NMT inhibitors, their preparation methods and uses

Abstract

The present invention provides NMT inhibitors, methods for preparing the same, and uses thereof, more specifically relating to compounds such as those represented by formula (1), methods for preparing the same, and pharmaceutical compositions of compounds such as those represented by formula (1) and / or pharmaceutically acceptable salts thereof, methods for preparing the same, and uses thereof as NMT inhibitors in the preparation of antitumor drugs. [C16] TIFF2026522099000036.tif46167

Description

[Technical Field]

[0001] The present invention relates to the field of medicinal chemistry, and more specifically to NMT inhibitors having a structure represented by formula (1), methods for preparing the same, and the use of such compounds in the preparation of pharmaceutical compositions for treating, modulating and / or preventing NMT-mediated diseases. [Background technology]

[0002] NMT (N-myristoyltransferase) is an enzyme that can catalyze the myristoylation of over 100 proteins in human cells and influences downstream related signaling pathways. In humans, protein myristoylation is mediated by two widely expressed N-myristoyltransferases, NMT1 and NMT2. Myristoylation is a translation-coupled and post-translational modification reaction in eukaryotes, transferring a myristoyl group to the N-terminal glycine of a substrate protein via the action of NMT1 and NMT2 [Cell Death and Disease, 2018, 9(12):1143]. By functioning like a "switch," it can trigger a variety of reversible protein-cell membrane and protein-protein interactions.

[0003] NMT1 is highly expressed in various tumor tissues, and in liver cancer, NMT1 is associated with a poor prognosis, with patients with high NMT1 expression having shorter survival rates compared to patients with low expression. NMT1 expression has significant clinical implications; a study of primary breast cancer tissue and peritumoral tissue in 20 breast cancer patients showed that NMT1 expression was significantly elevated in breast cancer tissue compared to peritumoral tissue, and particularly significantly elevated in triple-negative breast cancer tissue [Cell Death and Disease, 2018, 9(12):1143]. Elevated NMT1 is associated with tumor development and relatively short survival times in patients. In patients with colorectal cancer, NMT1 is highly expressed in peripheral blood and bone marrow and can be used as a diagnostic marker for colorectal cancer [J TranslMed. 2007, 5:58]. High expression of NMT1 is associated with a poor prognosis in ovarian cancer and the progression of liver cancer and brain tumors, etc. [Annals of medicine, 2023, 55(1):1422-1430].

[0004] NMT1 catalyzes its substrate proteins to form myristoylated proteins, activating downstream signaling pathways such as NF-KB, C-Myc, and ERK, thereby promoting tumor cell proliferation, migration, and metastasis. Inhibition of NMT1 can induce cell cycle arrest, inhibit cell proliferation, and malignant growth [Annals of Medicine, 2023, 55(1):1422-1430]. NMT1 is highly expressed in various tumors and is associated with tumor staging, prognosis, and survival, making it a potential target point for oncological precision therapy. NMT inhibitors can significantly inhibit the activity of hematological malignancy cells, including B lymphocytes, inhibit myristoylation of lymphoma cells, and inhibit B cell receptor signaling, thereby inducing cell death and inhibiting tumor growth in mouse tumor models [Nature Communications, 2020, 11(1):5348].

[0005] Although several NMT small molecule inhibitors have been disclosed, the development of new compounds with better activity and pharmacokinetics is still required. The NMT inhibitor compound having the structure shown in the general formula (1) of the present invention exhibits excellent effects and actions, and provides a new option for the precise treatment of tumors.

Summary of the Invention

Problems to be Solved by the Invention

[0006] The object of the present invention is to provide a new NMT inhibitor with high activity, a method for preparing the same, and applications thereof.

Means for Solving the Problems

[0007] The first aspect of the present invention provides a compound having a structure as shown in formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof,

Chemical formula

[0008] In another preferred example, in formula (1), each R 1 These are F, Cl, Br, CN, NO2, and C, respectively, independently. 1-3 Alkyl alkyl group, C 1-3 Alkyl halogenated compounds, C 1-3 Alkoxy group or C 1-3 Selected from the group consisting of halogenated alkoxy groups.

[0009] In another preferred example, in formula (1), R 2 -NR 6 R 7 And here, R 6 and R 7 These are H, D, and C, respectively, independently. 1-6 Alkyl alkyl group, C 1-6 Selected from the group consisting of alkyl halogens.

[0010] In another preferred example, in formula (1), R3 H, D, C 1-3 Alkyl alkyl group, C 1-3 Selected from the group consisting of alkyl halogens.

[0011] In another preferred example, in formula (1), R 4 C 1-3 Alkyl alkyl group, C 1-3 Selected from the group consisting of alkyl halogens.

[0012] In another preferred example, in formula (1), R 5 , CN, C 1-6 Alkyl alkyl group, C 1-6 Halogenated alkyl groups, hydroxysubstituted C 1-6 Alkyl alkyl, cyano-substituted C 1-6 Alkyl alkyl group or -C(O)NR 8 R 9 Selected from the group consisting of, Here, R 8 and R 9 These are H, D, and C, respectively, independently. 1-3 Alkyl alkyl group, C 1-3 Selected from the group consisting of alkyl halogens.

[0013] In another preferred example, a representative compound of the present invention has a structure selected from the group consisting of the following: [ka] TIFF2026522099000004.tif230170

[0014] A second aspect of the present invention provides a pharmaceutical composition for treating, modulating and / or preventing NMT-mediated disorders, the pharmaceutical composition is (1) A compound described in the first aspect of the present invention as an active ingredient, or its isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate, and (2) comprising any pharmaceutically acceptable excipient or carrier.

[0015] A third aspect of the present invention provides uses for the compounds described in the first aspect of the present invention, their isomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical compositions described in the second aspect of the present invention, for use in the preparation of drugs for treating, modulating and / or preventing NMT-mediated diseases.

[0016] In another preferred example, the NMT-mediated disease includes infectious diseases or hyperproliferative diseases.

[0017] In another preferred example, the infectious disease includes malaria and protozoan infections such as leishmania.

[0018] In another preferred example, the infectious disease includes viral infections such as human rhinovirus and HIV.

[0019] In another preferred example, the hyperproliferative disease is selected from the group consisting of lymphoma, leukemia, brain tumor, gastric cancer, liver cancer, lung cancer, colon cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer, and prostate cancer. [Effects of the Invention]

[0020] It should be understood that, within the scope of the present invention, new or preferred technical solutions can be constructed by combining the above-described technical features of the present invention with the technical features specifically described below (e.g., in the examples). Due to space limitations, this will not be repeated here. [Modes for carrying out the invention]

[0021] The inventors, through extensive and thorough research, numerous screenings, and tests, have discovered for the first time the class of compounds represented by formula (1), and these compounds have remarkable therapeutic effects against NMT-mediated diseases. The compounds of the present invention exhibit excellent inhibitory activity against the NMT1 enzyme and simultaneously possess good cell proliferation inhibitory activity against the MV-4-11 cell line, and based on this, the present invention has been completed.

[0022] Compounds of the present invention and their synthesis The present invention provides an inhibitor targeting NMT, that is, a compound of formula (1), or each isomer, crystalline form, pharmaceutically acceptable salt (inorganic salt or organic salt), hydrate or solvate thereof. Preferably, the compound of the present invention is as described in the first aspect.

[0023] The present invention further provides a method for preparing the compound of formula (1) of the present invention. Hereinafter, the method for preparing the compound of general formula (1) of the present invention will be specifically described, but these specific methods do not limit the present invention.

[0024] On the other hand, the compounds described in this specification follow methods well-known in the art. However, the conditions of the methods such as reactants, solvents, bases, amounts of compounds used, reaction temperature, time required for the reaction, etc. are not limited to the following description. The compound of the present invention can also be easily prepared by arbitrarily combining various synthesis methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art. On the other hand, the present invention further provides a method for preparing the compound represented by the general formula (1), which is prepared using the following general reaction process 1.

[0025] General reaction process 1:

Chemical formula

[0026] Embodiments of the compound of general formula (1) can be prepared according to general reaction process 1:, where Z is halogen, Q is boric acid or borate ester, M is halogen, OMs, OTos, etc., and R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , L, W, Y and n are as defined herein.

[0027] Related Definitions Unless otherwise specified, the following terms and phrases used herein shall have the meanings set forth below. No particular term or phrase should be construed as ambiguous or unclear unless specifically defined, and should be understood according to its ordinary meaning. Where a trade name is used herein, it refers to the corresponding product or its active ingredient.

[0028] As used herein, the term “pharmaceutically acceptable” means those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation, hypersensitivity reactions or other problems or complications commensurate with a reasonable benefit-risk ratio, within the bounds of sound medical judgment.

[0029] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention prepared with a compound having a specific substituent discovered in the present invention and a relatively non-toxic acid or base. If the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. If the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic and organic acid salts, wherein the inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, and phosphorous acid, and the organic acids include acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, transbutenic acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, and further include salts of amino acids (e.g., arginine) and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain basic and acidic functional groups, thereby allowing them to be converted into either a base addition salt or an acid addition salt.

[0030] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing an acidic or basic group by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acidic or basic form with a chemically measured appropriate base or acid in water, an organic solvent, or a mixture thereof.

[0031] The compounds of the present invention may exist in the form of specific geometric isomers or stereoisomers. The present invention includes all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and their racemic compounds and other mixtures (e.g., mixtures in which enantiomers and diastereomers are concentrated), and all of these mixtures are within the scope of the present invention. Substituents such as alkyl groups may have additional chiral carbon atoms. All of these isomers and mixtures thereof are within the scope of the present invention.

[0032] Unless otherwise specified, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0033] Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" derive from the fact that the double bond or the single bond of the ring carbon atom cannot rotate freely.

[0034] Unless otherwise specified, the term "diastereomer" refers to stereoisomers in which a molecule has two or more chiral centers and there is no enantiomer relationship between the molecules.

[0035] Unless otherwise specified, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0036] TIFF2026522099000006.tif51169

[0037] Unless otherwise specified, the terms "isomer excess" or "enantiomer excess" refer to the difference in the relative proportions of two isomers or two enantiomers. For example, if one isomer or enantiomer is present at 90% and the other isomer or enantiomer is present at 10%, the isomer or enantiomer excess (ee value) is 80%.

[0038] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis, chiral reagents, or other prior art. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization containing a chiral auxiliary, where the resulting diastereomer mixture is separated and the auxiliary groups are cleaved to obtain the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl group), a diastereomer salt is formed with a suitable optically active acid or base, and the diastereomer is then divided by a conventional method known in the art and recovered to obtain the pure enantiomer. Furthermore, the separation of enantiomers and diastereomers is usually achieved using chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (e.g., forming a carbamate from an amine).

[0039] The compounds of the present invention may contain an unusual proportion of atomic isotopes in one or more atoms constituting the compound. For example, tritium ( 3 H), Iodine-125( 125 I) or C-14 ( 14 Compounds can be labeled with radioactive isotopes such as C). For example, deuterated compounds can be formed by substituting a hydrogen atom with deuterium. The bond between deuterium and carbon is stronger than the bond between hydrogen and carbon, and deuterated drugs generally have advantages over non-deuterated drugs, such as reduced toxic side effects, increased drug stability, enhanced therapeutic effects, and extended in vivo half-life. All transformations of the compounds of the present invention, whether radioactive or otherwise, are included within the scope of the present invention.

[0040] "Optional" or "at your discretion" means that the events or situations described below may occur, but are not necessarily required to occur, and such descriptions include situations in which such events or situations occur, as well as situations in which such events or situations do not occur.

[0041] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, which can include deuterium and variants of hydrogen as long as the valence of the particular atom is a normal valence and the compound after substitution is stable. When the substituent is oxygen (i.e., =O), it refers to the replacement of two hydrogen atoms. Oxygen substitution does not occur on an aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents can be arbitrary based on chemical feasibility.

[0042] If any variable (e.g., R) appears one or more times in the composition or structure of a compound, its definition is independent for each appearance. Thus, for example, if a group is substituted by 0 to 2 R's, the group can be optionally substituted by up to two R's, and R in each situation has all independent options. Further, combinations of substituents and / or their variants are only permitted in situations where such combinations result in stable compounds.

[0043] When the number of one linking group is 0, such as -(CH2)0-, the linking group is a single bond.

[0044] When one of the variables is selected from a chemical bond, it indicates that the two groups it connects are directly linked. For example, in X-L-Y, if L represents a chemical bond, it represents that the structure is actually X-Y.

[0045] Unless otherwise specified, C n-n+m or C n -C n+m includes any specific situation of from n to n + m carbon atoms. For example, C 1-12 includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 and also includes any range from n to n + m. For example, C 1-12 is C1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 and C 9-12 This includes, for example, n-membered to n+m-membered rings, and similarly, n-membered to n+m-membered rings mean that the number of atoms on the ring is from n to n+m. For example, 3-12 membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings, 10-membered rings, 11-membered rings and 12-membered rings, and also include any range from n to n+m. For example, 3-12 membered rings include 3-6 membered rings, 3-9 membered rings, 5-6 membered rings, 5-7 membered rings, 6-7 rings, 6-8 membered rings and 6-10 membered rings, etc.

[0046] Unless otherwise specified, "C 1-6 "Alkyl group" refers to a linear or branched saturated aliphatic hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups are C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-4 , C 2-6 , C 3-5 It includes C5 and C6 alkyl groups, which may be monovalent (e.g., methyl group), divalent (e.g., methylene group), or polyvalent (e.g., methine group). 1-6 Non-limiting examples of alkyl groups include methyl group, ethyl group, propyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, and various branched isomers thereof.

[0047] Unless otherwise specified, "C 1-3 "Alkyl group" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups are C 1-2 Alkyl and C 2-3 It contains alkyl groups, which may be monovalent (e.g., methyl group), divalent (e.g., methylene group), or polyvalent (e.g., methine group). C 1-3 Non-exclusive examples of alkyl groups include methyl, ethyl, propyl, n-propyl, and isopropyl groups.

[0048] Unless otherwise specified, "C 1-3 An "alkoxy group" refers to an alkyl group containing 1 to 3 carbon atoms linked to the rest of the molecule via one oxygen atom. 1-3 The alkoxy group is C 1-2 , containing C2 and C3 alkoxy groups, C 1-3 Non-exclusive examples of alkoxy groups include methoxy groups, ethoxy groups, propoxy groups, n-propoxy groups, isopropoxy groups, and the like.

[0049] "Halogen" or "halogenation" refers to fluorine, chlorine, bromine, or iodine.

[0050] The term "hydroxyl group" refers to the -OH group.

[0051] The term "cyano group" refers to -CN.

[0052] Specific pharmaceutical and medical terms The term "acceptable," as used herein, means that a prescription ingredient or active ingredient does not cause undue adverse effects on health for general therapeutic purposes.

[0053] The terms “treatment,” “procedure,” or “therapy” as used herein include alleviation, inhibition, or improvement of the symptoms or condition of a disease; inhibition of the production of complications; improvement or prevention of potential metabolic syndrome; control of the disease or inhibition of the production of symptoms such as the progression of the condition; reduction of the disease or symptoms; regression of the disease or symptoms; reduction of complications caused by the disease or symptoms; or prevention or treatment of symptoms caused by the disease or symptoms. As used herein, a compound or pharmaceutical composition may, after administration, improve a disease, symptom, or condition, in particular, improve its severity, delay its onset, delay the progression of the disease, or reduce the duration of the disease. Whether the administration is fixed or temporary, continuous or intermittent, these conditions may be caused by or related to the administration.

[0054] The term "active ingredient" refers to the compound represented by general formula (1), and pharmaceutically acceptable inorganic or organic salts of the compound of formula (1). The compounds of the present invention may contain one or more chiral centers (axial chirality) and may appear in the form of racemates, racemic compounds, single enantiomers, diastereomer compounds, and single diastereomers. The presence of chiral centers may depend on the properties of various substituents on the molecule. Each such chiral center independently produces two optical isomers, and all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds, are within the scope of the present invention. The present invention is intended to include all such isomeric forms of these compounds.

[0055] The terms "compound," "composition," "agent," or "medicine or medicament" are interchangeable herein and refer to compounds or compositions that, when administered to an organism (human or animal), induce a desired pharmaceutical and / or physiological response via local and / or systemic effects.

[0056] The term "administered, administering, or administration" as used herein refers to the direct administration of a compound or composition, or the administration of a prodrug, derivative, or analog of an active compound.

[0057] The numerical ranges and parameters used to define the broader scope of the present invention are approximate values, and the relevant numerical values ​​in specific examples are presented herein as accurately as possible. However, any numerical value inevitably includes a standard deviation due to individual test methods. Here, “approximately” usually means that the actual numerical value is within ±10%, 5%, 1%, or 0.5% of a particular numerical value or range. Alternatively, the term “approximately” means that the actual numerical value is within the acceptable standard error of the mean value determined by those skilled in the art. Unless added to experimental examples or otherwise specifically indicated, all ranges, numbers, numerical values ​​and percentages used herein (e.g., amounts of material, durations of time, temperatures, operating conditions, ratios of numbers, and other similar terms) shall be understood to be modified by the word “approximately.” Accordingly, unless otherwise specifically indicated, all numerical parameters disclosed herein and in the appended claims are approximate values ​​and may be modified as necessary. At a minimum, these numerical parameters should be understood as numerical values ​​obtained by the indicated number of significant figures and common rounding rules.

[0058] Unless otherwise defined herein, scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art. Furthermore, unless otherwise noted, singular terms used herein include the plural form of the noun, and plural nouns used include the singular form of the noun.

[0059] Route of administration The compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various formulations, which include the compounds of the present invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers within a safe and effective dose range. Here, "safe and effective dose" refers to an amount of the compound sufficient to clearly improve the condition without causing serious side effects. The safe and effective dose of the compound is determined based on specific circumstances such as the age of the patient, the condition of the disease, and the duration of treatment.

[0060] "Pharmacologically acceptable excipients or carriers" means one or more compatible solid or liquid fillers or gels that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" means that each component of the composition can be blended with each other in relation to the compounds of the present invention and among them without significantly reducing the potency of the compounds. Some examples of pharmacochemically acceptable excipients or carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0061] When administering the compound of the present invention, it can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), or topically.

[0062] 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 inactive excipient (or vector), such as sodium citrate or dicalcium phosphate, or (a) fillers or compatibilizers such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants such as glycerin; (d) agar, calcium carbonate, potato tempura It is mixed with components such as (e) potato starch or tapioca starch, tapioca starch, alginic acid, certain complex silicates, and disintegrants such as sodium carbonate, (e) retarders such as paraffin, (f) absorption enhancers such as quaternary amine compounds, (g) wetting agents such as cetyl alcohol and glyceryl monostearate, (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also include a buffer.

[0063] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coating 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 compound from such compositions can be delayed in specific parts of the digestive tract. Examples of usable embedding components are polymers and waxes. If necessary, the active compound can form microcapsules with one or more of the above excipients.

[0064] 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 inert diluents conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, sesame oil, and sesame oil, or mixtures thereof.

[0065] In addition to these inert diluents, the composition may also include auxiliary agents such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0066] In addition to the active compound, the suspension may include suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures thereof.

[0067] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous vectors, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0068] Dosage forms of the compounds of the present invention used for topical administration include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable vector and any preservatives, buffers, or propellants as needed.

[0069] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0070] When the pharmaceutical composition is used, the compound of the present invention is applied to mammals (e.g., humans) in need of treatment, where the dose at the time of administration is the effective dose to be considered, and for a person weighing 60 kg, the daily dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dose must also take into account factors such as the route of administration and the patient's health condition, all of which are within the scope of the skills of a skilled physician.

[0071] The main advantages of the present invention are as follows: (a) Unexpectedly, the compound of formula (1) in the present invention exhibits excellent in vitro activity, including NMT1 enzyme inhibitory activity and MV-4-11 cell antiproliferative activity, making it more suitable for development as a drug. (b) The compounds of the present invention have excellent drug discovery potential.

[0072] The features referred to in the present invention or the features referred to in the examples can be combined in any way. All features disclosed herein can be used in any form of composition, and each feature disclosed herein can be replaced by any alternative feature that serves the same, equivalent, or similar purpose. Accordingly, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0073] The following description provides a detailed explanation of various specific embodiments, properties, and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions, in order to provide a better understanding of the present invention. Note that the following detailed description and examples illustrate specific examples and are for illustrative purposes only. After reading the description of the present invention, those skilled in the art can make various modifications or changes to the invention, and these equivalents are still limited to the scope of this application.

[0074] The structure of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art, and if the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by the prior art in the art. For example, single-crystal X-ray diffraction (SXRD) can be used to collect diffraction intensity data from single crystals cultured using a Bruker D8 venture diffractometer, with the light source being CuKα rays and the scanning mode being φ / ω scanning. After collecting the relevant data, the crystal structure can be further analyzed using a direct method (Shelxs97) to confirm the absolute configuration.

[0075] The solvents used in this invention are commercially available. The compounds are nominally defined according to the conventional nomenclature in the art or ChemDraw.

[0076] Compounds are named according to the software, and commercially available compounds are named according to the supplier's catalog name.

[0077] In all embodiments, 1 ¹H-NMR was recorded using a Varian Mercury 400 NMR spectrometer, chemical shifts are expressed in δ (ppm), separation silica gel is 200-300 mesh unless otherwise specified, and eluate ratios are all expressed by volume.

[0078] In this invention, the following abbreviations are used: (Boc)2O represents di-tert-butyl dicarbonate, CAN(CH3CN) represents acetonitrile, °C represents Celsius temperature, Cs2CO3 represents cesium carbonate, CD3OD represents deuterated methanol, EA(siRNA) represents ethyl acetate, DCM represents dichloromethane, DIEA(DIPEA) represents diisopropylethylamine, Dioxane represents 1,4-dioxane, DMF represents N,N-dimethylformamide, h represents time, HATU represents 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, H2O2 represents hydrogen peroxide, K2CO3 represents potassium carbonate, and K3PO4 represents potassium phosphate. LC-MS represents liquid chromatography-mass spectrometry, LiAlH4 represents lithium aluminum hydride, MS represents mass spectrometry, MsCl represents methanesulfonyl chloride, NaBH3CN represents sodium borohydride cyanohydride, NaHCO3 represents sodium bicarbonate, NaOH represents sodium hydroxide, NIS represents N-iodosuccinimide, NMR represents nuclear magnetic resonance, Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium, Pd(dppf)2Cl2 represents dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium, PE represents petroleum ether, POCl3 represents phosphorus oxychloride, and TEA represents triethylamine.

[0079] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are used solely for illustrative purposes and do not limit the scope of the invention. In the following embodiments, experimental methods that do not specify conditions are generally carried out under conventional conditions or conditions proposed by the manufacturer. Unless otherwise specified, percentages and parts are calculated as weight percentages and weight parts, respectively.

[0080] Preparation Example 1: Synthesis of 1,5-dimethyl-4-(2-(methanesulfonyl)oxy)ethyl)-1H-pyrazole-3-carboxylate ethyl (intermediate 1) [ka]

[0081] Step 1: Synthesis of Intermediate 1-1 1,5-dimethyl-1H-pyrazole-3-carboxylate ethyl (5g, 29.73 mmol) is dissolved in acetonitrile (100 mL), NIS (7.36 g, 32.70 mmol) is added, and the reaction is carried out with stirring at 50°C, while monitoring the completeness of the starting materials by LC-MS. Acetonitrile is removed by direct concentration, the mixture is poured into water (100 mL), extracted with EA (50 mL x 3), the organic phase is combined, dried, concentrated, and obtained by column chromatography (PE / EA = 20 / 1 to 5 / 1) to obtain a yellow solid intermediate 1-1 (8.21 g, yield 94%), ESI-MS m / z: 294.9 [M+H]. + .

[0082] Step 2: Synthesis of Intermediate 1-2 Intermediate 1-1 (8.21 g, 27.93 mmol) and potassium vinyltrifluoroborate (4.11 g, 30.72 mmol) are dissolved in dioxane / water (100 / 10 mL). Pd(dppf)Cl2 (2.04 g, 2.79 mmol) and K3PO4 (11.86 g, 55.86 mmol) are added, and the reaction is carried out with stirring at 90°C, while monitoring the completeness of the starting materials by LC-MS. Dioxane is removed by direct concentration, then poured into water (100 mL), extracted with EA (50 mL x 3), the organic phase is combined, dried, concentrated, and obtained by column chromatography (PE / EA = 10 / 1 to 5 / 1) to obtain intermediate 1-2 (4.86 g, yield 90%) as a white solid. ESI-MS m / z: 195.0 [M+H] + .

[0083] Stage 3: Synthesis of Intermediates 1-3 Intermediate 1-2 (4.86 g, 25.05 mmol) is dissolved in THF (50 mL), and BH3.THF (1 M, 25.05 mL) is slowly added at 0°C. The mixture is reacted with stirring at 0°C for 3 hours, then 30% sodium bicarbonate aqueous solution (20 mL) and hydrogen peroxide (30%, 20 mL) are added. The mixture is reacted with stirring at 0°C, and the complete completion of the starting material is monitored by LC-MS. The mixture is poured into water (100 mL), extracted with EA (50 mL x 3), the organic phase is combined, dried, concentrated, and obtained by column chromatography (PE / EA = 5 / 1 to 1 / 1) to obtain intermediate 1-3 (1.26 g, yield 24%) as a white solid. ESI-MS m / z: 213.0 [M+H] + .

[0084] Step 4: Synthesis of Intermediate 1 Dissolve 1-3 (1.26 g, 5.94 mmol) and TEA (1.20 g, 11.89 mmol) in DCM (30 mL), and under argon gas protection, add MsCl (748 mg, 6.53 mmol) while stirring at 0°C. After addition is complete, react at room temperature while stirring, and monitor for complete completion of the starting materials by LC-MS. Pour into water (50 mL), extract with DCM (30 mL x 3), combine the organic phase, dry, concentrate, and obtain intermediate 1 (1.59 g, yield 92%) as a yellow solid by column chromatography (PE / EA = 10 / 1 to 2 / 1). ESI-MS m / z: 291.0 [M+H] + .

[0085] Intermediates 2-4 can be obtained using the same synthesis method as in Preparation Example 1. [Table A]

[0086] Preparation Example 2: Synthesis of 4-(chloromethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate ethyl (intermediate 5) [ka]

[0087] Step 1: Synthesis of Intermediate 5 1,5-dimethyl-1H-pyrazole-3-carboxylate ethyl (2g, 11.90 mmol) and paraformaldehyde (714 mg, 23.81 mmol) are dissolved in 1,4-dioxane (30 mL). Hydrochloric acid (12 M, 2 mL) and H2SO4 (119 mg, 1.19 mmol, 98%) are added, and the mixture is reacted with stirring at 100°C. The complete reaction of the starting materials is monitored by LC-MS. 1,4-dioxane is removed by direct concentration, the mixture is poured into water (100 mL), extracted with EA (50 mL x 3), the organic phase is combined, dried, and concentrated to obtain intermediate 5 (8.21 g, yield 94%), a yellow solid. ESI-MS m / z: 217.0 [M+H] + .

[0088] Preparation Example 3: Synthesis of ethyl 2-(3-isopropyl-1,5-dimethyl-1H-pyrazole-4-yl)methanesulfonate (intermediate 6) [ka]

[0089] Step 1: Synthesis of Intermediate 6-1 Methyltriphenylphosphine bromide (6.21 g, 17.39 mmol) is dissolved in THF (50 mL), potassium tert-butoxide (1.95 g, 17.39 mmol) is added at room temperature, and the mixture is reacted with stirring for 10 minutes. Then, a solution of 1-(1,5-dimethyl-1H-pyrazole-3-yl)ethyl-1-one (2 g, 14.49 mmol) in THF (10 mL) is added, and the mixture is reacted with stirring at room temperature, while monitoring for complete completion of the starting material by LC-MS. The mixture is poured into water (100 mL), extracted with EA (50 mL x 3), the organic phase is combined, dried, concentrated, and obtained by column chromatography (PE / EA = 20 / 1 to 5 / 1) to obtain a yellow solid intermediate 6-1 (1.54 g, yield 78%). ESI-MS m / z: 137.0 [M+H] + .

[0090] Step 2: Synthesis of Intermediate 6-2 Intermediate 6-1 (1.54 g, 11.32 mmol) is dissolved in methanol (50 mL), Pd / C (150 mg, 10%) is added, the mixture is purged with hydrogen gas, and the reaction is carried out at room temperature with stirring, while monitoring the complete completion of the starting material by LC-MS. The mixture is then filtered by direct suction and concentrated to obtain intermediate 6-2 (1.48 g, 95% yield) as a white solid, with ESI-MS m / z: 139.0 [M+H]. + .

[0091] Intermediate 6 can be obtained in the subsequent steps using the same synthesis method as in Preparation Example 1. [Table B]

[0092] Preparation Example 4: Synthesis of ethyl 2-(3-fluoromethyl-1,5-dimethyl-1H-pyrazole-4-yl)methanesulfonate (intermediate 7) [ka]

[0093] Step 1: Synthesis of Intermediate 7-1 Dissolve 1,5-dimethyl-1H-pyrazole-3-methanol (2g, 15.87 mmol) in DCM (60 mL), add DAST (3.84 g, 23.81 mmol) at room temperature, and react with stirring at room temperature, monitoring for complete completion of the starting material by LC-MS. Pour into water (100 mL), extract with DCM (50 mL x 3), combine the organic phases, dry, concentrate, and obtain intermediate 7-1 (1.65 g, yield 82%) as a yellow solid by column chromatography (PE / EA = 20 / 1~5 / 1). ESI-MS m / z: 129.0 [M+H] + .

[0094] In the subsequent steps, intermediate 7 can be obtained using the same synthesis method as in Preparation Example 1. [Table C]

[0095] Preparation Example 5: Synthesis of ethyl 2-(3-cyanomethyl-1,5-dimethyl-1H-pyrazole-4-yl)methanesulfonate (intermediate 8) [ka]

[0096] Step 1: Synthesis of Intermediate 8-1 Dissolve 1,5-dimethyl-1H-pyrazole-3-methanol (2 g, 15.87 mmol) in DCM (60 mL), add thionyl chloride (3.78 g, 31.74 mmol) at room temperature, and react with stirring at room temperature, monitoring for complete completion of the starting materials by LC-MS. Direct concentration yields a yellow solid intermediate 8-1 (2.41 g, yield over 100%), with ESI-MS m / z: 145.0 [M+H]. + .

[0097] Step 2: Synthesis of Intermediate 8-2 Intermediate 8-1 (2.41 g, 15.87 mmol) was dissolved in ACN (60 mL), and TMSCN (3.15 g, 31.74 mmol) and TBAF (8.30 g, 31.74 mmol) were added at room temperature. The reaction was carried out with stirring at 60°C, and the complete completion of the starting materials was monitored by LC-MS. Subsequently, the mixture was poured into water (100 mL), extracted with EA (50 mL x 3), the organic phase was combined, dried, concentrated, and obtained by column chromatography (PE / EA = 10 / 1 to 5 / 1) to obtain intermediate 8-2 (1.36 g, yield 63%) as a yellow solid. ESI-MS m / z: 136.0 [M+H] + .

[0098] Intermediate 8 can be obtained in the subsequent steps using the same synthesis method as in Preparation Example 1. [Table D]

[0099] Example 1: Synthesis of 4-(2-(5-chloro-2-(3-((dimethylamino)methyl)pyrazolo[1,5-a]pyridine-5-yl)phenoxy)ethyl)-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide (Compound 1) [ka]

[0100] Stage 1: 1-1 synthesis Dissolve 5-bromopyrazolo[1,5-A]pyridine (1 g, 5.08 mmol) in DMF (20 mL), slowly add POCl3 (2.33 g, 15.2 mmol) at 0°C, and after addition is complete, react at room temperature with stirring, monitoring for complete completion of the starting material by LC-MS. Pour into water (30 mL), adjust pH to 10 with 1 M NaOH, extract with EA (30 mL x 3), combine the organic phases, dry, and concentrate to obtain a white solid 1-1 (965 mg, yield 77%), ESI-MS m / z: 224.9 [M+H]. + .

[0101] Stage 2: Synthesis of 1-2 Dissolve 1-1 (200 mg, 0.89 mmol) and 4-chloro-2-hydroxyphenylboronic acid (230 mg, 1.33 mmol) in Dioxane / water (10 / 2 mL), add Pd2(dba)3 (81.4 mg, 0.089 mmol), (Boc)2O (582 mg, 2.67 mmol), and K2CO3 (368 mg, 2.67 mmol), and react with stirring at 100°C, monitoring for complete reaction of the starting materials by LC-MS. Add water (30 mL), extract with EA (30 mL x 3), combine the organic phases, dry, concentrate, and obtain a yellow solid 1-2 (211 mg, yield 87%) by column chromatography (PE / EA = 10 / 1 to 3 / 1). ESI-MS m / z: 272.9 [M+H] + .

[0102] Stage 3: Synthesis of 1-3 Dissolve 1-2 (100 mg, 0.37 mmol) in acetonitrile (10 mL), add intermediate 1 (178 mg, 0.61 mmol) and Cs2CO3 (597 mg, 1.83 mmol), and react with stirring at 80°C, monitoring complete reaction by LC-MS. Add water (30 mL), extract with EA (30 mL x 3), combine the organic phases, dry, concentrate, and obtain yellow solid 2-3 (110 mg, yield 77%) by column chromatography (PE / EA = 20 / 1~2 / 1). ESI-MS m / z: 467.1 [M+H] + .

[0103] Stage 4: Synthesis of 1-4 Dissolve 1-3 (100 mg, 214 μmol) in THF / water (5 / 0.5 mL), add NaOH (12.9 mg, 321 μmol), and react at room temperature with stirring, monitoring complete reaction by LC-MS. Pour into water (30 mL), adjust pH to 5-6 with 1 M hydrochloric acid, extract with EA (30 mL x 3), combine the organic phases, dry, and concentrate to obtain a yellow solid 1-4 (40 mg, crude), ESI-MS m / z: 439.0 [M+H]. + .

[0104] Stage 5: Synthesis of 1-5 Dissolve 1-4 (40 mg, 91.1 μmol) in DMF (3 mL), and sequentially add dimethylamine hydrochloride (14.9 mg, 182 μmol), DIEA (58.9 mg, 456 μmol), and HATU (41.6 mg, 109 μmol). React at room temperature with stirring, and monitor for complete completion of the starting materials by LC-MS. Pour into water (20 mL), extract with EA (10 mL x 3), combine the organic phases, dry, and concentrate to obtain a yellow solid 1-5 (47 mg, crude), ESI-MS m / z: 465.1 [M+H]. + .

[0105] Stage 6:1 synthesis Dissolve 1-5 (47.0 mg, 101 μmol) in DCM (5 mL), add TEA (30.6 mg, 303 μmol), NaBH3CN (7.61 mg, 121 μmol), and dimethylamine hydrochloride (24.7 mg, 303 μmol), and react with stirring at room temperature, monitoring for complete completion of the starting materials by LC-MS. Pour into water (20 mL), extract with EA (20 mL x 3), combine the organic phases, dry, concentrate, and prepare to obtain yellow solid 1 (14 mg, yield 28%).

[0106] 1 H NMR(400MHz,CD3OD):δ 8.61(d,J=7.25Hz,1H),8.19(s,1H),7.92-7.95(m,1H),7.44(d,J=8.13Hz,1H),7.17-7.21(m,1H),7.10(br d,J=1.88Hz,2H),4.55-4.61(m,2H),4.20(t,J=6.69Hz,2H),3.68-3.71(m, 3H),2.97-3.07(m,6H),2.93-2.97(m,2H),2.92(s,6H),2.05(s,3H);ESI-MS m / z:495.1[M+H] + .

[0107] Example 2-27: Synthesis of compounds 2-11 and 13-28 The target compounds 2-11 and 13-28 can be obtained using the same synthesis method as in Example 1. [Table E] TIFF2026522099000018.tif226169TIFF2026522099000019.tif229170TIFF2026522099000020.tif207170TIFF2026522099000021.tif213170 TIFF2026522099000022.tif229170TIFF2026522099000023.tif231170TIFF2026522099000024.tif225170TIFF2026522099000025.tif151170

[0108] Example 28: Synthesis of (4-(2-(5-chloro-2-(3-((dimethylamino)methyl)pyrazolo[1,5-a]pyridine-5-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-yl)methanol (Compound 12) [ka]

[0109] Stage 1: Synthesis of 12-1 Dissolve 1-3 (200 mg, 0.43 mmol) in DCM (10 mL), add TEA (130 mg, 1.29 mmol), NaBH3CN (81 mg, 1.29 mmol), and dimethylamine hydrochloride (105 mg, 1.29 mmol), and react at room temperature with stirring, monitoring for complete completion of the starting materials by LC-MS. Pour into water (20 mL), extract with EA (20 mL x 3), combine the organic phases, dry, and concentrate to obtain a yellow solid 12-1 (220 mg, crude), ESI-MS m / z: 496.1 [M+H]. + .

[0110] Stage 2: 12 synthesis Dissolve 12-1 (220 mg, 0.43 mmol) in THF (10 mL), add LiAlH4 (33 mg, 0.86 mmol), and react at room temperature with stirring, monitoring the completeness of the starting material by LC-MS. Quench with saturated ammonium chloride aqueous solution, extract with EA (20 mL x 3), combine the organic phase, dry, concentrate, and prepare to obtain yellow solid 12 (84 mg, yield 43%).

[0111] 1H NMR(400MHz,CD3OD):δ 8.64(d,J=7.22Hz,1H),8.16(s,1H),7.92-7.97(m,1H),7.41(d,J=8.11Hz,1H),7.22(m,1H),7.12(br ESI-MS m / z:454.1[M+H] + .

[0112] Example 29: Synthesis of 2-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)pyrazolo[1,5-a]pyridine-5-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-yl)prop-2-ol (Compound 29) [ka]

[0113] Stage 1: Synthesis of 29-1 Dissolve 1-1 (500 mg, 2.22 mmol) and 3,4-difluoro-2-methoxyphenylboronic acid (418 mg, 2.22 mmol) in dioxane / water (30 mL / 3 mL), add Pd2(dba)3 (204 mg, 0.22 mmol) and K2CO3 (613 mg, 4.44 mmol), and react with stirring at 100°C, monitoring for complete completion of the starting materials by LC-MS. Add water (30 mL), extract with EA (30 mL x 3), combine the organic phases, dry, concentrate, and obtain a yellow solid 29-1 (420 mg, yield 66%) by column chromatography (PE / EA = 10 / 1 to 2 / 1). ESI-MS m / z: 288.9 [M+H] + .

[0114] Stage 2: Synthesis of 29-2 Dissolve 29-1 (420 mg, 1.46 mmol) in DCM (30 mL), add BBr3 (366 mg, 4.37 mmol) at room temperature, and react with stirring at room temperature, monitoring the completeness of the starting material by LC-MS. Slowly add water (30 mL) to quench, neutralize to a weak basic state with saturated NaHCO3, extract with EA (30 mL x 3), combine the organic phase, dry, concentrate, and obtain a yellow solid 29-2 (290 mg, yield 73%) by column chromatography (PE / EA = 5 / 1 to 1 / 1), with ESI-MS m / z: 274.9 [M+H]. + .

[0115] Stage 3: Synthesis of 29-3 Dissolve 29-2 (290 mg, 1.06 mmol) in DCM (20 mL), add TEA (321 mg, 3.18 mmol), AcOH (64 mg, 1.06 mmol), methylamine hydrochloride (143 mg, 2.12 mmol), and NaBH3CN (333 mg, 5.30 mmol), and react with stirring at room temperature, monitoring complete reaction by LC-MS. Then add Boc2O (462 mg, 2.12 mmol), react with stirring at room temperature, and monitor complete reaction by LC-MS. Pour into water (30 mL), extract with DCM (20 mL x 3), combine the organic phase, dry, concentrate, and obtain a yellow solid 29-3 (310 mg, yield 75%) by column chromatography (PE / EA = 5 / 1 to 1 / 1). ESI-MS m / z: 390.1 [M+H] + .

[0116] Stage 4: Synthesis of 29-4 Dissolve 29-3 (310 mg, 0.80 mmol) in DMF (30 mL), add intermediate 1 (279 mg, 0.96 mmol) and Cs2CO3 (521 mg, 1.60 mmol), and react with stirring at 100°C, monitoring for complete completion of the starting materials by LC-MS. Add water (30 mL), extract with EA (30 mL x 3), combine the organic phases, dry, concentrate, and obtain a yellow solid 29-4 (260 mg, yield 56%) by column chromatography (PE / EA = 20 / 1~3 / 1). ESI-MS m / z: 584.2 [M+H] + .

[0117] Stage 5: Synthesis of 29-5 Dissolve 29-4 (260 mg, 0.45 mmol) in THF (20 mL), add methylmagnesium bromide (1 M, 1.35 mL, 1.35 mmol) at -78°C, then slowly raise the temperature to room temperature and react with stirring, monitoring the completeness of the starting material by LC-MS. Pour into water (30 mL), extract with EA (20 mL x 3), combine the organic phase, dry, concentrate, and obtain a yellow solid 29-5 (130 mg, 51%) by column chromatography (PE / EA = 5 / 1 to 1 / 1). ESI-MS m / z: 570.2 [M+H] + .

[0118] Stage 6:29 Synthesis Dissolve 29-5 (130 mg, 0.23 mmol) in DCM (10 mL), add HCl / Dioxane (4 M, 1 mL), and react at room temperature with stirring, monitoring for complete completion of the starting material by LC-MS. Concentrate directly and prepare to obtain a yellow solid 29 (60 mg, yield 56%).

[0119] 1H NMR(400MHz,DMSO-d6):δ 8.66(d,J=7.8Hz,1H),8.18(s,1H),8.03(s,1H),7.41-7.29(m,2H),7.09(dd,J=7.2,1.8Hz,1H),4.69(s,1H),4. 34(s,2H),4.00(t,J=7.8Hz,2H),3.51(s,3H),2.88-2.82(m,2H),2.55(s,3H),1.86(s,3H),1.29(s,6H);ESI-MS m / z:470.1[M+H] + .

[0120] Example 30: Synthesis of Compound 33 The target compound 33 can be obtained using the same synthesis method as in Example 29. [Table F]

[0121] Example 31: Synthesis of 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)pyrazolo[1,5-a]pyridine-5-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-yl)-2,2-dimethylpropan-1-ol (Compound 30) [ka]

[0122] Stage 1:30-1 synthesis Dissolve 29-4 (200 mg, 0.34 mmol) in THF / water (10 / 1 mL), add NaOH (27 mg, 0.69 mmol), and react at room temperature with stirring, monitoring the completeness of the starting material by LC-MS. Pour into water (30 mL), adjust pH to 5-6 with 1 M hydrochloric acid, extract with EA (30 mL x 3), combine the organic phase, dry, and concentrate to obtain a yellow solid 30-1 (170 mg, 90%), ESI-MS m / z: 556.1 [M+H]. + .

[0123] Stage 2: Synthesis of 30-2 Dissolve 30-1 (170 mg, 0.31 mmol) in DMF (10 mL), and sequentially add N,O-dimethylhydroxylamine hydrochloride (45 mg, 0.47 mmol), DIEA (80 mg, 0.62 mmol), and HATU (179 mg, 0.47 mmol). React with stirring at room temperature, and monitor for complete completion of the starting materials by LC-MS. Pour into water (30 mL), extract with EA (20 mL x 3), combine the organic phases, dry, concentrate, and obtain a yellow solid 30-2 (160 mg, 86%) by column chromatography (PE / EA = 5 / 1 to 1 / 1). ESI-MS m / z: 599.2 [M+H] + .

[0124] Stage 3:30-3 synthesis Dissolve 30-2 (160 mg, 0.27 mmol) in THF (20 mL), add t-BuLi (1.3 M, 0.25 mL, 0.32 mmol) at -50°C, then slowly raise the temperature to room temperature and react with stirring, monitoring the completeness of the starting material by LC-MS. Pour into water (30 mL), extract with EA (20 mL x 3), combine the organic phase, dry, concentrate, and obtain a yellow solid 30-3 (70 mg, 44%) by column chromatography (PE / EA = 5 / 1 to 0 / 1). ESI-MS m / z: 598.2 [M+H] + .

[0125] Stage 4:30 synthesis Dissolve 30-3 (70 mg, 0.12 mmol) in DCM (10 mL), add HCl / Dioxane (4 M, 1 mL), and react at room temperature with stirring, monitoring complete completion of the starting material by LC-MS. Concentrate directly and prepare to obtain yellow solid 30 (32 mg, yield 53%).

[0126] 1H NMR(400MHz,DMSO-d6):δ 8.65(d,J=7.3Hz,1H),8.30(s,1H),8.07(s,1H),7.90(s,1H),7.37-7.30(m,2H),7.03(dd,J=7.2,1.8Hz,1H),4.10(d,J=7.9H) ESI-MS m / z:498.1[M+H] + .

[0127] Example 32: Synthesis of Compound 34 The target compound 34 can be obtained using the same synthesis method as in Example 30. [Table G]

[0128] Example 33: Synthesis of 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)pyrazolo[1,5-a]pyridine-5-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-yl)ethane-1-ol (Compound 31) [ka]

[0129] Stage 1: Synthesis of 31-1 Dissolve 30-2 (200 mg, 0.33 mmol) in THF (20 mL), add methylmagnesium bromide (1 M, 0.40 mL, 0.40 mmol) at -78°C, then slowly raise the temperature to room temperature and react with stirring, monitoring the completeness of the starting material by LC-MS. Pour into water (30 mL), extract with EA (20 mL x 3), combine the organic phase, dry, concentrate, and obtain a yellow solid 31-1 (110 mg, 59%) by column chromatography (PE / EA = 5 / 1 to 1 / 1), with ESI-MS m / z: 554.2 [M+H]. + .

[0130] Stage 2: Synthesis of 31-2 Dissolve 31-1 (110 mg, 0.20 mmol) in methanol (10 mL), add NaBH4 (11 mg, 0.30 mmol) at room temperature, and react with stirring at room temperature, monitoring the completeness of the starting material by LC-MS. Pour into water (30 mL), extract with EA (20 mL x 3), combine the organic phase, dry, concentrate, and obtain a yellow solid 31-2 (85 mg, 77%) by column chromatography (PE / EA = 5 / 1 to 0 / 1). ESI-MS m / z: 556.2 [M+H] + .

[0131] Stage 3:31 synthesis Dissolve 31-2 (85 mg, 0.15 mmol) in DCM (10 mL), add HCl / Dioxane (4 M, 1 mL), and react at room temperature with stirring, monitoring complete completion of the starting material by LC-MS. Direct concentration and preparation yield yellow solid 31 (22 mg, yield 33%).

[0132] 1 H NMR(400MHz,DMSO-d6):δ 8.61(d,J=7.7Hz,1H),8.19(s,1H),8.05(s,1H),7.41-7.26(m,2H),7.11(m,1H),4.66(s,1H),4.31(s,2H),4.0 1(t,J=7.8Hz,2H),3.81(m,1H),3.52(s,3H),2.88-2.80(m,2H),2.57(s,3H),1.88(s,3H),1.25(s,3H);ESI-MS m / z:446.1[M+H] + .

[0133] Examples 34-36: Synthesis of compounds 32, 35, and 36 Target compounds 32, 35, and 36 can be obtained using the same synthesis method as in Example 31. [Table H]

[0134] Example 37: Screening for NMT1 enzyme catalytic inhibitory activity This study evaluates the ability of the compound of the present invention to inhibit NMT1 catalytic activity in vitro. The experiment characterizes the NMT1 inhibitor under 1.25 μM myristoyCoA (lithium myristoyl coenzyme A salt, sigma, M4414) using FI fluorescence intensity analysis. In this experiment, the polypeptide HSPP60SRC (Nanjing Peptide Co., Ltd., NJP23953) with the sequence H-Gly-Ser-Asn-Lys-Ser-Lys-Pro-Lys-NH2 is synthesized as the reaction substrate. The final concentration of NMT1 enzyme is 6 nM, the final concentration of CPM (reactive thiol fluorescent probe, invitrogen, D346) is 1 μM, the final concentration of HSPP60 SRC is 20 μM, and the final concentration of DMSO is 0.5%.

[0135] The compound is dissolved in DMSO to obtain a 10 mM stock solution. A dose gradient reaction solution is prepared to an endpoint compound concentration of 3 mM, and then diluted threefold with DMSO to obtain a total of 10 data points. Using an ECHO ultrasonic pipetting system (BECKMAN, ECHO 655 system), 0.05 μL of the diluted compound solution is transferred to a 384-well analysis plate (Corning, CLS4514), 2.5 μL of NMT1 enzyme working solution is added to the 384-well analysis plate, and incubated at 25°C for 10 minutes. Then 5 μL of CPM and myristoy COA working solution is added, and the mixture is centrifuged at 1000 rpm for 1 minute. Subsequently, 2.5 μL of HSPP60 SRC working solution is added to allow the reaction to proceed, and the reaction is incubated at 25°C for 45 minutes. The FI signal (em: 320 nm, ex: 405 nm) is detected using the HTS high-throughput drug screening multifunctional microplate reader (BMG, PHERA star FSX).

[0136] The inhibition rate of compounds against NMT1 enzyme catalytic activity was calculated using the following formula: Inhibition rate (%) = 100 × (Average value of DMSO group - Average value of compound) / (Average value of DMSO group - Average value of blank control group). Furthermore, the IC of compounds was calculated based on a nonlinear regression equation using the software XLfit 5.5.0. 50 The curve is fitted. Table 1 shows the inhibitory activity of the compounds of the present invention against the NMT1 enzyme catalyst.

[0137] Example 38: Screening of compounds for MV-4-11 cell antiproliferative activity This study analyzes the cytotoxicity of MV-4-11 human myeloid monocytic leukemia cells after 3 days of treatment with an NMT1 inhibitor using cell proliferation experiments. The MV-4-11 cell line was purchased from Nanjing CoBioer Biotechnology Co., Ltd. and cultured in IMDM medium (Viva cell) in a cell incubator (Thermo) at 37°C with 5% carbon dioxide. In this experiment, the NMT1 inhibitor was dissolved in DMSO to obtain a 600 μM stock solution. A dose gradient reaction solution was prepared until the endpoint compound concentration reached 3 μM, and then diluted threefold with DMSO to obtain a total of eight data points. The final concentration of DMSO was 0.5%.

[0138] Seed MV-4-11 cells in a white 96-well plate and prepared an 80 μL cell suspension containing 6000 MV-4-11 cells per well. The cell plate was incubated overnight in a carbon dioxide incubator, then 20 μL of different concentrations of NMT1 inhibitor solution were added to each well plate, and the 96-well plate was incubated for 3 days. Another cell plate was prepared, and the signal value on the day of drug addition was read as the maximum value (Max value in the following formula), and the data was analyzed. 25 μL of cell viability chemiluminescence detection reagent was added to each well of this cell plate and incubated at room temperature for 10 minutes to stabilize the luminescence signal. The readings were obtained using a multi-label analyzer.

[0139] The raw data is converted to an inhibition rate using the formula (Sample-Min) / (Max-Min)×100%, and the IC 50 The values ​​are obtained by curve fitting using four parameters (obtained using the "log(inhibitor) vs.response - Variable slope" mode in GraphPad Prism). Min: 0.5% DMSO-treated cell wells, Max: Day 0 wells. Table 1 shows the inhibitory activity of the compounds of the present invention against MV-4-11 cell proliferation. [Table 1]

[0140] As can be seen from the data in the table above, the compounds of the present invention have very strong inhibitory activity against NMT1 enzyme catalysts, and at the same time, the compounds also have very strong antiproliferative activity against MV-4-11 cells. In particular, compounds 21, 27, 29, 30, 31, 32, 34 and 36 have very strong inhibitory activity against NMT1 enzyme catalysts and very strong antiproliferative activity against MV-4-11 cells, and the inhibitory activity against NMT1 enzyme catalysts IC 50 It is less than 2 nM and has antiproliferative activity against MV-4-11 cells IC 50 It is less than 10 nM.

[0141] All documents referenced in this invention are cited as references in this application, as if each document were cited individually. Furthermore, after reading the above teachings of this invention, persons skilled in the art can make various changes or modifications to the invention, and these equivalent forms are also included within the scope defined by the claims appended to this application.

Claims

1. A compound whose structure is shown in formula (1), or its isomer, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate, 【Chemistry 14】 In equation (1), n is 0, 1, 2, or 3. X １ and X ２ CH and CR are independent of each other. １ Or selected from the group consisting of N, W is selected from the group consisting of a chemical bond, O, S, or NH. Y is selected from the group consisting of a chemical bond, -(CH ２ ), -(CH ｍ－ ), -(CH ２ ), -(CH ｍ ), -(CH ２ ), -(CH ｍ ), -(CH ２ ), -(CH ｍ ), where m is selected from 1, 2 or 3, L is - (CH ２ ) ｍ－ And, Each R １ These are, independently, D, hydroxyl group, halogen, CN, and NO. ２ NH ２ , C １－４ Alkyl alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－４ Alkyl halogenated compounds, C １－４ Alkoxy group, C １－４ Halide alkoxy group, C ３－６ Alkyl saturated or partially unsaturated carbocyclic groups, 3- to 8-membered saturated or partially unsaturated heterocyclic groups, C ６－１０ Selected from the group consisting of aryl groups or 5- to 12-membered heteroaryl groups, R ２ -NR ６ R ７ And here, R ６ and R ７ These are H, D, and C, respectively, independently. １－６ Alkyl alkyl group, C １－６ Selected from the group consisting of halogenated alkyl groups, Or, R ６ and R ７ These, together with the nitrogen atom to which they are bonded, form a 3- to 8-membered saturated or partially unsaturated heterocyclic group or a 5- to 12-membered heteroaryl group. R ３ H, D, C １－４ Alkyl alkyl group, C １－４ Alkyl halogenated compounds, C １－４ Alkoxy group, C １－４ Halide alkoxy group, C ３－６ Alkyl saturated or partially unsaturated carbocyclic groups, 3- to 8-membered saturated or partially unsaturated heterocyclic groups, C ６－１０ Selected from the group consisting of aryl groups or 5- to 12-membered heteroaryl groups, R ４ C １－４ Alkyl alkyl group, C １－４ Alkyl halogenated compounds, C ３－６ Alkyl saturated or partially unsaturated carbocyclic groups, 3- to 8-membered saturated or partially unsaturated heterocyclic groups, C ６－１０ Selected from the group consisting of aryl groups or 5- to 12-membered heteroaryl groups, R ５ is a hydroxyl group, CN, C １－６ Alkyl alkyl group, C １－６ Halogenated alkyl groups, hydroxysubstituted C １－６ Alkyl alkyl, cyanosubstituted C １－６ Alkyl alkyl group or -C(O)NR ８ R ９ Selected from the group consisting of R ８ and R ９ These are H, D, and C, respectively, independently. １－６ Alkyl alkyl group, C １－６ Selected from the group consisting of halogenated alkyl groups, Or, R ８ and R ９ These, together with the nitrogen atom to which they are bonded, form a 3- to 8-membered saturated or partially unsaturated heterocyclic group or a 5- to 12-membered heteroaryl group. Here, the alkyl group, alkenyl group, alkynyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, carbocyclic group, heterocyclic group, aryl group, and heteroaryl group are each independently D, hydroxyl group, halogen, CN, and NO. ２ NH ２ , C １－４ Alkyl alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－４ Alkyl halogenated compounds, C １－４ Alkoxy group or C １－４ The compound, or its isomers, crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates, characterized by being optionally substituted with one or more substituents selected from the group consisting of halogenated alkoxy groups.

2. In the above formula (1), each R １ These are F, Cl, Br, CN, and NO, respectively, independently. ２ , C １－３ Alkyl alkyl group, C １－３ Alkyl halogenated compounds, C １－３ Alkoxy group or C １－３ A compound according to claim 1, characterized by being selected from the group consisting of halogenated alkoxy groups, or an isomer thereof, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

3. In the above formula (1), R ２ -NR ６ R ７ And here, R ６ and R ７ These are H, D, and C, respectively, independently. １－３ Alkyl alkyl group, C １－３ A compound according to claim 1, characterized by being selected from the group consisting of alkyl halides, or an isomer thereof, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

4. In the above formula (1), R ３ H, D, C １－３ Alkyl alkyl group, C １－３ A compound according to claim 1, characterized by being selected from the group consisting of alkyl halides, or an isomer thereof, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

5. In the above formula (1), R ４ C １－３ Alkyl alkyl group, C １－３ A compound according to claim 1, characterized by being selected from the group consisting of alkyl halides, or an isomer thereof, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

6. In the formula (1), R ５ is selected from the group consisting of CN, C １－６ alkyl group, C １－６ halogenated alkyl group, hydroxy-substituted C １－６ alkyl group, cyano-substituted C １－６ alkyl group or -C(O)NR ８ R ９ and is selected from the group consisting of Here, R ８ and R ９ These are H, D, and C, respectively, independently. １－６ Alkyl alkyl group, C １－６ A compound according to claim 1, characterized by being selected from the group consisting of alkyl halides, or an isomer thereof, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

7. The compound according to claim 1, or its isomers, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate, characterized in that the compound has a structure selected from the group consisting of the following. 【Chemistry 15】

8. A pharmaceutical composition for treating, modulating and / or preventing NMT-mediated disorders, wherein the pharmaceutical composition is (1) A compound as an active ingredient as described in any one of claims 1 to 7, or an isomer thereof, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, and A pharmaceutical composition for treating, modulating and / or preventing the NMT-mediated disease, comprising any (2) pharmaceutically acceptable excipient or carrier.

9. Uses of the compound, its isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate, as described in any one of claims 1 to 7, characterized in that they are used in the preparation of drugs for treating, modulating and / or preventing NMT-mediated diseases.

10. A method for treating, regulating and / or preventing an NMT-mediated disease, comprising the step of administering to an individual in need a compound according to any one of claims 1 to 7, its isomer, crystalline form, a pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition according to claim 8.

11. The use described in claim 9 or the method described in claim 10, characterized in that the NMT-mediated disease includes infectious diseases or hyperproliferative diseases.

12. The use or method according to claim 11, wherein the infectious disease includes protozoan infections and viral infections, preferably the protozoan infection includes malaria and leishmania, and preferably the viral infection includes human rhinovirus infection and HIV infection.

13. The use or method according to claim 11, characterized in that the hyperproliferative disease is selected from the group consisting of lymphoma, leukemia, brain tumor, gastric cancer, liver cancer, lung cancer, intestinal cancer, pancreatic cancer, breast cancer, cervical cancer, ovarian cancer, endometrial cancer, and prostate cancer.

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