Sulfur-containing compound and pharmaceutical composition thereof

Abstract

The present invention discloses a sulfur-containing compound, a pharmaceutical composition and application thereof. The present invention provides an application of a sulfur-containing compound or a pharmaceutically acceptable salt thereof in the preparation of a drug, wherein the drug is a drug for treating and / or preventing a disease mediated by Aβ40 and / or Aβ42 proteins or a drug for treating and / or preventing a neurodegenerative disease, Alzheimer's disease or aging, and the sulfur-containing compound is selected from the sulfur-containing compound shown in the following formula I or the sulfur-containing compound shown in formula II. The compound of the present invention has a good inhibitory effect on Aβ40 and Aβ42 proteins, and is expected to treat and / or prevent neurodegenerative diseases, Alzheimer's disease or aging drugs.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a sulfur-containing compound and a pharmaceutical composition thereof. Background Art

[0002] Alzheimer's disease (commonly known as senile dementia, Alzheimer's disease, AD) is a progressive neurodegenerative disease with cognitive and behavioral disorders as the main clinical manifestations. It is the most common senile dementia, mainly manifested by impaired recognition ability and rapid decline of memory function. The main pathophysiological characteristics are the deposition of β-amyloid protein (β-amyloid, Aβ) in the brain to form senile plaques, hyperphosphorylation of tau protein to form neurofibrillary tangles, brain glucose metabolism disorders and neuron / synapse loss. Due to the long course of the disease and the poor self-care ability of patients, it brings serious mental and economic burdens to families and society. However, there are currently no drugs that can prevent or delay the progression of the disease worldwide. The drugs currently sold on the market for the treatment of AD are only symptomatic drugs, which can only control or improve cognitive and functional symptoms for a period of time, and cannot prevent or delay the deterioration of the disease.

[0003] Studies have shown that benfotiamine can reduce the deposition of β-amyloid (Aβ) and phosphorylation of Tau protein in the brain and reduce the pathological damage of Alzheimer's disease by inhibiting the activity of Glycogen synthase kinase-3 (GSK-3). Therefore, the synthesis method and crystal form of benfotiamine and its application in the treatment of Alzheimer's disease have been studied and reported.

[0004] At present, the disclosed benfotiamine derivatives are mainly obtained by modifying the benzene ring in benfotiamine, such as CN111233927A, CN111233925A, and CN111233926A. In order to achieve better AD treatment effects and better meet market demand, it is urgent to develop new thiamine compounds. Summary of the invention

[0005] The technical problem to be solved by the present invention is that the existing Alzheimer's disease treatment drugs have few structural types, so the present invention provides a sulfur-containing compound and a pharmaceutical composition thereof. The compound has a novel structure and has better Aβ42 and / or Aβ40 inhibitory activity.

[0006] The present invention provides a use of a sulfur-containing compound or a pharmaceutically acceptable salt thereof in preparing a drug, wherein the drug is a drug for treating and / or preventing a disease mediated by Aβ40 and / or Aβ42 protein or a drug for treating and / or preventing a neurodegenerative disease or aging, and the sulfur-containing compound is selected from the sulfur-containing compound represented by the following formula I or the sulfur-containing compound represented by the following formula II:

[0007]

[0008] Among them, R 6 are independently hydroxyl or

[0009] R 8 are independently amino;

[0010] R is independently C1-C6 alkyl, C2-C6 alkenyl, benzyl, or

[0011] R 7 are independently C1-C6 alkyl, C2-C6 alkenyl, phenyl, 7-1 Substituted C2-C6 alkenyl, R 7-2 Substituted phenyl, C3-C8 cycloalkyl, C5-C6 cycloalkenyl, "a 5- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from one or both of N and O" or "a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from one or more of N, O and S";

[0012] R 7-1 are independently halogen;

[0013] R 7-2 are independently halogen, cyano, C1-C6 alkoxy or C1-C6 alkyl;

[0014] n is 0 or 1;

[0015] Wherein, the sulfur-containing compound or a pharmaceutically acceptable salt thereof can be in a therapeutically effective amount.

[0016] In a certain embodiment of the present invention, in the sulfur-containing compound or a pharmaceutically acceptable salt thereof as shown in Formula I, certain groups have the following definitions, and the definitions of the groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment of the present invention"), R is independently C1-C6 alkyl, R 7 are independently C1-C6 alkyl, R 7-2 are independently C1-C6 alkyl, wherein the C 1-6The alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,

[0017] In one embodiment of the present invention, R is independently C2-C6 alkenyl, R 7 are independently C2-C6 alkenyl, R 7-1 In the substituted C2-C6 alkenyl, the C2-C6 alkenyl is independently vinyl, propenyl, allyl,

[0018] In one embodiment of the present invention, R 7 In which the C2-C6 alkenyl groups are independently

[0019] In one embodiment of the present invention, R 7 In the above, the C5-C6 cycloalkenyl groups are independently cyclopentenyl or cyclohexenyl, preferably

[0020] In one embodiment of the present invention, R 7 In the above, the C3-C8 cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0021] In one embodiment of the present invention, R 7 In the above, the 5-6 membered heterocycloalkyl group “containing 1 or 2 heteroatoms, wherein the heteroatoms are selected from one or both of N and O” is a 5-6 membered monocyclic heterocycloalkyl group “containing 1 or 2 heteroatoms, wherein the heteroatoms are selected from one or both of N and O”, and more preferably

[0022] In one embodiment of the present invention, R 7 In the above, the 5- to 6-membered heteroaryl group "containing 1, 2 or 3 heteroatoms selected from one or more of N, O and S" is independently thienyl, furanyl, pyridyl, preferably

[0023] In one embodiment of the present invention, R 7-1 wherein the halogen is independently F, Cl, Br or I.

[0024] In one embodiment of the present invention, R 7-2 In the above, the C1-C6 alkoxy groups are independently methoxy, ethoxy, n-propoxy or isopropoxy.

[0025] In one embodiment of the present invention, R 7-2 wherein the halogen is independently F, Cl, Br or I.

[0026] In a certain embodiment of the present invention, the 7-1 The substituted C2-C6 alkenyl groups are independently

[0027] In a certain embodiment of the present invention, the 7-2 The substituted phenyl groups are independently

[0028] In a certain embodiment of the present invention, the R 7 are independently n-propyl, isopropyl, n-butyl, isobutyl, propenyl,

[0029] In one embodiment of the present invention, the R is independently methyl, ethyl, n-propyl, benzyl, vinyl,

[0030] In one embodiment of the present invention, the neurodegenerative disease is Alzheimer's disease.

[0031] In a certain embodiment of the present invention, the sulfur-containing compound represented by formula I or a pharmaceutically acceptable salt thereof is selected from the following structures:

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038] In one embodiment of the present invention, the compound represented by formula I is represented by formula IA:

[0039]

[0040] In one embodiment of the present invention, the compound represented by formula I is represented by formula IB:

[0041]

[0042] R-1 is independently C1-C3 alkyl or C2-C6 alkenyl.

[0043] In one embodiment of the present invention, the compound represented by formula I is represented by formula IC:

[0044]

[0045] R-2 is independently a C1-C5 alkyl group.

[0046] In one embodiment of the present invention, the compound represented by formula I is represented by formula ID:

[0047]

[0048] R-3 is independently C1-C6 alkyl, C2-C6 alkenyl or R 7-1 Substituted C2-C6 alkenyl.

[0049] In one embodiment of the present invention, the compound represented by formula I is represented by formula IE:

[0050]

[0051] R-4 is independently C3-C8 cycloalkyl, C5-C6 cycloalkenyl, phenyl or 7-2 Substituted phenyl.

[0052] In one embodiment of the present invention, the compound represented by formula I is represented by formula IF:

[0053]

[0054] R-5 is independently a 5-6 membered heterocycloalkyl group "containing 1 or 2 heteroatoms selected from one or both of N and O" or a 5-6 membered heteroaryl group "containing 1, 2 or 3 heteroatoms selected from one or more of N, O and S".

[0055] In one embodiment of the present invention, the compound represented by formula I is represented by formula IG:

[0056]

[0057] The present invention provides a sulfur-containing compound or a pharmaceutically acceptable salt thereof,

[0058]

[0059]

[0060]

[0061] In IC, R-2 is independently C1-C5 alkyl;

[0062] IE-1, R 7 are independently C5-C6 cycloalkenyl or R 7-2 Substituted phenyl;

[0063] IE-1, R 7-2 are independently halogen or C1-C6 alkoxy;

[0064] IE-2, R 7 are independently phenyl or R 7-2 Substituted phenyl;

[0065] IE-2, R 7-2 are independently halogen, C1-C6 alkyl or C1-C6 alkoxy.

[0066] In a certain embodiment of the present invention, the sulfur-containing compound is selected from the structure:

[0067]

[0068]

[0069]

[0070] In the present invention, the sulfur-containing compounds can be synthesized by methods similar to those known in the chemical field, and the steps and conditions can refer to the steps and conditions of similar reactions in the art, especially according to the description herein. The starting materials are usually from commercial sources, such as Aldrich, or can be easily prepared using methods known to those skilled in the art (obtained through SciFinder, Reaxys online database).

[0071] In the present invention, the sulfur-containing compounds can also be prepared by peripherally modifying the prepared sulfur-containing compounds using conventional methods in the art to obtain other sulfur-containing compounds.

[0072] The necessary raw materials or reagents for preparing the salts of sulfur-containing compounds can be obtained commercially or prepared by synthetic methods known in the art. The free base or its acid-added salt can be prepared as described in the following experimental section. The term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein and has all the effects of the parent compound.

[0073] The present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of the sulfur-containing compound or a pharmaceutically acceptable salt thereof as described above and a pharmaceutical excipient (or a pharmaceutically acceptable carrier).

[0074] The present invention also provides a use of the above-mentioned sulfur-containing compound or a pharmaceutically acceptable salt thereof in the preparation of an Aβ40 and / or Aβ42 protein inhibitor. In the above-mentioned application, the Aβ40 and / or Aβ42 protein inhibitor can be used in mammals; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of the effect of inhibiting Aβ40 and / or Aβ42 protein.

[0075] The present invention also provides a sulfur-containing compound or a pharmaceutically acceptable salt thereof as described above, and use thereof in the preparation of a drug, wherein the drug can be used to treat and / or prevent diseases mediated by Aβ40 and / or Aβ42 proteins; the sulfur-containing compound or a pharmaceutically acceptable salt thereof and its pharmaceutical composition are in a therapeutically effective amount.

[0076] The present invention also provides a use of the above-mentioned sulfur-containing compound or a pharmaceutically acceptable salt thereof in the preparation of a drug, wherein the drug is a drug for treating and / or preventing neurodegenerative diseases, Alzheimer's disease or aging; the sulfur-containing compound or a pharmaceutically acceptable salt thereof is a therapeutically effective amount.

[0077] The present invention also provides a method for inhibiting Aβ40 and / or Aβ42 protein, which comprises administering a therapeutically effective amount of the sulfur-containing compound or a pharmaceutically acceptable salt thereof as described above to a patient.

[0078] The present invention also provides a method for treating and / or preventing diseases mediated by Aβ40 and / or Aβ42 proteins, which comprises administering a therapeutically effective amount of the sulfur-containing compound or a pharmaceutically acceptable salt thereof as described above to a patient.

[0079] In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0080] As used herein, the sulfur-containing compounds or pharmaceutically acceptable salts thereof described in the present invention may contain one or more chiral centers and exist in different optically active forms. When the compound contains one chiral center, the compound contains enantiomers. The present invention includes these two isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When the sulfur-containing compounds or pharmaceutically acceptable salts thereof contain more than one chiral center, diastereomers may exist. The present invention includes resolved optically pure specific isomers and mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography. The term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds of the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomer forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, atropisomers, etc. The compounds of the present invention may also exist in any combination or any mixture of the aforementioned stereoisomers, such as meso-, racemic-, equal mixtures of atropisomers, etc., and also in the form of single enantiomers, single diastereomers or mixtures thereof, or single atropisomers or mixtures thereof. When the compounds of the present invention contain olefin double bonds, unless otherwise specified, they include cis-isomers and trans-isomers, and any combination thereof.

[0081] As mentioned above, the present invention provides compounds represented by the above-mentioned structures, or their cis-trans isomers, meso-isomers, racemates, enantiomers, diastereomers, atropisomers, tautomers or mixtures thereof, wherein "their mixtures" include any mixture of any stereoisomers (e.g., cis-trans isomers, enantiomers, diastereomers, atropisomers), tautomers and / or mixtures (meso-isomers, racemates) mentioned above, such as a mixture of cis-trans isomers, a mixture of enantiomers and diastereomers, a mixture of diastereomers, a mixture of atropisomers, or a mixture of cis-trans isomers and racemates, a mixture of enantiomers and a mixture of diastereomers, a mixture of cis-trans isomers and tautomers, a mixture of atropisomers and a mixture of diastereomers, etc.

[0082] The term "tautomer" refers to functional isomers that result from the rapid shift of an atom in two positions in a molecule.

[0083] The sulfur-containing compound as shown in Formula I or its pharmaceutically acceptable salt is intended to cover any isotope-labeled (or "radiolabeled") variant of the sulfur-containing compound as shown in Formula I or its pharmaceutically acceptable salt. Such a variant can be obtained by replacing one or more atoms in the sulfur-containing compound as shown in Formula I or its pharmaceutically acceptable salt with an atomic mass or mass number different from the atomic mass or mass number usually found in nature. The radionuclide used will depend on the specific application of the radiolabeled variant. For example, for in vitro receptor labeling and competition assays, 3 H or 14 C is often useful. For radiographic applications, 11 C or 18 F is often useful.

[0084] Certain isotopic variants of the compounds of the invention, particularly those into which one or more radioactive isotopes have been incorporated, can be useful, for example, in studying the mechanism of action or the distribution of the active ingredient in vivo; due to the relative ease of preparation and detectability, isotopic variants labeled with 3 H or 14 Compounds containing C isotopes are particularly suitable for this purpose. In addition, the inclusion of isotopes such as deuterium can produce special therapeutic benefits due to the better metabolic stability of the compound, such as extending the half-life in the body or reducing the effective dose required; therefore, such modifications of the compounds of the present invention may also constitute preferred embodiments of the present invention in some cases. Isotopic variants of the compounds of the present invention can be prepared by methods known to those skilled in the art, such as by the methods described below and by the methods described in the operating examples, by using corresponding isotopically modified specific reagents and / or starting compounds.

[0085] In this application, "pharmaceutical composition" refers to a preparation comprising a compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (e.g., humans). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0086] In this application, "pharmaceutically acceptable" refers to substances (such as pharmaceutical excipients) that do not affect the biological activity or properties of the compounds of the present invention and are relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

[0087] The term "pharmaceutical excipient" or "pharmaceutically acceptable carrier" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in pharmaceutical preparations except the active ingredients. See Part IV of the Pharmacopoeia of the People's Republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition). Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipient may be an inert filler, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0088] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0089] When used as a drug, the sulfur-containing compound or its pharmaceutically acceptable salt as shown in Formula I can be administered in any form of a pharmaceutical composition. These compositions can be prepared according to methods well known in the pharmaceutical field and can be administered in various ways, depending on the local or systemic treatment and the area to be treated. Administration can be local (including epidermal and transdermal, eye and mucosal, including intranasal, vaginal and rectal delivery), pulmonary (for example, by inhalation or insufflation of powder or aerosol, including by sprayer; intratracheal or intranasal), oral (solid and liquid preparations) or parenteral administration. Examples of solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules and tablets. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum preparations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, emulsions, ointments, gels, drops, suppositories, sprays, liquids, and powders. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols: such as nasal sprays or inhalers. Oral administration may include dosage forms formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion; or intracranial administration such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose, or may be by continuous infusion pump. Conventional pharmaceutical carriers, water, powder or oily bases, thickeners, etc. may be necessary or required. The pharmaceutical composition of the present invention may also be a controlled release or delayed release dosage form (e.g., liposomes or microspheres).

[0090] The term "treat" refers to therapeutic treatment or palliative measures. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition. "Treatment" may also mean prolonging survival as compared to expected survival if not receiving treatment.

[0091] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0092] The term "therapeutically effective amount" refers to an amount of a compound that is sufficient to effectively treat a disease or condition described herein when administered to a patient."Therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

[0093] The term "patient" refers to any animal that is about to or has been administered the compound or composition according to the embodiments of the present invention, preferably a mammal, and most preferably a human. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

[0094] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0095] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids and organic acids. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0096] In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds. When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents obtained when the structural formula is written from right to left.

[0097] Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, a C1-C4 alkyl or a C 1-4 Alkyl refers to an alkyl group as defined below having a total of 1, 2, 3 or 4 carbon atoms. The total number of carbon atoms in the shorthand notation does not include carbons that may be present in substituents of the group being described.

[0098] As used herein, numerical ranges defined in substituents such as 0 to 4, 1-4, 1 to 3, etc. indicate integers within the range, such as 1-6 is 1, 2, 3, 4, 5, 6.

[0099] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0100] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence state of the particular atom is normal and the compound after the substitution is stable.

[0101] In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other, that is, the more than one substituents may be different or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at each position in the same or different manner.

[0102] In various parts of this specification, substituents of compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. The term "C x -C y Alkyl" or "C x-y "Alkyl" refers to a straight or branched chain saturated hydrocarbon containing x to y carbon atoms. For example, the term "C1-C6 alkyl" or "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl disclosed independently; "C 1-4 The term "alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl (i.e. propyl, including n-propyl and isopropyl), C4 alkyl (i.e. butyl, including n-butyl, isobutyl, sec-butyl and tert-butyl).

[0103] As used herein, the terms "part", "moiety", "chemical moiety", "group", "chemical group" refer to a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

[0104] When a substituent is listed without indicating the atom through which it is bonded in a chemical formula (including a specific compound), such a substituent may be bonded via any atom thereof. Combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0105] When any variable (such as R 7 ) When a variable appears multiple times in the definition of a compound, the definition of the variable at each position is independent of the definitions at the remaining positions, and their meanings are independent of each other and do not affect each other.

[0106] When a group is listed without explicitly indicating that it has a substituent, such group is only meant to be unsubstituted. For example, when "C 1-4 When there is no “substituted or unsubstituted” before “alkyl”, it only refers to “C 1-4 Alkyl" itself or "unsubstituted C 1-4 alkyl".

[0107] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl", it should be understood that the "alkyl" represents a linked alkylene group.

[0108] In some specific structures, when an alkyl group is explicitly indicated as a linking group, the alkyl group represents a linking alkylene group, for example, the group "halo-C 1-4 C in "alkyl" 1-4 Alkyl is understood to be C 1-4 Alkylene.

[0109] The term "halogen" refers to fluorine, chlorine, bromine or iodine, in particular to F, Cl or Br.

[0110] In the present application, as a group or a part of other groups (for example, in haloalkyl, deuterated alkyl, etc.), the term "alkyl" refers to a saturated aliphatic hydrocarbon group including branched and straight chains with a specified number of carbon atoms, consisting only of carbon atoms and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6, most preferably 1 to 4) carbon atoms, and connected to the rest of the molecule by a single bond, wherein propyl is a C3 alkyl group (including isomers, such as n-propyl or isopropyl); butyl is a C4 alkyl group (including isomers, such as n-butyl, sec-butyl, isobutyl or tert-butyl); The butyl group is a C5 alkyl group (including isomers such as n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, isopentyl, tert-pentyl or neopentyl); the hexyl group is a C6 alkyl group (including isomers such as n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl and 2,3-dimethylbutyl). For example, it includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, nonyl and decyl and the like alkyl groups.

[0111] In the present application, as a group or part of other groups, the term "alkylene" means a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight or branched hydrocarbon group; that is, one hydrogen in an alkyl group is replaced, and the definition of alkyl group is as described above. Examples of alkylene groups include methylene (-CH2-), ethylene {including-CH2CH2- or-CH(CH3)-}, isopropylene {including-CH(CH3)CH2- or-C(CH3)2-}, and the like.

[0112] In the present application, as a group or part of other groups, the term "saturated or unsaturated non-aromatic ring group" means a carbocyclic substituent having a specified number of carbon atoms (such as 3 to 15 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms), a saturated or partially unsaturated monocyclic or polycyclic (such as a bicyclic, tricyclic or more cyclic bridged ring, a fused ring or a spirocyclic system), and which can be connected to the rest of the molecule through a single bond via any suitable carbon atom; for example, including "cycloalkyl" and "cycloalkenyl".

[0113] In the present application, as a group or part of other groups, the term "cycloalkyl" means a saturated monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms (e.g., having 3 to 15 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 7 carbon atoms), which may include a bridged ring system or a spiro ring system, and which may be connected to the rest of the molecule via a single bond via any suitable carbon atom, or may be cyclically connected or spirocyclically connected. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.

[0114] In the present application, as a group or part of other groups, the term "aryl" refers to an aromatic group of a conjugated hydrocarbon ring system consisting of carbon atoms that satisfies the 4n+2 rule, and each ring has aromaticity. In a certain embodiment, "aryl" refers to an aromatic group having 6 to 18 (preferably 6 to 10) carbon atoms. Examples of aryl include, but are not limited to, phenyl or naphthyl.

[0115] In the present application, as a group or part of other groups, the term "heteroaryl" means a conjugated ring system group having carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in this specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or more ring system. When it is a bicyclic, tricyclic or more ring (condensed ring), it can also include being fused with a cycloalkyl or heterocyclic group as defined herein, provided that the heteroaryl group is connected to the rest of the molecule through a single bond via an atom on the aromatic ring. Preferably, the 5-10-membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms selected from N, O and S, and more preferably contains 1, 2, 3 or 4 heteroatoms selected from N, O and S. The 5-6-membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, oxadiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoxazolyl, thiadiazolyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, and isoquinolyl.

[0116] The "-" at the end of a group means that the group is connected to other fragments in the molecule through this site.

[0117] It should be understood that as used herein, the singular forms, such as "a," and "an," include plural references unless otherwise specified.

[0118] The term "one or more" or "one or more than two" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0119] Unless otherwise specified, the present invention adopts conventional methods of mass spectrometry and elemental analysis, and each step and condition can refer to conventional operating steps and conditions in the art.

[0120] Unless otherwise indicated, the present invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical syntheses and chemical analyses.

[0121] In addition, it should be noted that, unless otherwise explicitly stated, the description method "... independently are" used in the present invention should be understood in a broad sense, meaning that the individuals described are independent of each other and can independently be the same or different specific groups. In more detail, the description method "... independently are" can mean that in different groups, the specific options expressed by the same symbols do not affect each other; it can also mean that in the same group, the specific options expressed by the same symbols do not affect each other.

[0122] Those skilled in the art will appreciate that, according to the conventions used in the art, the structural formulas used in this application to describe groups It means that the corresponding group R is connected to other fragments and groups in the compound through this site.

[0123] Unless otherwise specified, all technical and scientific terms used herein have the standard meaning in the field to which the claimed subject matter belongs. If there are multiple definitions for a term, the definition herein shall prevail.

[0124] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0125] The reagents and raw materials used in the present invention are commercially available.

[0126] The positive and progressive effect of the present invention is that the compounds provided by the present invention have a good inhibitory effect on Aβ40 and Aβ42 proteins, and are expected to treat and / or prevent neurodegenerative diseases, Alzheimer's disease or aging drugs. DETAILED DESCRIPTION

[0127] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0128] The structures of the compounds were determined by nuclear magnetic resonance ( 1 H NMR) or mass spectrometry (MS). NMR measurements were performed using a Bruker AVANCE-500 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated water (D2O), etc. as the measuring solvent, tetramethylsilane (TMS) as the internal standard, and chemical shifts (δ) given in parts per million (ppm).

[0129] The MS measurement instrument was an Agilent (ESI) mass spectrometer (manufacturer: Agilent, model: Agilent 6110).

[0130] Preparation method for high performance liquid chromatography:

[0131] Instrument model: Elite P3500, chromatographic column: Welch Ultimate XB-C18 (30×250mm, 10μm); chromatographic column temperature, 25℃; flow rate: 42mL / min; detection wavelength: 254nm; elution gradient: (0min: 10% A, 90% B; 25min: 90% A, 10% B; 35min: 90% A, 10% B; 38min: 10% A, 90% B; 40min: 10% A, 90% B); mobile phase: A: methanol, B: 0.05% formic acid aqueous solution.

[0132] abbreviation meaning DCM Dichloromethane DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide EA Ethyl acetate MeOH Methanol NaOH Sodium hydroxide TBSCl tert-Butyldimethylsilyl chloride THF Tetrahydrofuran

[0133] The compounds synthesized in the following examples are based on the compounds represented by the molecular formulas, and the Chinese and English names are for reference only.

[0134] Example 1: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(5-hydroxy-3-(methylthio)pent-2-en-2-yl)formamide hydrochloride (Compound 20)

[0135]

[0136] Steps: Dissolve 3.37g of compound 20a in 5.0g of water and stir to dissolve; begin to add sodium hydroxide solution (30%) dropwise to adjust the pH to 12; stir for 20 minutes, re-measure the pH, and adjust the pH to 12 until it stabilizes; add 20b (1.41g) dropwise while maintaining below 10°C; after addition, keep warm and react for 10 minutes; solid precipitates, filter, dissolve the filter cake with methanol, add ethyl acetate dropwise to precipitate, filter and dry to obtain the title compound 20 (600mg, off-white solid).

[0137] MS m / z(ESI):297[M+1] +

[0138] 1 H NMR(400MHz,DMSO-d6)δ9.06(brs,2H),8.16(s,1H),7.97(s,1H),4.78(brs,1 H), 4.45 (s, 2H), 3.48 (t, J = 6.4Hz, 2H), 2.51 (s, 5H), 2.00 (s, 3H), 1.99 (s, 3H).

[0139] Example 2: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(3-(thioethyl)-5-hydroxypent-2-en-2-yl)carboxamide hydrochloride (Compound 21)

[0140]

[0141] Compound 20a (5 g, 0.0148 mol) was dissolved in water (15 mL), cooled to 5 ° C in an ice bath under stirring, and the pH was adjusted to 12-13 with 30% sodium hydroxide solution. The temperature was kept at 0-10 ° C during the adjustment process. After the adjustment, the pH was kept at 12-13, the temperature was kept at 10-20 ° C, and stirred for 30 minutes. A solution of compound 21b (3.46 g, 0.0222 mol) in tetrahydrofuran (7 mL) was added dropwise, and the temperature was kept at 10-20 ° C and the pH value was 12-13. After the addition was completed, the mixture was stirred at room temperature for 15 minutes. The reaction solution was extracted twice with ethyl acetate (50 mL, 20 mL), and the aqueous phase was stirred overnight to precipitate pale yellow crystals, which were filtered, and the filter cake was washed with water and dried to obtain the title compound 21 (3.5 g, pale yellow solid).

[0142] MS m / z(ESI):311[M+1] +

[0143] 1 H NMR (400MHz, CD3OD) δ8.13(s,1H),8.00(s,1H),4.55(s,2H),3.70(t,J=6.6Hz,2 H),2.61(t,J=6.6Hz,2H),2.54–2.46(m,5H),2.11(s,3H),0.98(t,J=7.3Hz,3H).

[0144] Example 3: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(5-hydroxy-3-(propylthio)pent-2-en-2-yl)formamide hydrochloride (Compound 22)

[0145]

[0146] Step 1: Using the synthetic route of Example 2, the raw material ethyl iodide was replaced with propyl bromide to obtain a white solid 22A.

[0147] Step 2: Add compound 22A (0.3 g, 0.92 mmol) into a 100 mL single-necked bottle, add 10 mL of ethyl acetate, cool in an ice bath, add 2 mL of isopropanol hydrochloric acid solution, stir for 0.5 hours, filter and dry to obtain the title compound 22 (30 mg, white solid).

[0148] MS m / z(ESI):325[M+1] +

[0149] 1H NMR (400MHz, CD3OD) δ8.06(s,1H),8.00(s,1H),4.53(br,2H),3.69(t,J=6.6Hz,2H),2.60(t,J=6.6H z,2H),2.53(s,3H),2.44(t,J=7.4Hz,2H),2.09(s,3H),1.32(h,J=7.3Hz,2H),0.88(t,J=7.4Hz,3H).

[0150] Example 4: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(3-(benzylmercapto)-5-hydroxypent-2-en-2-yl)formamide hydrochloride (Compound 23)

[0151]

[0152] Steps: Add compound 20a (3.4 g, 0.01 mol) into a 250 mL three-necked flask, add 10 mL of water, and cool to 0-10°C in an ice bath; begin to dropwise add 30% sodium hydroxide solution, adjust the pH to 11, stir at room temperature for 1 hour, then add 23b (1.71 g, 0.01 mol), stir at room temperature for 1 hour; add dichloromethane to extract, separate the liquids, dry the organic phase, concentrate, and purify by column chromatography to obtain an oil; add 10 mL of methanol to dissolve, then dropwise add hydrochloric acid isopropanol solution, stir and react for 1 hour; add 50 mL of ethyl acetate, a white solid precipitates, filter, and use ethyl acetate to pulp again for 1 hour; filter, wash the filter cake with ethyl acetate, and dry to obtain the title compound 23 (0.8 g, white solid).

[0153] MS m / z(ESI):373[M+1] +

[0154] 1 H NMR (400MHz, CD3OD) δ7.97(s,1H),7.42(s,1H),7.29(t,J=7.3Hz,2H),7.24(d,J=7.0Hz,1H),7.15( d,J=7.4Hz,2H),4.44(br,2H),3.81–3.72(m,4H),2.71(t,J=6.5Hz,2H),2.52(s,3H),2.04(s,3H).

[0155] Example 5: Synthesis of (Z)-4-(N-(((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-3-(methylthio)pent-3-en-1-yl dihydrogen phosphate (Compound 24)

[0156]

[0157] Steps: Dissolve compound 24a (6.6 g) in 10 g of water and stir to dissolve; begin to drop sodium hydroxide solution (30%) to adjust the pH to 12; stir for 20 minutes, re-measure the pH, and adjust the pH to 12 until it stabilizes; add 20b dropwise while maintaining below 10°C, and after the addition, keep warm for 10 minutes; add acetone to precipitate a solid; filter, dissolve the filter cake with methanol, and drop ethyl acetate to precipitate; filter and dry to obtain the title compound 24 (170 mg, off-white solid).

[0158] MS m / z(ESI):377[M+1] +

[0159] 1 H NMR(400MHz,DMSO-d6)δ7.96(s,1H),7.94(s,1H),4.42(s,2H),3.78(q,J=7.0Hz,2H ), 2.63 (t, J = 7.2Hz, 2H), 2.39 (d, J = 3.5Hz, 3H), 2.00 (d, J = 5.8Hz, 3H), 1.96 (s, 3H).

[0160] Example 6: Synthesis of (Z)-4-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamide)-3-(mercaptoethyl)pent-3-en-1-yl dihydrogen phosphate (Compound 25)

[0161]

[0162] The title compound 25 (white solid) was prepared by the same synthetic route as in Example 2, except that the raw material 20a in the step of Example 2 was replaced by 24a.

[0163] MS m / z(ESI):391[M+1] +

[0164] 1 H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.92(s,1H),7.86–7.57(br,2H),4.42(s,2H),3.81(d,J=6 .7Hz,2H),2.61(s,2H),2.44(d,J=7.0Hz,2H),2.38(s,3H),2.02(s,3H),0.89(t,J=7.3Hz,3H).

[0165] Example 7: Synthesis of (Z)-4-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-3-(thiopropyl)pent-3-en-1-yl dihydrogen phosphate (Compound 26)

[0166]

[0167] The title compound 25 (white solid) was prepared by the same synthetic route as in Example 3, except that the raw material 20a in the step of Example 3 was replaced by 24a.

[0168] MS m / z(ESI):405[M+1] +

[0169] 1 H NMR (400MHz, DMSO-d6) δ7.89-7.80(m,2H),4.49–4.27(m,2H),3.79(s,2H),2.57(t,J=7.6Hz, 2H),2.33-2.28(m,5H),1.97(s,3H),1.21-1.09(d,J=7.7Hz,2H),0.76(dd,J=8.4,6.5Hz,3H).

[0170] Example 8: Synthesis of (Z)-4-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-3-(benzylthio)pent-3-en-1-yl dihydrogen phosphate (Compound 27)

[0171]

[0172] Steps: Add 24a (content 83%) (3.0g, 0.009mol) to the reaction bottle and dissolve in 15g water, stir to dissolve. Add sodium hydroxide solution (30%) dropwise to adjust the pH to 11.5-12.0, maintain the system temperature at 25°C, stir for 30 minutes, add sodium hydroxide to pH = 12, add 23b (1.63g, 0.0099mol) dropwise within 2 minutes, stir for 1 hour, and send the sample to the central control; adjust the pH of the aqueous phase to 3-4, the system becomes turbid, let it stand and take out the oil layer below, dissolve it with methanol, prepare some samples, and freeze-dry to obtain the title compound 27 (600mg, white solid).

[0173] MS m / z(ESI):453[M+1] +

[0174] 1H NMR (400MHz, DMSO-d6) δ7.81(s,1H),7.43(s,1H),7.25(d,J=7.3Hz,2H),7.21(d,J=7.0Hz,1H),7.13(d ,J=7.2Hz,2H),4.29(s,2H),3.85(q,J=6.3Hz,2H),3.67(s,2H),2.67(s,2H),2.33(s,3H),1.92(s,3H).

[0175] Example 9: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(5-hydroxy-3-(vinylmercapto)pent-2-en-2-yl)formamide (Compound 28)

[0176]

[0177] Steps: Add compound 20a (3.37 g, 10 mmol) into a 100 mL three-necked flask, add 10 mL 30% NaOH, 10 mL of compound 28b, and 0.337 g tetrabutylammonium iodide, and stir at room temperature for 12 hours; filter, slurry with methanol, filter, and dry the filter cake to obtain the title compound 28 (0.08 g, white solid).

[0178] MS m / z(ESI):309[M+1] +

[0179] 1 H NMR (400MHz, DMSO-d6) δ7.90(d,J=2.3Hz,1H),7.82(s,1H),6.65(s,2H),6.24–6.11(m,1H),5.20–5.10(m,1H),4.93(dd,J=16.6, 2.3Hz,1H),4.65(s,1H),4.35(s,2H),3.43(t,J=7.2Hz,2H),2.46(d,J=7.3Hz,2H),2.25(d,J=2.3Hz,3H),2.00(d,J=1.9Hz,3H).

[0180] Example 10: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(5-hydroxy-3-(propyldisulfide)pent-2-en-2-yl)formamide (Compound 29)

[0181]

[0182] Step 1: Add compound 22b (3.0 g, 24.39 mmol), ethanol (20 mL), sodium thiosulfate (3.86 g, 24.39 mmol) and water (15 mL) into a reaction flask. Reflux the reaction solution for 8 hours. Evaporate under reduced pressure to obtain compound 29b (3.0 g, white solid).

[0183] Step 2: Add compound 20a (1.0 g, 2.96 mmol) and water (5 mL) to the reaction bottle, add 30% NaOH solution to pH = 12, and stir the reaction at room temperature for 1.5 hours. 29b (1.06 g, 5.93 mmol, 2.0 eq.) was added to the reaction system, and a white solid precipitated. Stir at room temperature for 2 hours. Add dichloromethane (10 mL) to the reaction system, stir for 3 minutes, separate the organic phase, dry, and concentrate to obtain a crude product, which was separated and purified by silica gel column (eluent: DCM: MeOH = 10: 1), collect the target component, concentrate and dry, and obtain the title compound 29 (0.38 g, white solid).

[0184] MS m / z(ESI):357[M+1]

[0185] 1 H NMR (400MHz, DMSO-d6) δ7.91(s,1H),7.81(s,1H),6.73(br,2H),4.67(t,J=5.7Hz,1H),4.34(d,J=11.3Hz,2H),3.40(q,J=6.7 Hz,2H),2.65(t,J=7.1Hz,2H),2.31(t,J=7.0Hz,2H),2.24(s,3H),1.98(s,3H),1.38(q,J=7.2Hz,2H),0.82(t,J=7.3Hz,3H).

[0186] Example 11: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(5-hydroxy-3-(isopropyldisulfide)pent-2-en-2-yl)formamide (Compound 30)

[0187]

[0188] The title compound 30 (white solid) was prepared by the same synthetic route as in Example 10, except that the raw material 22b in step 1 of Example 10 was replaced by 30a.

[0189] MS m / z(ESI):357[M+1] +

[0190] 1H NMR(400MHz, DMSO-d6)δ7.93(s,1H),7.81(s,1H),6.74(br,2H),4.67(t,J=5.7Hz,1H),4.43–4.24(m,2H),3.38 (q,J=6.7Hz,2H),2.65(t,J=7.0Hz,2H),2.57(q,J=6.7Hz,1H),2.23(s,3H),1.98(s,3H),0.99(d,J=6.7Hz,6H).

[0191] Example 12: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(3-(butyldisulfanyl)-5-hydroxypent-2-en-2-yl)formamide (Compound 31)

[0192]

[0193] The title compound 31 (white solid) was prepared by the same synthetic route as in Example 29, except that the raw material 22b in step 1 of Example 10 was replaced by 31a.

[0194] MS m / z(ESI):371[M+1] +

[0195] 1 H NMR (400MHz, DMSO-d6) δ7.90(s,1H),7.80(s,1H),6.72(br,2H),4.67(t,J=5.7Hz,1H),4.32(s,2H),3.40(q,J=6.6Hz,2H),2.65(t, J=7.1Hz,2H),2.34(t,J=7.1Hz,2H),2.24(s,3H),1.98(s,3H),1.35(p,J=7.1Hz,2H),1.25(p,J=7.3Hz,2H),0.81(t,J=7.3Hz,3H).

[0196] Example 13: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(3-(sec-butyldisulfonyl)-5-hydroxypent-2-en-2-yl)formamide (Compound 32)

[0197]

[0198] The title compound 32 (white solid) was prepared by the same synthetic route as in Example 10, except that the raw material 22b in step 1 of Example 10 was replaced by 32a.

[0199] MS m / z(ESI):371[M+1]

[0200] 1 H NMR (400MHz, DMSO-d6) δ7.93(s,1H),7.81(s,1H),6.73(br,2H),4.66(t,J=5.7Hz,1H),4.33(s,2H),3.39(q,J=6.6Hz,2H),2.67(t,J=7.1Hz,2H) ,2.38(q,J=6.6Hz,1H),2.24(s,3H),1.98(s,3H),1.36(dt,J=14.1,7.1 Hz,1H),1.30–1.22(m,1H),0.98(d,J=6.7Hz,3H),0.81(t,J=7.3Hz,3H).

[0201] Example 14: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(5-hydroxy-3-(pent-3-yldisulfanyl)pent-2-en-2-yl)formamide (Compound 33)

[0202]

[0203] The title compound 33 (white solid) was prepared by the same synthetic route as in Example 10, except that the raw material 22b in step 1 of Example 10 was replaced by 33a.

[0204] MS m / z(ESI):385[M+1] +

[0205] 1 H NMR (400MHz, DMSO-d6) δ7.91(s,1H),7.81(s,1H),6.73(br,2H),4.67(t,J=5.6Hz,1H),4.32(s,2H),3.40(q,J=6.6Hz,2H),2.6 8(t,J=7.1Hz,2H),2.24(s,3H),2.20(t,J=6.5Hz,1H),1.98(s,3H),1.31(ddd,J=16.5,13.9,7.4Hz,4H),0.80(t,J=7.3Hz,6H).

[0206] Example 15: (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(5-hydroxy-3-((3-methyl-2-en-1-yl)disulfanyl)pent-2-en-2-yl)formamide

[0207] Synthesis of (Compound 34)

[0208]

[0209] Step 1: Dissolve compound 34a (5.0 g, 33.7 mmol) in 20 g of water and stir to dissolve; add sodium thiosulfate (5.3 g, 33.7 mmol) and 20 mL of ethanol, heat to reflux and stir for 5 hours; concentrate to remove ethanol, and the obtained crude intermediate 34b is directly used for the next step.

[0210] Step 2: Dissolve compound 20a (4.5 g, 13.5 mmol) in 20 g of water and stir to dissolve; begin to drop sodium hydroxide solution (30%) to adjust pH = 10-12; stir for 1 hour, re-measure pH, and adjust pH = 10-12 until it stabilizes; add compound 34b and stir at room temperature for 0.5 hour; add ethyl acetate for extraction, dry and concentrate the organic phase, and obtain the title compound 34 (0.05 g, white solid) after column chromatography.

[0211] MS m / z(ESI):383[M+1] +

[0212] 1 H NMR (400MHz, DMSO-d6) δ7.91(s,1H),7.83(s,1H),6.74(s,2H),5.06(t,J=8.2Hz,1H),4.70(t,J=5.8Hz,1H),4.36(br,2H) ,3.44(q,J=6.7Hz,2H),2.91(d,J=8.1Hz,2H),2.69(t,J=7.1Hz,2H),2.22(s,3H),2.02(s,3H),1.66(s,3H),1.57(s,3H).

[0213] Example 16: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(3-((1,1-difluoroallyl)disulfanyl)-5-hydroxypent-2-en-2-yl)formamide (Compound 35)

[0214]

[0215] The title compound 35 (off-white solid) was prepared by the same synthetic route as in Example 15, except that the raw material 34a in step 1 of Example 15 was replaced by 35a.

[0216] MS m / z(ESI):391[M+1] +

[0217] 1H NMR (400MHz, DMSO-d6) δ7.93(d,J=2.1Hz,1H),7.83(d,J=1.9Hz,1H),6.75(br,2H),4.74–4.67(m,1H),4.67–4.50(m,1H),4.37(b r,J=7.9Hz,2H),3.44(q,J=6.5Hz,2H),3.00(d,J=8.4Hz,2H),2.67(t,J=7.0Hz,2H),2.24(d,J=2.2Hz,3H),2.01(d,J=1.9Hz,3H).

[0218] Example 17: Synthesis of N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-((Z)-3-(((E)-but-2-en-1-yl)disulfanyl)-5-hydroxypent-2-en-2-yl)formamide (Compound 36)

[0219]

[0220] The title compound 36 (off-white solid) was prepared by the same synthetic route as in Example 15, except that the raw material 34a in step 1 of Example 15 was replaced by 36a.

[0221] MS m / z(ESI):369[M+1] +

[0222] 1 H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.83(s,1H),6.74(s,2H),5.65–5.46 (m,1H),5.28(dt,J=15.0,7.5Hz,1H),4.71(q,J=5.1Hz,1H),4.36(d,J=10. 4Hz,2H),3.44(t,J=6.6Hz,2H),2.97(dd,J=14.7,7.8Hz,2H),2.67(q,J=6 .0Hz,2H),2.23(d,J=4.8Hz,3H),2.01(d,J=7.2Hz,3H),1.66–1.57(m,3H).

[0223] Example 18: Synthesis of (Z)-N-(3-(allyldisulfide)-5-hydroxypent-2-en-2-yl)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamide (Compound 37)

[0224]

[0225] Step 1: Dissolve compound 37a (10 g, 83 mmol) in 60 g of ethanol and stir to dissolve; dissolve sodium thiosulfate (13.12 g, 83 mmol) in 60 g of water, add to the above reaction solution, and reflux at elevated temperature for 4 hours; concentrate and remove the solvent to obtain the crude compound 37b (20 g, white solid) which is directly used for the next step.

[0226] Step 2: Add compound 20a (13.9 g, 41.3 mmol) into a 250 mL three-necked flask, add 20 mL of water, stir, and cool in an ice bath; dissolve compound 37b (20 g) in 10 mL of water, stir to dissolve, add to the above reaction solution, and stir for 5 minutes; extract with ethyl acetate, dry the organic phase, concentrate, and purify by column chromatography to obtain the title compound 37 (1.1 g, white solid).

[0227] MS m / z(ESI):355[M+1]

[0228] 1 H NMR (400MHz, DMSO-d6) δ7.94(s,1H),7.83(s,1H),6.73(s,2H),5.65(tt,J=17.0,5.3Hz,1H ),5.15–5.05(m,2H),4.70(t,J=5.7Hz,1H),4.36(d,J=10.6Hz,2H),3.43(q,J=6.6Hz,2H),3 .03 (d, J = 7.3 Hz, 2H), 2.67 (t, J = 7.1 Hz, 2H), 2.26 (d, J = 9.2 Hz, 3H), 2.00 (s, 3H). Example 19: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(5-hydroxy-3-(((tetrahydrofuran-2-yl)methyl)disulfanyl)pent-2-en-2-yl)formamide (Compound 38)

[0229]

[0230] The title compound 38 (white solid) was prepared by the same synthetic route as in Example 10, except that the raw material 22b in step 1 of Example 10 was replaced by 38a.

[0231] MS m / z(ESI):399[M+1] +

[0232] 1H NMR(400MHz, DMSO-d6)δ7.91(s,1H),7.80(s,1H),6.80–6.60(m,2H),4.66(t,J= 5.7Hz,1H),4.33(s,2H),3.75(p,J=6.5Hz,1H),3.72–3.65(m,1H),3.56(t,J=7.2 Hz,1H),3.41(q,J=6.7Hz,2H),2.66(q,J=6.5Hz,2H),2.48(s,2H),2.25(s,3H), 1.97(s,3H),1.94–1.85(m,1H),1.77(dt,J=14.3,6.8Hz,2H),1.49–1.38(m,1H).

[0233] Example 20: Synthesis of (Z)-N-(4-amino-2-methylpyrimidin-5-yl)-N-(3-(cyclohexane-2-en-1-yldisulfanyl)-5-hydroxypent-2-en-2-yl)formamide (Compound 39)

[0234]

[0235] The title compound 39 (off-white solid) was prepared by the same synthetic route as in Example 315, except that the raw material 34a in step 1 of Example 15 was replaced by 39a.

[0236] MS m / z(ESI):395[M+1] +

[0237] 1 H NMR (400MHz, DMSO-d6) δ7.94(s,1H),7.83(s,1H),6.75(br,2H),5.82(dd,J=9.4,4.5Hz,1H),5.55–5.45(m,1H),4.70(t,J=5.7Hz,1H), 4.37(br,J=13.4Hz,2H),3.42(q,J=6.7Hz,2H),2.70(t,J=7.1Hz,2H),2.24(s,3H),2.01(s,3H),1.97–1.91(m,2H),1.66–1.51(m,4H).

[0238] Example 21: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(5-hydroxy-3-(pyridin-2-yldisulfanyl)pent-2-en-2-yl)carboxamide (Compound 40)

[0239]

[0240] Steps: Add compound 20a (3.4 g, 0.01 mol) into a 250 mL three-necked flask, add 30 mL of water, and cool to 0-10°C in an ice bath; begin to dropwise add 30% sodium hydroxide solution, adjust the pH to 11, and stir at room temperature for 1 hour; add compound 40b (1.1 g, 0.01 mol), stir at room temperature; dropwise add potassium ferrocyanide aqueous solution, react for 3 hours; add dichloromethane to extract, separate the liquids, add methanol to the aqueous phase to force out the inorganic salt, filter, and spin-dry the filtrate; prepare and purify to obtain the title compound 40 (35 mg, white solid).

[0241] MS m / z(ESI):392[M+1] +

[0242] 1H NMR (400MHz, CD3OD) δ8.39(d,J=4.5Hz,1H),8.24(s,1H),8.09(s,1H),7.95(d,J=8.2Hz,1H),7.74(t,J=7.8Hz,1H),7.38(d, J=8.1Hz,1H),7.26–7.18(m,1H),4.75–4.30(m,2H),3.58(t,J=6.7Hz,2H),2.68(t,J=6.6Hz,2H),2.41(s,3H),2.10(s,3H).

[0243] Example 22: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(5-hydroxy-3-(phenyldisulfanyl)pent-2-en-2-yl)carboxamide (Compound 41)

[0244]

[0245] Steps: Dissolve compound 20a (5 g, 0.0148 mol) in water (50 mL), cool to 5 ° C in an ice bath while stirring, add 30% sodium hydroxide solution (9.87 g) in batches, and keep the temperature at 10-20 ° C during the addition process. Remove the ice bath after the addition is completed, stir at room temperature for 0.5 hours, add compound 41b (1.96 g), stir evenly, and the system becomes turbid. Add potassium ferrocyanate (12.2 g, 0.037 mol) and the system will warm up and a large amount of solid will appear. Stir at room temperature for 1 hour, extract with ethyl acetate (60 mL), separate the liquids, and prepare the title compound 41 (30 mg, light yellow solid) after the ethyl acetate layer is spin-dried.

[0246] MS m / z(ESI):391.0[M+1] +

[0247] 1H NMR(400MHz, DMSO-d6)δ7.89–7.74(m,2H),7.53(d,J=7.7Hz,1H),7.43–7.21(m,4H),6.81-6.64(m,2H),4.32 (s,2H),3.35(q,J=6.5Hz,2H),2.60(t,J=6.6Hz,1H),2.40(s,1H),2.32–2.26(m,3H),1.97(d,J=11.1Hz,3H).

[0248] Example 23: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(3-((2-bromophenyl)disulfanyl)-5-hydroxypent-2-en-2-yl)carboxamide (Compound 42)

[0249]

[0250] Steps: Compound 20a (3.37 g, 0.01 mol) was dissolved in water (7 mL), 30% sodium hydroxide solution (9.87 g) was added in batches, pH was adjusted to about 11, and the mixture was reacted at room temperature for 1 hour. A solution of 42b (1.89 g, 0.01 mol) in THF (4 mL) was added to the reaction solution, and 30% sodium hydroxide solution was added to adjust the pH of the reaction solution to above 11. A solution of potassium ferrocyanate (8.23 g, 0.025 mol) in water (20 mL) was added dropwise, and the reaction was continued for 30 minutes after the addition was completed. The mixture was extracted with ethyl acetate and dried to obtain a crude product, which was initially purified by column chromatography and then prepared to obtain the title compound 42 (10 mg, off-white solid).

[0251] MS m / z(ESI):469,471[M+1] +

[0252] 1 H NMR (400MHz, CD3OD) δ7.90(s,1H),7.82(s,1H),7.57(d,J=8.0Hz,1H),7.38(dt,J=14.8,7.6Hz,2H) ,7.18(t,J=7.3Hz,1H),4.49(br,2H),3.56(t,J=6.2Hz,2H),2.69(s,2H),2.42(s,3H),2.09(s,3H).

[0253] Example 24: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(5-hydroxy-3-((2-methoxyphenyl)disulfanyl)pent-2-en-2-yl)carboxamide (Compound 43)

[0254]

[0255] Steps: Dissolve compound 20a (3.37 g, 10 mmol) in 20 g of water and stir to dissolve; begin to add sodium hydroxide solution (30%) to adjust the pH to 10-12; stir for 1 hour, re-measure the pH, and adjust the pH to 10-12 until it stabilizes; add 43b (1.4 g, 10 mmol), dissolve potassium ferrocyanide (8.23 g, 25 mmol) in 20 mL of water, add dropwise to the reaction solution, and stir at room temperature for 0.5 hour; add ethyl acetate to extract twice, combine the organic phases, and concentrate to obtain the title compound 43 (0.09 g, white solid) after preparation.

[0256] MS m / z(ESI):421[M+1] +

[0257] 1 H NMR(400MHz,CD3OD)δ7.76(s,1H),7.60(s,1H),7.35–7.20(m,2H),7.02–6.85(m,2H),4.38( br,2H),3.84(s,3H),3.54(t,J=6.9Hz,2H),2.80(d,J=7.1Hz,2H),2.37(s,3H),2.03(s,3H).

[0258] Example 25: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(5-hydroxy-3-((3-methoxyphenyl)disulfanyl)pent-2-en-2-yl)carboxamide (Compound 44)

[0259]

[0260] The title compound 44 (white solid) was prepared by the same synthetic route as in Example 42, except that the raw material 42b was replaced by 44b.

[0261] MS m / z(ESI):421[M+1] +

[0262] 1H NMR (400MHz, CD3OD) δ7.85(s,1H),7.72(s,1H),7.24(t,J=7.9Hz,1H),6.94(s,1H),6.90(d,J=7.6Hz,1H),6.85(d,J=8 .2Hz,1H),4.46(br,2H),3.79(d,J=2.4Hz,3H),3.55(t,J=6.4Hz,2H),2.78(d,J=6.0Hz,2H),2.43(s,3H),2.05(s,3H).

[0263] Example 26: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(3-((3-fluorophenyl)disulfanyl)-5-hydroxypent-2-en-2-yl)carboxamide (Compound 45)

[0264]

[0265] The title compound 45 (white solid) was prepared by the same synthetic route as in Example 24, except that the raw material 43b was replaced by 45b.

[0266] MS m / z(ESI):409[M+1] +

[0267] 1 H NMR(400MHz,CD3OD)δ7.90–7.75(m,2H),7.41–7.19(m,2H),7.18–6.91(m,2H),4.46(br,2H), 3.51(q,J=6.1Hz,2H),2.72(t,J=6.9Hz,1H),2.50(s,1H),2.39(d,J=4.4Hz,3H),2.06(s,3H).

[0268] Example 27: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(3-((3-chlorophenyl)disulfanyl)-5-hydroxypent-2-en-2-yl)carboxamide (Compound 46)

[0269]

[0270] The title compound 46 (white solid) was prepared by the same synthetic route as in Example 24, except that the raw material 43b was replaced by 46b.

[0271] MS m / z(ESI):425[M+1] +

[0272] 1 H NMR(400MHz,CD3OD)δ7.89–7.75(m,2H),7.53–7.19(m,4H),4.46(br,2H),3.52(q,J =6.6Hz,2H),2.72(t,J=7.0Hz,1H),2.50(s,1H),2.40(d,J=3.3Hz,3H),2.06(s,3H).

[0273] Example 28: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(5-hydroxy-3-((3-methoxybenzyl)disulfanyl)pent-2-en-2-yl)carboxamide (Compound 47)

[0274]

[0275] The title compound 47 (white solid) was prepared by the same synthetic route as in Example 15, except that the raw material 34a in step 1 of Example 15 was replaced by 47a.

[0276] MS m / z(ESI):435[M+1] +

[0277] 1 H NMR (400MHz, DMSO-d6) δ7.94(d,J=2.2Hz,1H),7.85(d,J=2.4Hz,1H),7.21(td,J=8.1,2.2Hz,1H),6.87–6.81(m,2H),6.77–6.72(m,3H),4.73 –4.67(m,1H),4.37(br,J=8.5Hz,2H),3.73(d,J=2.2Hz,3H),3.45(q,J=6.7Hz,2H),2.63(q,J=8.5Hz,2H),2.15(d,J=2.1Hz,3H),2.00(s,3H).

[0278] Example 29: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(3-(benzyldisulfanyl)-5-hydroxypent-2-en-2-yl)carboxamide (Compound 48)

[0279]

[0280] The title compound 48 (white solid) was prepared by the same synthetic route as in Example 10, except that the raw material 22b in step 1 of Example 10 was replaced by 23b.

[0281] MS m / z(ESI):405[M+1]+

[0282] 1 H NMR (400MHz, DMSO-d6) δ7.92(s,1H),7.83(s,1H),7.26(dd,J=12.6,6.8Hz,3H),7.16(d,J=7.2Hz,2H),6.74(br,2H),4.67( t,J=5.7Hz,1H),4.35(d,J=7.1Hz,2H),3.52(s,2H),3.42(q,J=6.6Hz,2H),2.61(t,J=7.0Hz,2H),2.10(s,3H),1.98(s,3H).

[0283] Example 30: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(3-((3-chlorobenzyl)disulfanyl)-5-hydroxypent-2-en-2-yl)formamide formate (Compound 49)

[0284]

[0285] Step 1: Add m-chlorobenzyl bromide (3 g, 0.0146 mol), sodium thiosulfate (2.3 g, 0.0146 mol), ethanol (20 mL), and water (12 mL) to a 100 mL single-mouth bottle, and heat to reflux for 7 hours under nitrogen protection. Cool to room temperature, spin dry the solvent, and obtain a crude compound 49b (white solid), which is used directly in the next step without purification.

[0286] Step 2: Dissolve compound 20a (0.82 g, 0.00244 mol) in water (6 mL), add 30% sodium hydroxide solution in batches, adjust the pH to about 12, and react at room temperature for 1 hour. Add a solution of 49b in water (10 mL) dropwise to the reaction solution, and the addition is completed in about 10 minutes. React at room temperature for 1 hour, extract with EA, and remove the solvent to obtain a crude product. After the crude product is prepared, the title compound 49 (50 mg, white solid) is obtained.

[0287] MS m / z(ESI):439[M+1] +

[0288] 1H NMR (400MHz, CD3OD) δ7.98(s,1H),7.92(s,1H),7.29(d,J=6.4Hz,2H),7.22(s,1H),7.13(d,J=6 .4Hz,1H),4.51(br,2H),3.61(d,J=9.5Hz,4H),2.74(t,J=6.6Hz,2H),2.30(s,3H),2.10(s,3H).

[0289] Example 31: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(3-((3-cyanobenzyl)disulfanyl)-5-hydroxypent-2-en-2-yl)carboxamide (Compound 50)

[0290]

[0291] Step 1: Add compound 50a (6 g, 0.0306 mol), sodium thiosulfate (4.84 g, 0.0306 mol), ethanol (40 mL), and water (24 mL) to a 250 mL single-mouth bottle, and heat to reflux for 7 hours under nitrogen protection. Cool to room temperature, spin dry the solvent, and obtain the crude intermediate 50b (white solid), which is used directly in the next step without purification.

[0292] Step 2: Dissolve 20a (5.16 g, 0.0153 mol) in water (30 mL), add 30% sodium hydroxide solution in batches, adjust the pH to about 11, and react at room temperature for 1 hour. Dissolve the crude intermediate 50b in water (40 mL), adjust the pH to 12, and a white precipitate is produced. The ring-opening solution of 20a is quickly added to the solution of 50b in batches, a large amount of solid is produced, the system is viscous and difficult to stir, and it is transferred to a powerful stirrer and stirred rapidly for 30 minutes. Filter, wash the filter cake with water, drain and directly prepare to obtain the title compound 50 (35 mg, light yellow solid).

[0293] MS m / z(ESI):430[M+1] +

[0294] 1 H NMR (400MHz, CD3OD) δ8.00(s,1H),7.93(s,1H),7.62(d,J=7.0Hz,1H),7.57(d,J=7.7Hz,1H),7.50(d,J=6.7 Hz,2H),4.65(br,2H),3.70(s,2H),3.63(t,J=6.4Hz,2H),2.75(t,J=6.3Hz,2H),2.29(s,3H),2.11(s,3H).

[0295] Example 32: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(3-((3-bromophenyl)disulfanyl)-5-hydroxypent-2-en-2-yl)carboxamide (Compound 51)

[0296]

[0297] The title compound 51 (white solid) was prepared by the same synthetic route as in Example 23, except that the raw material 42b was replaced by 51b.

[0298] MS m / z(ESI):469,471[M+1] +

[0299] 1 H NMR (400MHz, CD3OD) δ7.89(s,1H),7.81(s,1H),7.57(s,1H),7.46(d,J=7.6Hz,1H),7.32(d,J=7.8Hz,1H), 7.27(t,J=7.7Hz,1H),4.50(s,2H),3.56(t,J=6.4Hz,2H),2.74(t,J=6.2Hz,2H),2.44(s,3H),2.09(s,3H).

[0300] Example 33: Synthesis of (Z)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-N-(5-hydroxy-3-(m-tolyldisulfanyl)pent-2-en-2-yl)formamide (Compound 52)

[0301]

[0302] The title compound 52 (white solid) was prepared by the same synthetic route as in Example 24, except that the raw material 43b was replaced by 52b.

[0303] MS m / z(ESI):405[M+1] +

[0304] 1 H NMR(400MHz,CD3OD)δ7.76(s,1H),7.63(s,1H),7.28–7.18(m,2H),7.11(t,J=6.5Hz,2H),4.40 (br,2H),3.53(t,J=6.8Hz,2H),2.76(t,J=7.0Hz,2H),2.38(s,3H),2.32(s,3H),2.02(s,3H).

[0305] Example 34: Synthesis of (Z)-4-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamide)-3-((3-fluorophenyl)disulfanyl)pent-3-en-1-yl dihydrogen phosphate (Compound 53)

[0306]

[0307] The title compound 53 (white solid) was prepared by the same synthetic route as in Example 24, except that the raw material 43b was replaced by 45b and the raw material 20a was replaced by 24a.

[0308] MS m / z(ESI):489[M+1] +

[0309] 1 H NMR(400MHz, DMSO-d6)δ7.92(s,1H),7.80–7.75(m,1H),7.41(dd,J=14.8,7.4Hz,2H),7.23(d,J=8.9Hz,1H),7.17 (d,J=7.1Hz,1H),4.40(br,2H),3.75(d,J=7.8Hz,2H),2.72(t,J=6.9Hz,2H),2.36(s,3H),2.01(d,J=14.5Hz,3H).

[0310] Example 35: Synthesis of (Z)-4-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamide)-3-((3-bromophenyl)disulfanyl)pent-3-en-1-yl dihydrogen phosphate (Compound 54)

[0311]

[0312] The title compound 54 (off-white solid) was prepared by the same synthetic route as in Example 24, except that the raw material 43b was replaced by 5b and the raw material 20a was replaced by 24a.

[0313] MS m / z(ESI):549,551[M+1] +

[0314] 1H NMR (400MHz, CD3OD) δ8.08(d,J=11.2Hz,1H),7.57(s,1H),7.54(s,1H),7.49(d,J=7.9Hz,1H),7.40(d, J=7.9Hz,1H),7.29(t,J=7.9Hz,1H),4.44(br,2H),3.94(s,2H),2.89(s,2H),2.58(s,3H),2.14(s,3H).

[0315] Example 36: Synthesis of (Z)-4-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido-3-((3-chlorophenyl)disulfanyl)pent-3-en-1-yl dihydrogen phosphate (Compound 55)

[0316]

[0317] The title compound 55 (white solid) was prepared by the same synthetic route as in Example 24, except that the raw material 43b was replaced by 46b and the raw material 20a was replaced by 24a.

[0318] MS m / z(ESI):505[M+1] +

[0319] 1 H NMR (400MHz, DMSO-d6) δ7.92(s,1H),7.82–7.71(m,1H),7.50(t,J=5.8Hz,1H),7.39(d,J=7.4Hz,2H),7.29(dd ,J=5.5,3.6Hz,1H),4.40(br,2H),3.80–3.66(m,2H),2.79–2.54(m,2H),2.37(s,3H),2.02(d,J=13.7Hz,3H).

[0320] Example 37: Synthesis of (Z)-4-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido-3-(m-tolyldialkyl)pentyl-3-en-1-yl dihydrogen phosphate (Compound 56)

[0321]

[0322] The title compound 56 (white solid) was prepared by the same synthetic route as in Example 24, except that the raw material 43b was replaced by 56b and the raw material 20a was replaced by 24a.

[0323] MS m / z(ESI):485[M+1] +

[0324] 1 H NMR (400MHz, DMSO-d6) δ7.91(s,1H),7.64(d,J=1.9Hz,1H),7.24(dd,J=13.3,5.7Hz,2H),7.12(d,J=7.7Hz,2H) ,4.39(br,2H),3.76(q,J=6.7Hz,2H),2.82–2.69(m,2H),2.40–2.35(m,3H),2.29(d,J=3.2Hz,3H),2.02(s,3H).

[0325] Example 38: Synthesis of (Z)-4-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamide)-3-((3-methoxyphenyl)disulfanyl)pent-3-en-1-yl dihydrogen phosphate (Compound 57)

[0326]

[0327] The title compound 57 (light yellow solid) was prepared by the same synthetic route as in Example 23, except that the raw material 42a was replaced by 44b and the raw material 20a was replaced by 24a.

[0328] MS m / z(ESI):501[M+1] +

[0329] 1 H NMR (400MHz, CD3OD) δ8.32(s,1H),8.01(s,1H),7.46(s,1H),7.25(t,J=8.1Hz,1H),6.95(d,J=6.9Hz,2H),6 .88(d,J=7.7Hz,1H),4.44(br,2H),3.97–3.87(m,2H),3.80(s,3H),2.90(s,2H),2.53(s,3H),2.12(s,3H).

[0330] Example 39: Synthesis of (Z)-4-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamide)-3-(pyridin-2-yldisulfanyl)pentyl-3-en-1-yl dihydrogen phosphate (Compound 58)

[0331]

[0332] The title compound 58 (white solid) was prepared by the same synthetic route as in Example 21, except that the raw material 40b in the step of Example 21 was replaced by 39a and the raw material 20a was replaced by 24a.

[0333] MS m / z(ESI):472[M+1] +

[0334] 1 H NMR (400MHz, CD3OD) δ8.42(d,J=4.8Hz,1H),8.11(s,2H),7.75(t,J=7.8Hz,1H),7.51(d,J=8.1Hz,1H ),7.24(t,J=6.3Hz,1H),4.62(br,2H),3.94(q,J=5.7Hz,2H),2.82(s,2H),2.57(s,3H),2.16(s,3H).

[0335] Example 81: Synthesis of (Z)-4-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamide)-3-(((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)disulfanyl)pent-3-en-1-yl dihydrogen phosphate (Compound 81)

[0336]

[0337] Steps: Compound 81a (4.6 g, 12 mmol) was dissolved in 20 g of water and stirred to dissolve; sodium hydroxide solution (30%) was added dropwise to adjust the pH to 10-12; the mixture was stirred for 1 hour, the pH was retested, and the pH was adjusted to 10-12 until it stabilized; potassium ferrocyanide (7.5 g) was dissolved in 15 mL of water, added dropwise to the reaction solution, and stirred at room temperature for 2 hours; the mixture was filtered, and the title compound 81 (50 mg, white solid) was obtained after solid preparation.

[0338] MS m / z(ESI):723[M+1] + ;

[0339] 1 H NMR (400MHz, D2O) δ7.83 (d, J = 14.4Hz, 4H), 4.65 (s, 4H), 3.76 (s, 4H), 2.59 (s, 4H), 2.43 (s, 6H), 2.02 (s, 6H).

[0340] Example 82: Synthesis of N,N'-((2Z,2'Z)-disulfanediylbis(5-hydroxypent-2-ene-3,2-diyl)bis(N-(4-amino-2-methylpyrimidin-5-yl)methyl)formamide) dihydrochloride (Compound 82)

[0341]

[0342] Step 1: The title compound 82A (white solid) was prepared by the same synthetic route as in Example 81, except that the starting material 81a was replaced by 82a.

[0343] Step 2: Dissolve compound 82A (0.5 g) in 8 mL of methanol and stir to dissolve; add 20% HCl isopropanol solution (2 mL) and stir for 0.5 hour; filter to obtain the title compound 82 (0.1 g, white solid).

[0344] MS m / z(ESI):563[M+1] + ;

[0345] 1 H NMR (400MHz, D2O) δ7.91 (s, 2H), 7.85 (s, 2H), 4.65 (s, 4H), 3.50 (t, J = 6.7Hz, 4H), 2.47 (s, 10H), 1.99 (s, 6H).

[0346] Example 84: Synthesis of (2S,2'S,3R,3'R,4S,4'S)-1,1'-disulfanediylbis(6-(2,4-dichlorophenyl)hexane-2,3,4-triol) (Compound 84)

[0347]

[0348] Step 1: Compound 84a (262 g, 1.44 mol), water (262 mL), and concentrated hydrochloric acid (54 mL) were added to a flask, mixed and stirred, cooled in an ice bath to 0-5°C, and benzaldehyde (230 g, 2.16 mol) was quickly added dropwise; after the addition was completed, solids gradually precipitated, a large amount of solids precipitated during the reaction, and stirring was difficult, and water (100 mL) was added. The reaction was carried out at room temperature for 4 hours, filtered, and the filter cake was slurried with water (360 mL) and ethyl acetate (260 mL), filtered, and the filter cake was added to water (400 mL). Sodium carbonate (22 g, 0.2 mol) was added under stirring, and the mixture was heated to 100°C for reaction for 1 hour; cooled to room temperature, filtered, the filter cake was washed with water, and dried, and the wet filter cake compound 84A (235.6 g) was directly used for the next reaction.

[0349] Step 2: Add compound 84A (180 g), sodium carbonate (3 g), and dioxane (1500 mL) into a flask, stir and control the temperature to about 10°C in an ice bath, add sodium periodate (153 g, 0.771 mol) in water (300 mL) to the system in batches, and a large amount of solid is generated during the reaction. Add dioxane (300 mL) and react at room temperature for 1 hour. Filter and wash the filter cake with a large amount of ethanol; remove most of the solvent from the filtrate, add ethyl acetate (750 mL) to the residue and slurry for 30 minutes, filter, wash the filter cake with ethyl acetate, and dry to obtain compound 84B (75 g, off-white solid).

[0350] Step 3: Dissolve 2,4-dichlorobenzyl bromide (72 g, 0.3 mol) and triphenylphosphine (78 g, 0.3 mol) in toluene (750 mL) and reflux for 5 hours. After the reaction is completed, cool to room temperature, filter, wash the filter cake with toluene, and dry to obtain compound 84b (145.8 g, white solid).

[0351] Step 4: Add compound 84b (145.8 g) and anhydrous DMF (560 mL) into a flask, stir to dissolve, protect with nitrogen, cool to 0-5°C in an ice bath, add potassium tert-butoxide (46.2 g, 0.4116 mol) under nitrogen protection, and react for 2 hours; add a DMF suspension of compound 84B (70 g, 0.294 mol) into the system, react at room temperature for 1 hour, add an ice-water mixture (4480 g) under stirring, and stir to crystallize for 30 minutes; filter, wash the filter cake with water, slurry the filter cake with ethanol (420 mL) for 1 hour, filter, wash the filter cake with ethanol, and dry to obtain compound 84C (28 g, white solid).

[0352] Step 5: Compound 84C (28 g) was dissolved in DCM (175 mL), and imidazole (9.52 g, 0.14 mol) was added. The system was protected by a balloon and then cooled in an ice bath to 0-5°C. TBSCl (15.82 g, 0.105 mol) was added, and the temperature was naturally raised. The reaction mixture was reacted at room temperature overnight. The reaction solution was washed with water (210 mL), separated, and the aqueous phase was extracted with DCM (140 mL). The DCM layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain compound 84D (29 g, white solid).

[0353] Step 6: Compound 84D (28 g) was added with DMAP (41.3 g) and DCM (175 mL), and the mixture was cooled to 0-5°C in an ice-salt bath. A solution of benzoyl chloride (23.8 g, 0.16968 mol) in DCM (35 mL) was added dropwise. After the addition was complete, the mixture was reacted at room temperature for 5 hours. After the reaction was completed, water (350 mL) was added to wash the reaction solution, the layers were separated, and the aqueous phase was extracted with DCM (210 mL). The DCM layers were combined. The DCM layer was washed with water, the layers were separated, the DCM layer was dried over anhydrous sodium sulfate, and concentrated to obtain compound 84E (35.7 g, yellow oil).

[0354] Step 7: Compound 84E (33.3 g) was added with pyridine hydrofluoride (33.3 g) and tetrahydrofuran (360 mL) and reacted at room temperature overnight. The reaction solution was concentrated and subjected to column chromatography to obtain compound 84F (23.4 g, colorless gum).

[0355] Step 8: Compound 84F (23.4 g) was added with DMAP (29.2 g) and DCM (422 mL). The mixture was cooled in an ice bath until the system temperature dropped to 5-10°C. A solution of methanesulfonyl chloride (10.9 g, 0.0954 mol) in DCM (47 mL) was added dropwise. After the addition was complete, the mixture was reacted at room temperature overnight. The mixture was filtered, the filter cake was washed with DCM, and the filtrate was concentrated and subjected to column chromatography (eluent: DCM:MeOH=100:1-5:1) to give compound 84G (21.6 g, viscous oil).

[0356] Step 9: Dissolve compound 84G (21.6 g) in anhydrous ethyl acetate (216 mL), add 10% Pd / C (8.64 g), replace with hydrogen three times, and react at room temperature overnight; after the reaction is completed, filter, wash the filter cake with ethyl acetate (the filter cake cannot be drained), and concentrate the filtrate to obtain the crude compound 84H, which is directly used in the next step.

[0357] Step 10: Dissolve the crude compound 84H in acetone (200 mL), add potassium thiobenzoate (13.7 g, 0.0777 mol), and heat under reflux for 3 hours. After the reaction is completed, cool to room temperature, filter, wash the filter cake with DCM, and concentrate the filtrate for column chromatography to obtain compound 84I (2.9 g, yellow oil).

[0358] Step 11: Add compound 84I (1.7 g), sodium methoxide (0.36 g, 0.0066 mol), and methanol (20 mL) to a 100 mL single-mouth bottle, and react overnight at room temperature; adjust the pH of the reaction solution to 6-7 with acetic acid, remove the solvent by rotary evaporation, and combine multiple batches for column chromatography (eluent: DCM:MeOH=100:1~10:1) to obtain a crude product; the crude product is freeze-crystallized in a DCM / MeOH mixed solvent (DCM:MeOH=50:1), filtered, and the filter cake is washed with frozen DCM and freeze-dried to obtain the title compound (0.6 g, white solid).

[0359] MS m / z(ESI):621[M+1] +

[0360] 1 H NMR (400MHz, CD3OD) δ7.38(d,J=2.1Hz,2H),7.30(d,J=8.3Hz,2H),7.23(dd,J=8.2,2.2Hz,2H),3.96(ddd,J=8.3,5.6,3.0Hz,2H),3.73(dt,J=8.7 ,4.4Hz,2H),3.49(dd,J=4.8,3.1Hz,2H),3.00(dd,J=13.6,5.5Hz,2H),2 .96–2.83(m,4H),2.76(ddd,J=13.7,10.2,6.2Hz,2H),1.92–1.70(m,4H).

[0361] Biological tests

[0362] In the following examples, comparative example 1 was tested without adding the test sample stock solution, and the culture medium was used as a blank control to perform biological tests, and the results are listed in Tables 1 and 2.

[0363] Experimental materials and methods

[0364] (1) The BCA protein concentration assay kit was purchased from Biotech, the Aβ40 and Aβ42 detection kits were purchased from Wako, and the cell culture-related reagents were purchased from Gibico.

[0365] (2) HEK293APP / sw overexpressing cell culture: The cells were cultured in a 48-well plate with DMEM culture medium (containing 10% FBS, 100 μg / mL G418 (Geneticin) and double antibody). When the cell density was 70%, 4 mM test sample stock solution (the test sample was dissolved in DMEM culture medium) was taken and diluted to 400 μM with DMEM culture medium. 500 μL was added to each well and cultured for 24 hours.

[0366] (3) Take the culture supernatant and add BCA reagent to incubate at room temperature for 30 minutes. Then measure the absorbance of each well at OD570 nm on a microplate reader and calculate the total protein concentration based on the protein standard curve. At the same time, take the supernatant to determine the concentration of Aβ40 and / or Aβ42. Add the supernatant to the coated 96-well plate and incubate overnight at 4°C. After removing and washing the reagent, add HRP (horseradish oxidase) labeled antibody and incubate at 4°C for 2 hours. After removing and washing the reagent, add TMB colorimetric solution and incubate at room temperature for 30 minutes. After adding the stop solution to terminate the reaction, measure the absorbance of each well at OD450 nm on a microplate reader and calculate the concentration of Aβ40 and Aβ42 based on the standard curves of Aβ40 and Aβ42, respectively. Finally, adjust the concentration of Aβ40 and Aβ42 with the total protein concentration to obtain the final concentration.

[0367] Table 1

[0368]

[0369]

[0370] Table 2

[0371]

[0372] According to the above experimental results, compared with the blank of comparative example 1, Aβ42 and / or Aβ40 in all examples were reduced, indicating that the thiamine compounds in all examples have an inhibitory effect on Aβ42 and / or Aβ40.

Claims

1. Use of a sulfur-containing compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament, wherein the medicament is a medicament for treating and / or preventing a disease mediated by Aβ40 and / or Aβ42 protein, wherein the disease is Alzheimer's disease; The sulfur-containing compound is selected from the sulfur-containing compound shown in Formula I or the sulfur-containing compound shown in Formula II: The compound represented by formula I is independently represented by formula IA, IB, IC or the following compounds: in, R 6 are independently hydroxyl or R-1 is independently C1-C3 alkyl or C2-C6 alkenyl; R-2 is independently a C1-C5 alkyl group.

2. The use according to claim 1, characterized in that It meets one or more of the following conditions: (1) R-1 is independently a C1-C3 alkyl group, wherein the C1-C3 alkyl group is independently a methyl group, an ethyl group, a n-propyl group, or an isopropyl group; (2) R-2 is independently C1-C5 alkyl, wherein the C1-C5 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, (3) R-1 is independently C2-C6 alkenyl, R-3 is independently R 7-1 In the substituted C2-C6 alkenyl, the C2-C6 alkenyl is independently vinyl, propenyl, allyl, 3. The use according to claim 1, characterized in that It meets one or both of the following conditions: (1) The R-1 described is independently methyl, ethyl, n-propyl or vinyl; (2) The R-2 described above is independently methyl, ethyl or n-propyl.

4. Use of a sulfur-containing compound or a pharmaceutically acceptable salt thereof in the preparation of a drug, characterized in that: The drug is a drug for treating and / or preventing diseases mediated by Aβ40 and / or Aβ42 proteins, and the disease is Alzheimer's disease; the sulfur-containing compound or a pharmaceutically acceptable salt thereof is selected from the following structures:

5. A sulfur-containing compound or a pharmaceutically acceptable salt thereof, In IC, R-2 is independently a C1-C5 alkyl group.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, characterized in that: In IC, the C1-C5 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, characterized in that In IC, the C1-C5 alkyl group is independently methyl, ethyl or n-propyl.

8. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, characterized in that: The sulfur-containing compound is selected from the structure:

9. A pharmaceutical composition comprising a therapeutically effective amount of the sulfur-containing compound or a pharmaceutically acceptable salt thereof according to any one of claims 5 to 8 and a pharmaceutical excipient.

10. Use of the sulfur-containing compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 5 to 8 as an inhibitor of Aβ40 and / or Aβ42 protein in the preparation of a kit; The sulfur-containing compound or a pharmaceutically acceptable salt thereof is in a therapeutically effective amount.

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