Polycyclic compound and use thereof

Abstract

The present invention belongs to the technical field of medicine. Particularly disclosed are a polycyclic compound as represented by formula I and a use thereof. The polycyclic compound of the present invention has a structure represented by formula I, wherein the definition of each group and substituent is as described in the description. The compound of the present invention can be used for treating or preventing neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, progressive multiple sclerosis, and amyotrophic lateral sclerosis.

Description

Polycyclic compounds and their applications Technical Field

[0001] The present invention relates to the field of medical technology, and specifically discloses a polycyclic compound represented by formula I and an application thereof. Background Art

[0002] Alzheimer's disease, commonly known as senile dementia, is a common neurodegenerative disease accompanied by symptoms such as memory loss and neuronal death. The main clinical hallmark is neurofibrillary tangles. The pathological changes in Alzheimer's disease are quite complex. Currently, countries around the world are researching effective treatments for Alzheimer's disease, but the results are limited. There is currently no specific treatment for Alzheimer's disease or therapeutic drugs that can reverse the progression of the disease. More than a decade ago, the US FDA approved two categories of five therapeutic compounds, including cholinesterase inhibitors and NMDA receptor antagonists, but they can only temporarily improve the symptoms of the disease and cannot prevent the disease from progressing.

[0003] It is generally believed that the primary pathogenesis of Alzheimer's disease is the accumulation of beta-amyloid protein in brain tissue, abnormalities in cerebral vascular structure, which activates microglia and astrocytes to produce inflammatory mediators. This leads to increased free radical production in the brain, accompanied by a weakened antioxidant capacity, and an imbalance between the acetylcholine and anti-acetylcholine systems in the brain. These factors, combined with other factors, lead to structural and functional damage to the brain tissue, increased levels of inflammatory mediators in the hippocampus, and decreased antioxidant capacity in the hippocampus, ultimately inducing Alzheimer's disease. Pharmaceutical companies have developed a variety of vaccines targeting Abeta protein and inhibitors of the phosphorylation of various enzymes involved in its formation, but to date, these efforts have been ineffective. We believe that it is too late to reduce the toxicity of Abeta protein after the onset of the disease. The development of therapeutic drugs should focus on reducing the amount of Abeta protein. Summary of the Invention

[0004] The present invention aims to develop a polycyclic compound represented by formula I and also provides its application in the preparation of medicines. The compound provided by the present invention can be used to prepare medicines for treating diseases such as neurodegenerative diseases.

[0005] Specifically, in the first aspect, the present invention provides a polycyclic compound, wherein the compound is a compound represented by Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof:

[0006] in:

[0007] R1, R2, R3, R4 and R5 each independently represent H or D, and at least one of R1, R2, R3, R4 and R5 is D;

[0008] R6, R7 and R8 each independently represent H, D or F;

[0009] R9 and R 10 Each independently represents H or F.

[0010] As an embodiment of the present invention, in Formula I, at least two of R1, R2, R3, R4, R5, R6, R7 and R8 represent D.

[0011] As an embodiment of the present invention, in Formula I, R1, R2 and R3 are all H, or are all D.

[0012] As an embodiment of the present invention, in Formula I, R4 and R5 are both H, or both D.

[0013] As an embodiment of the present invention, in Formula I, R6, R7 and R8 are all H, or all D, or all F.

[0014] As an embodiment of the present invention, in Formula I, R9, R 10 All are H, or any one of them is F.

[0015] As an embodiment of the present invention, the compound of the present invention is selected from the compounds represented by any of the following structural formulas:

[0016] In a second aspect, the present invention provides a pharmaceutical composition comprising a preventive and / or therapeutically effective amount of the compound of the present invention and a pharmaceutically acceptable carrier.

[0017] In a third aspect, the present invention provides uses of the compounds and pharmaceutical compositions of the present invention.

[0018] The use of the compound or composition of the present invention for preparing a medicament for treating a disease selected from the group consisting of neurodegenerative diseases, cancer, progressive supranuclear palsy, mast cell activation syndrome (MCAS), rheumatoid arthritis, asthma, Crohn's disease, sickle cell disease, and coronavirus disease 2019 (COVID-19).

[0019] As an embodiment of the present invention, the neurodegenerative disease of the present invention is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, progressive multiple sclerosis, and amyotrophic lateral sclerosis.

[0020] As an embodiment of the present invention, the cancer described in the present invention is selected from the group consisting of: prostate cancer, pancreatic cancer, gastric cancer, liver cancer, multiple myeloma, and colorectal cancer.

[0021] The novel compound provided by the present invention can be used to prepare drugs for treating neurodegenerative diseases and the like, and has significant applications in treating or preventing diseases such as Alzheimer's disease, Parkinson's disease, progressive multiple sclerosis, and amyotrophic lateral sclerosis. It has better pharmacodynamics and pharmacokinetic properties, and the compound of the present invention has lower toxic side effects.

[0022] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0023] After extensive and in-depth research, the present inventors unexpectedly discovered a class of compounds with excellent therapeutic potential for cancer and neurodegenerative diseases. Furthermore, these compounds exhibit enhanced pharmacodynamics and pharmacokinetic properties. Based on this discovery, the present invention was completed.

[0024] the term

[0025] Unless otherwise stated, the following terms used in this application (including the specification and claims) have the definitions given below.

[0026] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0027] "Alkyl (alone or as part of another group)" refers to a monovalent straight or branched chain saturated hydrocarbon group containing 1 to 12 carbon atoms consisting solely of carbon and hydrogen atoms. Alkyl is preferably a C1-C6 alkyl (i.e., containing 1, 2, 3, 4, 5, or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. In this application, alkyl is also intended to include substituted alkyls, i.e., one or more positions in the alkyl group are substituted, particularly 1-4 substituents, which may be substituted at any position. "Haloalkyl" refers to an alkyl as defined herein in which one or more hydrogens are replaced by the same or different halogens. Examples of haloalkyls include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyls (e.g., -CF3), and the like.

[0028] "Alkylene" refers to a divalent radical of an alkyl group, for example, -CH2-, -CH2CH2-, and -CH2CH2CH2-.

[0029] "Alkoxy (alone or as part of another group)" refers to an alkyl group having an oxy group attached thereto, having an alkylO- structure, wherein alkyl has the definition described above. Preferably, alkoxy is a C1-C6 alkoxy group. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy, and the like. "Haloalkoxy" refers to a group of the formula -OR, where R is a haloalkyl group as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and the like.

[0030] "Thioalkyl" refers to an alkyl group in which a carbon is replaced by S, S(O), or S(O)2.

[0031] "Alkenyl (alone or as part of another group)" refers to an aliphatic group containing at least one double bond, typically having 2 to 20 carbon atoms. In the present invention, "C2-C6 alkenyl" refers to an alkenyl group containing 2, 3, 4, 5 or 6 carbon atoms. Alkenyl includes, but is not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. In the present invention, alkenyl includes substituted alkenyl.

[0032] "Alkenylene" refers to an alkenyl group with two points of attachment. For example, "vinylene" refers to the group -CH=CH-. Alkenylene can also be unsubstituted or substituted with one or more substituents.

[0033] "Alkynyl (alone or as part of another group)" refers to a straight or branched hydrocarbon chain containing two or more carbon atoms and characterized by one or more triple bonds, typically having 2 to 20 carbon atoms. In the present invention, "C2-6 alkynyl" refers to an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment for an alkynyl substituent. In the present invention, alkynyl groups also include substituted alkynyl groups.

[0034] "Alkynylene" refers to an alkynyl group with two points of attachment. For example, "ethynylene" refers to the group: -C≡C-. Alkynylene groups can be unsubstituted or substituted with one or more substituents.

[0035] "Aliphatic group" refers to a straight-chain, branched-chain or cyclic hydrocarbon group, including saturated and unsaturated groups such as alkyl, alkenyl and alkynyl groups.

[0036] "Aromatic ring system" means a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which at least one ring is aromatic.

[0037] "Aryl (alone or as part of another group)" refers to a monovalent radical of an aromatic ring system. Representative aryl groups include fully aromatic ring systems such as phenyl, naphthyl, and anthracenyl; and ring systems in which an aromatic carbocyclic ring is fused to one or more non-aromatic carbocyclic rings, such as indanyl, phthalimidyl, naphthylimide, or tetrahydronaphthyl, among others. In the present invention, aryl is preferably a C6-C12 aryl group. In the present invention, aryl is also intended to include substituted aryl groups.

[0038] "Arylalkyl" or "aralkyl" refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. Aralkyl groups include groups in which one or more hydrogen atoms are replaced by an aryl group, with aryl and alkyl having the same meanings as described above. Examples of "arylalkyl" or "aralkyl" groups include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, diphenylmethyl, and triphenylmethyl.

[0039] "Aryloxy" means an -O-(aryl) group wherein the aryl portion is as defined herein.

[0040] "Heteroalkyl" refers to a substituted alkyl group having one or more backbone chain atoms selected from atoms other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus, or a combination thereof. A numerical range can be given, for example, C1-C6 heteroalkyl refers to the number of carbons in the chain, which includes 1 to 6 carbon atoms. For example, a -CH2OCH2CH3 group is referred to as a "C3" heteroalkyl group. Connection to the rest of the molecule can be through a heteroatom or carbon in the heteroalkyl chain. "Heteroalkylene" refers to an optionally substituted divalent alkyl group having one or more backbone chain atoms selected from atoms other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus, or a combination thereof.

[0041] "Carbocyclic ring system" refers to a monocyclic, bicyclic, or polycyclic hydrocarbon ring system in which each ring is fully saturated or contains one or more units of unsaturation, but in which none of the rings are aromatic.

[0042] "Carbocyclyl" refers to a monovalent group of a carbon ring system, including, for example, cycloalkyl (cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, etc.) and cycloalkenyl (cyclopentenyl, cyclohexenyl, cyclopentadienyl, etc.).

[0043] "Cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of a mono- or bicyclic ring having 3-12, preferably 3-10, and more preferably 3-8 ring atoms. A cycloalkyl group may be optionally substituted with one or more substituents, each of which is independently hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0044] "Cycloalkyloxy" refers to a radical of the formula -OR, where R is a cycloalkyl radical as defined herein. Exemplary cycloalkyloxy radicals include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. "Cycloalkylalkyl" refers to a -(cycloalkyl)-alkyl radical where the cycloalkyl and alkyl radicals are as disclosed herein. "Cycloalkylalkyl" is bonded to the parent molecular structure through the cycloalkyl radical.

[0045] "Heteroaromatic ring system" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (6-12-membered), or polycyclic ring system in which at least one ring is both aromatic and contains at least one heteroatom (e.g., N, O, or S); and in which none of the other rings is a heterocyclyl (as defined below). In some cases, the ring that is aromatic and contains a heteroatom contains 1, 2, 3, or 4 ring heteroatoms in the ring. At least one of the rings is heteroaromatic, and the remaining rings may be saturated, partially unsaturated, or fully unsaturated.

[0046] "Heteroaryl" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (e.g., 8-10-membered) or tricyclic group of 5 to 12 ring atoms, which contains at least one aromatic ring containing 1, 2 or 3 ring heteroatoms selected from N, O or S, and the remaining ring atoms are C. It should be understood that the point of attachment of the heteroaryl group should be located on the aromatic ring. Examples of heteroaryl groups include, but are not limited to, imidazolyl, Azolyl, iso Azolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzofuranyl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzo Azolyl, benzo oxadiazole, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, aza Base, diazepine A heteroarylene group refers to a heteroaryl group having two attachment sites.

[0047] "Heterocyclic ring system" refers to monocyclic, bicyclic, and polycyclic ring systems in which at least one ring is saturated or partially unsaturated (but non-aromatic) and the ring contains at least one heteroatom. The heterocyclic ring system may be attached to a pendant group at any heteroatom or carbon atom that creates a stable structure and any ring atom may be optionally substituted.

[0048] "Heterocyclyl" refers to a monovalent radical of a heterocyclic ring system, generally a stable monocyclic ring (e.g., 3-8 members, i.e., 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered) or bicyclic ring (e.g., 5-12 members, i.e., 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered) or polycyclic ring (e.g., 7-14 members, i.e., 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered or 14-membered), including fused, spiro and / or bridged ring structures, which are saturated, partially unsaturated, and which contain carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. Representative heterocyclyl groups include ring systems in which (1) each ring is non-aromatic and at least one ring contains a heteroatom, for example, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl; (2) at least one ring is Non-aromatic and containing heteroatoms and at least one other ring is an aromatic carbocyclic ring, for example, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and (3) at least one ring is non-aromatic and contains heteroatoms and at least one other ring is aromatic and contains heteroatoms, for example, 3,4-dihydro-1H-pyrano[4,3-c]pyridine and 1,2,3,4-tetrahydro-2,6-naphthyridine. Heterocyclylene refers to a heterocyclyl having two connection sites. In the present invention, preferably, the heterocyclylene is a bicyclic ring, one of which is a heteroaryl group, and is connected to the other parts in the general formula through the heteroaryl group. In the present invention, preferably, the heterocyclylene is a 5-6 membered monocyclic heterocyclylene or an 8-10 membered bicyclic heterocyclylene.

[0049] In the present invention, the heterocyclylene group is preferably a bicyclic ring, one of which is a heteroaryl group, and is connected to the other parts of the general formula through the heteroaryl group. In the present invention, the heterocyclylene group is preferably a 5-6 membered monocyclic heterocyclylene group or an 8-10 membered bicyclic heterocyclylene group.

[0050] "Heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein the heterocyclyl group and the alkyl group are as defined above.

[0051] The "alkylamino group" refers to a group having an alkyl-NR- structure, wherein R is H, or an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or the like as described above.

[0052] "Cycloalkylamino" refers to a group of the formula -NR a R b group, where R a is H, alkyl as defined herein or cycloalkyl as defined herein, R b is a cycloalkyl group as defined herein, or R a and R bTogether with the nitrogen atom to which it is attached, it forms a 3-10 membered N-containing monocyclic or bicyclic heterocyclic group, such as tetrahydropyrrolyl. As used in the present invention, C3-C8 cycloalkylamino refers to an amino group containing 3-8 carbon atoms.

[0053] In the present invention, "ester group" refers to a group having a -C(O)-OR or RC(O)-O- structure, wherein R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, as defined above.

[0054] As used herein, the term "amido" refers to a group having the structure -CONRR', wherein R and R' independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different in the dialkylamine moiety.

[0055] In the present invention, the term "sulfonamide" refers to a group having the structure -SO2NRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.

[0056] "Ketocarbonyl" refers to RC(=O)-, where R is alkyl, cycloalkyl, etc. as described above.

[0057] When a substituent is non-terminal, it is a substituent of the corresponding group, for example, alkyl for alkylene, cycloalkyl for cycloalkylene, heterocyclyl for heterocyclylene, alkoxy for alkyleneoxy, and the like.

[0058] In the present invention, each of the above-mentioned alkyl, alkoxy, cycloalkyl, heteroalkyl, aryl, heteroaryl, cycloheteroalkyl, alkenyl, alkyne, heterocycle, heterocyclyl, etc. may be substituted or unsubstituted.

[0059] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is the substituent described above, or the substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. It will be understood by those skilled in the art that the combination of substituents contemplated by the present invention is those that are stable or chemically feasible. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., a monohalogen substituent or a polyhalogen substituent, the latter such as a trifluoromethyl group or an alkyl group containing Cl3), cyano, nitro, oxo (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocycle, aromatic ring, ORa SR a 、S(=O)R e 、S(=O)2R e 、P(=O)2R e 、S(=O)2OR e , P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e 、S(=O)2NR b R c 、P(=O)2NR b R c 、C(=O)OR d 、C(=O)R a 、C(=O)NR b R c 、OC(=O)R a 、OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e , where R a R may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic or aromatic rings. b 、R c and R d may independently represent hydrogen, deuterium, an alkyl group, a cycloalkyl group, a heterocyclic ring or an aromatic ring, or R b and R c Together with the N atom, it can form a heterocyclic ring; R eand alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle, or aromatic ring. The above typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aromatic ring, may be optionally substituted. Examples of such substituents include, but are not limited to, halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 urea.

[0060] "Cyano" refers to a -CN group.

[0061] "Nitro" refers to -NO2.

[0062] "Hydroxyl" refers to -OH.

[0063] "Amino" refers to -NH2 or RNH-, where R is ketocarbonyl, sulfonyl, sulfonamide, Ra-C(=O)-, RaRbN-C(=O)-, etc., where Ra and Rb are alkyl, cycloalkyl, aryl or heteroaryl, etc.

[0064] "Halogen" refers to any halogen radical, for example, -F, -Cl, -Br, or -I.

[0065] "Deuterated compound" refers to a compound in which one or more hydrogen atoms (H) are replaced by deuterium atoms (D).

[0066] In the present invention, the term "plurality" independently refers to 2, 3, 4, or 5.

[0067] The structural formula of the carbamate group is -NH-C(=O)-OR, wherein R is an alkyl group, an aryl group, a heteroaryl group, or the like.

[0068] Active ingredient

[0069] As used herein, the terms "compound of the present invention" or "active ingredient of the present invention" are used interchangeably to refer to a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound (such as a deuterated compound), or prodrug thereof. The term also includes racemates and optical isomers.

[0070] The compound of formula I has the following structure:

[0071] wherein each group is as defined above.

[0072] The salts that may be formed by the compounds of the present invention also fall within the scope of the present invention. Unless otherwise indicated, the compounds of the present invention are understood to include their salts. The term "salt" as used herein refers to acidic or basic salts formed with inorganic or organic acids and bases. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and contains an acidic fragment, including but not limited to carboxylic acid, the zwitterions ("inner salts") that may be formed are included within the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in separation or purification steps during the preparation process. The compounds of the present invention may form salts, for example, compound I reacts with a certain amount, such as an equivalent amount, of an acid or base, salts out in a medium, or is obtained by freeze-drying in an aqueous solution.

[0073] The compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (e.g., acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,

[0014] Examples of the present invention include, for example, hydroxyethylsulfonates, lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, and the like.

[0074] sulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, and the like.

[0075] Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hepamine (salt formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can react with halide quaternary ammonium salts, such as small molecular alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate), long chain halides (such as chlorides, bromides and iodides of decyl, dodecyl, tetradecyl and tetradecyl), aralkyl halides (such as benzyl and phenyl bromide), etc.

[0076] Prodrugs and solvates (or solvates) of the compounds of the present invention are also encompassed within the scope.

[0077] The term "prodrug" herein refers to a compound that undergoes chemical transformation by metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when treating a related disease. The compounds of the present invention include solvates, such as hydrates.

[0078] The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imino ethers). All such tautomers are part of the present invention.

[0079] All stereoisomers of the compounds (e.g., those that may exist due to asymmetric carbon atoms for various substitutions), including enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist with other isomers (e.g., as a pure or substantially pure optical isomer having a particular activity), or may be mixtures, such as racemates, or mixtures with all other stereoisomers or portions thereof. The chiral centers of the present invention have either S or R configurations, as defined by the 1974 recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, such as fractional crystallization, or by crystallization of diastereomers derived from them, or by separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.

[0080] The compounds of the present invention, obtained by sequential preparation, isolation, and purification, are described in the text to a concentration of 90% or greater by weight, for example, 95% or greater, or 99% or greater ("very pure" compounds). Such "very pure" compounds of the present invention are also considered part of the present invention.

[0081] All configurational isomers of the compounds of the present invention are encompassed, whether in mixture, pure or very pure form. The definition of the compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

[0082] Throughout the specification, groups and substituents may be chosen to provide stable fragments and compounds.

[0083] Specific functional groups and chemical term definitions are detailed below. For the purposes of this invention, chemical elements are referred to in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The definitions of specific functional groups are consistent with those in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito, 1999, which is incorporated by reference in its entirety.

[0084] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, asymmetric carbon atoms may represent substituents, such as alkyl groups. All isomers and mixtures thereof are encompassed by the present invention.

[0085] According to the present invention, mixtures of isomers can contain various ratios of isomers. For example, mixtures containing only two isomers can have the following ratios: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios, as well as ratios for more complex mixtures of isomers, are readily understood by those skilled in the art and are also within the scope of the present invention.

[0086] The present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as 3 H and 14 Radioisotopes of C are also included and are useful in tissue distribution experiments of drugs and substrates. 3 H and carbon-14, i.e. 14C, are easier to prepare and detect. They are the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2 H, due to its excellent metabolic stability, has advantages in certain therapeutics, such as increasing half-life in vivo or reducing dosage, and therefore, may be preferred in some cases. Isotopically labeled compounds can be prepared using conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

[0087] If a synthesis of a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, followed by separation of the resulting diastereomeric mixture and removal of the chiral auxiliary to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with a suitable optically active acid or base, followed by separation by conventional means such as fractional crystallization or chromatography to obtain the pure enantiomer.

[0088] As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to expand their scope. Generally, the term "substituted," whether preceded or followed by the term "optionally," in formulas of the present invention including substituents, refers to the replacement of a hydrogen radical with a substituent of the specified structure. When multiple positions in a particular structure are substituted with multiple substituents of the specified structure, the substituents may be the same or different at each position. As used herein, the term "substituted" includes all permissible substitutions in organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. For example, heteroatoms of nitrogen may be substituted with hydrogen or any of the permissible organic compounds described above to supplement their valences. Furthermore, the present invention is not intended to limit the permissible substitutions in any way to organic compounds. The present invention recognizes that combinations of substituents and variables are advantageous for providing stable compounds for the treatment of diseases. As used herein, the term "stable" refers to compounds that are stable and maintain the structural integrity of the compound over a period of time sufficient to be detected, preferably over a period of time sufficient to be effective, as used herein for the purposes described above.

[0089] The assay is performed over a period of time sufficient to maintain the structural integrity of the compound, preferably over a period of time sufficient to be effective for the purposes herein.

[0090] The metabolites of the compounds and pharmaceutically acceptable salts thereof involved in the present application, as well as prodrugs that can be converted into the structures of the compounds and pharmaceutically acceptable salts involved in the present application and in vivo, are also included in the claims of the present application.

[0091] In another preferred embodiment, in the compound, any one of the groups is the corresponding group in the specific compound.

[0092] Preparation method

[0093] The following schemes and examples describe methods for preparing compounds of Formula I. Starting materials and intermediates were purchased from commercial sources, prepared by known procedures, or described otherwise. In some cases, the order in which the steps of the reaction schemes are performed may be altered to facilitate the reaction or to avoid unwanted side reaction products.

[0094] The preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art.

[0095] Generally, in the preparation process, each reaction is usually carried out in a suitable solvent under the protection of an inert gas.

[0096] Pharmaceutical compositions and methods of administration

[0097] The pharmaceutical composition of the present invention is used to prevent and / or treat neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, progressive multiple sclerosis, and amyotrophic lateral sclerosis). It is expected to be used to prepare a medicament for treating diseases selected from the group consisting of cancer, progressive supranuclear palsy, mast cell activation syndrome, rheumatoid arthritis, asthma, Crohn's disease, sickle cell disease, and COVID-19. The cancer is selected from the group consisting of prostate cancer, pancreatic cancer, gastric cancer, liver cancer, multiple myeloma, and colorectal cancer.

[0098] The compounds of Formula I may be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the original drug's route of administration and dosage can remain unchanged, while the compound of Formula I is administered simultaneously or subsequently. When the compound of Formula I is administered concurrently with one or more other drugs, a pharmaceutical composition containing both the one or more known drugs and the compound of Formula I may be preferably used. Drug combinations also include administering the compound of Formula I and one or more other known drugs during overlapping time periods. When the compound of Formula I is administered in combination with one or more other drugs, the dosage of the compound of Formula I or the known drug may be lower than when administered alone.

[0099] The dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, film, pill, external ointment, controlled release or sustained release or nano preparation.

[0100] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0101] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0102] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0103] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0104] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0105] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0106] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0107] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0108] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0109] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0110] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0111] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0112] The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of formula I of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, thereby forming a pharmaceutical composition.

[0113] The present invention also provides a treatment method, which comprises the steps of administering to a subject in need of treatment the compound of formula I described in the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, or administering the pharmaceutical composition described in the present invention, for treating or preventing neurodegenerative diseases.

[0114] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, were generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0115] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0116] The technical solution of the present invention is further described below, but the protection scope of the present invention is not limited thereto.

[0117] Example 1

[0118] The structural formula of the compound provided in this embodiment is as follows:

[0119] The synthesis process of the above compound T-01 is as follows:

[0120] 1. Synthesis of compound SM1

[0121] The synthetic route is:

[0122] The synthesis steps include:

[0123] S1: Synthesis of compound 2

[0124] N-Boc-piperazine (4.5 g) and cesium carbonate (10.6 g) were added to a 100 ml three-necked flask, followed by dissolution in 50 ml of N,N-dimethylformamide. After stirring at room temperature for 30 min, compound 1 (5.0 g) was added and the reaction continued at room temperature for 5 h. TLC indicated no residual starting material, indicating the reaction was complete. The reaction solution was diluted with ethyl acetate, washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was directly concentrated and purified by silica gel chromatography to yield 6.8 g of compound 2.

[0125] S2: Synthesis of compound 3

[0126] Compound 2 (5.0 g) was added to a 100 ml three-necked flask, 50 ml of dichloromethane was added and stirred to dissolve, trifluoroacetic acid (8.5 g) was added dropwise under ice bath, and the reaction was allowed to proceed at room temperature for 3 h. TLC showed that no starting material remained, and the reaction was complete. Saturated sodium bicarbonate solution was added under ice bath to adjust the pH to 7.5, and then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the organic phase was directly concentrated without purification to obtain 3.4 g of compound 3. LCMS: [M+H] + =253.1.

[0127] S3: Synthesis of compound SM1

[0128] Compound 3 (3.4 g) was added to a 100 ml three-necked flask. After nitrogen replacement three times, 34 ml of ultra-dry N,N-dimethylformamide was added under nitrogen protection to dissolve the mixture. The mixture was stirred under an ice bath and sodium hydride (0.7 g) was added in batches. After stirring for 30 minutes, deuterated iodomethane (3.2 g) was added and the mixture was reacted at room temperature for 3 hours. TLC showed that no starting material remained, and the reaction was completed. Water was added to the reaction solution, and then extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution in sequence, dried over anhydrous sodium sulfate, and the organic phase was directly concentrated and purified by silica gel chromatography to obtain 2.5 g of compound SM1.

[0129] 2. Synthesis of compound SM3

[0130] The synthetic route is:

[0131] The synthesis steps include:

[0132] S4: Synthesis of compound 5

[0133] Compound 4 (10.0 g) was added to a 100 mL three-necked flask, 150 ml of acetone was added to dissolve, ammonium thiocyanate (6.0 g) and acetyl chloride (5.6 ml) were added, and the mixture was reacted at room temperature overnight under nitrogen protection. TLC showed that no starting material remained, and the reaction was complete. Water was added to quench the reaction, and the mixture was filtered. The filter cake was washed with water and methyl tert-butyl ether in sequence, and the filter cake was dissolved in ethyl acetate and separated and purified by silica gel column chromatography to obtain 8.8 g of compound 5. LCMS: [M+H] + =254.1.

[0134] S5: Synthesis of compound 6

[0135] Compound 5 (8.8 g) was added to a 100 ml three-necked flask and dissolved in 90 ml of methanol. Potassium carbonate (14.4 g) and 3-(2-bromoacetyl)pyridine hydrobromide (9.8 g) were added in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. TLC showed that no starting material remained, indicating the reaction was complete. Water was added to quench the reaction, and the mixture was filtered. The filter cake was washed with water and methyl tert-butyl ether in sequence and dried at 60°C to obtain 9.5 g of compound 6. LCMS: [M+H] + =313.1.

[0136] S6: Synthesis of compound SM3

[0137] Compound 6 (9.0 g) was added to a 100 ml three-necked flask, and 135 ml of an ethanol / water mixture (5:1 / V:V) was added to dissolve the mixture. Ammonium chloride (4.6 g) and zinc powder (18.7 g) were added. After nitrogen replacement three times, the mixture was reacted at 80°C under nitrogen protection for 5 h. TLC showed that no starting material remained, indicating the reaction was complete. Filtered, the ethanol was evaporated, and the residue was added with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and directly concentrated to obtain 6.6 g of compound SM3. LCMS: [M+H] + =283.1.

[0138] 3. Synthesis of compound T-01

[0139] The synthetic route is:

[0140] The synthesis steps include:

[0141] S7: Synthesis of compound SM2

[0142] Compound SM1 (500 mg) was added to a 50 ml three-necked flask, 10 ml of tetrahydrofuran was added to dissolve, and 2 ml of an aqueous solution of lithium hydroxide (144 mg) was added dropwise. The reaction was allowed to react at room temperature for 6 h. TLC showed that no starting material remained, and the reaction was complete. 0.5 M hydrochloric acid was added to adjust the pH to 4.7, and then water was added. The mixture was extracted with ethyl acetate, and the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was directly concentrated to obtain 433 mg of compound SM2. LCMS: [MH] - =254.1.

[0143] S8: Synthesis of compound T-01

[0144] Compound SM2 (430 mg) was added to a 50 ml three-necked flask, 5 ml of N, N-dimethylformamide was added to dissolve, N, N, N', N'-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (1.2 g) was added, and after stirring at room temperature for 30 min, compound SM3 (560 mg) was added and reacted at room temperature overnight. TLC showed that no raw material remained and the reaction was completed. The reaction solution was added with water and then extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase was directly concentrated and purified by silica gel column chromatography to obtain 700 mg of compound T-01. LCMS: [M+H] + =520.1.

[0145] Example 2

[0146] The structural formula of the compound provided in this embodiment is as follows:

[0147] The synthesis process of the above compound T-02 is specifically as follows:

[0148] 1. Synthesis of compound SM4

[0149] The synthetic route is:

[0150] The synthesis steps include:

[0151] S1: Synthesis of compound 2

[0152] Compound 1 (5.0 g) was added to a 250 ml three-necked flask and dissolved in extra-dry tetrahydrofuran (100 ml). The mixture was cooled to 0°C under nitrogen and slowly added with deuterated lithium aluminum hydride (976 mg). The reaction was stirred at room temperature for 1 hour. TLC indicated no residual starting material, indicating the reaction was complete. The reaction solution was cooled to 0°C and quenched with saturated aqueous NH4Cl. The insoluble solid was removed by filtration. The filtrate was then added with water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated to yield 3.3 g of compound 2.

[0153] S2: Synthesis of compound 3

[0154] Compound 2 (3.3 g) was added to a 100 ml three-necked flask, dissolved in dichloromethane (30 ml), and then protected with nitrogen. The mixture was cooled to 0°C, and phosphorus tribromide (2.1 ml) was slowly added. The reaction was stirred at room temperature for 3 h. TLC showed no residual starting material, indicating the reaction was complete. The reaction solution was cooled to 0°C and quenched with saturated aqueous sodium carbonate solution. The reaction solution was extracted with dichloromethane, and the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 4.1 g of compound 3.

[0155] S3: Synthesis of compound 4

[0156] Compound 3 (4.1 g) was added to a 100 ml three-necked flask and dissolved in N,N-dimethylformamide (41 ml). N-Boc-piperazine (2.1 g) and cesium carbonate (7.9 g) were then added sequentially. The mixture was stirred at room temperature for 3 h. TLC indicated no residual starting material, indicating the reaction was complete. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to yield 5.2 g of compound 4.

[0157] S4: Synthesis of compound 5

[0158] Compound 4 (5.0 g) was added to a 500 ml reactor, dissolved in anhydrous ethanol (150 ml), and then DPPF palladium dichloride (1.0 g) and potassium acetate (4.1 g) were added sequentially. After CO was charged to 0.6 MPa, the mixture was heated at 100°C with stirring and reacted overnight. TLC showed no residual starting material, indicating the reaction was complete. The reaction solution was cooled to room temperature, filtered to remove insoluble solids, and the filtrate was concentrated to remove the solvent. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 3.8 g of compound 5.

[0159] S5: Synthesis of compound 6

[0160] Compound 5 (3.8 g) was added to a 100 ml three-necked flask, dissolved in dichloromethane (38 ml), and cooled to 0°C. Trifluoroacetic acid (10.7 ml) was slowly added and the mixture was stirred at room temperature for 5 h. TLC indicated no residual starting material, indicating the reaction was complete. The reaction solution was cooled to 0°C and adjusted to pH 7.6 with saturated sodium bicarbonate aqueous solution. The solution was then extracted with dichloromethane. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to yield 2.7 g of compound 6.

[0161] S6: Synthesis of compound SM4

[0162] Compound 6 (2.7 g) was added to a 250 ml three-necked flask and dissolved in ultra-dry N,N-dimethylformamide (72 ml). The mixture was cooled to 0°C under nitrogen and sodium hydride (390 mg) was slowly added. The reaction was stirred at 0°C for 0.5 h. Iodomethane (1.3 ml) was added and the reaction was stirred at room temperature for 3 h. TLC indicated no residual starting material, indicating the reaction was complete. The reaction solution was added with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 2.3 g of compound SM4.

[0163] 2. Synthesis of Compound T-02

[0164] The synthetic route is:

[0165] The synthesis steps include:

[0166] S7: Synthesis of compound SM5

[0167] Compound SM4 (1.0 g) was added to a 50 ml three-necked flask, 20 ml of tetrahydrofuran was added to dissolve it, 4 ml of an aqueous solution of lithium hydroxide (300 mg) was added dropwise, and the reaction was allowed to proceed at room temperature for 6 h. TLC showed that no starting material remained, and the reaction was complete. 0.5 M hydrochloric acid was added to the reaction solution to adjust the pH to 4.3, and then water was added, followed by extraction with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was directly concentrated to obtain 883 mg of compound SM5. LCMS: [MH] - =235.2.

[0168] S8: Synthesis of compound T-02

[0169] Compound SM5 (600 mg) was added to a 50 ml three-necked flask, 5 ml of N, N-dimethylformamide was added to dissolve, N, N, N', N'-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (1.7 g) was added, and after stirring at room temperature for 30 min, compound SM3 (790 mg) was added and reacted at room temperature overnight. TLC showed that no raw material remained and the reaction was completed. The reaction solution was added with water and extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase was directly concentrated and separated and purified by silica gel column chromatography to obtain 867 mg of compound T-02. LCMS: [M+H] + =501.2.

[0170] Example 3

[0171] The structural formula of the compound provided in this embodiment is as follows:

[0172] The synthesis process of the above compound T-03 is as follows:

[0173] 1. Synthesis of compound SM6

[0174] The synthetic route is:

[0175] The synthesis steps include:

[0176] Compound 1 (2.0 g) was added to a 100 ml three-necked flask, dissolved in N,N-dimethylformamide (20 ml), and then N-methylpiperazine (0.96 g) and cesium carbonate (4.2 g) were added in sequence. The mixture was stirred at room temperature for 3 h. TLC showed no residual starting material, and the reaction was complete. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 2.0 g of compound SM6.

[0177] 2. Synthesis of compound SM8

[0178] The synthetic route is:

[0179] The synthesis steps include:

[0180] S1: Synthesis of compound 3

[0181] Compound 2 (5.0 g) was added to a 100 ml three-necked flask, deuterated dimethyl sulfoxide (50 ml) was added to dissolve, potassium tert-butoxide (5.5 g) was added, and deuterated water (20 mL) was added. The reaction was allowed to react at room temperature overnight under nitrogen protection. Water was directly added to the reaction solution, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain 4.89 g of compound 3.

[0182] S2: Synthesis of compound 4

[0183] Compound 3 (4.8 g) was added to a 100 mL three-necked flask, 75 ml of acetone was added to dissolve, ammonium thiocyanate (2.9 g) and acetyl chloride (2.7 ml) were added, and the mixture was reacted at room temperature overnight under nitrogen protection. TLC showed that no starting material remained, and the reaction was complete. Water was added to quench the reaction, and the mixture was filtered. The filter cake was washed with water and methyl tert-butyl ether in sequence, and the filter cake was dissolved in ethyl acetate and separated and purified by silica gel column chromatography to obtain 3.8 g of compound 4. LCMS: [M+H] + =257.1.

[0184] S3: Synthesis of compound 5

[0185] Compound 4 (3.8 g) was added to a 100 ml three-necked flask, and 40 ml of methanol was added to dissolve the mixture. Potassium carbonate (6.1 g) and 3-(2-bromoacetyl)pyridine hydrobromide (4.1 g) were added in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. TLC showed that no starting material remained, indicating the reaction was complete. Water was added to quench the reaction, and the mixture was filtered. The filter cake was washed with water and methyl tert-butyl ether in sequence and dried at 60°C to obtain 3.9 g of compound 5. LCMS: [M+H] + =316.1.

[0186] S4: Synthesis of compound SM8

[0187] Compound 5 (3.9 g) was added to a 100 ml three-necked flask and dissolved in 60 ml of a mixture of ethanol and water (5:1 / V:V). Ammonium chloride (2.0 g) and zinc powder (8.0 g) were added. After nitrogen replacement three times, the mixture was protected by nitrogen and reacted at 80°C for 5 h. TLC showed that no starting material remained, and the reaction was complete. The mixture was filtered, the ethanol was evaporated, and the residue was added with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was directly concentrated to obtain 3.0 g of compound SM8. LCMS: [M+H] + =286.1.

[0188] 3. Synthesis of Compound T-03

[0189] The synthetic route is:

[0190] The synthesis steps include:

[0191] S5: Synthesis of compound SM7

[0192] Compound SM6 (1.0 g) was added to a 50 ml three-necked flask, dissolved in 20 ml of tetrahydrofuran, and a 4 ml aqueous solution of lithium hydroxide (300 mg) was added dropwise. The mixture was allowed to react at room temperature for 6 h. TLC showed that no starting material remained, and the reaction was complete. 0.5 M hydrochloric acid was added to adjust the pH to 4.8, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was directly concentrated to obtain 860 mg of compound SM7. LCMS: [MH] - =233.2.

[0193] S6: Synthesis of Compound T-03

[0194] Compound SM7 (850 mg) was added to a 50 ml three-necked flask, 5 ml of N, N-dimethylformamide was added to dissolve, N, N, N', N'-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (2.5 g) was added, and after stirring at room temperature for 30 min, compound SM8 (1.1 g) was added and reacted at room temperature overnight. TLC showed that no raw material remained and the reaction was completed. The reaction solution was added with water and extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase was directly concentrated and separated and purified by silica gel column chromatography to obtain 1.3 g of compound T-03. LCMS: [M+H] + =502.2.

[0195] Synthesis of some intermediates

[0196] Synthesis of intermediate 1

[0197] Synthesis route:

[0198] The synthesis process is as follows:

[0199] Synthesis of SM2:

[0200] Compound SM1 (6 g, 1.0 eq) was dissolved in THF (60 mL). The N2 atmosphere was replaced three times. LiAlD4 (1.08 g, 1.0 eq) was added portionwise in an ice bath (0°C). The mixture was allowed to return to room temperature and react for 3 h. TLC monitoring indicated the presence of product. Workup: The reaction was quenched with saturated NH4Cl in an ice bath. The THF was partially removed, and H2O and EA were added. The organic layer was filtered through celite and dried to afford SM2 (4.4 g).

[0201] Synthesis of SM3

[0202] SM2 (44.3 g, 1.0 eq) was dissolved in DCM (45 mL). The nitrogen was replaced three times. PBr3 (2.02 mL, 1.0 eq) was added in an ice bath (0°C). The mixture was allowed to react at room temperature for 3 h. TLC revealed product formation. Workup: Saturated NaHCO3 was added in an ice bath to adjust the pH to approximately 8. Most of the DCM was removed by vortexing. The mixture was extracted with H2O and EA, and dried to afford SM3 (3.6 g).

[0203] Synthesis of SM4

[0204] Compound SM3 (1.8 g, 1.0 eq), methylpiperazine (740 mg, 1.1 eq), and Cs2CO3 (3.3 g, 1.5 eq) were dissolved in DMF (18 mL), and the N2 was replaced three times. The reaction was allowed to proceed overnight at room temperature. TLC was used to monitor the production of the product. Post-treatment: extraction with H2O and EA, the EA layer was washed once with water and once with saturated NaCl, and the EA layer was dried to obtain SM4 (1.7 g).

[0205] Synthesis of SM5

[0206] SM4 (1.7 g, 1.0 eq) was dissolved in EtOH (170 mL), and Pd(dppf)Cl2 (432 mg, 0.1 eq) and AcOK (1.7 g, 3.0 eq) were added. CO was displaced and the reaction was heated to 100°C overnight. TLC was used to monitor the product. Workup: Filter through Celite, spin dry, and column chromatography was performed to obtain SM5 (1.46 g).

[0207] Synthesis of intermediate 1

[0208] SM5 (1.46 g, 1.0 eq) was dissolved in THF (29.2 mL), and LiOH (732 mg, 3.0 eq), water (14.6 mL), and EtOH (4.9 mL) were added. The N2 atmosphere was replaced three times, and the temperature was raised to 50°C and the reaction was allowed to proceed overnight. TLC monitoring indicated the formation of the product. Post-treatment: Filter through Celite, remove most of the THF, and adjust the pH to 2-3 by adding 1N HCl. Solid NaCl was then added to supersaturate the solution, resulting in the precipitation of solids. Filter the filter cake to obtain Intermediate 1 (1 g).

[0209] Synthesis of intermediate 2

[0210] Synthesis route:

[0211] The experimental process is as follows:

[0212] Synthesis of SM2

[0213] Compound SM1 (6 g, 1.0 eq) was dissolved in THF (60 mL). The N2 atmosphere was replaced three times. LiAlD4 (1.08 g, 1.0 eq) was added portionwise in an ice bath (0°C). The mixture was allowed to return to room temperature and react for 3 h. TLC monitoring indicated the presence of product. Workup: The reaction was quenched with saturated NH4Cl in an ice bath. The THF was partially removed, and H2O and EA were added. The organic layer was filtered through celite and dried to afford SM2 (4.4 g).

[0214] Synthesis of SM3

[0215] SM2 (44.3 g, 1.0 eq) was dissolved in DCM (45 mL). The nitrogen was replaced three times. PBr3 (2.02 mL, 1.0 eq) was added in an ice bath (0°C). The mixture was allowed to react at room temperature for 3 h. TLC revealed product formation. Workup: Saturated NaHCO3 was added in an ice bath to adjust the pH to approximately 8. Most of the DCM was removed by vortexing. The mixture was extracted with H2O and EA, and dried to afford SM3 (3.6 g).

[0216] Synthesis of SM4

[0217] Compound SM3 (1.8 g, 1.0 eq), methylpiperazine (763 mg, 1.1 eq), and Cs2CO3 (3.3 g, 1.5 eq) were dissolved in DMF (18 mL). The nitrogen was replaced three times and the reaction was allowed to react at room temperature overnight. TLC revealed product formation. Post-treatment: extraction with H2O and EA. The EA layer was washed once with water and once with saturated NaCl, and then dried to afford SM4 (1.27 g).

[0218] Synthesis of SM5

[0219] SM4 (1.27 g, 1.0 eq) was dissolved in EtOH (127 mL), and Pd(dppf)Cl2 (319 mg, 0.1 eq) and AcOK (1.3 g, 3.0 eq) were added. CO was displaced and the reaction was heated to 100°C overnight. TLC was used to monitor the product. Workup: Filter through Celite, spin dry, and column chromatography was performed to obtain SM5 (350 mg).

[0220] Synthesis of intermediate 2

[0221] SM5 (350 mg, 1.0 eq) was dissolved in THF (7 mL), and LiOH (155 mg, 3.0 eq), water (3.5 mL), and EtOH (1.75 mL) were added. The N2 atmosphere was replaced three times, and the temperature was raised to 50°C and the reaction was allowed to react overnight. TLC monitoring indicated the formation of the product. Post-treatment: Filter through celite, remove most of the THF, and add 1N HCl to adjust the pH to 2-3. Solid NaCl was then added to supersaturate the solution. Solid precipitated and was filtered to obtain the filter cake, Intermediate 2 (320 mg).

[0222] Synthesis of intermediate 3

[0223] Synthesis route:

[0224] The experimental process is as follows:

[0225] Synthesis of SM3

[0226] Compound SM1 (2.2 g, 1.0 eq), SM2 (1 g, 1.0 eq), Cs2CO3 (6.3 g, 2.0 eq), Xantphos (561 mg, 0.10 eq), and Pd(OAc)2 (108 mg, 0.05 eq) were dissolved in ultra-dry 1,4-dioxane (22 mL). The atmosphere was replaced with nitrogen three times and heated to 105°C for 1 h. TLC monitoring indicated the presence of product. Post-treatment: dilution with EA, filtration through celite, and concentration of the filtrate to dryness. The sample was then spin-dried and purified by column chromatography to afford SM3 (1.46 g).

[0227] Synthesis of intermediate 3

[0228] SM3 (1.46 g, 1.0 eq) was dissolved in THF (29.2 mL), and LiOH (732 mg, 3.0 eq), water (14.6 mL), and EtOH (4.9 mL) were added. The N2 atmosphere was replaced three times, and the temperature was raised to 50°C and allowed to react overnight. TLC monitoring indicated product production. Post-treatment: Filter through Celite, remove most of the THF, and adjust the pH to 2-3 by adding 1N HCl. Solid NaCl was then added to supersaturate the solution, resulting in solid precipitation. Filter to obtain the filter cake intermediate 3 (1 g).

[0229] Synthesis of intermediate 4

[0230] Synthesis route:

[0231] The experimental process is as follows:

[0232] Synthesis of SM3

[0233] Compound SM1 (900 mg, 1.0 eq), SM2 (365 mg, 1.0 eq), Cs2CO3 (2.368 g, 2.0 eq), Xantphos (211 mg, 0.10 eq), and Pd(OAc)2 (41 mg, 0.05 eq) were dissolved in ultra-dry 1,4-dioxane (9 mL). The atmosphere was replaced with N2 three times and the mixture was heated to 105°C for 4 h. TLC monitoring indicated the presence of product. Post-treatment: dilution with EA, filtration through celite, and the filtrate was concentrated to dryness. The sample was then spin-dried and purified by column chromatography to afford SM3 (908 g).

[0234] Synthesis of intermediate 4

[0235] SM3 (908 mg, 1.0 eq) was dissolved in THF (36 mL), and LiOH (430 mg, 3.0 eq), water (9 mL), and EtOH (18 mL) were added. The atmosphere was replaced with N2 three times, and the temperature was raised to 50°C and allowed to react overnight. TLC monitoring indicated product production. Post-treatment: Filter through Celite, remove most of the THF, and adjust the pH to 2-3 by adding 1N HCl. Solid NaCl was then added to supersaturate the solution, resulting in the precipitation of solids. Filtering afforded the filter cake intermediate 4 (1.1 g).

[0236] The specific compounds shown in Table 1 below were synthesized by using commercially available raw materials and the intermediates synthesized above, referring to the synthesis methods of the above examples.

[0237] Table 1

[0238] Test Example 1 Enzyme activity test

[0239] The following biological activity tests were conducted on some of the compounds synthesized in the above examples and comparative examples. Their activities against c-Kit kinase were tested, and the results are shown in Table 2 below.

[0240] Table 2

[0241] Masitinib structural formula:

[0242] Test Example 2 Preclinical Pharmacokinetic Study in Rats

[0243] 1. Experimental Materials and Equipment

[0244] Healthy adult SD rats, male, 6-8 weeks old, weighing 200-300 g, were purchased from Weitonglihua Company; EDTA-Na2 anticoagulant; analytical balance, animal weighing scale, magnetic stirrer, refrigerated centrifuge, single-channel manual pipette, etc.

[0245] 2. Experimental Process

[0246] 1. Drug preparation: Accurately weigh approximately 10 mg of the sample to be tested, dissolve it in 5% DMSO, then add 10% solutol HS-15 and 85% saline, sonicate, and vortex to mix to obtain a 1 mg / mL solution. Prepare freshly before use.

[0247] A 0.2 mL sample was taken into a 1.5 mL centrifuge tube and stored at -80°C for concentration analysis of the dosing solution.

[0248] 2. Animal Preparation: Animals were housed in rat cages and fasted for at least 10 hours, but not water, starting the day before the experiment. On the day of the experiment, each animal was weighed and tail-marked. Blank blood was collected from each animal before dosing. Blood was collected from the tail vein.

[0249] 3. Medication:

[0250] Route of administration: oral administration (po);

[0251] Dosage: 10 mg / kg;

[0252] Dosing volume: 10 mL / kg;

[0253] Operation procedure: Use your left hand wearing a bite-proof glove to catch the rat, make it stand upright, insert a No. 16 gavage needle into the mouth and throat, and try to insert the needle when there is no obvious resistance, and then inject the drug into the stomach.

[0254] 4. Sample Collection: Collect 0.1 ml of whole blood from the test animals before administration and 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration. Place the tube in an EDTA-Na2 anticoagulant and mix thoroughly by inverting it 3-4 times. Centrifuge at 10,000 g for 5 min at 4°C to separate the plasma, which is then stored at -80°C until testing. Blood is collected from the tail vein.

[0255] Procedure: Secure the rat in a fixture, fully exposing its tail. Wipe the rat's tail with alcohol to allow the surface skin to absorb the alcohol, significantly relaxing the veins. Select a suitable vein on either side and insert the needle approximately one-third of the way from the tip of the tail. Use an insulin syringe with the needle facing upward. Insert the needle until the skin is pierced and the needle immediately becomes parallel. If you feel the needle sliding into the vein with minimal resistance and blood returning to the syringe, it has entered the vein. Draw approximately 0.1-0.2 ml of whole blood. Remove the needle and apply pressure to stop bleeding.

[0256] 3. Sample Analysis

[0257] Preparation of standard curve: 25 μL of blank rat plasma was taken into centrifuge tubes, 25 μL of prepared standard series solution (prepared in methanol) was added, and then 200 μL of internal standard solution (prepared in methanol) was added. The mixture was vortexed for 2 min and centrifuged at 10,000 g for 10 min at 4°C.

[0258] For unknown plasma sample preparation, aspirate 25 μL of drug-containing rat plasma, add 25 μL of methanol and 200 μL of internal standard solution, vortex mix for 2 minutes, and centrifuge at 10,000 g for 10 minutes at 4°C. The supernatant is analyzed by LC / MS / MS.

[0259] 4. Data Processing

[0260] A quantitative assay for the test compound was established using a Shimadzu liquid chromatography and Triple Quad™ 6500+AB mass spectrometer. The unchanged drug concentration in plasma was determined. Plasma concentration-time curves were plotted, and key pharmacokinetic parameters were calculated using a non-compartmental model in Winnonlin Phoenix software. The pharmacokinetic results are shown in Table 3 below.

[0261] Table 3

[0262] Test Example 3 Brain Pharmacokinetics Test

[0263] 1. Drug preparation

[0264] Dosing solvent: 5% DMSO + 10% Solutol HS15 + 85% normal saline

[0265] Preparation process: Weigh an appropriate amount of powder, add an appropriate volume of DMSO, vortex, add an appropriate volume of Solutol solution, vortex, add an appropriate amount of physiological saline, vortex and sonicate to form a uniform and clear preparation solution.

[0266] Before administration, keep two samples of the preparation and the remaining preparation after administration and store them in an environment of 2-8°C.

[0267] 2. Experimental Animals

[0268] Experimental animals were housed in an animal room equipped with an air-conditioning system for good ventilation. The room temperature was maintained between 20 and 26°C, and the humidity was maintained between 40 and 70%. Artificial lighting was used, with a 12-hour light cycle and a 12-hour dark cycle (except when operating lights were required for experimental procedures or cleaning). Animals had free access to food and water.

[0269] Animals were fed normally for at least 3 days after purchase. Rats with satisfactory physical condition were enrolled in this experiment and each rat was labeled with a tail number. Animals in the oral administration group were fasted overnight before administration and resumed feeding 4 hours after administration, with free access to water.

[0270] The sources and numbers of animals used in this experiment are shown in Table 4 below.

[0271] Table 4

[0272] Note: 3 per group.

[0273] 3. Administer medication

[0274] Route of administration: oral administration (po)

[0275] Dosing concentration: 1mg / ml

[0276] Dosage: 10 mg / kg

[0277] Dosing volume: 10mL / kg

[0278] Dosage frequency: single

[0279] Before administration, check the state of the dosage formulation and ensure the uniformity of the formulation by vortexing, stirring or shaking. Calculate the theoretical dosage volume for each SD rat in each group according to the following formula.

[0280] 4. Sample collection and processing

[0281] The experimental rats were sampled at 1h, 2h, 4h, 6h, 8h, and 24h after administration.

[0282] Plasma: At each time point, 0.25 mL of whole blood was collected from the jugular vein and placed in a tube containing the anticoagulant EDTA-K2 (7 μL of a 10% EDTA-K2 solution). The tubes were stored on wet ice and centrifuged within 1 hour (2,000 g, 2-8°C, 10 minutes) to collect plasma. Plasma was transferred to pre-chilled centrifuge tubes, snap-frozen in dry ice, and then stored in an ultra-low temperature freezer at -60°C or below until analysis by LC-MS / MS.

[0283] Cerebrospinal fluid (CSF): Euthanize the rat using carbon dioxide puncture and obtain ~60 μL of CSF. Use a 1 mL syringe with the needle bevel facing up and the tip of the needle nearly horizontally into the subarachnoid space. Secure the needle and slowly withdraw the CSF. Store the sample on dry ice within 30 minutes of collection and then transfer to -90 to -60°C.

[0284] Brain tissue: Perform cardiac perfusion prior to brain tissue removal. Under deep terminal anesthesia, perform cardiac perfusion with approximately 80 ml of saline to flush any remaining blood from the brain tissue. After brain removal, gently wash once with ice-cold saline, blot dry, weigh, and freeze at -90 to -60°C.

[0285] 5. Sample Analysis and Data Processing

[0286] 5.1 Sample analysis

[0287] Using Shimadzu liquid phase and Triple Quad TM 6500 + AB mass spectrometry is used to establish a quantitative detection method for the test compound. The concentration of the parent drug in the sample is analyzed. The results are then compared with quality control samples for variability control. The accuracy of the quality control samples should be between 80% and 120%.

[0288] 5.2 Data Processing

[0289] Winnonlin Phoenix 8.1.0.3530 was used to calculate the pharmacokinetic parameters: Tmax, Cmax, AUC(0-t), AUC(0-∞), T1 / 2, MRT(0-∞) and other parameters.

[0290] Through the above tests, the pharmacokinetic data of the test samples were obtained and are shown in Table 5 below.

[0291] Table 5

[0292] The brain tissue / plasma total drug ratio (B / P) = brain tissue total drug concentration / plasma total drug concentration.

[0293] Compared to the control drug, masitinib, our compound has higher drug exposure and brain drug exposure. Therefore, the compound of the present invention has greater potential for the treatment of diseases such as brain tumors, Alzheimer's disease, Parkinson's disease, and ALS.

[0294] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A polycyclic compound, characterized in that: The compound is a compound represented by Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof: in: R1, R2, R3, R4 and R5 each independently represent H or D, and at least one of R1, R2, R3, R4 and R5 is D; R6, R7 and R8 each independently represent H, D or F; R9 and R 10 Each independently represents H or F.

2. The compound according to claim 1, characterized in that At least two of R1, R2, R3, R4, R5, R6, R7 and R8 represent D.

3. The compound according to claim 1 or 2, characterized in that The R1, R2 and R3 are all H, or all D.

4. The compound according to any one of claims 1 to 3, characterized in that The R4 and R5 are both H, or both D.

5. The compound according to any one of claims 1 to 4, characterized in that The R6, R7 and R8 are all H, or all D, or all F.

6. The compound according to claim 1, characterized in that The compound is selected from any of the following compounds:

7. A pharmaceutical composition, characterized in that Contains a preventive and / or therapeutically effective amount of the compound according to any one of claims 1 to 6, and a pharmaceutically acceptable carrier.

8. Use of the compound according to any one of claims 1 to 6 or the composition according to claim 7, characterized in that: Used for preparing a drug for treating a disease selected from the following: neurodegenerative diseases, cancer, progressive supranuclear palsy, mast cell activation syndrome, rheumatoid arthritis, asthma, Crohn's disease, sickle cell disease, and COVID-19.

9. The use according to claim 8, characterized in that The neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, progressive multiple sclerosis, and amyotrophic lateral sclerosis.

10. The use according to claim 8, characterized in that The cancer is selected from the group consisting of: prostate cancer, pancreatic cancer, gastric cancer, liver cancer, multiple myeloma, and colorectal cancer.

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