includes the following steps: Step 1: Mix the active ingredients with the matrix material evenly, and optionally add surfactants, plasticizers or flow aids (anti-sticking agents); Step 2: Heat the mixture obtained in Step 1 to a certain temperature, and then use a screw to shear and mix the mixture at high speed and extrude it into shape; Step 3: Crush the extrudate from Step 2 to obtain the composition. A pharmaceutical composition, characterized in that, It comprises the composition according to any one of claims 1-7 and at least one pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 9, characterized in that, The unit formulation of the pharmaceutical composition contains 10-200 mg of the active ingredient according to any one of claims 1-7; Preferably, the unit formulation of the pharmaceutical composition comprises 12.5 mg, 25 mg, 50 mg, 75 mg, or 100 mg of the active ingredient according to any one of claims 1-7. The pharmaceutical composition according to claim 9 or 10 is characterized in that, The pharmaceutical composition is in the form of tablets, capsules, granules or other oral dosage forms. The pharmaceutical composition according to any one of claims 9-11 is characterized in that, The pharmaceutically acceptable carrier is one or more of the following: filler, disintegrant, binder, flow aid, and lubricant; The filler is one or more selected from mannitol, mannitol complex, sorbitol, lactose, sucrose, lactose complex, microcrystalline cellulose, microcrystalline cellulose derivatives (such as silicified microcrystalline cellulose), starch, pregelatinized starch, modified starch, calcium phosphate, calcium carbonate, and dicalcium phosphate; preferably, the filler is one or more selected from mannitol, mannitol complex, microcrystalline cellulose, microcrystalline cellulose derivatives (such as silicified microcrystalline cellulose), and dicalcium phosphate. The disintegrant is one or more selected from croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch; preferably, the disintegrant is croscarmellose sodium. The adhesive is one or more selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, methylcellulose, and polyvinyl alcohol; preferably, the adhesive is one or more selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, and copovidone. The flow aid is one or more of colloidal silica, silica, fumed silica, and talc; preferably, the flow aid is one or two of colloidal silica and silica. The lubricant is one or more of magnesium stearate, calcium stearate, magnesium lauryl stearate, stearic acid, sodium stearate, glyceryl sorbate, and hydrogenated castor oil; preferably, the lubricant is one or both of magnesium stearate and sodium stearate. The pharmaceutical composition according to any one of claims 9-12 is characterized in that, The pharmaceutical composition comprises the following components in weight percentages: 25%-85.7% composition, 5%-73.8% filler, 1%-10% disintegrant, 0%-5% binder, 0.1%-2% flow aid, and 0.1%-2% lubricant; Preferably, the pharmaceutical composition comprises the following components in weight percentage: 42.9%-83.3% composition, 10%-53.1% filler, 3%-7% disintegrant, 0%-3% binder, 0.5%-1.5% flow aid, and 0.5%-1.5% lubricant; More preferably, the pharmaceutical composition comprises the following components in weight percentages: 57.1%-80% composition, 13%-38.9% filler, 3%-5% disintegrant, 0.5%-1% flow aid, and 0.5%-1% lubricant. The method for preparing the pharmaceutical composition according to any one of claims 9-13, wherein the pharmaceutical composition is a solid dispersion tablet, characterized in that, The method includes the following steps: (1) Premixing; the composition according to any one of claims 1-7 is mixed uniformly with optional fillers, disintegrants, binders, and flow aids; (2) Sieving: Pass the premix through a sieve with a mesh size of 20-60 mesh; (3) Final mixing: Add the sieved premix to the lubricant and mix thoroughly; (4) Tableting: The mixture is compressed into tablets with a hardness controlled at 50-180N; (5) Coating: Coating the tablet core, with the weight gain controlled at 1%-6%. Use of the composition according to any one of claims 1-7 or the pharmaceutical composition according to any one of claims 9-13 in the preparation of a medicament for the prevention and / or treatment of NaV1.8-related diseases; preferably, the NaV1.8-related disease is pain; more preferably, the NaV1.8-related disease is selected from chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from bunion removal, hernia repair, or abdominoplasty) and visceral pain; even more preferably, the NaV1.8-related disease is postoperative pain.

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