WO2025113494A1 - Polycyclic compound and use thereof - Google Patents

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

The present invention relates to the field of medical technology, and specifically discloses a polycyclic compound represented by formula I and also discloses the application thereof.

Background Art

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 sign is nerve fiber tangles. The pathological changes of Alzheimer's disease are quite complicated. At present, countries around the world are studying effective therapeutic drugs 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 ten years ago, the US FDA approved a total of five therapeutic compounds in two categories, including cholinesterase inhibitors and NMDA receptor antagonists, but they can only temporarily improve the symptoms of the disease and cannot stop the course of the disease.

It is generally believed that the main pathogenesis of Alzheimer's disease is the deposition of beta-amyloid protein in the brain tissue of the body, abnormal cerebral vascular structure causing activation of microglia and astrocytes in the brain tissue to produce inflammatory mediators, increased production of free radicals in the brain tissue accompanied by weakened antioxidant capacity of the body, imbalance of acetylcholine system and anti-acetylcholine system in the brain tissue, etc., which lead to structural and functional damage to the brain tissue of patients with Alzheimer's disease, increased content of inflammatory mediators in the hippocampus, weakened antioxidant capacity of the hippocampus, etc., and ultimately induce Alzheimer's disease. Pharmaceutical companies have developed a variety of vaccines targeting Abeta protein and phosphorylation inhibitors of various enzymes in the formation process of the protein, but so far, these efforts have ended in ineffectiveness. We believe that it is too late to reduce the toxicity of Abeta protein after the patient becomes ill, and therapeutic drugs should be developed by reducing the amount of the protein.

Summary of the invention

The purpose of the present invention is 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.

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:

in:

R ₁ , R ₂ , R ₃ , R ₄ and R ₅ each independently represent H or D, and at least one of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ is D;

R ₆ , R ₇ and R ₈ each independently represent H, D or F;

_R9 and _R10 each independently represent H or F.

As an embodiment of the present invention, in Formula I, at least two of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ represent D.

As an embodiment of the present invention, in Formula I, R ₁ , R ₂ and R ₃ are all H, or all D.

As an embodiment of the present invention, in Formula I, _R4 and _R5 are both H, or both D.

As an embodiment of the present invention, in Formula I, R ₆ , R ₇ and R ₈ are all H, or all D, or all F.

As an embodiment of the present invention, in Formula I, R ₉ and R ₁₀ are both H, or either of them is F.

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:

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.

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

The use of the compound or composition of the present invention is for preparing a medicament for treating a disease selected from the following: 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).

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

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.

The new compound provided by the present invention can be used to prepare drugs for treating neurodegenerative diseases and the like, and has significant applications in drugs for 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.

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 specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here.

DETAILED DESCRIPTION

After extensive and in-depth research, the inventors unexpectedly discovered a class of compounds with excellent therapeutic effects on cancer and neurodegenerative diseases. In addition, the compounds have better pharmacodynamics/pharmacokinetic properties. On this basis, the present invention was completed.

the term

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

When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, _-CH2O- is equivalent to _-OCH2- .

"Alkyl (alone or as part of another group)" refers to a monovalent straight or branched saturated hydrocarbon group containing 1 to 12 carbon atoms consisting only 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 the present application, alkyl is also intended to include substituted alkyl, i.e., one or more positions in the alkyl are substituted, especially 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 haloalkyl include -CH ₂ Cl, -CH ₂ CF ₃ , -CH ₂ CCl ₃ , perfluoroalkyl (e.g., -CF ₃ ), and the like.

"Alkylene" refers to a divalent radical of _an alkyl group, for example, _-CH2- , _{-CH2CH2- ,} and _{-CH2CH2CH2- .}

"Alkoxy (alone or as part of another group)" refers to an alkyl group to which an oxy group is attached, which has an alkylO-structure, wherein the alkyl group has the definition as described above. Preferably, the alkoxy group is a C1 to C6 alkoxy group. Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, tert-butoxy, and the like. "Haloalkoxy" refers to a group of the formula -OR, wherein 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.

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

"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 containing 2, 3, 4, 5 or 6 carbon atoms. Alkenyl includes, but is not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-butene-1-yl, etc. In the present invention, alkenyl includes substituted alkenyl.

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

"Alkynyl (alone or as part of another group)" refers to a straight or branched hydrocarbon chain containing more than 2 carbon atoms and characterized by having 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.

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

"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.

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

"Aryl (alone or as part of another group)" refers to a monovalent group 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, phthalimide, naphthylimide or tetrahydronaphthyl, etc. 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.

"Arylalkyl" or "aralkyl" refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. Aralkyl includes groups in which one or more hydrogen atoms are replaced by an aryl group, and aryl and alkyl have the definitions described above. Examples of "arylalkyl" or "aralkyl" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, diphenylmethyl, and triphenylmethyl, etc.

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

"Heteroalkyl" refers to a substituted alkyl having one or more backbone chain atoms selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or a combination thereof. A numerical range may be given, e.g., 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 . Connection to the rest of the molecule may be through a heteroatom or carbon in the heteroalkyl chain. "Heteroalkylene" refers to an optionally substituted divalent alkyl having one or more backbone chain atoms selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or a combination thereof.

"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.

"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.).

"Cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of a mono- or bicyclic ring having 3-12, preferably 3-10, more preferably 3-8 ring atoms. The 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, etc.

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

"Heteroaromatic ring system" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (6-12-membered) or polycyclic ring system, wherein at least one ring is both aromatic and contains at least one heteroatom (e.g., N, O or S); and wherein none of the other rings is a heterocyclyl (as defined below). In some cases, the ring that is aromatic and contains heteroatoms 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 rings.

"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 clear 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, furanyl, pyranyl, pyridinyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolyl, isoquinolyl, benzofuranyl, benzofuranyl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzo Azolyl, benzo oxadiazole, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazine, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, aza Base, diazepine Heteroarylene refers to a heteroaryl group having two attachment sites.

"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.

"Heterocyclyl" refers to a monovalent group of a heterocyclic ring system, usually a stable monocyclic ring (such as 3-8 members, i.e. 3, 4, 5, 6, 7 or 8 members) or bicyclic ring (such as 5-12 members, i.e. 5, 6, 7, 8, 9, 10, 11 or 12 members) or polycyclic ring (such as 7-14 members, i.e. 7, 8, 9, 10, 11, 12, 13 or 14), including fused, spiro and/or bridged ring structures, which are saturated, partially unsaturated, and 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 heteroatoms, 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 (3) at least one ring is non-aromatic and contains heteroatoms and at least one other ring is an aromatic carbocyclic ring, for example, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl; and (4) 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. A heterocyclyl group refers to a heterocyclyl group having two attachment sites. In the present invention, preferably, the heterocyclyl group 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 heterocyclyl group is a 5-6-membered monocyclic heterocyclyl group or an 8-10-membered bicyclic heterocyclyl group.

In the present invention, the heterocyclylene group is preferably a bicyclic group, 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, the heterocyclylene group is preferably a 5-6 membered monocyclic heterocyclylene group or an 8-10 membered bicyclic heterocyclylene group.

"Heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl group, wherein the heterocyclyl group and the alkyl group are as defined above.

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.

"Cycloalkylamino" refers to a _radical of the formula _-NRaRb , wherein _Ra is H, an alkyl radical as defined herein, or a cycloalkyl radical as defined herein, and _Rb is a cycloalkyl radical as defined herein, or _Ra and _Rb together with the N atom to which they are attached form a 3-10 membered N-containing monocyclic or bicyclic heterocyclic radical, such as tetrahydropyrrolyl. As used herein, C3-C8 cycloalkylamino refers to an amine radical containing 3-8 carbon atoms.

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

In the present invention, the term "amide group" refers to a group with the structure -CONRR', 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 fragment.

In the present invention, the term "sulfonamide" refers to a group with 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 fragment.

"Ketocarbonyl" refers to R-C(=O)-, wherein R is alkyl, cycloalkyl, etc. as described above.

When a substituent is a non-terminal substituent, 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.

In the present invention, each of the above-mentioned alkyl, alkoxy, cycloalkyl, heteroalkyl, aryl, heteroaryl, cycloheteroalkyl, alkenyl, alkyne, heterocycle, heterocyclic group and the like may be substituted or unsubstituted.

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 a substituent described above, or a 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 combinations of substituents contemplated by the present invention are 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., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl3), cyano, nitro, oxo (such as =O), trifluoromethyl, trifluoromethoxy, _cycloalkyl , alkenyl, alkynyl, heterocyclic, aromatic, ORa, _SRa , S(=O) _Re , S(=O) _2Re , _P (=O) _2Re , S(=O) _{2ORe , P} (=O _{) 2ORe , NRbRc} , _NRbS ( ₌ O) _2Re , _NRbP ( ₌ O) _2Re , S(=O) _2NRbRc , _P (=O) _2NRbRc , C(=O) _ORd , _C (=O _{) Ra} , C(=O) _NRbRc , OC(= _{O ) Ra} , OC(＝O)NR _b R _c , NR _b C(＝O)OR _e , NR _d C(＝O)NR _b R _c , NR _d S(＝O) ₂ NR _b R _c , NR _d P(＝O) ₂ NR _b R _c , NR _b C(＝O)R _a , or NR _b P(＝O) ₂ R _e , wherein _Ra can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic ring or aromatic ring, R _b , R _c and R _d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic ring or aromatic ring, or R _b and R _c together with the N atom can form a heterocyclic ring; _Re can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic ring or aromatic ring. The above typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring can be optionally substituted. The 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 heterocyclic group, aryl, heteroaryl, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amine group, C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1-C6 urea group, etc.

"Cyano" refers to a -CN group.

"Nitro" refers to _-NO2 .

"Hydroxyl" refers to -OH.

"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.

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

The term "deuterated compound" refers to a compound in which one or more hydrogen atoms (H) are replaced by deuterium atoms (D).

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

The structural formula of the carbamate group is -NH-C(=O)-O-R, wherein R is an alkyl group, an aryl group, a heteroaryl group, etc.

Active ingredients

As used herein, the term "compound of the present invention" or "active ingredient of the present invention" is 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.

The compound of formula I has the following structure:

wherein each group is as defined above.

The salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise specified, the compounds of the present invention are understood to include their salts. The term "salt" used herein refers to an acidic or basic salt formed with an inorganic or organic acid and a base. 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 in 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 in the preparation process. The compounds of the present invention may form salts, for example, Compound I reacts with a certain amount of acid or base, such as an equivalent amount, and is salted out in a medium, or freeze-dried in an aqueous solution.

The compounds of the present invention contain basic fragments, 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 (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor salt, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide [0013] The invention also includes but is not limited to the following: esters, isothioates (e.g., 2-hydroxyethanesulfonate), 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., formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonates, dodecanoates, and the like.

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., formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, and the like.

Certain compounds of the present invention may contain acidic fragments, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts and salts formed with organic bases (such as 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, etc. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule 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 bromides), etc.

Prodrugs and solvates (or solvates) of the compounds of the present invention are also within the scope of this invention.

The term "prodrug" herein refers to a compound that undergoes chemical transformation by metabolism 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.

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

All stereoisomers of the compounds (e.g., those due to asymmetric carbon atoms that may exist 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 simultaneously 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 two configurations, S or R, 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 diastereoisomers derived therefrom, or by separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods, such as recrystallization after salt formation with an optically active acid.

The compounds of the present invention are prepared, separated and purified to obtain compounds with a weight content of equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), which are listed in the text description. Such "very pure" compounds of the present invention are also considered part of the present invention.

All configurational isomers of the compounds of the present invention are included in the scope, 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.

Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.

Specific functional groups and chemical term definitions are described in detail below. For purposes of the present invention, chemical elements are as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, ^75th Ed. Definitions of specific functional groups are also described therein. In addition, the basic principles of organic chemistry as well as specific functional groups and reactivity are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, which is incorporated by reference in its entirety.

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. In addition, asymmetric carbon atoms may represent substituents, such as alkyl. All isomers and their mixtures are included in the present invention.

According to the present invention, the ratio of isomers contained in the mixture of isomers can be various. For example, in the mixture of only two isomers, there can be the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present invention. Similar ratios that are easily understood by ordinary technicians in this profession, and ratios for more complex mixtures of isomers are also within the scope of the present invention.

The present invention also includes isotopically labeled compounds, which 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 from the original atoms. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as ^2H , ^3H , ^13C , ^11C , ^14C , ^15N , ^18O , ^17O , ^31P , ^32P , ^35S , ^18F and ^36Cl , respectively. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, 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 radioactive isotopes of ^3H and ^14C , are also included, which are useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. ^3H and carbon-14, i.e. 14C, are relatively easy to prepare and detect. is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e., ² H, may be preferred in some cases due to their good metabolic stability, which has advantages in certain therapies, such as increasing half-life in vivo or reducing dosage. Isotope-labeled compounds can be prepared by general methods by replacing readily available isotope-labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

If a synthesis of a specific enantiomer of the compound of the present invention is to be designed, it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting diastereomeric mixture can be separated, and the chiral auxiliary can be removed to obtain the pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a diastereomeric salt can be formed with a suitable optically active acid or base, and then separated by conventional means such as fractional crystallization or chromatography, and then the pure enantiomer can be obtained.

As described herein, the compounds of the present invention can be replaced with any number of substituents or functional groups to expand their scope. Generally, the term "substituted" appears before or after the term "optional", and the general formula including substituents in the formulation of the present invention refers to replacing hydrogen free radicals with designated structural substituents. When multiple positions in a specific structure are substituted by multiple specific substituents, the substituents can be the same or different at each position. The term "substituted" used herein includes all allowed organic compound substitutions. In a broad sense, allowed substituents include non-cyclic, cyclic, branched non-branched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, heteroatom nitrogen can have hydrogen substituents or any allowed organic compounds described above to supplement its valence. In addition, the present invention is not intended to limit the allowed substitution of organic compounds in any way. The present invention believes that the combination of substituents and variable groups is very good in the treatment of diseases in the form of stable compounds. As used herein, the term "stable" refers to compounds that are stable and that maintain the structural integrity of the compound over a period of time sufficient to be detected, and preferably over a period of time sufficient to be effective, as used herein for the purposes described above.

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 described above.

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.

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

Preparation method

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

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 a combination can be easily carried out by a technician in the field to which the present invention belongs.

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

Pharmaceutical compositions and methods of administration

The pharmaceutical composition of the present invention is used to prevent and/or treat neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, progressive multiple sclerosis, amyotrophic lateral sclerosis, etc.). It is expected to be used to prepare drugs for treating diseases selected from the following: 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.

The compounds of general formula I can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the administration method and dosage of the original drug can remain unchanged, and the compound of formula I can be taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formula I. Drug combination also includes taking the compound of formula I and one or more other known drugs in overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of them taken alone.

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.

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

"Pharmaceutically acceptable carrier" refers 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, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

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

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 starch 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.

Solid dosage forms such as tablets, pills, 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 opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

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, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

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

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

Compositions for parenteral injection may include 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.

Dosage forms for topical administration of the compounds of the 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.

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

When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

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.

The present invention also provides a treatment method, which comprises the steps of administering 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 to a subject in need of treatment, for treating or preventing neurodegenerative diseases.

The present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally carried out according to 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.

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

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

Example 1

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

The synthesis process of the above compound T-01 is specifically as follows:

1. Synthesis of compound SM1

The synthetic route is:

The synthesis steps include:

S1: Synthesis of compound 2

Add N-Boc-piperazine (4.5 g) and cesium carbonate (10.6 g) to a 100 ml three-necked flask, then add 50 ml N,N-dimethylformamide to dissolve, stir at room temperature for 30 min, add compound 1 (5.0 g), and continue to react at room temperature for 5 h. TLC shows that there is no raw material remaining, and the reaction is over. The reaction solution is diluted with ethyl acetate, washed with water and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, and the organic phase is directly concentrated and purified by silica gel chromatography to obtain 6.8 g of compound 2.

S2: Synthesis of compound 3

Compound 2 (5.0 g) was added to a 100 ml three-necked flask, 50 ml of dichloromethane was added, stirred and dissolved, trifluoroacetic acid (8.5 g) was added dropwise under ice bath, and the reaction was carried out at room temperature for 3 h. TLC showed that no raw material remained, and the reaction was completed. 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.

S3: Synthesis of compound SM1

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 to dissolve under nitrogen protection, stirred under ice bath, sodium hydride (0.7 g) was added in batches, and after stirring for 30 min, deuterated iodomethane (3.2 g) was added and reacted at room temperature for 3 h. TLC showed that there was no raw material remaining, 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 turn, dried over anhydrous sodium sulfate, and the organic phase was directly concentrated and separated and purified by silica gel chromatography to obtain 2.5 g of compound SM1.

2. Synthesis of compound SM3

The synthetic route is:

The synthesis steps include:

S4: Synthesis of compound 5

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 raw material remained, and the reaction was completed. 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 turn, 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.

S5: Synthesis of compound 6

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

S6: Synthesis of compound SM3

Compound 6 (9.0 g) was added to a 100 ml three-necked flask, 135 ml of ethanol/water mixture (5:1/V:V) was added to dissolve, ammonium chloride (4.6 g) and zinc powder (18.7 g) were added, and nitrogen was replaced three times, and the mixture was reacted at 80°C for 5 h under nitrogen protection. TLC showed that no raw material remained, and the reaction was completed. Filtered, ethanol was evaporated, water was added to the residue, and 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 6.6 g of compound SM3, LCMS: [M+H] ⁺ = 283.1.

3. Synthesis of compound T-01

The synthetic route is:

The synthesis steps include:

S7: Synthesis of compound SM2

Compound SM1 (500 mg) was added to a 50 ml three-necked flask, 10 ml of tetrahydrofuran was added to dissolve, 2 ml of aqueous solution of lithium hydroxide (144 mg) was added dropwise, and the reaction was carried out at room temperature for 6 h. TLC showed that no raw material remained, and the reaction was completed. 0.5 M hydrochloric acid was added to adjust the pH to 4.7, and then water was added, 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.

S8: Synthesis of compound T-01

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 there was no raw material remaining, and the reaction was completed. Water was added to the reaction solution, and then 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 and separated and purified by silica gel column chromatography to obtain 700 mg of compound T-01, LCMS: [M+H] ⁺ = 520.1.

Example 2

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

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

1. Synthesis of compound SM4

The synthetic route is:

The synthesis steps include:

S1: Synthesis of compound 2

Compound 1 (5.0 g) was added to a 250 ml three-necked flask, dissolved with ultra-dry tetrahydrofuran (100 ml), cooled to 0°C under nitrogen protection, and lithium aluminum hydride (976 mg) was slowly added. The mixture was stirred at room temperature for 1 hour. TLC showed that no raw material remained, and the reaction was completed. The reaction solution was cooled to 0°C and quenched with saturated NH ₄ Cl aqueous solution. The insoluble solid was removed by suction filtration. Water was added to the filtrate and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain 3.3 g of compound 2.

S2: Synthesis of compound 3

Compound 2 (3.3 g) was added to a 100 ml three-necked flask, dissolved with 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 mixture was stirred at room temperature for 3 h. TLC showed that no raw material remained, and the reaction was completed. The reaction solution was cooled to 0°C and quenched with a saturated aqueous sodium carbonate solution. The reaction solution was extracted with dichloromethane, and the organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The mixture was separated and purified by silica gel column chromatography to obtain 4.1 g of compound 3.

S3: Synthesis of compound 4

Compound 3 (4.1 g) was added to a 100 ml three-necked flask, dissolved with N, N-dimethylformamide (41 ml), and N-Boc-piperazine (2.1 g) and cesium carbonate (7.9 g) were added in sequence, and the mixture was stirred at room temperature for 3 h. TLC showed that no raw material remained, and the reaction was completed. 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 separated and purified by silica gel column chromatography to obtain 5.2 g of compound 4.

S4: Synthesis of compound 5

Compound 4 (5.0 g) was added to a 500 ml reactor, dissolved with anhydrous ethanol (150 ml), and DPPF palladium dichloride (1.0 g) and potassium acetate (4.1 g) were added in sequence. After CO was charged to 0.6 MPa, the mixture was heated and stirred at 100 ° C for overnight reaction. TLC showed that there was no residual raw material, and the reaction was completed. The reaction solution was cooled to room temperature, and the insoluble solid was removed by suction filtration. The filtrate was concentrated to remove the solvent, and water was added and extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. 3.8 g of compound 5 was obtained by separation and purification by silica gel column chromatography.

S5: Synthesis of compound 6

Compound 5 (3.8 g) was added to a 100 ml three-necked flask, dissolved with dichloromethane (38 ml), cooled to 0°C, trifluoroacetic acid (10.7 ml) was slowly added, and the reaction was stirred at room temperature for 5 h. TLC showed that no raw material remained, and the reaction was completed. The reaction solution was cooled to 0°C, adjusted to pH 7.6 with saturated sodium bicarbonate aqueous solution, then extracted with dichloromethane, and the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain 2.7 g of compound 6.

S6: Synthesis of compound SM4

Compound 6 (2.7 g) was added to a 250 ml three-necked flask, dissolved with ultra-dry N,N-dimethylformamide (72 ml), cooled to 0°C under nitrogen protection, sodium hydride (390 mg) was slowly added, and the reaction was continued at 0°C with stirring for 0.5 h. Methyl iodide (1.3 ml) was added and stirred at room temperature for 3 h. 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 aqueous solution, dried over anhydrous sodium sulfate, concentrated, and separated and purified by silica gel column chromatography to obtain 2.3 g of compound SM4.

2. Synthesis of compound T-02

The synthetic route is:

The synthesis steps include:

S7: Synthesis of compound SM5

Compound SM4 (1.0 g) was added to a 50 ml three-necked flask, 20 ml of tetrahydrofuran was added to dissolve, 4 ml of an aqueous solution of lithium hydroxide (300 mg) was added dropwise, and the reaction was carried out at room temperature for 6 h. TLC showed that no raw material remained, and the reaction was completed. 0.5 M hydrochloric acid was added to the reaction solution to adjust the pH to 4.3, and then water was added, and then ethyl acetate was extracted. 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.

S8: Synthesis of Compound T-02

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 there was no raw material remaining, and the reaction was completed. Water was added to the reaction solution, 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 and separated and purified by silica gel column chromatography to obtain 867 mg of compound T-02, LCMS: [M+H] ⁺ = 501.2.

Example 3

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

The synthesis process of the above compound T-03 is specifically as follows:

1. Synthesis of compound SM6

The synthetic route is:

The synthesis steps include:

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

2. Synthesis of compound SM8

The synthetic route is:

The synthesis steps include:

S1: Synthesis of compound 3

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 overnight at room temperature under nitrogen protection. Water was directly added to the reaction solution, extracted with ethyl acetate, and the organic phase was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain 4.89 g of compound 3.

S2: Synthesis of compound 4

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 raw material remained, and the reaction was completed. Water was added to quench the reaction, and the filter cake was washed with water and methyl tert-butyl ether in turn. 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.

S3: Synthesis of compound 5

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

S4: Synthesis of compound SM8

Compound 5 (3.9 g) was added to a 100 ml three-necked flask, and 60 ml of ethanol-water mixture (5:1/V:V) was added to dissolve, and ammonium chloride (2.0 g) and zinc powder (8.0 g) were added. After nitrogen replacement three times, nitrogen protection was used and the reaction was carried out at 80°C for 5 h. TLC showed that no raw material remained, and the reaction was completed. Filtered, ethanol was evaporated, water was added to the residue, 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.

3. Synthesis of compound T-03

The synthetic route is:

The synthesis steps include:

S5: Synthesis of compound SM7

Compound SM6 (1.0 g) was added to a 50 ml three-necked flask, 20 ml of tetrahydrofuran was added to dissolve, 4 ml of an aqueous solution of lithium hydroxide (300 mg) was added dropwise, and the reaction was carried out at room temperature for 6 h. TLC showed that no raw material remained, and the reaction was completed. 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.

S6: Synthesis of Compound T-03

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 the reaction was allowed to proceed overnight at room temperature. TLC showed that no raw material remained, and the reaction was completed. Water was added to the reaction solution, and the organic phase 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 and separated and purified by silica gel column chromatography to obtain 1.3 g of compound T-03, LCMS: [M+H] ⁺ = 502.2.

Synthesis of some intermediates

Synthesis of intermediate 1

Synthesis route:

The synthesis process is as follows:

Synthesis of SM2:

Compound SM1 (6 g, 1.0 eq) was dissolved in THF (60 mL), N ₂ was replaced three times, LiAlD ₄ (1.08 g, 1.0 eq) was added in batches under ice bath conditions (0°C), and the mixture was returned to room temperature for reaction for 3 h. The product was produced by TLC monitoring. Post-treatment: under ice bath conditions, the mixture was quenched with saturated NH ₄ Cl, some THF was removed by spinning, H ₂ O and EA were added, and the organic layer was dried by spinning after filtration through diatomaceous earth to obtain SM2 (4.4 g).

Synthesis of SM3

SM2 (44.3 g, 1.0 eq) was dissolved in DCM (45 mL), N ₂ was replaced three times, and PBr ₃ (2.02 mL, 1.0 eq) was added under ice bath condition (0°C). The reaction was returned to room temperature for 3 h, and the product was produced by TLC monitoring. Post-treatment: saturated NaHCO ₃ was added under ice bath condition, the pH was adjusted to about 8, most of DCM was removed by rotation, H ₂ O and EA were added for extraction, and SM3 (3.6 g) was obtained by rotation dryness.

Synthesis of SM4

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 N2 was replaced three times. The reaction was allowed to proceed overnight at room temperature, and the product was produced by TLC monitoring. Post-treatment: extraction with _H2O and EA, washing the EA layer once with clean water, washing the EA layer once with saturated NaCl, and drying to obtain SM4 (1.7 g).

Synthesis of SM5

SM4 (1.7 g, 1.0 eq) was dissolved in EtOH (170 mL), and Pd(dppf)Cl ₂ (432 mg, 0.1 eq) and AcOK (1.7 g, 3.0 eq) were added. CO was replaced, and the temperature was raised to 100°C for overnight reaction. The product was generated by TLC monitoring. Post-treatment: Filter through diatomaceous earth, spin dry the sample, and column chromatography was performed to obtain SM5 (1.46 g).

Synthesis of intermediate 1

SM5 (1.46 g, 1.0 eq) was dissolved in THF (29.2 mL), and LiOH (732 mg, 3.0 eq) and water (14.6 mL) and EtOH (4.9 mL) were added. N2 was replaced three times, and the temperature was raised to 50 °C for overnight reaction. The product was produced by TLC monitoring. Post-treatment: Filter with diatomaceous earth, remove most of the THF, add 1N HCl to adjust the pH to 2-3, continue to add NaCl solid to make the solution supersaturated, solid precipitated, and filter to obtain the filter cake intermediate 1 (1 g).

Synthesis of intermediate 2

Synthesis route:

The experimental process is as follows:

Synthesis of SM2

Compound SM1 (6 g, 1.0 eq) was dissolved in THF (60 mL), N ₂ was replaced three times, LiAlD ₄ (1.08 g, 1.0 eq) was added in batches under ice bath conditions (0°C), and the mixture was returned to room temperature for reaction for 3 h. The product was produced by TLC monitoring. Post-treatment: under ice bath conditions, the mixture was quenched with saturated NH ₄ Cl, some THF was removed by spinning, H ₂ O and EA were added, and the organic layer was dried by spinning after filtration through diatomaceous earth to obtain SM2 (4.4 g).

Synthesis of SM3

SM2 (44.3 g, 1.0 eq) was dissolved in DCM (45 mL), N ₂ was replaced three times, and PBr ₃ (2.02 mL, 1.0 eq) was added under ice bath condition (0°C). The reaction was returned to room temperature for 3 h, and the product was produced by TLC monitoring. Post-treatment: saturated NaHCO ₃ was added under ice bath condition, the pH was adjusted to about 8, most of DCM was removed by rotation, H ₂ O and EA were added for extraction, and SM3 (3.6 g) was obtained by rotation dryness.

Synthesis of SM4

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), and N2 was replaced three times. The reaction was carried out at room temperature overnight, and the product was produced by TLC monitoring. Post-treatment: extraction with _H2O and EA, washing the EA layer once with clean water and once with saturated NaCl, and spin-dried to obtain SM4 (1.27 g).

Synthesis of SM5

SM4 (1.27 g, 1.0 eq) was dissolved in EtOH (127 mL), and Pd(dppf)Cl ₂ (319 mg, 0.1 eq) and AcOK (1.3 g, 3.0 eq) were added. CO was replaced, and the temperature was raised to 100°C for overnight reaction. The product was produced by TLC monitoring. Post-treatment: Filter through diatomaceous earth, spin dry the sample, and column chromatography was performed to obtain SM5 (350 mg).

Synthesis of intermediate 2

SM5 (350 mg, 1.0 eq) was dissolved in THF (7 mL), and LiOH (155 mg, 3.0 eq) and water (3.5 mL) and EtOH (1.75 mL) were added. _N2 was replaced three times, and the temperature was raised to 50°C for overnight reaction. The product was produced by TLC monitoring. Post-treatment: Filtered with diatomaceous earth, most of the THF was removed by rotation, 1N HCl was added to adjust the pH to 2-3, and NaCl solid was added to make the solution supersaturated. Solids precipitated and filtered to obtain a filter cake, namely intermediate 2 (320 mg).

Synthesis of intermediate 3

Synthesis route:

The experimental process is as follows:

Synthesis of SM3

Compound SM1 (2.2 g, 1.0 eq), SM2 (1 g, 1.0 eq), Cs ₂ CO ₃ (6.3 g, 2.0 eq), Xantphos (561 mg, 0.10 eq), Pd(OAc) ₂ (108 mg, 0.05 eq) were dissolved in ultra-dry 1,4-dioxane (22 mL), replaced with N ₂ three times, heated to 105°C for 1 h, and the product was produced by TLC monitoring. Post-treatment: diluted with EA, filtered with diatomaceous earth, concentrated the filtrate to dryness, and spin-dried and mixed, and then subjected to column chromatography to obtain SM3 (1.46 g).

Synthesis of intermediate 3

SM3 (1.46 g, 1.0 eq) was dissolved in THF (29.2 mL), and LiOH (732 mg, 3.0 eq) and water (14.6 mL) and EtOH (4.9 mL) were added. _N2 was replaced three times, and the temperature was raised to 50°C for overnight reaction. The product was produced by TLC monitoring. Post-treatment: Filtered with diatomaceous earth, most of the THF was removed by rotation, 1N HCl was added to adjust the pH to 2-3, and NaCl solid was added to make the solution supersaturated. Solids were precipitated and filtered to obtain the filter cake intermediate 3 (1 g).

Synthesis of intermediate 4

Synthesis route:

The experimental process is as follows:

Synthesis of SM3

Compound SM1 (900 mg, 1.0 eq), SM2 (365 mg, 1.0 eq), Cs ₂ CO ₃ (2.368 g, 2.0 eq), Xantphos (211 mg, 0.10 eq), Pd(OAc) ₂ (41 mg, 0.05 eq) were dissolved in ultra-dry 1,4-dioxane (9 mL), replaced with N ₂ three times, heated to 105°C for 4 h, and the product was produced by TLC monitoring. Post-treatment: diluted with EA, filtered with diatomaceous earth, the filtrate was concentrated to dryness, and the sample was spin-dried and mixed, and then subjected to column chromatography to obtain SM3 (908 g).

Synthesis of intermediate 4

SM3 (908 mg, 1.0 eq) was dissolved in THF (36 mL), and LiOH (430 mg, 3.0 eq) and water (9 mL) and EtOH (18 mL) were added. _N2 was replaced three times, and the temperature was raised to 50°C for overnight reaction. The product was produced by TLC monitoring. Post-treatment: Filtered with diatomaceous earth, most of the THF was removed by rotation, 1N HCl was added to adjust the pH to 2-3, and NaCl solid was added to make the solution supersaturated. Solids precipitated and filtered to obtain the filter cake intermediate 4 (1.1 g).

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

Table 1

Test Example 1 Enzyme Activity Test

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

Table 2

Masitinib structural formula:

Test Example 2 Preclinical rat pharmacokinetic study

1. Experimental Materials and Equipment

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

2. Experimental process

1. Drug preparation: Accurately weigh about 10 mg of the sample to be tested, add 5% DMSO to dissolve it, then add 10% solutol HS-15 and 85% saline, ultrasonically treat, vortex mix to obtain a solution with a concentration of 1 mg/mL; prepare freshly before use.

0.2 mL of sample was pipetted into a 1.5 mL centrifuge tube and stored at -80°C for analysis of dosing solution concentration.

2. Animal preparation: The animals were kept in rat cages and fasted from the day before the experiment (for no less than 10 hours), but water was not allowed. They were weighed and marked on the tail on the day of the experiment. Blank blood was collected before administration. Blood was collected from the tail vein.

3. Drug administration:

Route of administration: oral administration (p.o.);

Dosage: 10 mg/kg;

Dosing volume: 10mL/kg;

Operation procedure: Use your left hand wearing a bite-proof glove to hold the rat upright, insert a No. 16 gavage needle into the rat's mouth and throat, and test to see if there is any obvious resistance when inserting the needle, then inject the drug into the stomach.

4. Sample collection: 0.1 ml of whole blood was collected from the test animals before administration and 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after administration, respectively, and placed in an EDTA-Na2 anticoagulant tube. The tube was inverted 3-4 times to mix well, centrifuged at 4°C, 10000g for 5min to separate plasma, and stored at -80°C for testing. Blood was collected from the tail vein.

Specific operation: Fix the rat on the fixator so that its tail can be completely exposed. Wipe the rat's tail with alcohol to make the surface skin absorb alcohol to achieve obvious venous dilation. Select suitable veins from both sides and insert the needle about one-third of the distance from the tail tip. Use an insulin syringe with the needle bevel upward. After piercing the skin, you can feel that the needle is parallel immediately. You can feel that the sliding resistance of the needle in the vein is small. There is blood returning in the syringe, which means that it has entered the vein. Draw about 0.1-0.2ml of whole blood. After pulling out the needle, press to stop bleeding.

3. Sample Analysis

Preparation of standard curve: Pipette 25 μL of blank rat plasma into a centrifuge tube, add 25 μL of the prepared standard series solution (prepared in methanol), then add 200 μL of internal standard solution (prepared in methanol), vortex mix for 2 min, and centrifuge at 4°C, 10000g for 10 min.

Treatment of unknown plasma samples: 25 μL of rat drug-containing plasma was taken, and 25 μL of methanol and 200 μL of internal standard solution were added in sequence, vortexed for 2 min, and centrifuged at 10000 g for 10 min at 4 °C. The supernatant was taken for LC/MS/MS detection.

4. Data Processing

The quantitative detection method of the test compound was established using Shimadzu liquid chromatography and Triple Quad TM 6500+AB mass spectrometry. The concentration of the original drug in plasma was measured. The blood drug concentration-time curve was drawn, and the main pharmacokinetic parameters were calculated using the non-compartmental model in Winnonlin Phoenix software. The pharmacokinetic results are shown in Table 3 below.

Table 3

Test Example 3 Brain Pharmacokinetic Test

1. Drug preparation

Dosing solvent: 5% DMSO + 10% Solutol HS15 + 85% saline

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 ultrasonicate to form a uniform and clear preparation solution.

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

2. Experimental Animals

The experimental animals were kept in the animal room. The animal room was equipped with an air conditioning system and good ventilation. The indoor temperature was maintained at 20-26°C and the humidity was maintained at 40%-70%. Artificial lighting was used in the animal room, with 12 hours of light and 12 hours of dark (except for situations where working lighting was required for experimental operation and cleaning). The experimental animals were free to eat and drink.

The animals were fed normally for at least 3 days after purchase, and rats with satisfactory physical signs were enrolled in this experiment, and each rat was marked with a tail number. The animals in the oral administration group were fasted overnight the day before administration, and were fed again 4 hours after administration, with free access to water.

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

Table 4

Note: 3 in each group.

3. Drug administration

Route of administration: oral administration (p.o.)

Dosing concentration: 1mg/ml

Dosage: 10 mg/kg

Dosing volume: 10mL/kg

Dosing frequency: single

Before administration, the state of the drug administration preparation was checked, and the uniformity of the preparation was ensured by vortexing, stirring or shaking. The theoretical administration volume for each SD rat in each group was calculated according to the following formula.

4. Sample collection and processing

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

Plasma: 0.25 mL of whole blood was collected from the jugular vein at each time point, placed in a test tube containing the anticoagulant EDTA-K ₂ (7 μL, 10% EDTA-K ₂ solution), stored on wet ice, and centrifuged within 1 hour (2,000 g, 2-8°C, centrifuged for 10 minutes) to obtain plasma. Plasma was stored in pre-cooled centrifuge tubes, quickly frozen in dry ice, and then stored in an ultra-low temperature freezer at -60°C or lower until LC-MS/MS analysis.

Cerebrospinal fluid: The rats were euthanized by carbon dioxide method, and ~60 μL of cerebrospinal fluid was obtained by puncture. A 1 mL syringe was used with the needle bevel facing up and the tip of the needle nearly horizontally inserted into the subarachnoid space. The needle was fixed and the cerebrospinal fluid was slowly extracted. The samples were stored in dry ice within 30 minutes after collection and then transferred to a -90 to -60°C environment.

Brain tissue: First perform cardiac perfusion, then brain tissue extraction. Under deep terminal anesthesia, use about 80 ml of saline to perform cardiac perfusion to flush the remaining blood in the brain tissue out of the circulation. After the brain tissue is extracted, gently wash it once with ice-cold saline, absorb the water and weigh it, and then transfer it to -90 to -60℃ for freezing.

5. Sample analysis and data processing

5.1 Sample analysis

The quantitative detection method of the test compound was established using Shimadzu liquid chromatography and Triple Quad TM 6500 ⁺ AB mass spectrometry. The concentration of the original drug in the sample was analyzed. The analysis results were controlled for variation using quality control samples, and the accuracy of the quality control samples should be between 80% and 120%.

5.2 Data processing

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.

Through the above detection, the pharmacokinetic data of the test samples were obtained and are shown in Table 5 below.

Table 5

Among them, brain tissue/plasma total drug ratio (B/P) = brain tissue total drug concentration/plasma total drug concentration.

Compared with the control sample 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 brain tumors, Alzheimer's disease, Parkinson's disease, ALS and other diseases.

All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims (10)

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: R ₁ , R ₂ , R ₃ , R ₄ and R ₅ each independently represent H or D, and at least one of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ is D; R ₆ , R ₇ and R ₈ each independently represent H, D or F; _R9 and _R10 each independently represent H or F. The compound according to claim 1, characterized in that at least two of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ represent D. The compound according to claim 1 or 2, characterized in that R ₁ , R ₂ and R ₃ are all H, or all D. The compound according to any one of claims 1 to 3, characterized in that _R4 and _R5 are both H, or both D. The compound according to any one of claims 1 to 4, characterized in that R ₆ , R ₇ and R ₈ are all H, or are all D, or are all F. The compound according to claim 1, characterized in that the compound is selected from the compounds represented by any of the following structural formulas:

A pharmaceutical composition, characterized in that it 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. A use of the compound according to any one of claims 1 to 6 or the composition according to claim 7, characterized in that it is used to prepare a medicament 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. 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. The use according to claim 8 is characterized in that the cancer is selected from: prostate cancer, pancreatic cancer, gastric cancer, liver cancer, multiple myeloma, and colorectal cancer.