NMT inhibitor as well as preparation method and application thereof

Abstract

The invention provides an NMT inhibitor as well as a preparation method and application thereof, and particularly relates to a compound as shown in a formula (1) and a preparation method thereof, a pharmaceutical composition containing the compound as shown in the formula (1) and / or pharmaceutically acceptable salt thereof, a preparation method of the pharmaceutical composition and application of the pharmaceutical composition as the NMT inhibitor in preparation of antitumor drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and more specifically, to a class of NMT inhibitors having a structure as shown in formula (1), and a preparation method thereof and the use of such compounds in preparing a pharmaceutical composition for treating, regulating and / or preventing diseases mediated by NMT Background Art

[0002] NMT (N-myristoyltransferase, NMT, N-myristoyltransferase) is an enzyme that catalyzes the myristoylation of more than 100 proteins in human cells and affects downstream related signaling pathways. In humans, protein myristoylation is mediated by two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2. Myristoylation is a co-translational and post-translational modification reaction in eukaryotes. Through the action of NMT1 and NMT2, the myristoyl group is transferred to the N-terminal glycine of the substrate protein [Cell Death and Disease, 2018, 9(12): 1143]. It plays a role similar to a "switch" and can trigger a variety of reversible protein-cell membrane and protein-protein interactions.

[0003] NMT1 is highly expressed in a variety of tumor tissues. In liver cancer, NMT1 is associated with poor prognosis. Compared with patients with low expression, patients with high NMT1 expression have shorter survival. The expression of NMT1 has important clinical significance. The primary breast cancer tissue and adjacent tissue of 20 breast cancer patients were detected. The results showed that compared with adjacent tissue, the expression of NMT1 in breast cancer tissue was significantly increased, especially in triple-negative breast cancer tissue [Cell Death and Disease, 2018, 9 (12): 1143]. Elevated NMT1 is associated with tumor development and shorter survival of patients. In patients with colorectal cancer, NMT1 expression is elevated in peripheral blood and bone marrow, and can be used as a diagnostic marker for colorectal cancer [J Transl Med. 2007, 5: 58]. High expression of NMT1 is associated with poor prognosis of ovarian cancer and the progression of liver cancer, brain cancer, etc. [Annals of medicine, 2023, 55 (1): 1422-1430].

[0004] NMT1 catalyzes its substrate proteins to form myristoylated proteins, activates downstream signaling pathways such as NF-KB, C-Myc, ERK, and promotes 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 a variety of tumors and is associated with tumor staging, prognosis, and survival. It is a potential target for precision tumor treatment. NMT inhibitors can significantly inhibit the activity of blood tumor cells, including B lymphocytes, inhibit the myristoylation of lymphoma cells, and inhibit the signal transduction of B cell receptors, leading to cell death and inhibiting tumor growth in mouse tumor models [Nature communications, 2020, 11(1): 5348].

[0005] Although some NMT small molecule inhibitors have been disclosed, there is still a need to develop new compounds with better activity and pharmacokinetic properties. The NMT inhibitor compound having the structure shown in the general formula (1) of the present invention exhibits excellent effects and functions, and can provide a new option for the precise treatment of tumors. Summary of the invention

[0006] The purpose of the present invention is to provide a novel NMT inhibitor with high activity and its preparation method and use.

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

[0008]

[0009] In formula (1):

[0010] n is 0, 1, 2, or 3;

[0011] X 1 and X 2 Each independently selected from the following group: CH, CR 1 or N;

[0012] W is selected from the group consisting of a chemical bond, O, S or NH;

[0013] Y is selected from the group consisting of: chemical bonds, -(CH2) m -、-(CH2) m O- or -(CH2) m O-(CH2) m , wherein m is selected from 1, 2 or 3;

[0014] L is -(CH2) m -;

[0015] Each R 1 Each independently selected from the group consisting of D, hydroxyl, halogen, CN, NO2, NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 alkyl, saturated or partially unsaturated carbocyclic group, 3-8 membered saturated or partially unsaturated heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl;

[0016] R 2 For-NR 6 R 7 , where R 6 and R 7 Each independently selected from the following group: H, D, C 1-6 Alkyl, C 1-6 Haloalkyl;

[0017] Or, R 6 and R 7 and the nitrogen atom to which it is connected together form a 3-8 membered saturated or partially unsaturated heterocyclic group, or a 5-12 membered heteroaryl group;

[0018] R 3 Selected from the following group: H, D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 alkyl, saturated or partially unsaturated carbocyclic group, 3-8 membered saturated or partially unsaturated heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl;

[0019] R 4 Select from the following group: C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 alkyl, saturated or partially unsaturated carbocyclic group, 3-8 membered saturated or partially unsaturated heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl;

[0020] R 5 Selected from the group consisting of hydroxyl, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy substituted C 1-6 Alkyl or -C(O)NR 6 R 7 ;

[0021] Or, R 6 and R7 and the nitrogen atom to which it is connected together form a 3-8 membered saturated or partially unsaturated heterocyclic group, or a 5-12 membered heteroaryl group;

[0022] wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, carbocyclic, heterocyclic, aryl, and heteroaryl groups are each independently and optionally substituted with one or more substituents selected from the group consisting of D, hydroxyl, halogen, CN, NO2, NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy.

[0023] In another preferred embodiment, in the formula (1), each R 1 Each independently selected from the following group: F, Cl, Br, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy.

[0024] In another preferred embodiment, wherein in the formula (1), R 2 For-NR 6 R 7 , where R 6 and R 7 Each independently selected from the following group: H, D, C 1-3 Alkyl, C 1-3 Halogenated alkyl.

[0025] In another preferred embodiment, wherein in the formula (1), R 3 Selected from the following group: H, D, C 1-3 Alkyl, C 1-3 Halogenated alkyl.

[0026] In another preferred embodiment, wherein in the formula (1), R 4 Select from the following group: C 1-3 Alkyl, C 1-3 Halogenated alkyl.

[0027] In another preferred embodiment, wherein in the formula (1), R 5 Select from the following group:

[0028] CN, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy substituted C 1-4 Alkyl or -C(O)NR 6 R 7 ;

[0029] Among them, R 6 and R 7 Each independently selected from the following group: H, D, C 1-3 Alkyl, C 1-3 Halogenated alkyl.

[0030] In another preferred embodiment, the representative compound of the present invention has a structure selected from the following group:

[0031]

[0032]

[0033] In a second aspect of the present invention, a pharmaceutical composition for treating, regulating and / or preventing diseases mediated by NMT is provided, the pharmaceutical composition comprising:

[0034] (1) a compound as described in the first aspect of the present invention as an active ingredient, or an isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof; and

[0035] Optional (2) a pharmaceutically acceptable excipient or carrier.

[0036] In the third aspect of the present invention, there is provided a use of the compound as described in the first aspect of the present invention, its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition as described in the second aspect of the present invention, for preparing a pharmaceutical composition for treating, regulating and / or preventing diseases mediated by NMT.

[0037] In another preferred embodiment, the NMT-mediated related diseases include infectious diseases or hyperproliferative diseases, wherein the infectious diseases include protozoan infections such as malaria and leishmaniasis, viral infections such as human rhinovirus and HIV; hyperproliferative diseases such as lymphoma, leukemia, brain tumors, gastric cancer, liver cancer, lung cancer, intestinal cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer and prostate cancer.

[0038] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0039] After extensive and in-depth research, the inventors have discovered for the first time a class of compounds of formula (1) through a large number of screenings and tests, which have significant therapeutic effects on diseases related to NMT. ​​The compounds of the present invention have good inhibitory activity on the NMT1 enzyme and good cell proliferation inhibitory activity on the MV-4-11 cell line, and the present invention was completed on this basis.

[0040] Compounds of the present invention and their synthesis

[0041] The present invention provides an inhibitor targeting NMT, namely, a compound of formula (1), or its isomers, crystal forms, pharmaceutically acceptable salts (inorganic salts or organic salts), hydrates or solvates. Preferably, the compound of the present invention is as described in the first aspect.

[0042] The present invention also provides a method for preparing the compound of formula (1) of the present invention. The following specifically describes the method for preparing the compound of general formula (1) of the present invention, but these specific methods do not constitute any limitation to the present invention.

[0043] On the one hand, the compounds described herein are prepared according to methods known in the art. However, the conditions of the method, such as reactants, solvents, bases, the amount of compounds used, reaction temperature, reaction time, etc., are not limited to the following explanation. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such a combination can be easily performed by a person skilled in the art to which the present invention belongs. On the one hand, the present invention also provides a method for preparing the compound represented by the general formula (1), which is prepared using the following general reaction scheme 1:

[0044] General reaction scheme 1:

[0045]

[0046] The embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 1, wherein Z is a halogen, Q is a boronic acid or a boronic ester, M is a 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 above.

[0047] Related definitions

[0048] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0049] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0050] The term "pharmaceutically acceptable salt" refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases. When the compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds 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. When the compounds of the invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt.

[0051] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

[0052] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0053] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0054] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability of a ring to rotate freely about double bonds or single bonds of ring carbon atoms.

[0055] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0056] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0057] Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Represents a straight solid bond and straight dashed key

[0058] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0059] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine).

[0060] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14( 14 C). For another example, deuterium can be used to replace hydrogen atoms to form deuterated compounds. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs generally have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the half-life of drugs in vivo. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

[0061] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0062] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include a variant of deuterium and hydrogen, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be arbitrary on the basis of chemical achievable.

[0063] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0064] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a single bond.

[0065] When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0066] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 , 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 Etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring and 6-10-membered ring, etc.

[0067] Unless otherwise specified, “C 1-6 "Alkyl" is used to refer to a straight or branched saturated aliphatic hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-4 , C 2-6 , C 3-5, C5 and C6 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Non-limiting examples of C1-6 alkyl include methyl, ethyl, propyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, and various branched chain isomers thereof.

[0068] Unless otherwise specified, “C 1-3 "Alkyl" is used to refer to a straight or branched saturated aliphatic hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Non-limiting examples of alkyl groups include methyl, ethyl, propyl, n-propyl, isopropyl, and the like.

[0069] Unless otherwise specified, “C 1-3 "Alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom. 1-3 Alkoxy includes C 1-2 , C2 and C3 alkoxy, etc.; C 1-3 Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, and the like.

[0070] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0071] "Hydroxy" refers to -OH.

[0072] "Cyano" refers to -CN.

[0073] Specific pharmaceutical and medical terms

[0074] The term "acceptable," as used herein, means that a formulation component or active ingredient has no undue deleterious effect on health and well-being for the general purpose of treatment.

[0075] The terms "treat", "treatment" or "therapy" as used herein include alleviating, inhibiting or improving symptoms or conditions of a disease; inhibiting the occurrence of complications; improving or preventing potential metabolic syndrome; inhibiting the occurrence of a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating signs caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, after administration, can improve a disease, symptom or condition, especially improve its severity, delay the onset, slow the progression of the disease, or reduce the duration of the disease. Whether fixed or temporary administration, continuous administration or intermittent administration, can be attributed to or related to the administration.

[0076] "Active ingredient" refers to the compound shown in the general formula (1), and the pharmaceutically acceptable inorganic or organic salt of the compound of formula (1). The compounds of the present invention may contain one or more asymmetric centers (axial chirality) and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. The asymmetric centers that may exist depend on the properties of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0077] The terms "compound", "composition", "agent" or "medicine or medicament" are used interchangeably herein and refer to a compound or composition that, when administered to a subject (human or animal), is capable of inducing a desired pharmaceutical and / or physiological response through local and / or systemic effects.

[0078] The term "administered," "administering," or "administration" as used herein refers to directly administering the compound or composition, or administering a prodrug, derivative, or analog of the active compound.

[0079] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate values, the relevant numerical values ​​in the specific embodiments have been presented as accurately as possible. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. Here, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a specific value or range. Alternatively, the term "about" means that the actual value falls within the acceptable standard error of the mean value, depending on the consideration of those skilled in the art. Except for the experimental examples, or unless otherwise explicitly stated, it should be understood that all ranges, quantities, values ​​and percentages used herein (for example, to describe the amount of material used, the length of time, temperature, operating conditions, quantitative ratios and the like) are modified by "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in this specification and the attached claims are all approximate values ​​and can be changed as needed. At least these numerical parameters should be understood as the number of significant digits indicated and the values ​​obtained using the general rounding method.

[0080] Unless otherwise defined in this specification, the meanings of scientific and technical terms used herein are the same as those commonly understood by those skilled in the art. In addition, singular nouns used in this specification include plural forms of the nouns, and plural nouns used also include singular forms of the nouns, unless they conflict with the context.

[0081] Route of administration

[0082] The compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts within the safe and effective amount range and pharmacologically acceptable excipients or carriers. The "safe and effective amount" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the specific circumstances such as the age, condition, and course of treatment of the subject.

[0083] "Pharmaceutically acceptable excipients or carriers" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0084] The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

[0085] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0086] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0087] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0088] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0089] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0090] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0091] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0092] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0093] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0094] The main advantages of the present invention include:

[0095] (a) Unexpectedly, the compound of formula (1) of the present invention exhibits excellent in vitro activity, including NMT1 enzyme inhibitory activity and MV-4-11 cell antiproliferative activity, and is more suitable for development as a drug.

[0096] (b) The compounds of the present invention have good drugability.

[0097] The above features mentioned in the present invention or the features mentioned in the embodiments can be combined in any way. All the features disclosed in the specification of this case can be used in any combination form, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equal or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equal or similar features.

[0098] In the following description, each specific aspect, characteristic and advantage of the above-mentioned compounds, methods and pharmaceutical compositions will be described in detail to make the content of the present invention become very clear. It should be understood that the following detailed description and examples describe specific embodiments and are for reference only. After reading the description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent situations also fall within the scope defined by the application.

[0099] The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data of the cultured single crystal using a Bruker D8 venture diffractometer, with the light source being CuKα phase radiation and the scanning mode being: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0100] The solvent used in the present invention can be obtained from the market. The compounds are named according to the conventional naming principles in the art or using ChemDraw@ software, and the commercially available compounds are named according to the supplier's catalog name.

[0101] In all embodiments, 1 H-NMR was recorded using a Varian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts were expressed in δ (ppm). The silica gel used for separation was 200-300 mesh unless otherwise specified, and the ratios of the eluents were all by volume.

[0102] The present invention uses the following abbreviations: (Boc)2O represents di-tert-butyl dicarbonate; CAN(CH3CN) represents acetonitrile; °C represents degrees Celsius; Cs2CO3 represents cesium carbonate; CD3OD represents deuterated methanol; EA(EtOAc) represents ethyl acetate; DCM represents dichloromethane; DIEA(DIPEA) represents diisopropylethylamine; Dioxane represents 1,4-dioxane; DMF represents N,N-dimethylformamide; h represents hours; HATU represents 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; H2O2 represents hydrogen peroxide; K2C O3 stands for potassium carbonate; K3PO4 stands for potassium phosphate; LC-MS stands for liquid chromatography-mass spectrometry; LiAlH4 stands for lithium aluminum tetrahydride; MS stands for mass spectrometry; MsCl stands for methanesulfonyl chloride; NaBH3CN stands for sodium cyanoborohydride; NaHCO3 stands for sodium bicarbonate; NaOH stands for sodium hydroxide; NIS stands for N-iodosuccinimide; NMR stands for nuclear magnetic resonance; Pd2(dba)3 stands for tris(dibenzylideneacetone)dipalladium; Pd(dppf)2Cl2dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium; PE stands for petroleum ether; POCl3 stands for phosphorus oxychloride; TEA stands for triethylamine.

[0103] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the unrecorded specific conditions in the following examples are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0104] Preparation Example 1: Synthesis of 1,5-dimethyl-4-(2-(methylsulfonyl)oxy)ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (Intermediate 1)

[0105]

[0106] Step 1: Synthesis of intermediate 1-1

[0107] Dissolve 1,5-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester (5 g, 29.73 mmol) in acetonitrile (100 mL), add NIS (7.36 g, 32.70 mmol), stir at 50 ° C, monitor by LC-MS, and the reaction of the raw material is complete. Directly concentrate to remove acetonitrile, pour into water (100 mL), extract with EA (50 mL*3), combine the organic phases, dry, concentrate, and column chromatography (PE / EA=20 / 1 to 5 / 1) to obtain yellow solid intermediate 1-1 (8.21 g, yield 94%), ESI-MS m / z: 294.9 [M+H] + .

[0108] Step 2: Synthesis of intermediate 1-2

[0109] Dissolve the intermediate 1-1 (8.21 g, 27.93 mmol) and potassium trifluoroborate (4.11 g, 30.72 mmol) in Dioxane / water (100 / 10 mL), add Pd(dppf)Cl2 (2.04 g, 2.79 mmol) and K3PO4 (11.86 g, 55.86 mmol), stir at 90°C, monitor by LC-MS, and the reaction of the raw materials is complete. Directly concentrate to remove Dioxane, pour into water (100 mL), extract with EA (50 mL*3), combine the organic phases, dry, concentrate, and column chromatography (PE / EA=10 / 1 to 5 / 1) to obtain a white solid intermediate 1-2 (4.86 g, yield 90%), ESI-MS m / z: 195.0 [M+H] + .

[0110] Step 3: Synthesis of intermediate 1-3

[0111] The intermediate 1-2 (4.86 g, 25.05 mmol) was dissolved in THF (50 mL), and BH3.THF (1 M, 25.05 mL) was slowly added at 0°C. The reaction was stirred at 0°C for 3 h, and then 30% sodium bicarbonate aqueous solution (20 mL) and hydrogen peroxide (30%, 20 mL) were added. The reaction was stirred at 0°C. LC-MS monitoring showed that the reaction of the raw material was complete. The mixture was poured into water (100 mL), extracted with EA (50 mL*3), the organic phases were combined, dried, concentrated, and column chromatography (PE / EA=5 / 1 to 1 / 1) was performed to obtain a white solid intermediate 1-3 (1.26 g, yield 24%), ESI-MS m / z: 213.0 [M+H] + .

[0112] Step 4: Synthesis of Intermediate 1

[0113] 1-3 (1.26 g, 5.94 mmol) and TEA (1.20 g, 11.89 mmol) were dissolved in DCM (30 mL), and MsCl (748 mg, 6.53 mmol) was added under argon protection at 0°C with stirring. After addition, the mixture was stirred at room temperature and the reaction was completed. LC-MS monitoring showed that the reaction of the raw material was complete. The mixture was poured into water (50 mL), extracted with DCM (30 mL*3), the organic phases were combined, dried, concentrated, and column chromatography (PE / EA=10 / 1 to 2 / 1) was performed to obtain yellow solid intermediate 1 (1.59 g, yield 92%), ESI-MS m / z: 291.0 [M+H] + .

[0114] By adopting a similar synthetic method as in Preparation Example 1, intermediate 2-4 can be obtained.

[0115]

[0116] Preparation Example 2: Synthesis of ethyl 4-(chloromethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (Intermediate 5)

[0117]

[0118] Step 1: Synthesis of intermediate 5

[0119] SM1 (2 g, 11.90 mmol) and paraformaldehyde (714 mg, 23.81 mmol) were dissolved in 1,4-dioxane (30 mL), HCl (12 M, 2 mL) and H2SO4 (119 mg, 1.19 mmol, 98%) were added, and the reaction was stirred at 100 °C. LC-MS monitoring showed that the reaction of the raw materials was complete. The 1,4-dioxane was directly concentrated to remove the 1,4-dioxane, poured into water (100 mL), extracted with EA (50 mL*3), the organic phases were combined, dried, and concentrated to obtain a yellow solid intermediate 5 (8.21 g, yield 94%), ESI-MS m / z: 217.0 [M+H] + .

[0120] Example 1: Synthesis of 4-(2-(5-chloro-2-(3-((dimethylamino)methyl)pyrazolo[1,5-a]pyridin-5-yl)phenoxy)ethyl)-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide (Compound 1)

[0121]

[0122] Step 1: Synthesis of 1-1

[0123] SM1 (1 g, 5.08 mmol) was dissolved in DMF (20 mL), POCl3 (2.33 g, 15.2 mmol) was slowly added at 0 °C, and the reaction was stirred at room temperature after addition. The reaction of the raw material was completed by LC-MS monitoring. Pour into water (30 mL), adjust pH to 10 with 1 M NaOH, extract with EA (30 mL*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] + .

[0124] Step 2: Synthesis of 1-2

[0125] 1-1 (200 mg, 0.89 mmol) and 4-chloro-2-hydroxyphenylboronic acid (230 mg, 1.33 mmol) were dissolved in Dioxane / water (10 / 2 mL), Pd2(dba)3 (81.4 mg, 0.089 mmol), (Boc)2O (582 mg, 2.67 mmol) and K2CO3 (368 mg, 2.67 mmol) were added, and the reaction was stirred at 100°C. LC-MS monitoring showed that the reaction of the raw materials was complete. Water (30 mL) was added, and EA (30 mL*3) was used for extraction. The organic phases were combined, dried, concentrated, and column chromatography (PE / EA=10 / 1 to 3 / 1) was used to obtain a yellow solid 1-2 (211 mg, yield 87%), ESI-MS m / z: 272.9 [M+H] + .

[0126] Step 3: Synthesis of 1-3

[0127] 1-2 (100 mg, 0.37 mmol) was dissolved in acetonitrile (10 mL), and intermediate 1 (178 mg, 0.61 mmol) and Cs2CO3 (597 mg, 1.83 mmol) were added. The reaction was stirred at 80 °C and monitored by LC-MS. The reaction of the raw material was complete. Water (30 mL) was added, and EA (30 mL*3) was used for extraction. The organic phases were combined, dried, concentrated, and column chromatography (PE / EA=20 / 1 to 2 / 1) was used to obtain a yellow solid 2-3 (110 mg, yield 77%). ESI-MS m / z: 467.1 [M+H] + .

[0128] Step 4: Synthesis of 1-4

[0129] 1-3 (100 mg, 214 umol) was dissolved in THF / water (5 / 5 mL), and NaOH (12.9 mg, 321 umol) was added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction of the raw material was completed. Poured into water (30 mL), 1M hydrochloric acid was used to adjust the pH to 5-6, and EA (30 mL*3) was used for extraction. The organic phases were combined, dried, and concentrated to obtain a yellow solid 1-4 (40 mg, crude), ESI-MS m / z: 439.0 [M+H] + .

[0130] Step 5: Synthesis of 1-5

[0131] Dissolve 1-4 (40 mg, 91.1 umol) in DMF (3 mL), add dimethylamine hydrochloride (14.9 mg, 182 umol), DIEA (58.9 mg, 456 umol) and HATU (41.6 mg, 109 umol) in sequence, stir at room temperature, monitor by LC-MS, the reaction of the raw material is complete. Pour into water (20 mL), extract with EA (10 mL*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] + .

[0132] Step 6: 1 Synthesis

[0133] 1-5 (47.0 mg, 101 umol) was dissolved in DCM (5 mL), TEA (30.6 mg, 303 umol), NaBH3CN (7.61 mg, 121 umol) and dimethylamine hydrochloride (24.7 mg, 303 umol) were added, and the reaction was stirred at room temperature. LC-MS monitoring showed that the reaction of the raw material was complete. The mixture was poured into water (20 mL), extracted with EA (20 mL*3), the organic phases were combined, dried, and concentrated to obtain a yellow solid 1 (14 mg, yield 28%).

[0134] 1 H NMR (400MHz, CD3OD): δ8.61(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] + .

[0135] Example 2-19: Synthesis of Compounds 2-11, 13-20

[0136] Using a similar synthesis method as in Example 1, target compounds 2-11, 13-20 can be obtained.

[0137]

[0138]

[0139]

[0140]

[0141] Example 20: Synthesis of (4-(2-(5-chloro-2-(3-((dimethylamino)methyl)pyrazolo[1,5-a]pyridin-5-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)methanol (Compound 12)

[0142]

[0143] Step 1: Synthesis of 12-1

[0144] 1-3 (200 mg, 0.43 mmol) was dissolved in DCM (10 mL), TEA (130 mg, 1.29 mmol), NaBH3CN (81 mg, 1.29 mmol) and dimethylamine hydrochloride (105 mg, 1.29 mmol) were added, and the reaction was stirred at room temperature. LC-MS monitoring showed that the reaction of the raw material was complete. The mixture was poured into water (20 mL), extracted with EA (20 mL*3), the organic phases were combined, dried and concentrated to obtain a yellow solid 12-1 (220 mg, crude), ESI-MS m / z: 496.1 [M+H] + .

[0145] Step 2: 12 Synthesis

[0146] 12-1 (220 mg, 0.43 mmol) was dissolved in THF (10 mL), LiAlH4 (33 mg, 0.86 mmol) was added, and the reaction was stirred at room temperature. LC-MS monitoring showed that the reaction of the raw material was complete. The reaction was quenched with saturated ammonium chloride solution, extracted with EA (20 mL*3), and the organic phases were combined, dried, and concentrated to obtain a yellow solid 12 (84 mg, yield 43%).

[0147] 1 H NMR (400MHz, CD3OD): δ8.64(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 d,J=1.82Hz,2H),4.56(m,2H),4.35(s,2H),4.22(t,J=6.61Hz,2H),3.68-3.73(m,3H),3.05(s,6H),2.90(m,2H),2.01(s,3H); ESI-MS m / z:454.1[M+H] + .

[0148] Example 21: Screening of compounds for NMT1 enzyme catalytic inhibitory activity

[0149] This study evaluated the ability of the compounds of the present invention to inhibit the catalytic activity of NMT1 in vitro. The experiment used the FI fluorescence intensity analysis method to characterize NMT1 inhibitors at 1.25μM myristoyCoA (myristoy CoA lithium salt, sigma, M4414). In this experiment, a peptide HSPP60SRC (Nanjing Peptide Industry, NJP23953) with a sequence of H-Gly-Ser-Asn-Lys-Ser-Lys-Pro-Lys-NH2 was synthesized as a reaction substrate. The final concentration of NMT1 enzyme was 6nM, the final concentration of CPM (reactive thiol fluorescent probe, invitrogen, D346) was 1μM, the final concentration of HSPP60 SRC was 20μM, and the final concentration of DMSO was 0.5%.

[0150] The compound was dissolved in DMSO to obtain a stock solution with a concentration of 10 mM. A dose gradient reaction solution was prepared to have an endpoint compound concentration of 3 mM, and then three-fold dilutions were performed in DMSO for a total of ten data points. 0.05 μL of the diluted compound solution was transferred to a 384 assay plate (Corning, CLS4514) using an ECHO acoustic pipetting device (BECKMAN, ECHO 655 system), 2.5 μL of NMT1 enzyme working solution was added to the 384-well assay plate, incubated at 25°C for 10 minutes, and then 5 μL of CPM and myristoy COA working solution were added, centrifuged at 1000 rpm for 1 minute, and then 2.5 μL of HSPP60 SRC working solution was added for reaction, which was incubated at 25°C for 45 minutes. FI signal (em: 320 nm; ex: 405 nm) was detected under an HTS high-throughput drug screening multifunctional microplate reader (BMG, PHERA star FSX).

[0151] The inhibition rate of the compound on the catalytic activity of NMT1 enzyme was calculated using the following formula: Inhibition percentage (%) = 100*(mean value of DMSO group - mean value of compound) / (mean value of DMSO group - mean value of blank control group). The IC value of the compound was fitted according to the nonlinear regression equation using the software XLfit 5.5.0. 50 Table 1 provides the inhibitory activity of the compounds of the present invention on NMT1 enzyme catalysis.

[0152] Example 22: Screening of antiproliferative activity of compounds on MV-4-11 cells

[0153] In this study, a cell proliferation assay was used to analyze the cytotoxicity of MV-4-11 human myelomonocytic leukemia cells after three days of NMT1 inhibitor action. The MV-4-11 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. and cultured in a cell culture incubator (Thermo) at 37°C and 5% carbon dioxide using IMDM medium (Viva cell). In this experiment, the NMT1 inhibitor was dissolved in DMSO to obtain a stock solution with a concentration of 600 μM. Dose gradient reactions were prepared to have an endpoint compound concentration of 3 μM and three-fold dilutions were performed in DMSO for a total of eight data points. The final concentration of DMSO was 0.5%.

[0154] MV-4-11 cells were seeded in a white 96-well plate, with 80 μL of cell suspension per well, containing 6000 MV-4-11 cells. The cell plate was placed in a carbon dioxide incubator for overnight culture, and then 20 μL of NMT1 inhibitor solution of different concentrations was added to the well plate, and the 96-well plate was placed in the incubator for three days. Prepare another cell plate, and read the signal value on the day of drug addition as the maximum value (Max value in the equation below) for data analysis. Add 25 μL of cell viability chemiluminescent detection reagent to each well of this cell plate and incubate at room temperature for 10 minutes to stabilize the luminescent signal. Read using a multi-label analyzer.

[0155] The raw data were converted into inhibition rate, IC using the equation (Sample-Min) / (Max-Min)*100%. 50 The value can be obtained by four-parameter curve fitting (obtained in "log (inhibitor) vs. response--Variable slope" mode in GraphPad Prism). Min: 0.5% DMSO treated cell wells; Max: Day 0 wells. Table 1 provides the inhibitory activity of the compounds of the present invention on MV-4-11 cell proliferation.

[0156] Table 1: Inhibitory activity of compounds on NMT1 enzyme (IC 50 ) and antiproliferative activity against MV-4-11 cells (IC 50 )

[0157]

[0158]

[0159] From the data in the above table, it can be seen that the compounds of the present invention have strong inhibitory activity against NMT1 enzyme catalysis, and at the same time, the compounds also have strong anti-proliferation activity against MV-4-11 cells. In particular, compounds 1, 4, 5 and 14 have strong inhibitory activity against NMT1 enzyme catalysis and anti-proliferation activity against MV-4-11 cells, and the IC 50 Less than 2nM, IC value of antiproliferative activity against MV-4-11 cells 50 Less than 20nM.

[0160] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound having a structure as shown in formula (1), or its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate: In formula (1): n is 0, 1, 2, or 3; X 1 and X 2 Each independently selected from the following group: CH, CR 1 or N; W is selected from the group consisting of a chemical bond, O, S or NH; Y is selected from the group consisting of: chemical bonds, -(CH2) m -、-(CH2) m O- or -(CH2) m O-(CH2) m , wherein m is selected from 1, 2 or 3; L is -(CH2) m -; Each R 1 Each independently selected from the group consisting of D, hydroxyl, halogen, CN, NO2, NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 alkyl, saturated or partially unsaturated carbocyclic group, 3-8 membered saturated or partially unsaturated heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl; R 2 For-NR 6 R 7 , where R 6 and R 7 Each independently selected from the following group: H, D, C 1-6 Alkyl, C 1-6 Haloalkyl; Or, R 6 and R 7 and the nitrogen atom to which it is connected together form a 3-8 membered saturated or partially unsaturated heterocyclic group, or a 5-12 membered heteroaryl group; R 3 Selected from the following group: H, D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 alkyl, saturated or partially unsaturated carbocyclic group, 3-8 membered saturated or partially unsaturated heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl; R 4 Select from the following group: C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 alkyl, saturated or partially unsaturated carbocyclic group, 3-8 membered saturated or partially unsaturated heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl; R 5 Selected from the group consisting of hydroxyl, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxy substituted C 1-6 Alkyl or -C(O)NR 6 R 7 ; Or, R 6 and R 7 and the nitrogen atom to which it is connected together form a 3-8 membered saturated or partially unsaturated heterocyclic group, or a 5-12 membered heteroaryl group; in, The alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, carbocyclic, heterocyclic, aryl, and heteroaryl groups are each independently and optionally substituted with one or more substituents selected from the group consisting of D, hydroxyl, halogen, CN, NO2, NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy.

2. The compound according to claim 1, or its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein in the formula (1), each R 1 Each independently selected from the following group: F, Cl, Br, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy.

3. The compound according to claim 1, or its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein in the formula (1), R 2 For-NR 6 R 7 , where R 6 and R 7 Each independently selected from the following group: H, D, C 1-3 Alkyl, C 1-3 Halogenated alkyl.

4. The compound according to claim 1, or its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein in the formula (1), R 3 Selected from the following group: H, D, C 1-3 Alkyl, C 1-3 Halogenated alkyl.

5. The compound according to claim 1, or its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein in the formula (1), R 4 Select from the following group: C 1-3 Alkyl, C 1-3 Halogenated alkyl.

6. The compound according to claim 1, or its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein in the formula (1), R 5 Selected from the following group: CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy substituted C 1-4 Alkyl or -C(O)NR 6 R 7 ; in, R 6 and R 7 Each independently selected from the following group: H, D, C 1-3 Alkyl, C 1-3 Halogenated alkyl.

7. The compound, its isomer, crystalline form or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure selected from the group consisting of:

8. A pharmaceutical composition for treating, regulating and / or preventing diseases mediated by NMT, characterized in that: The pharmaceutical composition comprises: (1) a compound according to any one of claims 1 to 7, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as an active ingredient; and Optional (2) a pharmaceutically acceptable excipient or carrier.

9. Use of the compound according to any one of claims 1 to 7, its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, characterized in that: Used for preparing drugs for treating, regulating and / or preventing diseases mediated by NMT. In another preferred embodiment, the NMT-mediated related diseases include infectious diseases or hyperproliferative diseases; The infectious diseases include protozoan infections and viral infections; the protozoan infections include malaria and leishmaniasis; the viral infections include human rhinovirus infections and HIV infections; The proliferative diseases include 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.

10. A method for treating, regulating and / or preventing diseases mediated by NMT, characterized in that: The method comprises the steps of administering to an individual in need thereof the compound according to any one of claims 1 to 7, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition according to claim 8. In another preferred embodiment, the NMT-mediated related diseases include infectious diseases or hyperproliferative diseases; The infectious diseases include protozoan infections and viral infections; the protozoan infections include malaria and leishmaniasis; the viral infections include human rhinovirus infections and HIV infections; The proliferative diseases include 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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