Nano-injection, and preparation method therefor and use thereof

Abstract

Provided are a nano-injection, and a preparation method therefor and a use thereof. The nano-injection has good stability, a controllable particle size, and a narrow particle size distribution range; and the nano-injection can be used for intravenous injection, acts rapidly, can effectively control drug burst release during injection, ensures steady drug release, provides a long duration of action, exhibits an excellent analgesic effect, and offers good safety.

Description

Nano injection and preparation method and use thereof

[0001] Reference of Related Applications

[0002] The present disclosure claims priority to the invention patent application with the application number of 202411371126.X and the invention name of "Nano injection and preparation method and use thereof" filed with the China Patent Office on September 29, 2024, and the invention patent application with the application number of 202411448275.1 and the invention name of "Nano injection and preparation method and use thereof" filed with the China Patent Office on October 16, 2024, the contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0003] The present disclosure belongs to the field of pharmaceutical preparations, and relates to a nano injection and a preparation method and use thereof. BACKGROUND

[0004] The incidence of pain in the world is about 35% to 45%. According to the data of "China Pain Medicine Development Report (2020)", there are more than 300 million chronic pain patients in China, and the number is increasing by 10-20 million per year.

[0005] The pathogenesis of pain is relatively complex, which makes the effect of many treatment methods not satisfactory. The existing pain drugs usually have low tolerance, poor long-term safety, potential drug abuse, and the phenomenon of dependence on opioid drugs for moderate and severe pain. The commonly used analgesic drugs are mainly non-steroidal anti-inflammatory drugs and opioid analgesic drugs. The analgesic effect of non-steroidal anti-inflammatory drugs is weak, and there is a ceiling effect; the core mechanism of opioid drugs is to reduce the transmission and perception of pain signals by binding to opioid receptors, which plays a role in pain relief on the central and peripheral nervous systems. However, in addition to the pain transmission pathway, there are also opioid receptors in the central nervous system, so after using opioid drugs, other parts of the opioid receptors will also be stimulated, thereby producing various side effects and addiction, and further producing tolerance problems. Therefore, opioid analgesics generally have addiction problems, and drug abuse is serious. In 2016, the US Food and Drug Administration (FDA) has issued a warning to limit the use of opioid analgesics.

[0006] NaV1.8 is a tetrodotoxin-insensitive sodium channel mainly expressed on nociceptive neurons, which plays a key role in the pain signal transmission of the peripheral nervous system and is a main selective action target for pain treatment. NaV1.8 inhibitors can block the transmission of pain signals from the peripheral nervous system to the central nervous system, thereby producing analgesic effect. VX-548, a typical representative of the NaV1.8 inhibitors, is a product of Vertex, USA. The phase III clinical study of VX-548 showed positive results, and VX-548 does not produce addiction compared with opioid drugs in the treatment of moderate to severe acute pain. VX-548 has been granted fast track qualification and breakthrough therapy designation by the US FDA for the treatment of moderate to severe acute pain.

[0007] Currently, there are several NaV1.8 inhibitors in clinical or preclinical development, and their oral activity and high selectivity have been confirmed by research. These inhibitors are superior to opioid drugs in terms of analgesic effect and non-addiction. Research has found that most of these inhibitors are poorly soluble drugs with extremely low solubility at different human physiological pHs. It is difficult to prepare an injection using a solubilizer or an organic solvent. Oral dosage forms have problems such as slow onset of analgesic effect and unsuitable for oral swallowing after surgery. Therefore, it is necessary to develop an injection with rapid onset and convenient clinical use. SUMMARY

[0008] In one aspect, the present application provides a nano-injection containing an active ingredient and at least one pharmaceutically acceptable carrier, which has analgesic effect, especially for postoperative analgesia, has excellent analgesic effect, good stability, controllable particle size, narrow particle size distribution range, can be used for intravenous injection, has rapid onset, can effectively control drug burst during injection, has stable drug release, long action time, and excellent safety. The active ingredient is a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, polymorph, metabolite or prodrug thereof,

[0009] wherein:

[0010] R a is selected from

[0011] Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from O, S, N, N-R a1 and C-R a2 ;

[0012] R a1 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl and -S(O)2R1 ;

[0013] R a2 each independently is selected from the group consisting of H, halogen, hydroxyl, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 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 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy is optionally substituted with one or more substituents selected from the group consisting of hydroxyl and -NR 19 R 20 ;

[0014] or adjacent R a1 and R a2 or two R a2 with the atoms to which they are attached form a 5-6 membered heteroaromatic ring;

[0015] 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 independently is selected from the group consisting of H and C 1-6 alkyl;

[0016] R2 R 3 each independently selected from H, C 1-6 alkyl and carbonyl substituted C 1-6 alkyl;

[0017] R 4 each independently selected from C 1-6 alkyl, C 1-6 haloalkyl and C 2-6 alkenyl;

[0018] R 17 R 18 each independently selected from H and C 1-6 alkyl, or R 17 R 18 and the boron and oxygen atoms to which they are attached form a 5-6 membered heterocyclyl group, said 5-6 membered heterocyclyl group being optionally substituted by one or more substituents selected from H, halogen and C 1-6 alkyl;

[0019] Z 1 Z 2 Z 3 Z 4 Z 5 each independently selected from N, N + -O - and C-R a3 ;

[0020] R a3 each independently selected from H, halogen, hydroxyl, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 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 said C 1-6 alkyl, C 1-6haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy optionally substituted with one or more substituents selected from the group consisting of hydroxy and -NR 38 R 39 ; and

[0021] or two R a3 adjacent to each other form, together with the carbon atom to which they are attached, a 5-6 membered heterocyclyl or 5-6 membered heteroaryl ring, said 5-6 membered heterocyclyl or 5-6 membered heteroaryl ring being optionally substituted with one or more substituents selected from the group consisting of OH and C 1-6 alkyl;

[0022] 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 independently selected from the group consisting of H and C 1-6 alkyl;

[0023] R 21 , R 22 each independently selected from the group consisting of H, C 1-6 alkyl, carbonyl-substituted C 1-6 alkyl, carbonyl-substituted C 2-6 alkenyl and -C(O)OC 1-6 alkyl; preferably, R 21 , R 22 each independently selected from the group consisting of H, C 1-6 alkyl, carbonyl-substituted C 1-6 alkyl and -C(O)OC 1-6 alkyl;

[0024] R 23 each independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl and C 2-6 alkenyl;

[0025] R 36 , R 37 each independently selected from the group consisting of H and C 1-6 alkyl, or R 36 , R 37 together with the boron and oxygen atoms to which they are attached form a 5-6 membered heterocyclyl, said 5-6 membered heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of H, halogen and C1-6 Substituents of alkyl groups;

[0026] V is selected from N, N + -O - and CR a4 ;

[0027] R a4 Selected from H and C 1-6 alkyl;

[0028] R a5 Selected from H and C 1-6 alkyl;

[0029] R a6 Selected from H and C 1-6 alkyl;

[0030] R b1 and R b2 Each is independently selected from H and deuterium;

[0031] 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;

[0032] 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;

[0033] 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 1-6haloalkyl, C 2-6 alkenyl, -NR 40 R 41 , C 3-6 cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl, said 3-6 membered heterocyclyl or 5-6 membered heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen and C 1-6 alkyl;

[0034] R 40 , R 41 are each independently selected from the group consisting of H and C 1-6 alkyl;

[0035] X 1 , X 2 , X 3 , X 4 are each independently selected from the group consisting of N and C-R c1 ;

[0036] R c1 are each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0037] In some embodiments, the average particle size of the nano-injection ranges from 100 nm to 800 nm, preferably from 100 nm to 500 nm, more preferably from 100 nm to 300 nm, further preferably from 150 nm to 250 nm.

[0038] In another aspect, the present application also provides a method for preparing a nano-injection, the method comprising the following steps:

[0039] (a) preparing a surfactant-containing solution A, dispersing an active ingredient into the solution A to obtain a suspension B;

[0040] (b1) subjecting the suspension B to ball milling in a ball mill to obtain a suspension C; or,

[0041] (b2) subjecting the suspension B to homogenization to obtain a suspension D; or,

[0042] (b3) subjecting the suspension B to ball milling in a ball mill, and further subjecting to homogenization to obtain a suspension E; and

[0043] (c) adding a stabilizer.

[0044] In some embodiments, the method further comprises the following step:

[0045] (d) lyophilization.

[0046] In another aspect, the present application also provides use of the nano-injection of the present application in the preparation of a medicament for preventing and / or treating a NaV1.8 related disease, preferably the NaV1.8 related disease is pain.

[0047] In another aspect, the present application also provides the nano-injection of the present application for preventing and / or treating a NaV1.8 related disease, preferably the NaV1.8 related disease is pain.

[0048] In another aspect, the present application also provides a method for preventing and / or treating a NaV1.8 related disease, comprising administering to an individual a therapeutically effective amount of the nano-injection of the present application, preferably the NaV1.8 related disease is pain.

[0049] Definitions and Descriptions

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. References to techniques employed herein are intended to refer to the techniques as commonly understood by those skilled in the art, including variations or substitutions of techniques or equivalents of techniques that are apparent to those skilled in the art. Although the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate the understanding of the present disclosure.

[0051] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," or "involve" and other variations thereof, are intended to cover a non-exclusive inclusion such that a process, method, article, or apparatus that comprises, includes, has, contains, or involves a list of elements does not include only those elements but can include other elements not expressly listed or inherent to such process, method, article, or apparatus.

[0052] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. References to techniques employed herein are intended to refer to the techniques as commonly understood by those skilled in the art, including variations or substitutions of techniques or equivalents of techniques that are apparent to those skilled in the art. Although the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate the understanding of the present disclosure.

[0053] The term "alkyl" herein is a saturated straight or branched chain aliphatic hydrocarbon radical of from 1 to 20 carbon atoms, wherein the alkyl group can be independently optionally substituted with one or more substituents described in the present disclosure. The term "C 1-6 The term "alkyl" refers to a straight chain or branched chain radical having from 1 to 6 carbon atoms. The term "C 1-4 The term "alkyl" refers to a straight chain or branched chain radical having from 1 to 4 carbon atoms, optionally substituted with one or more (such as 1 to 4) suitable substituents such as halogen. Examples of alkyl groups also include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), 2-methylpropyl or isobutyl (-CH2CH(CH3)2), 1-methylpropyl or sec-butyl (-CH(CH3)CH2CH3), t-butyl (-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-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-l-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, and the like. The terms "alkyl" and its prefix "alk" as used herein, encompass both straight chain and branched saturated carbon chains.

[0054] The term "carbonyl-substituted C 1-6 The term "carbonyl-substituted C 1-6 The term "carbonyl-substituted C 1-6The 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.

[0055] 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.

[0056] 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(=0) t NH2, triazolyl, tetrazolyl, -(CR 3b R 3c ) n -NH2, alkyl, alkyl-S(=0) t -, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, amino, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, halo, nitro, aryloxy, hydroxyalkoxy, alkanoyl, benzyl, cyclopropyl, phenyl, alkyl-C(=0)-, alkyl-C(=0)-NH-, carboxamido or alkoxyalkyl, etc., and t is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. For example, C3-8cycloalkyl, C3-6cycloalkyl.

[0057] Examples of cycloalkyl further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-allyl, 1-cyclopentyl-2-allyl, 1-cyclopentyl-3-allyl, cyclohexyl, 1-cyclohexyl-1-allyl, 1-cyclohexyl-2-allyl, 1-cyclohexyl-3-allyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl, and the like.

[0058] As used herein, the term "halogen" group is defined to include fluorine, chlorine, bromine, or iodine.

[0059] As used herein, the term "halo" refers to substitution by one or more (such as 1 to 3) same or different halogen atoms.

[0060] As used herein, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) same or different halogen atoms. For example, the term "C 1-6 haloalkyl" refers to haloalkyl groups having 1 to 6 carbon atoms, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3, and the like.

[0061] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted by one or more (such as 1 to 3) same 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, and the like.

[0062] As used herein, the term "alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and in which one of the hydrogen atoms has been replaced by a bond. The alkenyl group can be straight 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 ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl, and decenyl. The alkenyl group can be unsubstituted alkenyl, or substituted with one or more substituents, each substituent being independently selected from halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxyl, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH2, -NH(alkyl), -N(alkyl)2, -NH(cycloalkyl), -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, -C(O)OH, and -C(O)O-alkyl. The term "C 2-6 alkenyl" refers to an alkenyl group of 2 to 6 carbon atoms.

[0063] The term "carbonyl-substituted C 2-6 alkenyl" refers to a C 2-6 alkenyl group in which a hydrogen atom is replaced by an oxo group (=O), the term "C 2-6 alkenyl" is as previously described, "carbonyl-substituted C 2-6 alkenyl" includes, but is not limited to and the like.

[0064] As used herein, the term "heterocycle" or "heterocyclyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or multicyclic ring group, e.g., having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O, or S(O) t (where t is 0, 1, or 2), e.g., 3-12 membered heterocyclyl, 3-10 membered heterocyclyl, 3-9 membered heterocyclyl, 3-8 membered heterocyclyl, 3-7 membered heterocyclyl, 3-6 membered heterocyclyl, 5-6 membered heterocyclyl, etc. Representative examples of heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolinyl, hexahydro-lH-pyrrolin, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, tetrahydropyridinyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, etc.

[0065] As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused-ring polycyclic ring system that has a conjugated pi-electron system. For example, the term "C6-10 Aryl” or “C 6-10 Aryl” or “C 1-6 Aryl” or “C

[0066] In the present context, the term “heteroaryl” refers to a cyclic group having aromaticity, wherein at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom, a boron atom, or a sulfur atom. Optionally, a ring atom in the cyclic structure (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) can be oxidized. Particular 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, and the like, such as furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, 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-pyridonyl, 4-pyridonyl, pyrimidinyl, 1,4-dioxinyl, 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, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azepinyl, 1,3-diazepinyl, azocinyl, and the like.

[0067] In the groups referred to in the present disclosure, the hydrogens can be replaced by isotopes such as protium, deuterium, tritium, and the like.

[0068] The term “substituted” means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0069] If a substituent group is described as being "optionally substituted" the substituent group can be (1) unsubstituted or (2) substituted. If a carbon of a substituent group is described as being optionally substituted with one or more of a list of substituents, then one or more hydrogens on the carbon (to the extent there are any hydrogens present) can be replaced with the substituents, individually and / or together, with the independently selected substituents. If a nitrogen of a substituent group is described as being optionally substituted with one or more of a list of substituents, then one or more hydrogens on the nitrogen (to the extent there are any hydrogens present) can each be replaced with the independently selected substituents, or none.

[0070] If a substituent group is described as being "independently selected from" a group of groups, then each substituent is selected independently of the other. Thus, each substituent can be the same as or different from the other substituent(s).

[0071] As used herein, the term "one or more" means 1 or more than 1, for example 2, 3, 4, 5, 6, 7, 8, 9, or 10, under reasonable conditions.

[0072] As used herein, is represented as a bond.

[0073] Unless indicated, as used herein, the point of attachment of a substituent group can be from any suitable position of the substituent group.

[0074] When the bond of a substituent group is shown as going through a bond connecting two atoms in a ring, then such substituent group can be bonded to either atom in the ring that can be substituted.

[0075] The present disclosure also includes all pharmaceutically acceptable isotopically-labeled compounds, which are identical to the compounds of the present disclosure, except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the present disclosure include, but are not limited to, isotopes of hydrogen, such as 2 H, 3 H, deuterium D, tritium T); isotopes of carbon, such as 11 C, 13 C and 14 C); isotopes of chlorine, such as 37 Cl); isotopes of fluorine, such as 18 F); isotopes of iodine, such as 123 I and 125 I); isotopes of nitrogen, such as 13 N and 15 N); isotopes of oxygen, such as 15 O, 17 O and 18 O); isotopes of phosphorus, such as 32P); and isotopes of sulfur (e.g. 35 S). Certain isotopically-labeled compounds of the present disclosure, for example those into which radioactive isotopes are 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose. Substitution with positron emitting isotopes (e.g. 11 C, 18 F, 15 O and 13 N) are useful in positron emission tomography (PET) studies for testing substrate receptor occupancy. Isotopically-labeled compounds of the present disclosure can generally be prepared by

[0076] The term "stereoisomer" denotes isomers that have the same molecular formula but different structures, due to the difference in the configuration of the asymmetric center(s). In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, the racemic mixture, single enantiomer, mixture of diastereomers, and individual diastereomers are possible. A particular individual molecule can also exist as geometric isomers (cis / trans). Similarly, compounds of the present disclosure can exist as mixtures of two or more structurally distinct forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is understood that the scope of the present application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0077] The present disclosure encompasses all possible crystalline forms or polymorphs of the compounds of the present disclosure, which can be a single polymorph or a mixture of more than one polymorph in any proportion.

[0078] It will also be appreciated that certain of the compounds of the present disclosure can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. In this disclosure, a pharmaceutically acceptable derivative includes, but is not limited to, a pharmaceutically acceptable salt, solvate, metabolite, or prodrug, which upon administration to a patient in need thereof is capable of providing, directly or indirectly, a compound of the present disclosure or a metabolite or residue thereof. Accordingly, as referenced herein, a reference to a "compound of the present disclosure" is intended to also encompass all such derivative forms of the compound.

[0079] Pharmaceutically acceptable salts of the compounds of the present disclosure include acid addition salts and base addition salts. Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. A review of suitable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present disclosure are known to those skilled in the art.

[0080] The compounds of the present disclosure can exist in solvate (preferably hydrate) form, wherein a compound of the present disclosure contains a polar solvent, in particular water, as a structural element of the crystal lattice of said compound. The amount of polar solvent, in particular water, can be present in stoichiometric or non-stoichiometric amounts.

[0081] One skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires an available lone pair of electrons to oxidize to an oxide; one skilled in the art will recognize which nitrogen-containing heterocycles are capable of forming N-oxides. One skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of the heterocycle or tertiary amine with peroxy acids such as peroxyacetic acid and meta-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, 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. Cheeseman and E. S. G. Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.

[0082] Also included within the scope of the disclosure are metabolites of the compounds of the disclosure, i.e., substances formed in vivo following administration of a compound of the disclosure. Such products can result, for example, from oxidation, reduction, hydrolysis, am idation, deam idation, esterification, enzymatic cleavage, and the like, of administered compounds. Accordingly, the disclosure includes metabolites of compounds of the disclosure, made by the process of contacting a compound of the disclosure with a mammal for a period of time sufficient to yield a metabolic product thereof.

[0083] The present disclosure further includes within its scope prodrugs of the compounds of the disclosure, which are certain derivatives of the compounds of the disclosure that can have little or no pharmacological activity themselves, but, upon administration, are converted by metabolic processes into compounds of the disclosure that are pharmaceutically active. Typically, such prodrugs will be functional derivatives of the compounds that readily undergo chemical conversion by mild metabolic processes. For example, other information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association). Prodrugs of the present disclosure can be prepared by replacing appropriate functionalities present in the compounds of the disclosure with certain moieties known to those skilled in the art as "pro-moieties" (for example, as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985).

[0084] The term "about" means within ±10% of the stated value, preferably within ±5%, more preferably within ±2%.

[0085] As used herein, the term "parts" refers to parts by weight, unless otherwise specified.

[0086] 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 of the particle size measured by the principle 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 a Malvern Nanosizer.

[0087] As used herein, the term "PDI" refers to particle size distribution, the larger the PDI, the wider the particle size distribution; the smaller the PDI, the narrower the particle size distribution, the more uniform the particle size.

[0088] As used herein, the term "ball milling" refers to the process of impacting, extruding and grinding the material by the movement of the ball milling beads inside the cylinder caused by the rotation of the cylindrical barrel, so as to achieve the crushing and grinding of the material.

[0089] As used herein, the term "homogenization" refers to the process of micronizing and uniformizing the dispersed particles in the suspension system, which simultaneously reduces the size of the dispersed particles and improves the uniformity of the distribution of the dispersed particles.

[0090] The application is in no way limited to the methods and materials described herein. In the event of inconsistency between one or more of the incorporated documents, patents and similar materials, including but not limited to defined terms, term application, described techniques, etc., the description of the present application and the accompanying structural formulae shall prevail.

[0091] All the technical features disclosed in the present specification, or the steps in all the disclosed methods or processes, can be combined in any manner, except for mutually exclusive technical features and / or steps.

[0092] Nano injection

[0093] It is an object of the present application to provide a nano injection comprising an active ingredient and at least one pharmaceutically acceptable carrier.

[0094] The nano injection of the present application, the active ingredient is a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, polymorph, metabolite or prodrug thereof,

[0095] wherein:

[0096] R a is selected from

[0097] Y 1 , Y 2 , Y 3 , Y 4 each independently selected from O, S, N, N-R a1 and C-R a2 ;

[0098] R a1 each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl and -S(O)2R 1 ;

[0099] R a2 each independently selected from H, halogen, hydroxyl, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 3-6 cycloalkyl, -NR 2 R 3 , -NHC(O)R 4 , -C(O)OR 5 , -C(O)NR 6 R7 -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 said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy is optionally substituted with one or more substituents selected from the group consisting of hydroxy and -NR 19 R 20 ;

[0100] or adjacent R a1 and R a2 or two R a2 with the atoms to which they are attached form a 5-6 membered heteroaromatic ring;

[0101] 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 are each independently selected from the group consisting of H and C 1-6 alkyl;

[0102] R 2 , R 3 are each independently selected from the group consisting of H, C 1-6 alkyl and carbonyl-substituted C 1-6 alkyl;

[0103] R 4 are each independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl and C 2-6 alkenyl;

[0104] R 17 , R 18 are each independently selected from the group consisting of H and C 1-6 alkyl, or R 17 , R18 together with the linking boron and oxygen atoms form a 5-6 membered heterocyclyl group, which is optionally substituted by one or more substituents selected from the group consisting of H, halogen and C 1-6 substituted by one or more substituents selected from the group consisting of H, halogen and C

[0105] Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from the group consisting of N, N + -O - and C-R a3 ;

[0106] R a3 are each independently selected from the group consisting of H, halogen, hydroxyl, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 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 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy is optionally substituted by one or more substituents selected from the group consisting of hydroxyl and -NR 38 R 39 ;

[0107] or two adjacent R a3 and the carbon atoms to which they are attached form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl ring, which is optionally substituted by one or more substituents selected from the group consisting of OH and C 1-6 alkyl;

[0108] R 24 , R25 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 independently is selected from H and C 1-6 alkyl;

[0109] R 21 R 22 each independently is selected from H, C 1-6 alkyl, carbonyl-substituted C 1-6 alkyl, carbonyl-substituted C 2-6 alkenyl and -C(O)OC 1-6 alkyl; preferably, R 21 R 22 each independently is selected from H, C 1-6 alkyl, carbonyl-substituted C 1-6 alkyl and -C(O)OC 1-6 alkyl;

[0110] R 23 each independently is selected from C 1-6 alkyl, C 1-6 haloalkyl and C 2-6 alkenyl;

[0111] R 36 R 37 each independently is selected from H and C 1-6 alkyl, or R 36 R 37 together with the boron and oxygen atoms to which they are attached form a 5-6 membered heterocyclyl group, said 5-6 membered heterocyclyl group being optionally substituted by one or more substituents selected from H, halogen and C 1-6 alkyl;

[0112] V is selected from N, N + -O - and C-R a4 ;

[0113] R a4 is selected from H and C 1-6 alkyl;

[0114] R a5 is selected from H and C 1-6 alkyl;

[0115] R a6 is selected from H and C1-6 alkyl;

[0116] R b1 and R b2 Each is independently selected from H and deuterium;

[0117] 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;

[0118] 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;

[0119] 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;

[0120] R 40 R 41 Each is independently selected from H and C. 1-6 alkyl;

[0121] X 1, X 2 , X 3 , X 4 each independently selected from N and C-R c1 ;

[0122] R c1 each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

[0123] In some embodiments, the present application is directed to compounds of Formula I, wherein:

[0124] R a is selected from

[0125] Y 1 , Y 2 , Y 3 , Y 4 each independently selected from O, S, N, N-R a1 , and C-R a2 ;

[0126] R a1 each independently selected from H, C 1-4 alkyl (e.g., methyl, ethyl, propyl, butyl), C 1-4 haloalkyl (e.g., CF3, CHF2, CH2F), and -S(O)2R 1 (e.g., -S(O)2CH3);

[0127] R a2 each independently selected from H, halogen (e.g., fluorine, chlorine, bromine, iodine), hydroxyl, -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 haloalkoxy, 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 said C 1-4 1-6C-alkyl, C 1-4 1-6C-haloalkyl, C 1-4 1-6C-alkoxy or C 1-4 1-6C-haloalkoxy is optionally substituted by one or more substituents selected from the group consisting of hydroxyl and -NR 19 R 20 ;

[0128] or adjacent R a1 and R a2 or two R a2 with the atoms to which they are attached form a 5-6 membered heteroaromatic ring;

[0129] 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 are each independently selected from the group consisting of H and C 1-4 1-6C-alkyl;

[0130] R 2 , R 3 are each independently selected from the group consisting of H, C 1-4 1-6C-alkyl and carbonyl-substituted C 1-4 1-6C-alkyl;

[0131] R 4 are each independently selected from the group consisting of C 1-4 1-6C-alkyl, C 1-4 1-6C-haloalkyl and C 2-6 2-6C-alkenyl;

[0132] R 17 , R 18 are each independently selected from the group consisting of H and C 1-4 1-6C-alkyl, or R 17 , R 18 together with the boron and oxygen atoms to which they are attached form a 5-6 membered heterocyclyl, said 5-6 membered heterocyclyl being optionally substituted by one or more substituents selected from the group consisting of H, halogen and C 1-4 1-6C-alkyl;

[0133] Z1 , Z 2 , Z 3 , Z 4 , Z 5 each independently is selected from N, N + -O - and C-R a3 ;

[0134] R a3 each independently is selected from H, halogen (e.g. fluorine, chlorine, bromine, iodine), hydroxyl, -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 haloalkoxy, 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 said C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy is optionally substituted with one or more substituents selected from hydroxyl and -NR 38 R 39 ;

[0135] or two R a3 adjacent to each other form, together with the carbon atoms to which they are attached, a 5-6 membered heterocyclyl or 5-6 membered heteroaryl ring, said 5-6 membered heterocyclyl or 5-6 membered heteroaryl ring being optionally substituted with one or more substituents selected from OH and C 1-6 alkyl;

[0136] R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R30 R 31 R 32 R 33 R 34 R 35 R 38 R 39 each independently is selected from H and C 1-4 alkyl;

[0137] R 21 R 22 each independently is selected from H, C 1-4 alkyl, carbonyl-substituted C 1-4 alkyl, carbonyl-substituted C 2-4 alkenyl and -C(O)OC 1-4 alkyl; preferably, R 21 R 22 each independently is selected from H, C 1-4 alkyl, carbonyl-substituted C 1-4 alkyl and -C(O)OC 1-4 alkyl;

[0138] R 23 each independently is selected from C 1-4 alkyl, C 1-4 haloalkyl and C 2-6 alkenyl;

[0139] R 36 R 37 each independently is selected from H and C 1-4 alkyl, or R 36 R 37 together with the boron and oxygen atoms to which they are attached form a 5-6 membered heterocyclyl group, said 5-6 membered heterocyclyl group being optionally substituted by one or more substituents selected from H, halogen and C 1-4 alkyl;

[0140] V is selected from N, N + -O - and C-R a4 ;

[0141] R a4 is selected from H and C 1-4 alkyl (e.g. methyl, ethyl, propyl, butyl);

[0142] R a5 is selected from H and C 1-4 alkyl (e.g. methyl, ethyl, propyl, butyl);

[0143] R a6 is selected from H and C 1-4 alkyl (e.g. methyl, ethyl, propyl, butyl).

[0144] In some embodiments, the compounds of Formula I of the present application are those wherein:

[0145] R a is selected from

[0146] Y 1 , Y 2 , Y 3 , Y 4 each independently is selected from O, S, N, N-R a1 , and C-R a2 ;

[0147] R a1 each independently is selected from H, methyl, CF3, CHF2, and -S(O)2CH3;

[0148] R a2 each independently is selected from H, fluorine, chlorine, methyl, CF3, CHF2, -C(O)NH2, -NH2, and

[0149] or adjacent R a1 and R a2 or two R a2 form, with the atoms to which they are attached, a 5-6 membered heteroaromatic ring;

[0150] R 17 , R 18 each independently is selected from H and C 1-4 alkyl, or R 17 , R 18 together with the boron and oxygen atoms to which they are attached form a 5-6 membered heterocyclyl, said 5-6 membered heterocyclyl being optionally substituted with one or more substituents selected from H, halogen, and C 1-4 alkyl;

[0151] Z 1 , Z 2 , Z 3 , Z 4 , Z 5 each independently is selected from N, N + -O - , and C-R a3 ;

[0152] R a3each independently selected from the group consisting of H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, ethenyl, 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 independently is selected from the group consisting of H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, ethenyl, 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

[0153] or two R a3 adjacent to each other form, together with the carbon atoms to which they are attached, a 5-6 membered heterocyclyl or a 5-6 membered heteroaromatic ring, said heterocyclyl being optionally substituted by one or more hydroxyl or methyl groups;

[0154] R 24 , R25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 R 34 R 35 each independently is selected from H and C 1-4 alkyl;

[0155] R 21 R 22 each independently is selected from H, C 1-4 alkyl, carbonyl-substituted C 1-4 alkyl, carbonyl-substituted C 2-4 alkenyl and -C(O)OC 1-4 alkyl; preferably, R 21 R 22 each independently is selected from H, C 1-4 alkyl and carbonyl-substituted C 1-4 alkyl;

[0156] R 23 each independently is selected from C 1-4 alkyl, C 1-4 haloalkyl and C 2-6 alkenyl;

[0157] R 36 R 37 each independently is selected from H and C 1-4 alkyl, or R 36 R 37 together with the boron and oxygen atoms to which they are attached form a 5-6 membered heterocyclyl group, said 5-6 membered heterocyclyl group being optionally substituted with one or more substituents selected from H, halogen and C 1-4 alkyl;

[0158] V is selected from N, N + -O - and C-R a4 ;

[0159] R a4 is selected from H and methyl;

[0160] R a5 is selected from H and methyl;

[0161] R a6 is selected from H and methyl.

[0162] In some embodiments, in the compounds of formula I according to the application, Z 1 , Z 2 , Z3 , Z 4 , Z 5 each is independently selected from N and C-R a3 .

[0163] In some embodiments, the compounds of Formula I of the present application are those wherein:

[0164] R a3 each is independently selected from H, fluoro, chloro, bromo, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, ethenyl, 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

[0165] or two R a3 attached to the same carbon atom form a

[0166] 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;

[0167] R 21 , R 22 each is independently selected from H, C 1-4 alkyl and carbonyl-substituted C 1-4 alkyl;

[0168] R 23each independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl and C 2-6 alkenyl.

[0169] In some embodiments, in the compounds of formula I according to the application, R a3 each independently selected from the group consisting of H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, ethenyl, cyclopropyl, -CH2OH, -C(CH3)2OH, -CH(OH)CH2(OH), -CH(OH)CH2F, -CH(NH2)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)NH2, -SH, -SCH3, -S(O)CH3, -S(O)2CH3, -S(O)2NH2, -S(O)(NH)CH3, -S(O)(NCH3)CH3, -P(O)(CH3)2and Preferably, R a3 each independently selected from the group consisting of H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, ethenyl, 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)2and

[0170] or two R a3 form together with the carbon atom to which they are attached a

[0171] More preferably, R a3 each independently selected from the group consisting of H, fluorine, chlorine, bromine, -C(O)NH2and

[0172] Further preferably, R a3 each independently selected from the group consisting of H and -C(O)NH2.

[0173] In some embodiments, in the compounds of formula I according to the application, Rb3 and R b4 each independently is selected from H, deuterium, C 1-4 alkyl (e.g., methyl, ethyl, propyl, and butyl), C 1-4 haloalkyl, and C 3-6 cycloalkyl.

[0174] In some embodiments, in the compounds of Formula I of the present application, R b3 and R b4 each independently is selected from H, deuterium, and methyl.

[0175] In some embodiments, in the compounds of Formula I of the present application, R b3 and R b4 each independently is selected from H and deuterium.

[0176] In some embodiments, in the compounds of Formula I of the present application, R b3 and R b4 is H.

[0177] In some embodiments, in the compounds of Formula I of the present application, R b5 and R b6 each independently is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl, or R b5 , R b6 together with the carbon atom to which they are attached form a C 3-5 cycloalkyl or 4-6 membered heterocyclyl (e.g., 4-6 membered oxygen-containing heterocyclyl).

[0178] In some embodiments, in the compounds of Formula I of the present application, R b5 and R b6 each independently is selected from H, methyl, cyclopropyl, and trifluoromethyl, or R b5 , R b6 and the carbon atom to which they are attached form a cyclobutyl, cyclopentyl, or 4-6 membered oxygen-containing heterocyclyl.

[0179] In some embodiments, in the compounds of Formula I of the present application, R b5 and R b6 each independently is selected from H, methyl, cyclopropyl, and trifluoromethyl, or R b5 , R b6 and the carbon atom to which they are attached form a cyclobutyl or

[0180] In some embodiments, in the compounds of Formula I of the present application, R b5 and R b6 each independently is selected from methyl and trifluoromethyl.

[0181] In some embodiments, in the compounds of Formula I of the present application, R c is selected from H, hydroxy, halo, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 deuteroalkoxy, C 1-4 haloalkoxy, C 2-6 alkenyl, and -O-C 3-6 cycloalkyl, said C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, or C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from hydroxy, carboxy, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-6 alkenyl, -NR 40 R 41 , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, and 5-6 membered heteroaryl, said 3-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted with one or more substituents selected from halo and C 1-4 alkyl; R 40 , R 41 are each independently selected from H and C 1-4 alkyl.

[0182] In some embodiments, in the compounds of Formula I of the present application, X 1 , X 2 , X 3 , X 4 are each independently selected from C-R c1 .

[0183] In some embodiments, in the compounds of Formula I of the present application, R c1 are each independently selected from H, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy.

[0184] In some embodiments, in the compounds of Formula I of the present application, R c1 are each independently selected from H, F, Cl, methyl, ethyl, propyl, butyl, fluoromethyl, fluoroethyl, fluoropropyl, methoxy, ethoxy, propoxy, butoxy, fluoromethoxy, fluoroethoxy, and fluoropropoxy.

[0185] In some embodiments, in the compounds of Formula I of the present application, R c1 each is independently selected from H, F, methyl, difluoromethyl, trifluoromethyl, difluoromethoxy, methoxy, and difluoromethoxy.

[0186] In some embodiments, in the compounds of Formula I of the present application, R c1 each is independently selected from H and F.

[0187] In some embodiments, in the compounds of Formula I of the present application, wherein R a is selected from:

[0188] In some embodiments, in the compounds of Formula I of the present application, wherein R a is selected from:

[0189] In some embodiments, in the compounds of Formula I of the present application, wherein R a is selected from:

[0190] In some embodiments, in the compounds of Formula I of the present application, wherein R a is selected from:

[0191] In some embodiments, in the compounds of Formula I of the present application, wherein R a is selected from:

[0192] In some embodiments, in the compounds of Formula I of the present application, wherein R c is selected from H, -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -OCH2CF3, -OCH2CF2CH3, -OCH2CHF2, -OCHF2,

[0193] In some embodiments, in the compounds of Formula I of the present application, wherein R c is selected from -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -OCH2CF3, -OCH2CF2CH3, -OCH2CHF2, and -OCHF2.

[0194] In some embodiments, in the compounds of Formula I of the present application, wherein R c is -OCH3.

[0195] In some embodiments, in the compounds of Formula I of the present application, For

[0196] In some embodiments, the compounds of Formula I of the present application are those wherein:

[0197] R a is selected from wherein:

[0198] Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from S and C-R a2 ;

[0199] R a2 are each independently selected from H and

[0200] Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from N and C-R a3 ;

[0201] R a3 are each independently selected from H, fluoro, chloro, bromo, -C(O)NH2, and

[0202] V is selected from C-R a4 ;

[0203] R a4 is selected from H and methyl;

[0204] R a5 is selected from H and methyl;

[0205] R a6 is selected from H and methyl;

[0206] R b1 and R b2 are each independently selected from H and deuterium;

[0207] R b3 and R b4 are each independently selected from H and deuterium;

[0208] R b5 and R b6 are each independently selected from methyl and trifluoromethyl;

[0209] R cselected from -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -OCH2CF3, -OCH2CF2CH3, -OCH2CHF2, and -OCHF2; preferably, R c is -OCH3;

[0210] X 1 , X 2 , X 3 , X 4 are each independently selected from C-R c1 ;

[0211] R c1 are each independently selected from H and F.

[0212] In some embodiments, the compound of the present disclosure is selected from:

[0213] In some embodiments, the active ingredient is a stereoisomer of a compound of Formula I.

[0214] In some embodiments, the active ingredient is a compound of Formula II:

[0215] In some embodiments, the injection is an injection solution.

[0216] In some embodiments, the active ingredient comprises 1-30%, preferably 2.5-20%, more preferably 5-15%, further preferably 5-10%, more further preferably 8-10%, for example 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15%, 20%, 25%, 30% by weight of the injection solution.

[0217] In some embodiments, the injection comprises one or more of a surfactant, a stabilizer, a pH adjuster, an osmotic pressure adjuster.

[0218] In some embodiments, the surfactant is one or more of polysorbate (e.g., Tween 20, Tween 40, Tween 60, Tween 80), sorbitan fatty acid ester (e.g., Span 20, Span 40, Span 60, Span 80), poloxamer, sodium dodecyl sulfate, monoglyceride fatty acid, polyoxyethylene castor oil, cholic acid and its salts (e.g., glycocholic acid, deoxycholic acid, ursodeoxycholic acid, chenodeoxycholic acid, sodium salt or potassium salt), oleic acid salt (e.g., sodium oleate, potassium oleate, ammonium oleate), 15-hydroxystearic acid polyethylene glycol ester (HS15), lecithin, etc., preferably one or more of Tween 80, HS15, sodium oleate, sodium glycocholate, sodium deoxycholate, and sodium ursodeoxycholate, more preferably one or more of sodium glycocholate and sodium deoxycholate.

[0219] In some embodiments, the cholic acid salt can be prepared by dissolving cholic acid and a base in water, for example, sodium glycocholate can be prepared by dissolving glycocholic acid and sodium hydroxide in water, sodium deoxycholate can be prepared by dissolving deoxycholic acid and sodium hydroxide in water.

[0220] In some embodiments, the surfactant accounts for 0.01% to 2%, preferably 0.1% to 2%, more preferably 0.1% to 1.6%, further preferably 0.5% to 1.6%, more further preferably 0.8% to 1.6% by weight of the injection solution, for example, 0.01%, 0.05%, 0.1%, 0.2%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%.

[0221] In some embodiments, the stabilizer is one or more of cyclodextrin, carboxymethyl cellulose and its sodium salt, polyethylene glycol, polyvinylpyrrolidone (PVP), hydroxypropyl methyl cellulose, polyethylene glycol vitamin E succinate (TPGS), etc., preferably polyvinylpyrrolidone, for example, PVP K12, PVP K17, PVP K30. Among them, K12, K17 and K30 represent the model of polyvinylpyrrolidone.

[0222] In some embodiments, the stabilizer accounts for 0.1% to 10%, preferably 0.2% to 8%, more preferably 0.2% to 2%, further preferably 0.2% to 1%, more further preferably 0.3% to 0.6% by weight of the injection solution, for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 1.0%, 1.2%, 1.5%, 2%, 5%, 10%.

[0223] In some embodiments, the pH adjusting agent is one or more of disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate, hydrochloric acid, lactic acid, sodium hydroxide, sodium citrate, and tartrate, preferably hydrochloric acid or sodium hydroxide. In some embodiments, the pH adjusting agent is hydrochloric acid. In some embodiments, the pH adjusting agent is sodium hydroxide.

[0224] In some embodiments, the pH adjusting agent comprises 0% to 1%, preferably 0% to 0.5% by weight of the injection solution.

[0225] In some embodiments, the osmotic pressure adjusting agent is one or more of sodium chloride, glucose, sucrose, glycerol, and mannitol, preferably sodium chloride, sucrose, or mannitol. In some embodiments, the osmotic pressure adjusting agent is sodium chloride. In some embodiments, the osmotic pressure adjusting agent is sucrose. In some embodiments, the osmotic pressure adjusting agent is mannitol.

[0226] In some embodiments, the osmotic pressure adjusting agent comprises 0% to 10%, preferably 0% to 8% by weight of the injection solution.

[0227] In some embodiments, there is provided an injection solution comprising 1% to 30% by weight of the injection solution of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically-labeled compound, polymorph, metabolite, or prodrug thereof, 0.01% to 2% of a surfactant, and optionally 0.1% to 10% of a stabilizer.

[0228] In some embodiments, there is provided an injection solution comprising 2.5% to 20% by weight of the injection solution of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically-labeled compound, polymorph, metabolite, or prodrug thereof, 0.1% to 2% of a surfactant, and optionally 0.2% to 8% of a stabilizer.

[0229] In some embodiments, there is provided an injection solution comprising 5% to 15% by weight of the injection solution of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically-labeled compound, polymorph, metabolite, or prodrug thereof, 0.1% to 1.6% of a surfactant, and optionally 0.2% to 2% of a stabilizer.

[0230] In some embodiments, there is provided an injection solution comprising 5% to 10% by weight of the injection solution of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically-labeled compound, polymorph, metabolite, or prodrug thereof, 0.5% to 1.6% of a surfactant, and optionally 0.2% to 1% of a stabilizer.

[0231] In some embodiments, there is provided an injection solution comprising 8-10% of a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, polymorph, metabolite, or prodrug thereof, by weight percent of the injection solution, 0.8-1.6% of a surfactant, and optionally 0.3-0.6% of a stabilizer.

[0232] In some embodiments, there is provided an injection solution comprising 1-30% of a compound of Formula II, 0.01-2% of a surfactant, and optionally 0.1-10% of a stabilizer, by weight percent of the injection solution.

[0233] In some embodiments, there is provided an injection solution comprising 2.5-20% of a compound of Formula II, 0.1-2% of a surfactant, and optionally 0.2-8% of a stabilizer, by weight percent of the injection solution.

[0234] In some embodiments, there is provided an injection solution comprising 5-15% of a compound of Formula II, 0.1-1.6% of a surfactant, and optionally 0.2-2% of a stabilizer, by weight percent of the injection solution.

[0235] In some embodiments, there is provided an injection solution comprising 5-10% of a compound of Formula II, 0.5-1.6% of a surfactant, and optionally 0.2-1% of a stabilizer, by weight percent of the injection solution.

[0236] In some embodiments, there is provided an injection solution comprising 8-10% of a compound of Formula II, 0.8-1.6% of a surfactant, and optionally 0.3-0.6% of a stabilizer, by weight percent of the injection solution.

[0237] In some embodiments, the injection is a lyophilized composition.

[0238] In some embodiments, the active ingredient is 10-80%, preferably 20-70%, more preferably 25-70%, further preferably 25-60%, more further preferably 40-60%, for example 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, by weight percent of the lyophilized composition.

[0239] In some embodiments, the injection comprises one or more of a surfactant, a stabilizer, a pH adjusting agent, an osmotic pressure adjusting agent, and a lyoprotectant.

[0240] In some embodiments, the surfactant is one or more of polysorbate (e.g., Tween 20, Tween 40, Tween 60, Tween 80), sorbitan fatty acid ester (e.g., Span 20, Span 40, Span 60, Span 80), poloxamer, sodium dodecyl sulfate, monoglyceride fatty acid, polyoxyethylene castor oil, bile acid and its salts (bile acid, e.g., glycocholic acid, deoxycholic acid, ursodeoxycholic acid, chenodeoxycholic acid, salts, e.g., sodium salt or potassium salt), oleate (e.g., sodium oleate, potassium oleate, ammonium oleate), 15-hydroxystearic acid polyethylene glycol ester (HS15), lecithin, etc., preferably one or more of Tween 80, HS15, sodium oleate, sodium glycocholate, sodium deoxycholate, and sodium ursodeoxycholate, more preferably one or more of sodium glycocholate and sodium deoxycholate.

[0241] In some embodiments, the bile acid salt can be prepared by dissolving bile acid and a base in water, for example, sodium glycocholate can be prepared by dissolving glycocholic acid and sodium hydroxide in water, sodium deoxycholate can be prepared by dissolving deoxycholic acid and sodium hydroxide in water.

[0242] In some embodiments, the surfactant accounts for 1% to 20%, preferably 1% to 15%, more preferably 1% to 12%, further preferably 5% to 12%, more further preferably 5% to 10%, for example, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 18%, 20% of the weight percentage of the lyophilized composition.

[0243] In some embodiments, the stabilizer is one or more of cyclodextrin, carboxymethyl cellulose and its sodium salt, polyethylene glycol, polyvinylpyrrolidone (PVP), hydroxypropyl methyl cellulose, polyethylene glycol vitamin E succinate (TPGS), etc., preferably polyvinylpyrrolidone, for example, PVP K12, PVP K17, PVP K30. Among them, K12, K17 and K30 represent the model of polyvinylpyrrolidone.

[0244] In some embodiments, the stabilizer accounts for 0.5% to 8%, preferably 0.5% to 7%, more preferably 0.5% to 5%, more preferably 1% to 5%, for example, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the weight percentage of the lyophilized composition.

[0245] In some embodiments, the pH regulator is one or more of disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate, hydrochloric acid, lactic acid, sodium hydroxide, sodium citrate, and tartrate, preferably hydrochloric acid or sodium hydroxide. In some embodiments, the pH regulator is hydrochloric acid. In some embodiments, the pH regulator is sodium hydroxide.

[0246] In some embodiments, the pH adjusting agent comprises 0% to 5%, preferably 0% to 3%, more preferably 0% to 1% by weight of the lyophilized composition.

[0247] In some embodiments, the osmotic pressure adjusting agent is one or more of sodium chloride, dextrose, sucrose, glycerol, and mannitol, preferably sodium chloride, sucrose, or mannitol. In some embodiments, the osmotic pressure adjusting agent is sodium chloride. In some embodiments, the osmotic pressure adjusting agent is sucrose. In some embodiments, the osmotic pressure adjusting agent is mannitol.

[0248] In some embodiments, the osmotic pressure adjusting agent comprises 0% to 50%, preferably 0% to 30% by weight of the lyophilized composition.

[0249] In some embodiments, the lyophilization protecting agent is one or more of lactose, maltose, dextrose, sucrose, trehalose, glycerol, mannitol, sorbitol, and albumin, preferably sucrose, mannitol, or trehalose. In some embodiments, the lyophilization protecting agent is sucrose, in some embodiments, the lyophilization protecting agent is mannitol, in some embodiments, the lyophilization protecting agent is trehalose.

[0250] In some embodiments, the lyophilization protecting agent comprises 0% to 80%, preferably 25% to 70%, more preferably 25% to 50%, for example, 0%, 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80% by weight of the lyophilized composition.

[0251] In some embodiments, a lyophilized composition is provided comprising 10% to 80% by weight of the lyophilized composition of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically-labeled compound, polymorph, metabolite, or prodrug thereof, 1% to 20% of a surfactant, optionally 0.5% to 8% of a stabilizer, and optionally 0% to 80% of a lyophilization protecting agent.

[0252] In some embodiments, a lyophilized composition is provided comprising 20% to 70% by weight of the lyophilized composition of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically-labeled compound, polymorph, metabolite, or prodrug thereof, 1% to 15% of a surfactant, optionally 0.5% to 7% of a stabilizer, and optionally 25% to 70% of a lyophilization protecting agent.

[0253] In some embodiments, a lyophilized composition is provided comprising 25-70% of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically-labeled compound, polymorph, metabolite, or prodrug thereof, 1-12% of a surfactant, optionally 0.5-5% of a stabilizer, and optionally 25-50% of a lyophilization cryoprotectant, by weight percent of the lyophilized composition.

[0254] In some embodiments, a lyophilized composition is provided comprising 25-60% of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically-labeled compound, polymorph, metabolite, or prodrug thereof, 5-12% of a surfactant, optionally 1-5% of a stabilizer, and optionally 25-50% of a lyophilization cryoprotectant, by weight percent of the lyophilized composition.

[0255] In some embodiments, a lyophilized composition is provided comprising 40-60% of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically-labeled compound, polymorph, metabolite, or prodrug thereof, 5-10% of a surfactant, optionally 1-5% of a stabilizer, and optionally 25-50% of a lyophilization cryoprotectant, by weight percent of the lyophilized composition.

[0256] In some embodiments, a lyophilized composition is provided comprising 10-80% of a compound of Formula II, 1-20% of a surfactant, optionally 0.5-8% of a stabilizer, and optionally 0-80% of a lyophilization cryoprotectant, by weight percent of the lyophilized composition.

[0257] In some embodiments, a lyophilized composition is provided comprising 20-70% of a compound of Formula II, 1-15% of a surfactant, optionally 0.5-7% of a stabilizer, and optionally 25-70% of a lyophilization cryoprotectant, by weight percent of the lyophilized composition.

[0258] In some embodiments, a lyophilized composition is provided comprising 25-70% of a compound of Formula II, 1-12% of a surfactant, optionally 0.5-5% of a stabilizer, and optionally 25-50% of a lyophilization cryoprotectant, by weight percent of the lyophilized composition.

[0259] In some embodiments, a lyophilized composition is provided comprising 25-60% of a compound of Formula II, 5-12% of a surfactant, optionally 1-5% of a stabilizer, and optionally 25-50% of a lyophilization cryoprotectant, by weight percent of the lyophilized composition.

[0260] In some embodiments, a lyophilized composition is provided comprising 40-60% of the compound of Formula II, 5-10% of a surfactant, optionally 1-5% of a stabilizer, and optionally 25-50% of a lyophilization protectant, by weight percent of the lyophilized composition.

[0261] In some embodiments, the nano-injection has an average particle size ranging from 100 nm to 800 nm, preferably from 100 nm to 500 nm, more preferably from 100 nm to 300 nm, further preferably from 150 nm to 250 nm, for example from 150 nm to 250 nm, from 150 nm to 240 nm, from 150 nm to 230 nm, from 150 nm to 220 nm, from 150 nm to 210 nm, from 150 nm to 200 nm, from 150 nm to 190 nm, from 150 nm to 180 nm, from 150 nm to 170 nm, from 150 nm to 160 nm, from 160 nm to 250 nm, from 160 nm to 240 nm, from 160 nm to 230 nm, from 160 nm to 220 nm, from 160 nm to 210 nm, from 160 nm to 200 nm, from 160 nm to 190 nm, from 160 nm to 180 nm, from 160 nm to 170 nm, from 170 nm to 250 nm, from 170 nm to 240 nm, from 170 nm to 230 nm, from 170 nm to 220 nm, from 170 nm to 210 nm, from 170 nm to 200 nm, from 170 nm to 190 nm, from 170 nm to 180 nm, from 180 nm to 250 nm, from 180 nm to 240 nm, from 180 nm to 230 nm, from 180 nm to 220 nm, from 180 nm to 210 nm, from 180 nm to 200 nm, from 180 nm to 190 nm, from 190 nm to 250 nm, from 190 nm to 240 nm, from 190 nm to 230 nm, from 190 nm to 220 nm, from 190 nm to 210 nm, from 190 nm to 200 nm, from 200 nm to 250 nm, from 200 nm to 240 nm, from 200 nm to 230 nm, from 200 nm to 220 nm, from 200 nm to 210 nm, from 210 nm to 250 nm, from 210 nm to 240 nm, from 210 nm to 230 nm, from 210 nm to 220 nm, from 220 nm to 250 nm, from 220 nm to 240 nm, from 220 nm to 230 nm, from 230 nm to 250 nm, from 230 nm to 240 nm, from 240 nm to 250 nm, 100 nm, 120 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm.

[0262] In some embodiments, the average particle size of the nano-injection is detected by the detection method of the Chinese Pharmacopoeia, and the detection equipment can be a Malvern nanoparticle size analyzer.

[0263] The nano-injection of the present application has good stability, controllable particle size, and narrow particle size distribution range, can be used for intravenous injection, has rapid effect, can effectively control drug burst during injection, has stable drug release, long action time, excellent analgesic effect, small toxic and side effects, good safety, can effectively replace the use of opioid analgesic drugs, reduce addiction, and can provide a new solution for the analgesic field.

[0264] Preparation method

[0265] Another purpose of the present application is to further provide a method for preparing a nano-injection, comprising the following steps:

[0266] (a) preparing a solution A containing a surfactant, dispersing an active ingredient into the solution A to obtain a suspension B;

[0267] (b1) placing the suspension B in a ball mill for ball milling to obtain a suspension C; or,

[0268] (b2) homogenizing the suspension B to obtain a suspension D; or,

[0269] (b3) placing the suspension B in a ball mill for ball milling, and further homogenizing to obtain a suspension E; and

[0270] (c) adding a stabilizer.

[0271] In some embodiments, the method further comprises the following step:

[0272] (d) freeze-drying.

[0273] In some embodiments, the nano-injection is the nano-injection of any one of the preceding.

[0274] In some embodiments, the dispersion of the active ingredient in step (a) is by stirring.

[0275] In some embodiments, the dispersion of the active ingredient in step (a) is by shearing.

[0276] In some embodiments, the dispersion of the active ingredient in step (a) is carried out in an ice bath.

[0277] In some embodiments, the ball milling beads in step (b1) have a size of 0.1 mm to 0.5 mm, preferably 0.1 mm to 0.4 mm, for example 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, or 0.5 mm.

[0278] In some embodiments, the amount of grinding balls used in step (b1) is 50% to 70% of the filling volume of the ball mill cavity, preferably 60% to 70%. In some embodiments, the amount of grinding balls used in step (b1) is 1 to 3 times the weight of suspension B, preferably 1 to 2 times, more preferably 1 to 1.5 times, and even more preferably 1.3 to 1.5 times.

[0279] In some embodiments, the ball milling speed in step (b1) is 1000 rpm to 3000 rpm, preferably 1500 rpm to 2000 rpm.

[0280] In some embodiments, the pump speed for ball milling in step (b1) is 100 ml / min to 500 ml / min, preferably 150 ml / min to 400 ml / min, and more preferably 150 ml / min to 200 ml / min.

[0281] In some embodiments, the homogenizing equipment in step (b2) is a high-pressure homogenizer. In some embodiments, the homogenizing pressure in step (b2) is not less than 500 bar, preferably not less than 800 bar, more preferably not less than 1000 bar, and even more preferably not less than 1500 bar. In some embodiments, the homogenizing time is not less than 10 minutes, preferably not less than 20 minutes, more preferably not less than 1 hour, and even more preferably not less than 3 hours.

[0282] In some embodiments, the homogenizing equipment in step (b2) is a high-pressure microfluidic nano-homogenizer. In some embodiments, the homogenizing pressure in step (b2) is not less than 500 bar, preferably not less than 800 bar, more preferably not less than 1200 bar, and even more preferably not less than 2000 bar. In some embodiments, the number of cycles is not less than 10, preferably not less than 20, and more preferably not less than 30.

[0283] In some embodiments, the ball milling beads used in step (b3) are 0.1mm to 0.5mm in size, preferably 0.1mm to 0.4mm, for example 0.1mm, 0.2mm, 0.3mm, 0.4mm, 0.5mm.

[0284] In some embodiments, the amount of grinding balls used in step (b3) is 50% to 70% of the filling volume of the ball mill cavity, preferably 60% to 70%. In some embodiments, the amount of grinding balls used in step (b3) is 1 to 3 times the weight of suspension B, preferably 1 to 2 times, more preferably 1 to 1.5 times, and even more preferably 1.3 to 1.5 times.

[0285] In some embodiments, the rotation speed of the ball mill in step (b3) is 1000 rpm to 3000 rpm, preferably 1500 rpm to 2000 rpm.

[0286] In some embodiments, the pump speed of the ball mill in step (b3) is 100 ml / min to 500 ml / min, preferably 150 ml / min to 400 ml / min, more preferably 150 ml / min to 200 ml / min.

[0287] In some embodiments, the homogenization device in step (b3) is a high pressure homogenizer. In some embodiments, the homogenization pressure in step (b3) is not less than 500 bar, preferably not less than 800 bar, more preferably not less than 1000 bar, further preferably not less than 1500 bar. In some embodiments, the homogenization time is not less than 5 minutes, preferably not less than 10 minutes, more preferably not less than 20 minutes.

[0288] In some embodiments, the homogenization device in step (b3) is a high pressure microfluidic nanohomogenizer. In some embodiments, the homogenization pressure in step (b3) is not less than 500 bar, preferably not less than 800 bar, more preferably not less than 1200 bar, further preferably not less than 2000 bar. In some embodiments, the cycle number is not less than 10, preferably not less than 20, more preferably not less than 30.

[0289] In some embodiments, a pH adjusting agent is added in step (c).

[0290] In some embodiments, an osmotic pressure adjusting agent is added in step (c).

[0291] In some embodiments, a lyoprotectant is added in step (c).

[0292] The method for preparing the nano-injection provided in the present application can effectively control the nanoparticle size, has good process repeatability, and is easy to scale up for industrial production.

[0293] Therapeutic methods and uses

[0294] The present application also provides the use of the nano-injection of the present application in the preparation of a medicament for preventing and / or treating a NaV1.8 related disease, preferably the NaV1.8 related disease is pain.

[0295] The present application also provides the use of the nano-injection of the present application in the preparation of a medicament for preventing and / or treating a NaV1.8 related disease, preferably the NaV1.8 related disease is pain.

[0296] The present application also provides a method for preventing and / or treating a NaV1.8 related disease, comprising administering to an individual a therapeutically effective amount of the nano-injection of the present application. Preferably, the NaV1.8 related disease is pain.

[0297] In some embodiments, the pain is selected from, but not limited to, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-surgical pain (e.g., post-bunionectomy pain, post-herniorrhaphy pain, or post-abdominoplasty pain), visceral pain, and the like, particularly post-surgical pain.

[0298] In some embodiments, the nano-injection of the present application is used simultaneously, separately or sequentially with another therapeutic or prophylactic agent.

[0299] In some embodiments, the another therapeutic or prophylactic agent is an analgesic.

[0300] The term "effective amount" as used herein refers to an amount that is sufficient to achieve the desired prophylactic or therapeutic effect, e.g., an amount that achieves the alleviation of one or more symptoms associated with the disease being treated.

[0301] The dosage regimen will be adjusted to provide the optimum desired response. For example, a single bolus can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is important that dosage values be titrated to the individual patient needs and to the judgment of the person administering or supervising the administration of the nano-injection of the present disclosure.

[0302] The amount of the nano-injection of the present disclosure administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the judgment of the prescribing physician. In some instances, dosage levels below the lower range set forth can be more than adequate, while in other cases still larger doses can be employed without causing any harmful side effects, provided that they are divided into several small doses for administration throughout the day.

[0303] The term "treatment" as used herein, means reversing, alleviating, ameliorating, or inhibiting the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0304] The term "prevention" refers to inhibiting and delaying the onset of a disease, and includes not only prevention prior to the development of a disease, but also prevention of the recurrence of a disease after treatment.

[0305] As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include a human individual (referred to as a patient) having a disease (e.g., a disease described herein) or a normal individual. "Non-human animals" in the present disclosure include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles), and mammals, e.g., non-human primates, farm animals, and / or domestic animals (e.g., sheep, dog, cat, cow, pig, etc.). BRIEF DESCRIPTION OF DRAWINGS

[0306] Figure 1 is a particle size distribution profile of the nanosuspension of Example 1. DETAILED DESCRIPTION

[0307] In order to make the objects, technical solutions and contents of the present disclosure clearer, the embodiments of the present disclosure are described in detail below with reference to the embodiments. However, those skilled in the art will understand that the following embodiments are only used to illustrate the present disclosure, and should not be regarded as limiting the scope of the present disclosure. If the specific conditions are not specified in the examples, the operations are carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the reagents or instruments used are not specified by the manufacturer, they are all conventional products that can be obtained by purchase on the market.

[0308] The following abbreviations are used in the present disclosure: nuclear magnetic resonance (NMR); liquid chromatography-mass spectrometer (LC-MS); preparative liquid chromatograph (pre-HPLC); methanol (MeOH); N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (TCFH); N-methylimidazole (NMI); N,N-dimethylformamide (DMF).

[0309] If not otherwise specified in the examples, the temperature of the reaction is room temperature (20-35°C).

[0310] The structure of the compounds in all examples is recorded by nuclear magnetic resonance (1H-NMR) Vian Mercury 400 nuclear magnetic resonance instrument, and the chemical shift is expressed in δ (ppm).

[0311] The preparation method of the preparative liquid chromatograph is as follows: instrument model: Agilent 1260, chromatographic column: Waters SunFire Prep C18 OBD (19 mm x 150 mm x 5.0 μm); column temperature: 25°C; flow rate: 20.0 mL / min; monitoring wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: acetonitrile; mobile phase B: 0.05% methanol aqueous solution.

[0312] The particle size of the nanosuspension in all examples is detected by Malvern nanoparticle size analyzer.

[0313] Preparation of (3-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5- (trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenyl)boronic acid (Compound 9)

[0314] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 3- aminobenzoic 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, and the reaction was continued to stir for 1 h after natural recovery to room temperature. LC-MS monitoring showed that the raw material was completely reacted, and 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 (400 MHz, DMSO) δ 10.17 (s, 1H), 8.00 (s, 2H), 7.76 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.20 - 7.11 (m, 2H), 4.62 (d, J = 10.7 Hz, 1H), 4.31 - 4.19 (m, 1H), 3.96 (d, J = 1.6 Hz, 3H), 2.39 (t, J = 12.9 Hz, 1H), 2.35 - 2.25 (m, 1H), 1.73 (s, 3H).

[0315] Preparation of (3-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5- (trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenyl)boronic acid (Compound 9)

[0316] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 3- aminobenzoic 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, and the reaction was continued to stir for 1 h after natural recovery to room temperature. LC-MS monitoring showed that the raw material was completely reacted, and the target compound (79 mg, 0.04 mmol, yield 50%) was obtained by Pre-HPLC separation. MS: m / z = 476.2, [M+H] + , 1H NMR (400 MHz, DMSO) δ 10.07 (s, 1H), 7.96 (s, 2H), 7.45 - 7.40 (m, 2H), 7.19 - 7.12 (m, 2H), 7.00 (d, J = 8.0 Hz, 1H), 4.59 (d, J = 10.8 Hz, 1H), 4.34 - 4.22 (m, 1H), 3.96 (d, J = 1.6 Hz, 3H), 2.42 - 2.27 (m, 1H), 1.72 (s, 3H).

[0317] Preparation of (3-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5- (trifluoromethyl)tetrahydrothiophene-2-carboxamido)-4-fluorophenyl)boronic acid (Compound 18)

[0318] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 3-amino-5-fluorobenzoic 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, and the reaction was continued to stir for 1 h after natural recovery to room temperature. LC-MS monitoring showed that the raw material was completely reacted, and 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 (400 MHz, DMSO) δ 10.07 (s, 1H), 7.96 (s, 2H), 7.45 - 7.40 (m, 2H), 7.19 - 7.12 (m, 2H), 7.00 (d, J = 8.0 Hz, 1H), 4.59 (d, J = 10.8 Hz, 1H), 4.34 - 4.22 (m, 1H), 3.96 (d, J = 1.6 Hz, 3H), 2.42 - 2.27 (m, 1H), 1.72 (s, 3H).

[0319] Preparation of (3-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5- (trifluoromethyl)tetrahydrothiophene-2-carboxamido)-4-fluorophenyl)boronic acid (Compound 18)

[0320] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 3- amino-4-fluorobenzoic 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, and the reaction was continued to stir for 1 h after natural recovery to room temperature. LC-MS monitoring showed that the raw material was completely reacted, and the target compound (16 mg, 0.03 mmol, yield 40.50%) was obtained by Pre-HPLC separation. MS: m / z = 494.2, [M+H] + , 1 H NMR (400 MHz, DMSO) δ 9.92 (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).

[0321] 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)

[0322] Compound 1-7 (301 mg, 0.8 mmol) was dissolved in anhydrous DMF (5 mL), 5- amino-2-fluorobenzoic 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, and the reaction was continued to stir for 1 h after natural recovery to room temperature. LC-MS monitoring showed that the raw material was completely reacted, and 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 (400 MHz, DMSO) δ 10.22 (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 = 10.7 Hz, 1H), 4.33-4.24 (m, 1H), 3.96 (d, J = 1.5 Hz, 3H), 2.45-2.35 (m, 1H), 2.32-2.25 (m, 1H), 1.73 (s, 3H).

[0323] Preparation of (3-cyano-5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5- (trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenyl)boronic acid (Compound 26)

[0324] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in DMF (5 mL), 3-amino-5- cyanobenzoic acid (62 mg, 0.24 mmol) was added, TCHF (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath, and the reaction was continued to stir for 1 h after natural recovery to room temperature. LC-MS monitoring showed that the raw material was completely reacted, and 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 (400 MHz, DMSO) δ 10.59 (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 = 10.8 Hz, 1H), 4.36-4.25 (m, 1H), 4.00 (d, J = 1.6 Hz, 3H), 2.54-2.32 (m, 2H), 1.76 (s, 3H).

[0325] Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 31)

[0326] Compound 1-7 (30.0 mg, 0.084 mmol) was dissolved in DMF (1.5 mL), 6- aminobenzo[c][1,2]oxaborol-1(3H)-ol (19.0 mg, 0.126 mmol) was added, NMI (55.3 mg, 0.673 mmol), TCHF (94.0 mg, 0.337 mmol) was added under ice bath, and the reaction was continued to react for 4 h after natural warming to room temperature. LC-MS monitoring showed that the reaction was completed. After the reaction was completed, the target compound (23.5 mg, 0.048 mmol, yield 57.4%) was obtained by Pre-HPLC separation. MS: m / z = 488.1, [M+H] + , 1H NMR (400 MHz, DMSO) δ 10.28 (s, 1H), 9.20 (s, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.50 (dd, J = 8.3, 2.0 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.23 - 7.11 (m, 2H), 4.90 (s, 2H), 4.62 (d, J = 10.7 Hz, 1H), 4.34 - 4.23 (m, 1H), 3.97 (d, J = 1.7 Hz, 3H), 2.47-2.15 (m, 2H), 1.73 (s, 3H).

[0327] Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5- (trifluoromethyl)tetrahydrothiophene-2-carboxamido)thiophen-2-yl)boronic acid (Compound 48)

[0328] Compound Intermediate 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 4-aminothiophene-2-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, and the reaction was continued to stir for 1 h after natural recovery to room temperature. LC-MS monitoring showed that the raw material was completely reacted, and 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 (400 MHz, DMSO) δ 10.64 (s, 1H), 8.27 (s, 2H), 7.67 (d, J = 0.6 Hz, 1H), 7.53 (d, J = 0.8 Hz, 1H), 7.20-7.16 (m, 1H), 4.62 (d, J = 10.8 Hz, 1H), 4.34 - 4.26 (m, 1H), 3.99 (d, J = 1.6 Hz, 3H), 2.43-2.33 (m, 1H), 1.75 (s, 3H).

[0329] Preparation of (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5- (trifluoromethyl)tetrahydrothiophene-2-carboxamido)thiophen-3-yl)boronic acid (Compound 49)

[0330] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 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, and the reaction was continued to stir for 1 h after natural recovery to room temperature. LC-MS monitoring showed that the raw material was completely reacted, and 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 (400 MHz, DMSO) δ 10.64 (s, 1H), 8.27 (s, 2H), 7.67 (d, J = 0.6 Hz, 1H), 7.53 (d, J = 0.8 Hz, 1H), 7.20 - 7.16 (m, 1H), 4.62 (d, J = 10.8 Hz, 1H), 4.34 - 4.26 (m, 1H), 3.99 (d, J = 1.6 Hz, 3H), 2.43 - 2.33 (m, 1H), 1.75 (s, 3H).

[0331] Preparation Example 10: Preparation of (6-(3-(3,4-difluoro-2-methoxyphenyl)-5- methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-1H-indol-4-yl)boronic acid (Compound 53)

[0332] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 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, and the reaction was continued to stir for 1 h after natural recovery to room temperature. LC-MS monitoring showed that the raw material was completely reacted, and 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 (400 MHz, DMSO) δ 10.85 (s, 1H), 10.09 (s, 1H), 7.91 (s, 1H), 7.76 (s, 2H), 7.23 - 7.11 (m, 4H), 6.66 (s, 1H), 4.67 (d, J = 10.8 Hz, 1H), 4.35 - 4.26 (m, 1H), 3.97 (s, 3H), 2.42 - 2.28 (m, 2H), 1.74 (s, 3H).

[0333] Preparation 11: Preparation of (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5- (trifluoromethyl)tetrahydrothiophene-2-carboxamido)-lH-indazol-7-yl)boronic acid (Compound 54)

[0334] Compound 1-7 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), (5-amino- lH-indazole-7-carboxylic 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, and stirring was continued for 1 h after natural recovery to room temperature. LC-MS monitoring showed that the starting material was completely reacted, and 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 (400 MHz, DMSO) δ 12.32 (s, 1H), 10.22 (s, 1H), 8.36 (s, 2H), 8.09 (s, 1H), 7.99 (s, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.27 - 7.15 (m, 2H), 4.69 (d, J = 10.8 Hz, 1H), 4.37 - 4.29 (m, 1H), 4.00 (d, J = 1.6 Hz, 3H), 2.46 - 2.33 (m, 2H), 1.77 (s, 3H).

[0335] Preparation 12: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5- (trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenyl)boronic acid (Compound 82)

[0336] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 4- aminobenzoic 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, and stirring was continued for 1 h after natural recovery to room temperature. LC-MS monitoring showed that the starting material was completely reacted, and 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 (400 MHz, DMSO) δ 10.24 (s, 1H), 7.89 (s, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.22 - 7.09 (m, 2H), 4.61 (d, J = 10.7 Hz, 1H), 4.35 - 4.23 (m, 1H), 3.97 (d, J = 1.4 Hz, 3H), 2.47-2.25 (m, 2H), 1.73 (s, 3H).

[0337] 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)

[0338] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 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, and after natural recovery to room temperature, stirring was continued for 1 h. LC-MS monitoring showed that the raw material was completely reacted, and Pre-HPLC separation gave the target compound (19.7 mg, 0.04 mmol, yield 50.01%), MS: m / z = 494.2, [M+H] + , 1 H NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 8.12 (s, 2H), 7.79 (t, J = 7.8 Hz, 1H), 7.53 - 7.49 (m, 2H), 7.19-7.15 (m, 2H), 4.84 (d, J = 10.8 Hz, 1H), 4.30-4.23 (m, 1H), 3.95 (d, J = 1.2 Hz, 3H), 2.37-2.31 (m, 2H), 1.73 (s, 3H).

[0339] Preparation Example 14: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5- methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-3-methoxyphenyl)boronic acid (Compound 94)

[0340] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 4- amino-3-methoxybenzoic 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, and it was allowed to return to room temperature naturally, and stirring was continued for 1 h. LC-MS monitoring showed that the raw material was completely reacted, and Pre-HPLC separation gave the target compound (17 mg, 0.03 mmol, yield 42.10%), MS: m / z = 506.2, [M+H] + , 1 H NMR (400 MHz, DMSO) δ 9.42 (s, 1H), 8.01 (s, 2H), 7.88 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.28 - 7.15 (m, 2H), 5.00 (d, J = 10.7 Hz, 1H), 4.29 (d, J = 8.0 Hz, 1H), 3.96 (d, J = 1.2 Hz, 3H), 3.81 (s, 3H), 2.36 - 2.31 (m, 2H), 1.75 (s, 3H).

[0341] Preparation Example 15: Preparation of (2-(3-(3,4-difluoro-2-methoxyphenyl)-5- methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)pyrimidin-5-yl)boronic acid (Compound 111)

[0342] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 2- aminopyrimidine-5-boronic 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, and it was allowed to return to room temperature naturally, and stirring was continued for 1 h. LC-MS monitoring showed that the raw material was completely reacted, and Pre-HPLC separation gave the target compound (23.9 mg, 0.05 mmol, yield 62.50%), MS: m / z = 478.2, [M+H] + , 1 H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 8.83 (s, 2H), 8.46 (s, 2H), 7.19 - 7.14 (m, 2H), 4.92 (d, J = 10.2 Hz, 1H), 4.36 - 4.28 (m, 1H), 3.95 (d, J = 1.6 Hz, 3H), 2.40 - 2.28 (m, 2H), 1.72 (s, 3H).

[0343] Preparation of 4-(3-(3,4-difluoro-2-methoxyphenyl)-5,5-dimethylthiophene-2- carboxamido)pyridine amide (Compound 134)

[0344] Step one: Synthesis of methyl 4-(3-(3,4-difluoro-2-methoxyphenyl)-5,5- dimethylthiophene-2-carboxamido)pyridine-3-carboxylate

[0345] Into a dry round bottom flask was added 2-7 (500 mg, 1.65 mmol), acetonitrile (10 mL), NMI (583 mg, 5.7 mmol) and methyl 4-aminopyridine-3-carboxylate (275 mg, 1.82 mmol), followed by stirring until uniform, then adding TCFH (693 mg, 2.4 mmol), continuing to stir at room temperature for 1 h. The reaction was quenched by adding water, concentrated under reduced pressure, the residue was added to water, extracted with ethyl acetate 3 times, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by Pre-HPLC to obtain the target compound (523 mg, 1.2 mmol, yield 78.1%). MS: m / z = 437.1, [M+H] + .

[0346] Step two: Synthesis of 4-(3-(3,4-difluoro-2-methoxyphenyl)-5,5-dimethylthiophene-2- carboxamido)pyridine amide

[0347] Into an autoclave was added the product of step one (523 mg, 1.2 mmol), 2M ammonia in methanol (10 mL). The reaction was heated to 60°C and stirred overnight, the system was cooled to room temperature, concentrated under reduced pressure, 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 (400 MHz, DMSO) δ 10.60 (s, 1H), 8.45 (d, J = 5.2 Hz, 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).

[0348] Chiral separation method: column OJ-H, column temperature 30 °C, mobile phase (n-hexane-absolute 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).

[0349] Preparation Example 17: Preparation of 4-(3-(3,4-difluoro-2-methoxyphenyl)-5- methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)picolinamide (Compound 139)

[0350] Step one: synthesis of methyl 4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5- (trifluoromethyl)tetrahydrothiophene-2-carboxamido)picolinate (139-1)

[0351] Into a dry round-bottom flask was added intermediate 1-7 (837 mg, 2.35 mmol), DMF (30 mL), NMI (1.17 g, 11.4 mmol) and methyl 4-aminopicolinate (550 mg, 3.64 mmol), TCFH (2.08 mg, 7.2 mmol) was added under ice bath, and the reaction was allowed to return to room temperature and stirred for 1 h. The reaction was quenched by adding water (20 mL), extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by Pre-HPLC to give the target compound (910 mg, 1.86 mmol, 78.99% yield), MS: m / z = 491.1, [M+H] + .

[0352] Step two: synthesis of 4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5- (trifluoromethyl)tetrahydrothiophene-2-carboxamido)picolinamide (Compound 139)

[0353] Into an autoclave was added the product of step one (910 mg, 1.86 mmol) and 2M ammonia in methanol (15 mL). 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 give the target compound (711 mg, 1.5 mmol, 80.6% yield), MS: m / z = 476.3, [M+H] + , 1H NMR (400 MHz, DMSO) δ 10.81 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 8.03 (s, 1H), 7.67 (dd, J = 5.5, 2.0 Hz, 1H), 7.60 (s, 1H), 7.28 - 7.09 (m, 2H), 4.61 (d, J = 10.6 Hz, 1H), 4.39 - 7.18 (m, 1H), 3.97 (d, J = 1.5 Hz, 3H), 2.47 - 2.13 (m, 2H), 1.74 (s, 3H).

[0354] The product of Step two was separated by chiral separation method as follows: column AD-H, column temperature 30 °C, mobile phase (n-hexane-absolute ethanol-isopropanol-diethylamine = 80: 16: 4: 0.05), flow rate 1 mL / min, the component with retention time about 5.3 min was dried to give the compound of formula II.

[0355] Preparation Example 18: Preparation of N-(3-carbamoyl-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)thiophene-2-carboxamide (Compound 146).

[0356] Step one: synthesis of methyl 5-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5- (trifluoromethyl)thiophene-2-carboxamido)-2-fluorobenzoate (Compound 146-1).

[0357] Compound 1-7 (50.7 mg, 0.1 mmol) was dissolved in 3 mL of dry DMF, and then methyl 5-amino-2-fluorobenzoate (169.1 mg, 0.1 mmol), NMI (240.2 mg, 3.0 mmol), TCFH (420 mg, 0.15 mmol) were added successively under ice bath, and the mixture was allowed to return to room temperature and reacted for 4 hours. The reaction was quenched by adding water (10 mL), extracted with ethyl acetate (20 mL x 3), and the organic phase was combined, washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by Pre-HPLC to give the target compound (22.3 mg, 0.044 mmol, yield 44.0%), MS: m / z = 508.2, [M+H] + .

[0358] Step two: synthesis of N-(3-carbamoyl-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)thiophene-2-carboxamide (Compound 146)

[0359] The product of Step one (22.3 mg, 0.044 mmol) was added to 7M NH3 in MeOH (2 mL) and stirred at room temperature overnight. After the reaction was complete, it was concentrated to give a crude product, which was separated by Pre-HPLC to give the target compound (17 mg, 0.034 mmol, 77.2% yield). MS: m / z = 493.2, [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.42 (s, 1H), 7.80 (dd, J = 6.4, 2.8 Hz, 1H), 7.71 - 7.56 (m, 3H), 7.18 (dt, J = 10.8, 8.5 Hz, 3H), 4.57 (d, J = 10.7 Hz, 1H), 4.32 - 4.20 (m, 1H), 3.96 (d, J = 1.8 Hz, 3H), 2.43 - 2.29 (m, 2H), 1.73 (s, 3H).

[0360] Preparation Example 19: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-oxo- 1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)thiophene-2-carboxamide (Compound 170)

[0361] Compound 1-7 (30.0 mg, 0.084 mmol) was dissolved in 1.0 mL of dry MeCN, and T3P (267.8 mg, 0.842 mmol), Et3N (68.16 mg, 0.673 mmol) were added successively, and the reaction was carried out at 60 °C for 0.5 h, and 4-aminopyridin-2(lH)-one (13.9 mg, 0.126 mmol) was added, and the reaction was continued at 60 °C for 3.0 h, and the target compound (13.0 mg, 0.289 mmol, 34.43% yield) was separated by Pre-HPLC, MS: m / z = 449.2, [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.23 (s, 1H), 10.31 (s, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.20 - 7.14 (m, 2H), 6.60 (d, J = 2.0 Hz, 1H), 6.18 (dd, J = 7.2, 1.9 Hz, 1H), 4.55 (d, J = 10.6 Hz, 1H), 4.29 - 4.18 (m, 1H), 3.96 (d, J = 1.9 Hz, 3H), 2.44 - 2.37 (m, 1H), 2.33 - 2.26 (m, 1H), 1.71 (s, 3H).

[0362] 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)thiophene-2-carboxamide (Compound 172)

[0363] Compound 1-7 (30 mg, 0.084 mmol) was dissolved in DMF (2 mL), 4-amino-1- methylpyridin-2(1H)-one (16 mg, 0.13 mmol) was added, NMI (33 mg, 0.4 mmol) was added, and the reaction bottle was stirred in an ice bath. TCFH (56 mg, 0.2 mmol) was weighed and added to the reaction bottle at one time, and the reaction was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction, and ethyl acetate (20 mL x 3) was extracted. The organic phase was 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 (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.23 (d, J = 7.4 Hz, 1H), 7.02 (d, J = 6.2 Hz, 1H), 6.95-6.78 (m, 2H), 6.54 (s, 1H), 4.49 (d, J = 10.7 Hz, 1H), 4.29-4.11 (m, 1H), 4.00 (d, J = 2.0 Hz, 3H), 3.52 (s, 3H), 2.47-2.16 (m, 2H), 1.75 (s, 3H).

[0364] Preparation Example 21: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(6- oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)thiophene-2-carboxamide (Compound 176)

[0365] Compound 1-7 (30.0 mg, 0.084 mmol) was dissolved in DMF (1.5 mL), 5- aminopyridin-2(1H)-one (15.0 mg, 0.126 mmol) was added, HOBt (24.0 mg, 0.168 mmol) was added, and the reaction bottle was placed in an ice water bath, DIC (33.0 mg, 0.252 mmol) was added, and after natural warming to room temperature, the reaction was continued for 4 hours. The reaction 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 (400 MHz, DMSO) δ 11.25 (s, 1H), 10.06 (s, 1H), 7.77 (d, J = 2.8 Hz, 1H), 7.30 (dd, J = 9.7, 2.9 Hz, 1H), 7.20 - 7.10 (m, 2H), 6.30 (d, J = 9.7 Hz, 1H), 4.50 (d, J = 10.8 Hz, 1H), 4.29 - 4.16 (m, 1H),, 3.95 (d, J = 1.8 Hz, 3H), 2.45 - 2.23 (m, 2H), 1.71 (s, 3H).

[0366] 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)

[0367] Compound 1-8 (40.0 mg, 0.112 mmol) was dissolved in DMF (2.0 mL), 5- amino pyridine-2(lH)-one (18.0 mg, 0.168 mmol), HOBt (30.0 mg, 0.224 mmol), DIC (42.0 mg, 0.336 mmol) were added at 0 °C, and the reaction was continued for 4 hours after natural warming to room temperature. 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 (400 MHz, DMSO) δ 11.25 (s, 1H), 10.06 (s, 1H), 7.77 (d, J = 2.8 Hz, 1H), 7.30 (dd, J = 9.7, 2.9 Hz, 1H), 7.20 - 7.10 (m, 2H), 6.30 (d, J = 9.7 Hz, 1H), 4.50 (d, J = 10.8 Hz, 1H), 4.29 - 4.16 (m, 1H),, 3.95 (d, J = 1.8 Hz, 3H), 2.45 - 2.23 (m, 2H), 1.71 (s, 3H).

[0368] Preparation Example 23: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 178)

[0369] Compound 1-7 (30.0 mg, 0.084 mmol) was dissolved in 1.0 mL dry MeCN, T3P (267.8 mg, 0.842 mmol), Et3N (68.16 mg, 0.673 mmol) were added successively, stirred at 60 °C for 0.5 h, 5-amino-1-methylpyridin-2(1H)-one (15.6 mg, 0.126 mmol) was added, and stirring was continued at 60 °C for 3.0 h. The reaction solution was separated by Pre-HPLC to give the target compound (13.0 mg, 0.028 mmol, 33.45% yield), MS: m / z = 463.2, [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.42 (s, 1H), 7.80 (dd, J = 6.4, 2.8 Hz, 1H), 7.71 - 7.56 (m, 3H), 7.24 - 7.11 (m, 3H), 4.57 (d, J = 10.7 Hz, 1H), 4.32 - 4.20 (m, 1H), 3.96 (d, J = 1.8 Hz, 3H), 2.43 - 2.31 (m, 2H), 1.73 (s, 3H).

[0370] Preparation 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-deuterium-2-carboxamide (Compound 179)

[0371] Compound 1-8 (35 mg, 0.098 mmol) was dissolved in anhydrous DMF (2 mL), 5-amino-1- methylpyridin-2(1H)-one (18 mg, 0.14 mmol), NMI (33 mg, 0.4 mmol) were added, and stirring was carried out at 0 °C. TCFH (56 mg, 0.2 mmol) was weighed and added to the reaction bottle at one time, and stirring was carried out at room temperature for 2 h. The reaction solution was separated by Pre-HPLC to give the target compound (15 mg, 0.032 mmol, 32% yield). MS: m / z = 464.2, [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 8.07 (d, J = 2.8 Hz, 1H), 7.30 - 7.21 (m, 1H), 7.20 - 7.14 (m, 2H), 6.35 (d, J = 9.7 Hz, 1H), 4.27 - 4.17 (m, 1H), 3.96 (d, J = 1.8 Hz, 3H), 3.36 (s, 3H), 2.44 - 2.25 (m, 2H), 1.71 (s, 3H).

[0372] Example 1

[0373] Weigh 0.155 g of sodium hydroxide, add 133 g of purified water, and stir to dissolve. Add 1.8 g of glycocoll acid, and stir to dissolve, to obtain solution A. Add 15 g of the compound of formula II to solution A, and stir to disperse uniformly, to obtain suspension B.

[0374] Place 206 g of 0.4 mm ball milling beads and suspension B into a ball mill, and perform ball milling at a rotation speed of 1500 rpm and a pump speed of 150 ml / min, with a condensate water circulation temperature of 10°C. After 2 hours of ball milling, suspension C is obtained, and the average particle size is measured to be 206.4 nm.

[0375] Add 0.15 g of polyvinylpyrrolidone K17 and 3.5 g of sucrose to 6.35 g of water, and stir to dissolve. Add 40 g of suspension C, and stir to obtain a nanoinjection. The average particle size of the nanoinjection is measured to be 195.8 nm, and the PDI is 0.176. The particle size distribution is shown in FIG. 1.

[0376] Example 2

[0377] Weigh 0.154 g of sodium hydroxide, add 133 g of purified water, and stir to dissolve. Add 1.8 g of glycocoll acid, and stir to dissolve, to obtain solution A. Add 15 g of the compound of formula II to solution A, and stir to disperse uniformly, to obtain suspension B.

[0378] Add suspension B to a high-pressure homogenizer, and perform homogenization. The homogenization pressure is gradually increased from 0 bar to 500 bar over the first 30 minutes, and then adjusted to 1500 bar, and homogenization is continued for 3 hours, to obtain suspension D, and the average particle size is measured to be 240.6 nm.

[0379] Add 0.25 g of polyvinylpyrrolidone K17 and 3.5 g of sucrose to 6.25 g of water, and stir to dissolve. Add 40 g of suspension D, and stir to obtain a nanoinjection. The average particle size of the nanoinjection is measured to be 232.8 nm.

[0380] Example 3

[0381] Weigh 0.183 g of sodium hydroxide, add 133 g of purified water, and stir to dissolve. Add 1.5 g of deoxycholic acid, and stir to dissolve, to obtain solution A. Add 15 g of the compound of formula II to solution A, and stir to disperse uniformly, to obtain suspension B.

[0382] Place 206 g of 0.1 mm ball milling beads and suspension B into a ball mill, and perform ball milling at a rotation speed of 1500 rpm and a pump speed of 200 ml / min, with a condensate water circulation temperature of 10°C. After 4 hours of ball milling, suspension C is obtained, and the average particle size is measured to be 158.4 nm.

[0383] Dissolve 0.15 g of polyvinylpyrrolidone K30 and 3.5 g of sucrose in 6.35 g of purified water. Add 40 g of the suspension C and stir to obtain the nano-injection. The average particle size of the nano-injection is 149.8 nm.

[0384] Example 4

[0385] Dissolve 0.153 g of sodium hydroxide in 133 g of purified water. Add 1.5 g of ursodeoxycholic acid and stir to obtain the solution A. Add 15 g of the compound of formula II in the solution A and stir to obtain the suspension B.

[0386] Put 206 g of 0.4 mm ball milling beads and the suspension B into a ball mill and mill at a speed of 1500 rpm and a pump speed of 150 ml / min, and a condensate water circulation temperature of 10 °C. Mill for 2 hours, and the average particle size is 221.5 nm. Then use a high-pressure homogenizer to homogenize at a pressure of 1500 bar. Homogenize for 20 minutes to obtain the suspension E, and the average particle size is 167.8 nm.

[0387] Dissolve 0.3 g of polyvinylpyrrolidone K30 and 3.5 g of sucrose in 6.2 g of purified water. Add 40 g of the suspension E and stir to obtain the nano-injection. The average particle size of the nano-injection is 175.5 nm.

[0388] Example 5

[0389] Dissolve 6 g of Tween 80 in 114 g of purified water to obtain the solution A. Add 30 g of the compound of formula II in the solution A and stir to obtain the suspension B.

[0390] Put 206 g of 0.4 mm ball milling beads and the suspension B into a ball mill and mill at a speed of 1500 rpm and a pump speed of 150 ml / min, and a condensate water circulation temperature of 5 °C. Mill for 4 hours to obtain the suspension C, and the average particle size is 219.2 nm.

[0391] Dissolve 0.3 g of polyvinylpyrrolidone K12 and 7 g of sucrose in 52.7 g of purified water. Add 40 g of the suspension C and stir to obtain the nano-injection. The average particle size of the nano-injection is 225.4 nm.

[0392] Example 6

[0393] Dissolve 4.5 g of HS15 in 115.5 g of purified water to obtain the solution A. Add 30 g of the compound of formula II in the solution A and stir to obtain the suspension B.

[0394] Put 206g of 0.4mm size ball mill beads and suspension B into a ball mill for ball milling, the ball milling speed is 1500rpm, the pump speed is 150ml / min, and the condensate water circulation temperature is 5°C. Ball mill for 4 hours to obtain suspension C, and the average particle size is 205.6nm.

[0395] Put 0.3g of polyvinylpyrrolidone K17 and 7g of sucrose into 52.7g of water, and stir to dissolve. Add 40g of suspension C, and stir to obtain the nano-injection. The average particle size of the nano-injection is 198.2nm.

[0396] Example 7

[0397] Weigh 1.5g of sodium oleate, add 133.5g of purified water, and stir to dissolve to obtain solution A. Add 15g of the compound of formula II into solution A, and stir to disperse uniformly to obtain suspension B.

[0398] Put 206g of 0.3mm size ball mill beads and suspension B into a ball mill for ball milling, the ball milling speed is 1500rpm, the pump speed is 150ml / min, and the condensate water circulation temperature is 10°C. Ball mill for 2 hours to obtain suspension C, and the average particle size is 219.5nm. Then use a high-pressure homogenizer to homogenize, and the homogenization pressure is 1500bar. Homogenize for 20 minutes to obtain suspension E, and the average particle size is 154.2nm.

[0399] Put 0.3g of polyvinylpyrrolidone K17 and 3.5g of sucrose into 6.2g of water, and stir to dissolve. Add 40g of suspension E, and stir to obtain the nano-injection. The average particle size of the nano-injection is 147.9nm.

[0400] Example 8

[0401] Weigh 0.183g of sodium hydroxide, add 133g of purified water, and stir to dissolve to obtain solution A. Add 1.5g of deoxycholic acid, and stir to dissolve to obtain solution A. Add 15g of the compound of formula II into solution A, and stir to disperse uniformly to obtain suspension B.

[0402] Put 206g of 0.4mm size ball mill beads and suspension B into a ball mill for ball milling, the ball milling speed is 1500rpm, the pump speed is 150ml / min, and the condensate water circulation temperature is 10°C. Ball mill for 2 hours to obtain suspension C, and the average particle size is 210.3nm. Then use a high-pressure micro-jet nano-homogenizer to homogenize, and the homogenization pressure is 2000bar. Homogenize for 30 cycles to obtain suspension E, and the average particle size is 164.8nm.

[0403] Take 0.15g polyvinylpyrrolidone K12 and 3.5g sucrose into 6.35g water, stir to dissolve. Add 40g suspension E, stir to uniform, then the nano-injection is obtained. The average particle size of the nano-injection is 215.3nm.

[0404] Example 9

[0405] Take 0.157g sodium hydroxide, add 133g purified water, stir to dissolve. Add 1.8g glycocoll acid, stir to dissolve, then solution A is obtained. Add 15g compound of formula II into solution A, cut in ice bath for 10 minutes to disperse uniformly, then suspension B is obtained.

[0406] Put 206g 0.3mm ball mill beads and suspension B into ball mill, ball mill at 1500rpm, pump speed 400ml / min, condensate water circulation temperature is 10℃. Ball mill for 2 hours, then suspension C is obtained, the average particle size is 225.8nm.

[0407] Take 0.125g polyvinylpyrrolidone K17 and 1.75g sucrose into 3.125g water, stir to dissolve. Add 20g suspension C, stir to uniform, the average particle size is 222.8nm. Dispense into a vial, then freeze-dry according to the process parameters in table 1, then the nano-injection is obtained. Add water to reconstitute, the average particle size of the nano-injection is 235.9nm.

[0408] Table 1 freeze-drying process parameters

[0409] Example 10

[0410] Take 0.122g sodium hydroxide, add 133.7g purified water, stir to dissolve. Add 1.2g deoxycholic acid, stir to dissolve, then solution A is obtained. Add 15g compound of formula II into solution A, stir to disperse uniformly, then suspension B is obtained.

[0411] Put 206g 0.4mm ball mill beads and suspension B into ball mill, ball mill at 1500rpm, pump speed 200ml / min, condensate water circulation temperature is 10℃. Ball mill for 3 hours, the average particle size is 223.6nm. Then use high-pressure homogenizer to homogenize, homogenization pressure is 1500bar. Homogenize for 30 minutes, then suspension E is obtained, the average particle size is 163.5nm.

[0412] Take 0.15g polyvinylpyrrolidone K30 and 2.5g mannitol into 7.35g water, stir to dissolve. Add 40g suspension E, stir to uniform, the average particle size is 160.4nm. Dispense into a vial, then freeze-dry according to the process parameters in table 1 of example 9, then the nano-injection is obtained. Add water to reconstitute, the average particle size of the nano-injection is 186.6nm.

[0413] Example 11

[0414] Weigh 1.2 g of sodium oleate, add 133.8 g of purified water, stir and dissolve to obtain solution A. Add 15 g of the compound of formula II to solution A, stir and disperse to obtain suspension B.

[0415] Put 206 g of 0.1 mm ball milling beads and suspension B into a ball mill, and carry out ball milling at a rotation speed of 2000 rpm and a pump speed of 200 ml / min, with the circulating temperature of condensed water being 5°C. After 3 hours of ball milling, suspension C is obtained, and the average particle size is measured to be 191.9 nm.

[0416] Add 0.15 g of polyvinylpyrrolidone K17 and 2.5 g of mannitol to 7.35 g of water, stir and dissolve. Add 40 g of suspension C, stir and disperse, and the average particle size is measured to be 208.7 nm. Dispense into a vial, and carry out freeze-drying according to the process parameters in Table 1 of Example 9 to obtain a nano-injection. After reconstitution with water, the average particle size of the nano-injection is measured to be 222.6 nm.

[0417] Example 12

[0418] Weigh 0.16 g of sodium hydroxide, add 133 g of purified water, stir and dissolve. Add 2 g of ursodeoxycholic acid, stir and dissolve to obtain solution A. Add 15 g of the compound of formula II to solution A, and disperse uniformly in an ice bath for 10 minutes to obtain suspension B.

[0419] Put 206 g of 0.3 mm ball milling beads and suspension B into a ball mill, and carry out ball milling at a rotation speed of 2000 rpm and a pump speed of 400 ml / min, with the circulating temperature of condensed water being 10°C. After 2 hours of ball milling, suspension C is obtained, and the average particle size is measured to be 218.2 nm.

[0420] Add 0.125 g of polyvinylpyrrolidone K17 and 2 g of trehalose to 3 g of water, stir and dissolve. Add 20 g of suspension C, stir and disperse, and the average particle size is measured to be 225.6 nm. Dispense into a vial, and carry out freeze-drying according to the process parameters in Table 1 of Example 9 to obtain a nano-injection. After reconstitution with water, the average particle size of the nano-injection is measured to be 220.4 nm.

[0421] Pharmacokinetic study of the nano-injection of Example 1 in SD rats

[0422] Preparation of injection

[0423] Nano-injection: the nano-injection prepared according to the method of Example 1 is diluted with normal saline to a concentration of 4 mg / mL of the compound of formula II.

[0424] Ordinary injection: Compound II is dissolved in dimethyl sulfoxide (DMSO) at a final volume of 5%, and then polyoxyethylene castor oil (Cremophor EL) at a final volume of 10% and physiological saline (Saline) at a final volume of 85% are added sequentially and mixed well to obtain an ordinary injection with a concentration of compound II of 4 mg / mL.

[0425] Three male SD rats in each group were injected via tail vein with either the aforementioned nano-injection or a conventional injection, at a dose of 20 mg / kg (based on compound II). Blood samples of 0.25 ml were collected from the jugular vein before administration (0 h) and at 0.0833 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 1 day (24 h) after administration, and were anticoagulated with EDTA-K2. The collected whole blood was temporarily stored on wet ice and centrifuged at 6000 g for 5 min within 1 h to separate the plasma. The collected plasma was stored at -70℃ for analysis. The plasma drug concentration was determined, a drug-time curve was fitted, and pharmacokinetic parameters were calculated.

[0426] Following administration, all three rats that received the conventional injection showed mild respiratory distress, which subsided after approximately 15 minutes. No significant abnormal reactions were observed in the three rats that received the nano-injection.

[0427] 0.0833 h after administration, the blood drug concentration in the nano-injection group was 6530±164 ng / mL, while the blood drug concentration in the conventional injection group was 23667±4532 ng / mL. This demonstrates that nano-injections can rapidly release the drug after administration and effectively control the drug burst, which is beneficial for rapid efficacy, better safety, and reduced adverse reactions after injection.

[0428] Nanoparticle injection group t 1 / 2 The t-day duration was 2.50 h for the conventional injection group. 1 / 2 The duration of action was 1.02 h, indicating that nano-injection can achieve a sustained-release effect and has a long duration of action.

[0429] Experimental Example 2: Monitoring the effect of the test substance on the stable overexpression of Nav1.8 channel current using manual patch-clamp technique.

[0430] Experimental methods:

[0431] 1. Reagent Preparation

[0432] The test compound is soluble in dimethyl sulfoxide (DMSO).

[0433] Extracellular solution: 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 10 mM D-Glucose, 10 mM HEPES, 1.25 mM NaH2PO4·2H2O, pH 7.4 adjusted with NaOH. Intracellular solution: 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, 20 mM EGTA, pH 7.2 adjusted with CsOH.

[0434] 2 Experimental materials and instruments

[0435] 1) Patch-clamp amplifier: EPC 10 (HEKA)

[0436] 2) Micromanipulator: MP225 (Sutter Instrument)

[0437] 3) Inverted microscope: MF53 (Mshot)

[0438] 4) Microelectrode puller: P97 (Sutter Instrument)

[0439] 5) Capillary glass tube: BF150-86-10 (Sutter Instrument)

[0440] 3 Experimental steps

[0441] 1) After the compound is prepared into a solution of the specified concentration, it is added to the drug delivery system pipeline in turn and marked.

[0442] 2) Place the cell climbing sheet in the recording chamber, select the appropriate cell under the inverted microscope, and adjust the position of the drug delivery head.

[0443] 3) The capillary glass tube is pulled into a suitable recording electrode using a microelectrode puller, and the electrode filled with intracellular solution is installed in the microelectrode holder. Adjust the micromanipulator under the inverted microscope to make the recording electrode contact the cell, and apply negative pressure to the counter electrode to form a high-resistance seal. At this time, perform fast capacitance compensation, then continue to apply negative pressure to suck the cell membrane and form a whole-cell recording mode. Finally, perform slow capacitance compensation and record the relevant parameters.

[0444] 4) After the cell current is stable, start drug delivery, and each drug concentration is applied for five minutes or the current is monitored until the next concentration is stable. The drug solution is gravity-fed through the recording bath to the cell, and the peristaltic pump is used for liquid displacement during recording.

[0445] 4 Test voltage program (resting state) and results

[0446] When the whole-cell configuration was formed, the cell voltage was clamped at -120 mV, then depolarized to 0 mV with a 50 ms square wave pulse to obtain Nav1.8 current. The procedure was repeated every 20 s, and the maximum current induced by square wave was monitored, and the test compound was given when the current was stable. The strength of current block was calculated after the reaction was stable.

[0447] 5The test results are shown in Table 2 below:

[0448] Table 2 Inhibition rate determination results of the compounds of the present disclosure at a concentration of 10 nM

[0449] As can be seen from the data in Table 2, the compounds 9, 19, 31, 48, 82, 134, 134-A, 139, II, 170, 172 and 178 of the present disclosure all have good inhibition effect at a concentration of 10 nM.

[0450] Table 3 Inhibition rate IC of some compounds of the present disclosure 50 Determination results

[0451] As can be seen from the data in Table 3, the activity of the compound 139 of the present disclosure is 8 times that of VX-548, and the activities of the compounds 134 and VX-548 are comparable.

[0452] Experimental Example 3 Pharmacokinetic study of the compounds in SD rats

[0453] Experimental animals: SD rats, male, 6-8 weeks old.

[0454] Compound preparation: first add 5% DMSO to the final preparation volume to dissolve the test compound, then add 10% Cremophor EL and 85% Saline to the final preparation volume in sequence.

[0455] Test design: single intravenous and oral administration of the test compound to SD rats (injection of 2 mg / kg, oral administration of 10 mg / kg; n=3), no fasting and no water restriction in the injection group. The oral administration group was fasted overnight (>12 h) and not water restricted; food was given 4 h after administration. SD rats were injected 5 min, 15 min, 0.5, 1, 2, 4, 8, 24 h after administration, and orally administered 15 min, 0.5, 1, 2, 4, 6, 8, 24 h after administration. Blood was collected from the jugular vein after anticoagulation (blood samples were placed in ice bath after collection), centrifuged at 6000g for 5 min, and the plasma was separated and stored at -70°C for testing.

[0456] Sample monitoring: LC-MS / MS method was used to determine the drug concentration of the specified compound in plasma; Winnolin 8.3 non-compartment model was used to calculate the main pharmacokinetic parameters.

[0457] The test results are shown in Table 4 below:

[0458] Table 4 Pharmacokinetic test results of some compounds of the present disclosure

[0459] From the data in Table 4, it can be seen that compound 139 of the present disclosure has more optimal pharmacokinetic properties in rats, in which the exposure after oral administration is 2 times that of VX-548, t 1 / 2 is also 2 times that of VX-548, indicating that compound 139 has stronger efficacy and longer analgesic time.

[0460] The above examples do not limit the solutions of the present application in any way. Various modifications of the present disclosure, in addition to those described herein, will be apparent to those of ordinary skill in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present application, including all patents, patent applications, journal articles, books, and any other disclosure, is incorporated by reference herein in its entirety.

Claims

1. A nanoinjection comprising an active ingredient and at least one pharmaceutically acceptable carrier, 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, wherein: R a selected from Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from O, S, N, N-R a1 and C-R a2 ; R a1 each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl and -S(O)2R 1 ; R a2 each independently selected from H, halogen, hydroxyl, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 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 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy is optionally substituted with one or more substituents selected from the group consisting of hydroxy and -NR 19 R 20 substituents; or adjacent R a1 and R a2 or two R a2 with the atom to which they are attached form a 5-6 membered heteroaromatic ring; 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 are each independently selected from H and C 1-6 alkyl; R 2 , R 3 are each independently selected from the group consisting of H, C 1-6 alkyl and carbonyl-substituted C 1-6 alkyl; R 4 each independently is selected from C 1-6 alkyl, C 1-6 haloalkyl and C 2-6 alkenyl; R 17 , R 18 are each independently selected from the group consisting of H and C 1-6 alkyl, or R 17 , R 18 and the boron and oxygen atoms to which they are attached form a 5-6 membered heterocyclyl group, said 5-6 membered heterocyclyl group being optionally substituted with one or more substituents selected from the group consisting of H, halogen, and C 1-6 alkyl; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from N, N + -O - and C-R a3 ; R a3 each independently selected from H, halogen, hydroxyl, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 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 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy is optionally substituted with one or more substituents selected from the group consisting of hydroxy and -NR 38 R 39 ; or two R adjacent to each other a3 with the carbon atom to which it is attached forming a 5-6 membered heterocyclyl or 5-6 membered heteroaryl ring, said 5-6 membered heterocyclyl or 5-6 membered heteroaryl ring being optionally substituted with one or more substituents selected from the group consisting of OH and C 1-6 substituted with one or more substituents selected from the group consisting of OH and C 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 are each independently selected from H and C 1-6 alkyl; R 21 , R 22 are each independently selected from the group consisting of H, C 1-6 alkyl, carbonyl-substituted C 1-6 alkyl, carbonyl-substituted C 2-6 alkenyl and -C(O)OC 1-6 alkyl; preferably, R 21 , R 22 are each independently selected from the group consisting of H, C 1-6 alkyl, carbonyl-substituted C 1-6 alkyl and -C(O)OC 1-6 alkyl; R 23 each independently is selected from C 1-6 alkyl, C 1-6 haloalkyl and C 2-6 alkenyl; R 36 , R 37 each independently is selected from the group consisting of H and C 1-6 alkyl, or R 36 , R 37 and the boron and oxygen atoms to which they are attached form a 5-6 membered heterocyclyl group, said 5-6 membered heterocyclyl group being optionally substituted with one or more substituents selected from the group consisting of H, halogen and C 1-6 alkyl; V is selected from N, N + -O - and C-R 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 are each independently selected from H and deuterium; R b3 and R b4 are each independently selected from H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl; R b5 and R b6 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl, or R b5 , R b6 together with the carbon atom to which they are attached form a C 3-5 cycloalkyl or 4-6 membered heterocyclyl; R c selected from H, hydroxy, halo, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, and -O-C 3-6 cycloalkyl, said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from hydroxy, carboxy, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, -NR 40 R 41 , C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl, said 3- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl is optionally substituted with one or more substituents selected from halo and C 1-6 alkyl; R 40 , R 41 are each independently selected from the group consisting of H and C 1-6 alkyl; X 1 , X 2 , X 3 , X 4 are each independently selected from N and C-R c1 ; R c1 each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; wherein the average particle size of the nano-injection is in the range of 100-800 nm, preferably 100-500 nm, more preferably 100-300 nm, further preferably 150-250 nm.

2. Nanosuspension 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 are each independently selected from the group consisting of O, S, N, N-R a1 and C-R a2 ; R a1 each independently selected from H, C 1-4 alkyl (e.g., methyl, ethyl, propyl, butyl), C 1-4 haloalkyl (e.g., CF3, CHF2, CH2F), and -S(O)2R 1 (e.g., -S(O)2CH3); R a2 each independently selected from H, halogen (e.g., fluorine, chlorine, bromine, iodine), hydroxyl, -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 haloalkoxy, 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 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy is optionally substituted with one or more substituents selected from the group consisting of hydroxy and -NR 19 R 20 substituents; or adjacent R a1 and R a2 or two R a2 with the atom to which they are attached form a 5-6 membered heteroaromatic ring; 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 are each independently selected from H and C 1-4 alkyl; R 2 , R 3 are each independently selected from the group consisting of H, C 1-4 alkyl and carbonyl-substituted C 1-4 alkyl; R 4 each independently selected from C 1-4 alkyl, C 1-4 haloalkyl and C 2-6 alkenyl; R 17 , R 18 are each independently selected from the group consisting of H and C 1-4 alkyl, or R 17 , R 18 and the boron and oxygen atoms to which they are attached form a 5-6 membered heterocyclyl group, said 5-6 membered heterocyclyl group being optionally substituted with one or more substituents selected from the group consisting of H, halogen, and C 1-4 alkyl; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from N, N + -O - and C-R a3 ; R a3 each independently selected from H, halogen (e.g., fluorine, chlorine, bromine, iodine), hydroxyl, -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 haloalkoxy, 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 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy optionally substituted with one or more substituents selected from the group consisting of hydroxy and -NR 38 R 39 ; or two R adjacent to each other a3 with the carbon atom to which it is attached forming a 5-6 membered heterocyclyl or 5-6 membered heteroaryl ring, said 5-6 membered heterocyclyl or 5-6 membered heteroaryl ring being optionally substituted with one or more substituents selected from the group consisting of OH and C 1-6 substituted with one or more substituents selected from the group consisting of OH and C 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 are each independently selected from H and C 1-4 alkyl; R 21 , R 22 each independently is selected from H, C 1-4 alkyl, carbonyl-substituted C 1-4 alkyl, carbonyl-substituted C 2-4 alkenyl and -C(O)OC 1-4 alkyl; preferably, R 21 , R 22 each independently is selected from H, C 1-4 alkyl, carbonyl-substituted C 1-4 alkyl and -C(O)OC 1-4 alkyl; R 23 each independently selected from C 1-4 alkyl, C 1-4 haloalkyl and C 2-6 alkenyl; R 36 , R 37 are each independently selected from the group consisting of H and C 1-4 alkyl, or R 36 , R 37 and the boron and oxygen atoms to which they are attached form a 5-6 membered heterocyclyl group, said 5-6 membered heterocyclyl group being optionally substituted with one or more substituents selected from the group consisting of H, halogen, and C 1-4 alkyl; V is selected from N, N + -O - and C-R a4 ; R a4 selected from H and C 1-4 alkyl (e.g., methyl, ethyl, propyl, butyl); R a5 selected from H and C 1-4 alkyl (e.g., methyl, ethyl, propyl, butyl); R a6 selected from H and C 1-4 alkyl (e.g., methyl, ethyl, propyl, butyl); 2) R b3 and R b4 each independently is selected from H, deuterium, C 1-4 alkyl (e.g., methyl, ethyl, propyl, and butyl), C 1-4 haloalkyl, and C 3-6 cycloalkyl; 3) R b5 and R b6 each independently is selected from H, C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl, or R b5 , R b6 together with the carbon atom to which they are attached form a C 3-5 cycloalkyl or 4-6 membered heterocyclyl (e.g. 4-6 membered oxygen-containing heterocyclyl); 4) R c selected from H, hydroxy, halo, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 deuteroalkoxy, C 1-4 haloalkoxy, C 2-6 alkenyl, and -O-C 3-6 cycloalkyl, said C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, or C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from hydroxy, carboxy, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-6 alkenyl, -NR 40 R 41 , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, and 5-6 membered heteroaryl, said 3-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted with one or more substituents selected from halo and C 1-4 alkyl; R 40 , R 41 are each independently selected from H and C 1-4 alkyl; and 5) X 1 , X 2 , X 3 , X 4 are each independently selected from the group consisting of N and C-R c1 ; R c1 each independently selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy.

3. Nanosyringe according to claim 1 or 2, characterized in that, In the compound of Formula I, R a selected from Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from O, S, N, N-R a1 and C-R a2 ; R a1 are each independently selected from the group consisting of H, methyl, CF3, CHF2, and -S(O)2CH3; R a2 each independently selected from H, fluoro, chloro, methyl, CF3, CHF2, -C(O)NH2, -NH2, and or adjacent R a1 and R a2 or two R a2 with the atom to which they are attached form a 5-6 membered heteroaromatic ring; R 17 , R 18 each independently is selected from the group consisting of H and C 1-4 alkyl, or R 17 , R 18 and the boron and oxygen atoms to which they are attached form a 5-6 membered heterocyclyl group, said 5-6 membered heterocyclyl group being optionally substituted with one or more substituents selected from the group consisting of H, halogen and C 1-4 alkyl; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from N, N + -O - and C-R a3 ; R a3 each independently is selected from H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, ethenyl, 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 R adjacent to each other a3 with the carbon atom to which it is attached forming a 5-6 membered heterocyclyl or 5-6 membered heteroaryl ring, said heterocyclyl being optionally substituted with 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 are each independently selected from H and C 1-4 alkyl; R 21 , R 22 are each independently selected from the group consisting of H, C 1-4 alkyl, carbonyl-substituted C 1-4 alkyl, carbonyl-substituted C 2-4 alkenyl and -C(O)OC 1-4 alkyl; preferably, R 21 , R 22 are each independently selected from the group consisting of H, C 1-4 alkyl and carbonyl-substituted C 1-4 alkyl; R 23 each independently selected from C 1-4 alkyl, C 1-4 haloalkyl and C 2-6 alkenyl; R 36 , R 37 each independently is selected from the group consisting of H and C 1-4 alkyl, or R 36 , R 37 and the boron and oxygen atoms to which they are attached form a 5-6 membered heterocyclyl group, said 5-6 membered heterocyclyl group being optionally substituted with one or more substituents selected from the group consisting of H, halogen and C 1-4 alkyl; V is selected from N, N + -O - and C-R a4 ; R a4 selected from H and methyl; R a5 selected from H and methyl; R a6 is selected from H and methyl.

4. Nanosyringe according to any of claims 1 to 3, characterized in that In the compound of Formula I, R a3 each independently selected from H, fluoro, chloro, bromo, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, ethenyl, 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)NH2, -SH, -SCH3, -S(O)CH3, -S(O)2CH3, -S(O)2NH2, -S(O)(NH)CH3, -S(O)(NCH3)CH3, -P(O)(CH3)2, and R1is preferably selected from the group consisting of H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, ethenyl, 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)2and a3 each independently selected from the group consisting of H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, ethenyl, 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)2and or two R adjacent to each other a3 the carbon atom to which it is attached More preferably, R a3 each independently is selected from H, fluorine, chlorine, bromine, -C(O)NH2and 5. Nanosyringe according to any of claims 1 to 4, characterized in that In the compound of formula I, R a selected from the group consisting of: Preferably, R a selected from the group consisting of: More preferably, R a selected from the group consisting of:

6. Nanosyringe according to any of claims 1 to 5, characterized in that In the compound of Formula I, R c selected from H, -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -OCH2CF3, -OCH2CF2CH3, -OCH2CHF2, -OCHF2, Preferably, R c is selected from -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -OCH2CF3, -OCH2CF2CH3, -OCH2CHF2, and -OCHF2; More preferably, R c is -OCH3.

7. Nanosyringe according to any of claims 1 to 6, characterized in that The compounds of formula I are selected from the group consisting of:

8. Nanosyringe according to any of claims 1 to 7, characterized in that The injection is an injection solution, wherein the active ingredient accounts for 1-30% by weight of the injection solution, preferably 2.5-20%, more preferably 5-15%, further preferably 5-10%, more further preferably 8-10%.

9. Nanosyringe according to any of claims 1 to 8, characterized in that The injection comprises one or more of a surfactant, a stabilizer, a pH regulator, and an osmotic pressure regulator.

10. Nanosuspension according to claim 9, characterized in that The injection satisfies one or more of the following conditions: 1) the surfactant is one or more of polysorbate (e.g., Tween 20, Tween 40, Tween 60, Tween 80), sorbitan fatty acid ester (e.g., Span 20, Span 40, Span 60, Span 80), poloxamer, sodium dodecyl sulfate, monoglyceride fatty acid, polyoxyethylene castor oil, cholic acid and its salts (cholic acid, e.g., glycocholic acid, deoxycholic acid, ursodeoxycholic acid, chenodeoxycholic acid, salts, e.g., sodium or potassium salts), oleate (e.g., sodium oleate, potassium oleate, ammonium oleate), 15-hydroxystearic acid polyethylene glycol ester (HS15), lecithin, etc., preferably one or more of Tween 80, HS15, sodium oleate, sodium glycocholate, sodium deoxycholate, and sodium ursodeoxycholate, more preferably one or more of sodium glycocholate and sodium deoxycholate; 2) the stabilizer is one or more of cyclodextrin, carboxymethyl cellulose and its sodium salt, polyethylene glycol, polyvinylpyrrolidone (PVP), hydroxypropyl methyl cellulose, polyethylene glycol vitamin E succinate (TPGS), etc., preferably polyvinylpyrrolidone (e.g., PVP K12, PVP K17, PVP K30); 3) the pH regulator is one or more of disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate, hydrochloric acid, lactic acid, sodium hydroxide, sodium citrate, and tartrate, preferably hydrochloric acid or sodium hydroxide; and 4) the osmotic pressure regulator is one or more of sodium chloride, glucose, sucrose, glycerol, and mannitol, preferably sodium chloride, sucrose, or mannitol.

11. Nanoinjection according to claim 9 or 10, characterized in that, The injection satisfies one or more of the following conditions: 1) the surfactant accounts for 0.01-2% by weight of the injection solution, preferably 0.1-2%, more preferably 0.1-1.6%, further preferably 0.5-1.6%, more further preferably 0.8-1.6%; 2) the stabilizer accounts for 0.1-10% by weight of the injection solution, preferably 0.2-8%, more preferably 0.2-2%, further preferably 0.2-1%, more further preferably 0.3-0.6%; 3) the pH regulator accounts for 0-1% by weight of the injection solution, preferably 0-0.5%; and 4) the osmotic pressure regulator accounts for 0-1% by weight of the injection solution, preferably 0-0.5%. 4) the osmotic pressure adjusting agent is 0% to 10%, preferably 0% to 8% by weight of the injection solution.

12. Nanosyringe according to any one of claims 1 to 7, characterized in that The injection is a lyophilized composition, wherein the active ingredient is 10% to 80%, preferably 20% to 70%, more preferably 25% to 70%, further preferably 25% to 60%, more further preferably 40% to 60% by weight of the lyophilized composition.

13. Nanosyringe according to any of claims 1 to 7 and 12, characterized in that, The injection comprises one or more of a surfactant, a stabilizer, a pH adjusting agent, an osmotic pressure adjusting agent, and a lyoprotectant.

14. Nanosuspension according to claim 13, characterized in that The injection satisfies one or more of the following conditions: 1) the surfactant is one or more of polysorbate (e.g., Tween 20, Tween 40, Tween 60, Tween 80), sorbitan fatty acid ester (e.g., Span 20, Span 40, Span 60, Span 80), poloxamer, sodium dodecyl sulfate, monofatty acid glyceride, polyoxyethylene castor oil, cholic acid and its salts (cholic acid, e.g., glycocholic acid, deoxycholic acid, ursodeoxycholic acid, chenodeoxycholic acid, salts, e.g., sodium or potassium salts), oleic acid salts (e.g., sodium oleate, potassium oleate, ammonium oleate), 15-hydroxystearic acid polyethylene glycol ester (HS15), lecithin, etc., preferably one or more of Tween 80, HS15, sodium oleate, sodium glycocholate, sodium deoxycholate, and sodium ursodeoxycholate, more preferably one or more of sodium glycocholate and sodium deoxycholate; 2) the stabilizer is one or more of cyclodextrin, carboxymethylcellulose and its sodium salt, polyethylene glycol, polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose, polyethylene glycol vitamin E succinate (TPGS), etc., preferably polyvinylpyrrolidone (e.g., PVP K12, PVP K17, PVP K30); 3) the pH adjusting agent is one or more of disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydrogen carbonate, hydrochloric acid, lactic acid, sodium hydroxide, sodium citrate, and tartrate, preferably hydrochloric acid or sodium hydroxide; 4) the osmotic pressure adjusting agent is one or more of sodium chloride, glucose, sucrose, glycerol, and mannitol, preferably sodium chloride, sucrose, or mannitol; and 5) the lyoprotectant is one or more of lactose, maltose, glucose, sucrose, trehalose, glycerol, mannitol, sorbitol, and albumin, preferably sucrose, mannitol, or trehalose.

15. Nanoinjection according to claim 13 or 14, characterized in that, The injection satisfies one or more of the following conditions: 1) the surfactant is 1% to 20%, preferably 1% to 15%, more preferably 1% to 12%, further preferably 5% to 12%, more further preferably 5% to 10% by weight of the lyophilized composition; 2) the stabilizer is 0.5% to 8%, preferably 0.5% to 7%, more preferably 0.5% to 5%, further preferably 1% to 5% by weight of the lyophilized composition; 3) the pH adjusting agent is 0% to 5%, preferably 0% to 3%, more preferably 0% to 1% by weight of the lyophilized composition; 4) the osmotic pressure adjusting agent is 0% to 50%, preferably 0% to 30% by weight of the lyophilized composition; and 5) the lyoprotectant is 0% to 50%, preferably 0% to 30% by weight of the lyophilized composition. 5) the weight percentage of the lyophilized composition is 0% to 80%, preferably 25% to 70%, more preferably 25% to 50%.

16. A method of preparing the nano-injection according to any one of claims 1-15, characterized in that, The method comprises the following steps: (a) preparing a surfactant-containing solution A, dispersing the active ingredient into solution A to obtain a suspension B; (b1) placing suspension B in a ball mill for ball milling to obtain suspension C; or, (b2) homogenizing suspension B to obtain suspension D; or, (b3) placing suspension B in a ball mill for ball milling, further homogenizing to obtain suspension E; and (c) adding a stabilizer.

17. The method of claim 16, wherein, The method meets one or more of the following conditions: 1) the active ingredient is dispersed in step (a) by stirring or shearing; 2) the ball milling beads in step (b1) or (b3) have a size of 0.1 mm to 0.5 mm, preferably 0.1 mm to 0.4 mm; 3) the rotation speed of the ball milling in step (b1) or (b3) is 1000 rpm to 3000 rpm, preferably 1500 rpm to 2000 rpm; 4) the pump speed of the ball milling in step (b1) or (b3) is 100 ml / min to 500 ml / min, preferably 150 ml / min to 400 ml / min, more preferably 150 ml / min to 200 ml / min; 5) the homogenization equipment in step (b2) or (b3) is a high-pressure homogenizer or a high-pressure micro-jet nanometer homogenizer; 6) the homogenization equipment in step (b2) or (b3) is a high-pressure homogenizer, the homogenization pressure is not less than 500 bar, preferably not less than 800 bar, more preferably not less than 1000 bar, further preferably not less than 1500 bar, the homogenization time is not less than 5 minutes, preferably not less than 10 minutes, more preferably not less than 20 minutes; 7) the homogenization equipment in step (b2) or (b3) is a high-pressure micro-jet nanometer homogenizer, the homogenization pressure is not less than 500 bar, preferably not less than 800 bar, more preferably not less than 1200 bar, further preferably not less than 2000 bar, the cycle number is not less than 10 times, preferably not less than 20 times, more preferably not less than 30 times; and 8) one or more of a pH adjuster and an osmotic pressure adjuster is added in step (c).

18. The method according to claim 16 or 17, characterized in that The method further comprises the following step: (d) lyophilization.

19. The method according to any one of claims 16-18, characterized by, A lyoprotectant is added in step (c).

20. Use of the nano-injection of any one of claims 1-15 in the preparation of a medicament for preventing and / or treating a NaV1.8-related disease, preferably the NaV1.8-related disease is pain.

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