NMT inhibitor, preparation method therefor, and use thereof

Abstract

The present invention provides an NMT inhibitor, a preparation method therefor, and a use thereof, and specifically relates to a compound as shown in formula (1) and a preparation method therefor, and a composition containing the compound as shown in formula (1) and / or a pharmaceutically acceptable salt thereof, a preparation method therefor and a use thereof as an NMT inhibitor in the preparation of a drug for NMT-mediated related diseases.

Description

NMT inhibitors and their preparation and use Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and more specifically, to a class of NMT inhibitors having a structure as shown in formula (1), a preparation method thereof, and the use of such compounds in preparing pharmaceutical compositions 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 a shorter survival rate. 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, and 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 therapy. 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 of the present invention having the structure represented by general formula (1) exhibits excellent effects and functions, and can provide a new option for the precision treatment of tumors.

[0006] Summary of the Invention

[0007] The purpose of the present invention is to provide a novel NMT inhibitor with high activity and its preparation method and use.

[0008] In the first aspect of the present invention, there is provided a compound having a structure as shown in formula (1), an optical isomer, a polymorph or a pharmaceutically acceptable salt thereof:

[0009] In formula (1):

[0010] A is selected from the following group:

[0011] Wherein, the dashed line is a chemical bond or none; and It is an aromatic ring;

[0012] X is selected from the group consisting of CH or N, and when X is N, the dashed line connecting X is absent;

[0013] U is selected from the group consisting of CH or N;

[0014] W is selected from the group consisting of CH or N;

[0015] J is selected from the group consisting of O, S, and NH;

[0016] V is selected from the group consisting of CH or N;

[0017] Y is selected from the group consisting of O, S, NH, or N(C 1-3 alkyl);

[0018] m is 1 or 2;

[0019] n is 1 or 2;

[0020] p is 1, 2, or 3;

[0021] R 4 、R 5 、R 6 、R 7 、R 8 are independently selected from the group consisting of H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl or C 1-6 alkoxy;

[0022] R 9 Selected from the following group: H or C 1-3 alkyl;

[0023] j is 1, 2, 3, or 4;

[0024] R 1 Selected from the following group: H, C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0025] R 2 is a 5-7 membered heteroaryl group, which may be further substituted by 1, 2 or 3 R 2a Replaced by R 2a Selected from the following group: cyano, NO2, -OR a 、-C(=O)R a 、-NR c R d 、-C(=O)NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl and heterocycloalkyl groups may be optionally substituted by one or more R 2b replace;

[0026] R 2b Selected from the group consisting of halogen, CN, NO2, OH, SH, -OR a 、-NR c Rd 、-C(=O)NR c R d 、-NR b C(=O)NR c R d 、 -NR b C(=O)R a 、-NR b S(=O)2R a 、-C(=O)R a 、-OC(=O)R a 、-C(=O)OR b 、-NR b C(=O)OR b 、-OC(=O)NR c R d 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl and heterocycloalkyl groups may be optionally substituted with one or more R groups;

[0027] or two R on the same atom 2b Together constitute = O;

[0028] R a Independently selected from the following group: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl and heterocycloalkyl groups may be optionally substituted with one or more R;

[0029] R b Independently selected from the following groups: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl and heterocycloalkyl groups may be optionally substituted with one or more R groups;

[0030] R c and R d Independently selected from the following groups: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl and heterocycloalkyl groups may be optionally substituted with one or more R groups;

[0031] or R c and R d Together with the atoms to which they are attached, they form a 4-7 membered heterocycloalkyl group, which may be optionally substituted with one or more R groups;

[0032] Each R is independently selected from the group consisting of halogen, CN, OH, NH2, NHCH3, N(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0033] Each R 3 Independently selected from the group consisting of H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl or C 1-6 Alkoxy.

[0034] In another preferred embodiment, the compound of formula (1) has the structure shown in (2-1), (2-2) or (2-3):

[0035] Wherein, the definition of each group is as described in the first aspect of the present invention.

[0036] In another preferred embodiment, the compound has the structure shown in (3-1), (3-2) or (3-3):

[0037] Here, the definitions of the groups are as described above.

[0038] In another preferred embodiment, the Select from the following groups:

[0039] In another preferred embodiment, wherein in the formula (1), R 1 Selected from the group consisting of H, Me, Et, i- Pr, CHF2 or CH2CF3.

[0040] In another preferred embodiment, wherein in the formula (1), R 2 for Among them, R 10 Selected from H or C 1-6 Alkyl, R 11 Selected from H or C 1-6 Alkyl, R 12 The same definition as R in the first aspect of the present invention 2a .

[0041] In another preferred embodiment, wherein in the formula (1), R 2 for Among them, R 12 The same definition as R in the first aspect of the present invention 2a .

[0042] In another preferred embodiment, wherein in the formula (1), R 2 Select from the following groups:

[0043] In another preferred embodiment, wherein in the formula (1), R 3 、R 4 、R 5 、R 6 、R 7 、R 8 Each is independently selected from the group consisting of H, halogen, cyano, Me, Et, CF3, cyclopropyl, OMe, OEt or OCF3.

[0044] In another preferred embodiment, wherein in the formula (1), R 9 Selected from the group consisting of H or Me.

[0045] In another preferred embodiment, the representative compound of the present invention has a structure selected from the following group:

[0046] 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:

[0047] (1) a compound according to the first aspect of the present invention, or an isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient; and

[0048] Optional (2) a pharmaceutically acceptable excipient or carrier.

[0049] In the third aspect of the present invention, there is provided a use of the compound according to the first aspect of the present invention, or its isomers, polymorphs, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition according to the second aspect of the present invention, for preparing a pharmaceutical composition for treating, regulating and / or preventing diseases mediated by NMT.

[0050] 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.

[0051] In a fourth aspect, the present invention provides a method for treating, regulating and / or preventing diseases mediated by NMT, comprising the steps of administering to an individual in need thereof the compound according to the first aspect of the present invention, or its isomers, polymorphs, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition according to the second aspect of the present invention.

[0052] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] FIG1 shows the effects of compounds 2, 3, 13, and 45 on body weight in MV-4-11 xenograft model mice.

[0054] FIG2 shows the effects of compounds 2, 3, 13, and 45 on tumor volume in MV-4-11 xenograft model mice. DETAILED DESCRIPTION

[0055] After extensive and in-depth research, extensive screening, and testing, the present inventors have discovered for the first time a class of compounds represented by formula (1) that exhibit significant therapeutic effects on NMT-mediated diseases. The compounds of the present invention exhibit excellent inhibitory activity against the NMT1 enzyme, as well as good cell proliferation inhibition activity against the MV-4-11 cell line and anti-tumor activity in mice. The present invention was completed on this basis.

[0056] Compounds of the present invention and their synthesis

[0057] The present invention provides an inhibitor targeting NMT, namely a compound of formula (1), or its isomers, polymorphs, pharmaceutically acceptable salts (inorganic or organic salts), hydrates or solvates. Preferably, the compound of the present invention is as described in the first aspect.

[0058] The present invention also provides a method for preparing the compound of formula (1). The following specifically describes the method for preparing the compound of general formula (1), but these specific methods do not constitute any limitation to the present invention.

[0059] In one aspect, the compounds described herein are prepared according to methods known in the art. However, the conditions of the methods, such as reactants, solvents, bases, amounts of the compounds used, reaction temperatures, reaction times, etc., are not limited to the following explanations. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art. In one aspect, 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:

[0060] General reaction scheme 1:

[0061] The embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 1, wherein Z is halogen, OTf, boronic acid or boronic ester, R 1 、R 2 、R 3 , j and A are as defined above.

[0062] Related definitions

[0063] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0064] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that 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.

[0065] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or in 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 present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or in 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, bisulfate, hydroiodic acid, phosphorous acid, and the like; 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) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0066] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0067] 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, diastereomers, (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 groups. All such isomers and mixtures thereof are included within the scope of the present invention.

[0068] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0069] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0070] 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.

[0071] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0072] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond and straight dashed key

[0073] 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%.

[0074] Optically active (R)- and (S)-isomers, as well as 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 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), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. In addition, separation of enantiomers and diastereomers is typically accomplished by using chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., carbamate formation from an amine).

[0075] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute 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 example, deuterated compounds can be formed by replacing hydrogen atoms with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs generally have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug half-life in vivo. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0076] "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.

[0077] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, 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 unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0078] 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, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0079] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a single bond.

[0080] 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.

[0081] 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, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring and a 6-10-membered ring, etc.

[0082] Unless otherwise specified, “C 1-6 "Alkyl" is used to represent 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.

[0083] Unless otherwise specified, “C 1-3 "Alkyl" is used to represent 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 2-3Alkyl, etc.; it can 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.

[0084] 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 groups include 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.

[0085] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0086] "Hydroxyl" refers to -OH.

[0087] "Cyano" refers to -CN.

[0088] Specific pharmaceutical and medical terms

[0089] The term "acceptable," as used herein, means that a prescribed ingredient or active ingredient has no undue adverse effect on health and well-being for the general purpose of treatment.

[0090] The terms "treat," "treatment," or "therapy" as used herein include alleviating, inhibiting, or ameliorating the symptoms of a disease or condition; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing a regression of 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, upon administration, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. Whether the administration is fixed or temporary, continuous or intermittent, the circumstances attributable to or related to the administration can be explained.

[0091] "Active ingredient" refers to the compound shown in the general formula (1), as well as the pharmaceutically acceptable inorganic or organic salts 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.

[0092] 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), induces a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0093] The term "administered," "administering," or "administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound.

[0094] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate, the numerical values ​​of the specific examples are presented herein as precisely as possible. However, any numerical value inherently and inevitably contains standard deviations resulting from individual testing methods. As used herein, "about" generally refers to the actual value being within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the mean, as determined by one skilled in the art. Except in the experimental examples, or unless otherwise expressly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe material amounts, time periods, temperatures, operating conditions, quantitative ratios, and the like) are to be understood as modified by the word "about." Therefore, unless otherwise indicated, the numerical parameters disclosed in this specification and the appended claims are approximate and may be modified as needed. At a minimum, these numerical parameters should be understood to include the number of significant digits indicated and to include normal rounding.

[0095] Unless otherwise defined in this specification, the scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, unless otherwise defined in this specification, singular terms used in this specification include the plural form of the term, and plural terms also include the singular form of the term, unless otherwise defined in the context.

[0096] Route of administration

[0097] The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into various formulations containing a safe and effective amount of the compounds of the present invention or their pharmaceutically acceptable salts and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound will be determined based on the patient's age, condition, and duration of treatment, among other factors.

[0098] "Pharmaceutically acceptable excipients or carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of 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 (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0099] The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

[0100] 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 solubilizers, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0101] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0102] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0103] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0104] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0105] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0106] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0107] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0108] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0109] The main advantages of the present invention include:

[0110] (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 anti-proliferative activity, and is more suitable for development as a drug;

[0111] (b) The compounds of the present invention have excellent oral absorption and strong tumor inhibitory activity in mice;

[0112] (c) The compounds of the present invention have good drugability.

[0113] The features described above, or in the embodiments, may be combined in any combination. All features disclosed in this specification may be used in any combination, and each feature disclosed in this specification may be replaced by any alternative feature that serves the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the features disclosed are merely general examples of equivalent or similar features.

[0114] The following description will elaborate on various specific aspects, characteristics, and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions so that the present invention will be readily apparent. It should be understood that the following detailed description and examples describe specific embodiments and are provided for reference only. After reading the present description, those skilled in the art may make various changes or modifications to the present invention, and such equivalents are within the scope of the present invention.

[0115] The structures of the compounds of the present invention can be confirmed using conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed using conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is performed by collecting diffraction intensity data from a cultured single crystal using a Bruker D8 venture diffractometer with CuKα radiation and a φ / ω scanning mode. After collecting relevant data, the crystal structure can be further analyzed using a direct method (Shelxs97) to confirm the absolute configuration.

[0116] In all embodiments, 1 H-NMR was recorded on a Varian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts are expressed in δ (ppm). Silica gel used for separation was 200-300 mesh unless otherwise specified, and the eluent ratios were by volume.

[0117] The present invention uses the following abbreviations: (Boc)2O represents di-tert-butyl dicarbonate; ACN (CH3CN) represents acetonitrile; oC 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 hour; 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)2Cl2 stands for dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium; PE stands for petroleum ether; POCl3 stands for phosphorus oxychloride; and TEA stands for triethylamine.

[0118] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0119] Preparation Example 1: Synthesis of 3-ethyl-1,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1)

[0120] Step 1: Synthesis of intermediate 1-1

[0121] Methyltriphenylphosphonium bromide (8.63 g, 24.17 mmol) was dissolved in THF (100 mL) and added at -40 °C. n- BuLi (2.5M, 9.67 mL, 24.17 mmol) was stirred at -40°C for 1 h, followed by the addition of a THF solution of 1,5-dimethylpyrazole-3-carboxaldehyde (2 g, 16.11 mmol). The reaction was slowly warmed to room temperature. LC-MS monitoring confirmed the complete reaction. Saturated ammonium chloride was added for quenching, followed by extraction with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford intermediate 1-1 (1.65 g, 84% yield), a yellow liquid. ESI-MS m / z: 123.1 [M+H] + .

[0122] Step 2: Synthesis of Intermediate 1-2

[0123] Intermediate 1-1 (1.65 g, 13.52 mmol) was dissolved in MeOH (20 mL), and Pd / C (165 mg, 10%) was added. The mixture was replaced with hydrogen and stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was directly filtered, dried, and concentrated to give Intermediate 1-2 (1.64 g, 98% yield) as a pale yellow liquid. ESI-MS m / z: 125.1 [M+H] + .

[0124] Step 3: Synthesis of Intermediates 1-3

[0125] Intermediate 1-2 (1.64 g, 13.23 mmol) was dissolved in concentrated sulfuric acid (5 mL). Fuming nitric acid (15 mL) was slowly added at 0°C and the reaction was stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was slowly poured into water (100 mL) and neutralized to a weak alkaline state with saturated sodium bicarbonate. The mixture was extracted with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford Intermediate 1-3 (1.41 g, 63% yield) as a pale yellow oil. ESI-MS m / z: 170.1 [M+H] + .

[0126] Step 4: Synthesis of Intermediate 1

[0127] Intermediate 1-3 (1.41 g, 8.34 mmol) was dissolved in MeOH (20 mL), and Pd(OH)2 / C (141 mg, 10%) was added. The mixture was replaced with hydrogen and stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was directly filtered, dried, and concentrated to obtain Intermediate 1 (1.09 g, 94% yield) as a light yellow oil. ESI-MS m / z: 140.1 [M+H] + .

[0128] Intermediate 2 can be obtained by using a similar synthetic method to that in Preparation Example 1.

[0129] Preparation Example 2: Synthesis of 1,5-dimethyl-3-vinylpyrazole-4-amine (Intermediate 3)

[0130] Step 1: Synthesis of intermediate 3-1

[0131] Intermediate 1-1 (1.0 g, 8.13 mmol) was dissolved in concentrated sulfuric acid (5 mL). Fuming nitric acid (15 mL) was slowly added at 0°C and the reaction was stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was slowly poured into water (100 mL) and neutralized to a weak base with saturated sodium bicarbonate. The mixture was extracted with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford Intermediate 3-1 (653 mg, 48% yield) as a pale yellow oil. ESI-MS m / z: 168.1 [M+H] + .

[0132] Step 2: Synthesis of Intermediate 3

[0133] Intermediate 3-1 (653 mg, 3.91 mmol) was dissolved in ethanol / water (10 / 2 mL), and Fe powder (1.09 g, 19.55 mmol) and NH4Cl (1.05 g, 19.55 mmol) were added. The reaction was stirred at 80°C and monitored by LC-MS. The reaction was complete. The mixture was directly filtered and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 3 (348 mg, 65% yield) as a pale yellow oil. ESI-MS m / z: 138.1 [M+H] + .

[0134] Preparation Example 3: Synthesis of 3-cyclopropyl-1,5-dimethyl-1H-pyrazol-4-amine (Intermediate 4)

[0135] Step 1: Synthesis of intermediate 4-1

[0136] 3-Bromo-1,5-dimethylpyrazole (1 g, 5.71 mmol) and cyclopropylboronic acid (589 mg, 6.86 mmol) were dissolved in 1,4-dioxane / water (30 / 3 mL). Pd(PPh3)4 (330 mg, 0.29 mmol) and K3PO4 (2.42 g, 11.42 mmol) were added and stirred at 100°C. LC-MS monitoring indicated that the reaction was complete. The 1,4-dioxane was removed by concentration and the mixture was poured into water (50 mL). Extraction was performed with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford intermediate 7-1 (404 mg, 52% yield) as a yellow liquid. ESI-MS m / z: 137.1 [M+H] + .

[0137] Subsequently, a similar synthesis method as in Preparation Example 1 was used to obtain intermediate 4.

[0138] Preparation Example 4: Synthesis of 3-ethynyl-1,5-dimethyl-1H-pyrazol-4-amine (Intermediate 5)

[0139] Step 1: Synthesis of intermediate 5-1

[0140] 3-Bromo-1,5-dimethylpyrazole (1 g, 5.71 mmol) and trimethylethynylsilane (1.68 g, 17.13 mmol) were dissolved in THF (30 mL). Pd(PPh3)2Cl2 (400 mg, 0.57 mmol), CuI (109 mg, 0.57 mmol), and TEA (1.73 g, 17.13 mmol) were added and stirred at 50°C. LC-MS monitoring indicated that the reaction was complete. The mixture was poured into water (50 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford intermediate 5-1 (680 mg, 62% yield) as a yellow liquid. ESI-MS m / z: 193.1 [M+H] + .

[0141] Step 2: Synthesis of intermediate 5-2

[0142] Intermediate 5-1 (680 mg, 3.54 mmol) was dissolved in MeOH (20 mL), and K2CO3 (979 mg, 7.08 mmol) was added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. The mixture was poured into water (50 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford intermediate 5-2 (306 mg, yield 72%) as a yellow liquid. ESI-MS m / z: 121.1 [M+H] + .

[0143] Step 3: Synthesis of intermediate 5-3

[0144] Intermediate 5-2 (306 mg, 2.55 mmol) was dissolved in concentrated sulfuric acid (2 mL). Fuming nitric acid (6 mL) was slowly added at 0°C and the reaction was stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was slowly poured into water (50 mL) and neutralized to a weak alkaline state with saturated sodium bicarbonate. The mixture was extracted with EA (30 mL*3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 10 / 1) to afford Intermediate 5-3 (286 mg, 68% yield) as a pale yellow oil. ESI-MS m / z: 166.0 [M+H] + .

[0145] Step 4: Synthesis of Intermediate 5

[0146] Intermediate 5-3 (286 mg, 1.73 mmol) was dissolved in ethanol / water (10 / 2 mL). Fe powder (484 mg, 8.65 mmol) and NH4Cl (463 mg, 8.65 mmol) were added and stirred at 80°C. LC-MS monitoring indicated that the reaction was complete. The mixture was directly filtered and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 5 (187 mg, 80% yield) as a pale yellow oil. ESI-MS m / z: 136.1 [M+H] + .

[0147] Preparation Example 5: Synthesis of 3-cyano-1,5-dimethyl-1H-pyrazol-4-amine (Intermediate 6)

[0148] Using 3-cyano-1,5-dimethyl-1H-pyrazole as the starting material, a synthetic method similar to that in Preparation Example 2 was employed to obtain intermediate 6.

[0149] Preparation Example 6: Synthesis of 3-trifluoromethyl-1,5-dimethyl-1H-pyrazol-4-amine (Intermediate 7)

[0150] Using the corresponding substituted pyrazole as the starting material, referring to the synthetic route of intermediate 7, and adopting a synthetic method similar to that in Preparation Example 1, intermediate 7-9 can be obtained.

[0151] Preparation Example 7: Synthesis of 1,5-dimethyl-3-(pyrrolidin-1-yl)-1H-pyrazol-4-amine (Intermediate 10)

[0152] Step 1: Synthesis of Intermediate 10-1

[0153] 3-Bromo-1,5-dimethylpyrazole (1 g, 5.71 mmol) and pyrrolidine (487 mg, 6.85 mmol) were dissolved in dioxane (30 mL). Pd2(dba)3 (265 mg, 0.29 mmol), Xantphos (330 mg, 0.57 mmol), and Cs2CO3 (3.72 g, 11.42 mmol) were added and stirred at 100°C. LC-MS monitoring indicated that the reaction was complete. The mixture was concentrated to remove 1,4-dioxane and poured into water (50 mL). Extraction was performed with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford intermediate 10-1 (490 mg, 52% yield) as a yellow solid. ESI-MS m / z: 166.1 [M+H] + .

[0154] Subsequently, a similar synthesis method as in Preparation Example 1 was used to obtain intermediate 10.

[0155] Preparation Example 8: Synthesis of 4-amino-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide (Intermediate 11)

[0156] Step 1: Synthesis of Intermediate 11-1

[0157] 3-Carboxy-1,5-dimethylpyrazole (1 g, 7.14 mmol) and dimethylamine hydrochloride (582 mg, 7.14 mmol) were dissolved in DMF (30 mL). HATU (4.07 g, 10.71 mmol) and DIEA (2.76 g, 21.42 mmol) were added and stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was poured into water (50 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford intermediate 11-1 (1.03 g, 86% yield) as a yellow solid. ESI-MS m / z: 168.1 [M+H] + .

[0158] Subsequently, a similar synthesis method as in Preparation Example 1 was used to obtain intermediate 11.

[0159] Preparation Example 9: Synthesis of 2-(4-amino-1,5-dimethyl-1H-pyrazol-3-yl)acetonitrile (Intermediate 12)

[0160] Step 1: Synthesis of Intermediate 12-1

[0161] 1,5-Dimethyl-1H-pyrazole-3-methanol (2 g, 15.87 mmol) was dissolved in DCM (30 mL), and SOCl2 (5.67 g, 47.62 mmol) was slowly added. The reaction was stirred at room temperature. LC-MS monitoring showed that the reaction of the starting material was complete. Direct concentration gave intermediate 12-1 as a white solid (2.4 g, yield exceeding 100%). ESI-MS m / z: 145.0 [M+H] + .

[0162] Step 2: Synthesis of Intermediate 12-2

[0163] Intermediate 12-1 (1 g, 6.94 mmol) was dissolved in concentrated sulfuric acid (5 mL). Fuming nitric acid (15 mL) was slowly added at 0°C and the reaction was stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was slowly poured into water (100 mL) and neutralized to a weak base with saturated sodium bicarbonate. The mixture was extracted with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford Intermediate 12-2 (720 mg, 55% yield) as a pale yellow solid. ESI-MS m / z: 190.0 [M+H] + .

[0164] Step 3: Synthesis of Intermediate 12-3

[0165] Intermediate 12-2 (720 mg, 3.81 mmol) was dissolved in ACN (20 mL), and TMSCN (756 mg, 7.62 mmol) and TBAF (1.99 g, 7.62 mmol) were added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. Extraction was performed with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 5 / 1) to afford Intermediate 12-3 (328 mg, 48% yield) as a pale yellow solid. ESI-MS m / z: 181.1 [M+H] + .

[0166] Step 5: Synthesis of Intermediate 12

[0167] Intermediate 12-3 (328 mg, 1.82 mmol) was dissolved in ethanol / water (10 / 2 mL). Fe powder (510 mg, 9.11 mmol) and NH4Cl (487 mg, 9.11 mmol) were added and stirred at 80°C. LC-MS monitoring indicated that the reaction was complete. The mixture was directly filtered and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 12 (205 mg, 75% yield) as a pale yellow oil. ESI-MS m / z: 151.1 [M+H] + .

[0168] Preparation Example 10: Synthesis of 3-(((tert-butyldimethylsilyl)oxy)methyl)-1,5-dimethyl-1H-pyrazol-4-amine (Intermediate 13)

[0169] Step 1: Synthesis of Intermediate 13-1

[0170] Ethyl 1,5-dimethyl-1H-pyrazole-3-carboxylate (1 g, 5.95 mmol) was dissolved in concentrated sulfuric acid (5 mL). Fuming nitric acid (15 mL) was slowly added at 0°C and the reaction was stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was slowly poured into water (100 mL) and neutralized to a weak base with saturated sodium bicarbonate. The mixture was extracted with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford intermediate 13-1 (672 mg, 53% yield) as a pale yellow solid. ESI-MS m / z: 214.1 [M+H] + .

[0171] Step 2: Synthesis of Intermediate 13-2

[0172] Intermediate 13-1 (672 mg, 3.15 mmol) was dissolved in THF (20 mL), and LiAlH4 (179 mg, 4.73 mmol) was slowly added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. The mixture was quenched with saturated ammonium chloride, filtered, and extracted with EA (30 mL x 3). The organic phases were combined, dried, and concentrated to give Intermediate 13-2 (479 mg, 89% yield) as a pale yellow liquid. ESI-MS m / z: 172.1 [M+H] + .

[0173] Step 3: Synthesis of Intermediate 13-3

[0174] Intermediate 13-2 (200 mg, 1.17 mmol) was dissolved in THF (20 mL), and NaH (94 mg, 2.34 mmol) was slowly added. The mixture was stirred at room temperature for 10 min, followed by the addition of TBSCl (212 mg, 1.40 mmol). LC-MS monitoring indicated the reaction was complete. The mixture was quenched with saturated ammonium chloride and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford Intermediate 13-3 (303 mg, 91% yield) as a pale yellow liquid. ESI-MS m / z: 286.1 [M+H] + .

[0175] Step 2: Synthesis of intermediate 13

[0176] Intermediate 13-3 (303 mg, 1.06 mmol) was dissolved in MeOH (20 mL), and Pd(OH)2 / C (30 mg, 10%) was added. The mixture was replaced with hydrogen and stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was directly filtered, dried, and concentrated to obtain Intermediate 13 (249 mg, 92% yield) as a light yellow oil. ESI-MS m / z: 256.2 [M+H] + .

[0177] By adopting a similar synthetic method to that in Preparation Example 10, intermediate 14 can be obtained.

[0178] Preparation Example 11: Synthesis of 3-(Fluoromethyl)-1,5-dimethyl-1H-pyrazol-4-amine (Intermediate 15)

[0179] Step 1: Synthesis of Intermediate 15-1

[0180] (1,5-Dimethyl-1H-pyrazol-3-yl)methanol (1 g, 7.94 mmol) was dissolved in DCM (20 mL), and DAST (1.92 g, 11.90 mmol) was added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. Extraction was performed with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford Intermediate 15-1 (823 mg, 81% yield) as a pale yellow liquid. ESI-MS m / z: 129.1 [M+H] + .

[0181] Subsequently, a similar synthesis method as in Preparation Example 1 was used to obtain intermediate 15.

[0182] Preparation Example 12: Synthesis of 1,5-dimethyl-3-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine (Intermediate 16)

[0183] Step 1: Synthesis of Intermediate 16-1

[0184] 1,5-Dimethyl-1H-pyrazole-3-carbaldehyde (3.8 g, 30.61 mmol) was dissolved in THF (50 mL). TMSCF3 (7.4 g, 52.00 mmol) and TBAF (1 M, 6.1 mL) were added at room temperature. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. Extraction was performed with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford intermediate 16-1 (5.1 g, 86% yield) as a yellow solid. ESI-MS m / z: 195.1 [M+H] + .

[0185] Step 2: Synthesis of Intermediate 16-2

[0186] Intermediate 16-1 (2 g, 10.31 mmol) was dissolved in toluene (40 mL), and phenyl chlorothioformate (3.56 g, 20.62 mmol), 4A molecular sieves (2 g), and DMAP (2.52 g, 20.62 mmol) were added. The reaction was stirred at 60°C and monitored by LC-MS. The reaction was complete. Extraction was performed with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford intermediate 16-2 (2.8 g, 82% yield) as a yellow liquid. ESI-MS m / z: 331.1 [M+H] + .

[0187] Step 3: Synthesis of Intermediate 16-3

[0188] Intermediate 16-2 (2.8 g, 8.48 mmol) was dissolved in toluene (50 mL), and tri-n-butyltin hydride (9.88 g, 33.94 mmol) and AIBN (834 mg, 5.08 mmol) were added. The reaction was stirred at 80°C and monitored by LC-MS. The reaction was complete. Extraction was performed with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 16-3 (1.1 g, 73% yield) as a yellow liquid. ESI-MS m / z: 179.1 [M+H] + .

[0189] Subsequently, a similar synthesis method as in Preparation Example 1 was used to obtain intermediate 16.

[0190] Preparation Example 13: Synthesis of 3-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-1,5-dimethyl-1H-pyrazol-4-amine (Intermediate 17)

[0191] Step 1: Synthesis of Intermediate 17-1

[0192] Intermediate 12-3 (1 g, 5.56 mmol) was dissolved in EtOH (20 mL). Concentrated sulfuric acid (5 mL) was slowly added at 0°C. The reaction was stirred at 80°C and monitored by LC-MS. The reaction was complete. The mixture was slowly poured into water (50 mL) and neutralized to a weak base with saturated sodium bicarbonate. The mixture was extracted with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford Intermediate 17-1 (1.05 g, 83% yield) as a pale yellow solid. ESI-MS m / z: 228.1 [M+H] + .

[0193] Step 2: Synthesis of Intermediate 17-2

[0194] Intermediate 17-1 (1.05 g, 4.63 mmol) was dissolved in THF (20 mL). Methylmagnesium bromide (1 M in THF, 13.89 mL) was slowly added at 0°C. The reaction was stirred at 0°C and monitored by LC-MS. The reaction was complete. The mixture was quenched with saturated ammonium chloride, filtered, and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 17-2 (601 mg, 61% yield) as a pale yellow liquid. ESI-MS m / z: 214.1 [M+H] + .

[0195] Subsequently, a similar synthesis method as in Preparation Example 10 was used to obtain intermediate 17.

[0196] Preparation Example 14: Synthesis of 3-(2-fluoro-2-methylpropyl)-1,5-dimethyl-1H-pyrazol-4-amine (Intermediate 18)

[0197] Step 1: Synthesis of Intermediate 18-1

[0198] Intermediate 17-2 (300 mg, 1.41 mmol) was dissolved in DCM (20 mL), and DAST (341 mg, 2.11 mmol) was added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. Extraction was performed with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford Intermediate 18-1 (212 mg, 70% yield) as a pale yellow liquid. ESI-MS m / z: 216.1 [M+H] + .

[0199] Subsequently, a similar synthesis method as in Preparation Example 1 was used to obtain intermediate 18.

[0200] Preparation Example 15: Synthesis of 3-(4-amino-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropionitrile (Intermediate 19)

[0201] Step 1: Synthesis of Intermediate 19-1

[0202] Intermediate 17-2 (300 mg, 1.41 mmol) was dissolved in TFA (10 mL), and TMSCN (420 mg, 4.23 mmol) was added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. The mixture was neutralized with saturated sodium bicarbonate until weakly alkaline, and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford Intermediate 19-1 (172 mg, 55% yield) as a pale yellow liquid. ESI-MS m / z: 223.1 [M+H] + .

[0203] Subsequently, a similar synthesis method as in Preparation Example 2 was used to obtain intermediate 19.

[0204] Preparation Example 16: Synthesis of 3-(cyclopropylmethyl)-1,5-dimethyl-1H-pyrazol-4-amine (Intermediate 20)

[0205] Step 1: Synthesis of Intermediate 20-1

[0206] Intermediate 13-2 (1 g, 5.99 mmol) was dissolved in DCM (20 mL), and active manganese dioxide (5.21 g, 59.88 mmol) was added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. The mixture was directly filtered and concentrated to obtain a light yellow solid intermediate 20-1 (950 mg, yield 94%). ESI-MS m / z: 170.0 [M+H] + .

[0207] Step 2: Synthesis of Intermediate 20-2

[0208] Intermediate 20-1 (950 mg, 5.62 mmol) was dissolved in THF (20 mL). Cyclopropylmagnesium bromide (1 M in THF, 11.24 mL) was slowly added at -40°C. The reaction was stirred at -40°C and monitored by LC-MS. The reaction was complete. The mixture was quenched with saturated ammonium chloride, filtered, and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 20-2 (620 mg, 53% yield) as a pale yellow liquid. ESI-MS m / z: 212.1 [M+H] + .

[0209] Step 3: Synthesis of Intermediate 20-3

[0210] Intermediate 20-2 (620 mg, 2.94 mmol) was dissolved in DCM (20 mL). Boron trifluoride etherate (1.25 g, 8.82 mmol) and triethylsilane (1.02 g, 8.82 mmol) were slowly added at 0°C. The reaction was stirred at 0°C and monitored by LC-MS. The reaction was complete. An appropriate amount of water was added to quench the reaction, and the mixture was filtered and extracted with DCM (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 20-3 (220 mg, 38% yield) as a pale yellow liquid. ESI-MS m / z: 196.1 [M+H] + .

[0211] Subsequently, a similar synthesis method as in Preparation Example 1 was used to obtain intermediate 20.

[0212] Using a similar synthetic method as in Preparation Example 16, intermediate 21-22 can be obtained.

[0213] Preparation Example 17: Synthesis of 3-((3,3-difluorocyclobutyl)methyl)-1,5-dimethyl-1H-pyrazol-4-amine (Intermediate 23)

[0214] Step 1: Synthesis of Intermediate 23-1

[0215] (1,5-Dimethyl-1H-pyrazol-3-yl)methanol (1 g, 7.94 mmol) was dissolved in DCM (20 mL), and SOCl2 (1.42 g, 11.90 mmol) was added. The reaction was stirred at room temperature. LC-MS monitoring showed that the reaction of the starting material was complete. Direct concentration gave the intermediate 23-1 as a white solid (1.09 g, yield 95%). ESI-MS m / z: 145.0 [M+H] + .

[0216] Step 2: Synthesis of Intermediate 23-2

[0217] Intermediate 23-1 (1.09 g, 7.57 mmol) was dissolved in DMF (20 mL), and tributylphosphine (2.29 g, 11.36 mmol) was added. The reaction was stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was directly concentrated and purified by column chromatography (DCM / MeOH = 20 / 1 to 10 / 1) to afford Intermediate 23-2 (2.18 g, 83% yield) as a white solid. ESI-MS m / z: 312.3 [M+H] + .

[0218] Step 3: Synthesis of Intermediate 23-3

[0219] Intermediate 23-2 (2.18 g, 6.28 mmol) was dissolved in THF (30 mL) and added at -78 °C. n- BuLi (2.5M, 3 mL, 7.54 mmol) was added and stirred at 0°C for 1 h. The mixture was then cooled to -78°C and a THF solution of 3,3-difluorocyclobutanone (799 mg, 7.54 mmol) was added. The reaction was slowly warmed to room temperature. LC-MS monitoring confirmed the complete reaction. Saturated ammonium chloride was added for quenching, and the mixture was extracted with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford intermediate 23-3 (435 mg, 35% yield) as a yellow liquid. ESI-MS m / z: 199.1 [M+H] + .

[0220] Subsequently, a similar synthesis method as in Preparation Example 1 was used to obtain intermediate 23.

[0221] Using a similar synthetic method as in Preparation 17, intermediate 24 can be obtained.

[0222] Preparation Example 18: Synthesis of 3-((dimethylamino)methyl)-1,5-dimethyl-1H-pyrazol-4-amine (Intermediate 25)

[0223] Step 1: Synthesis of Intermediate 25-1

[0224] 1,5-Dimethylpyrazole-3-carboxaldehyde (1 g, 8.06 mmol) and dimethylamine hydrochloride (1.31 g, 16.13 mmol) were dissolved in DCM (20 mL). TEA (2.44 g, 24.18 mmol) and NaBH3CN (1.52 g, 24.18 mmol) were added and the reaction was stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. Extraction with DCM (30 mL x 3) was performed, and the organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH = 20 / 1 to 10 / 1) to afford intermediate 25-1 (521 mg, 42% yield) as a yellow liquid. ESI-MS m / z: 154.1 [M+H] + .

[0225] Subsequently, a similar synthesis method as in Preparation Example 1 was used to obtain intermediate 25.

[0226] Using a similar synthetic method as in Preparation Example 18, intermediates 26-29 can be obtained.

[0227] Preparation Example 19: Synthesis of 1-((4-amino-1,5-dimethyl-1H-pyrazol-3-yl)methyl)pyrrolidin-2-one (Intermediate 30)

[0228] Step 1: Synthesis of Intermediate 30-1

[0229] 2-Pyrrolidone (155 mg, 1.82 mmol) was dissolved in DMF (20 mL). NaH (73 mg, 1.82 mmol) was added in an ice bath and stirred at room temperature for 10 min. A DMF solution of Intermediate 12-1 (300 mg, 1.52 mmol) was then added and stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. Saturated ammonium chloride was added for quenching, and the mixture was extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford Intermediate 30-1 (223 mg, 76% yield) as a yellow solid. ESI-MS m / z: 194.1 [M+H] + .

[0230] Subsequently, a similar synthesis method as in Preparation Example 1 was used to obtain intermediate 30.

[0231] Preparation Example 20: Synthesis of 2-(4-amino-1,5-dimethyl-1H-pyrazol-3-yl)acetamide (Intermediate 31)

[0232] Step 1: Synthesis of Intermediate 31-1

[0233] Intermediate 17-1 (500 mg, 2.20 mmol) was dissolved in THF / H2O (20 / 4 mL), and hydrogenated LiOH (106 mg, 4.40 mmol) was added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. 1M hydrochloric acid was used to neutralize the mixture until it was weakly acidic. The mixture was extracted with EA (50 mL*3). The organic phases were combined, dried, and concentrated to afford Intermediate 31-1 (398 mg, 91% yield) as a pale yellow solid. ESI-MS m / z: 200.1 [M+H] + .

[0234] Step 2: Synthesis of Intermediate 31-2

[0235] Intermediate 31-1 (398 mg, 2.00 mmol) was dissolved in DMF (20 mL), and NH4Cl (321 mg, 6.00 mmol), HATU (1.14 g, 3.00 mmol), and TEA (606 mg, 6.00 mmol) were added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. Extraction was performed with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 31-2 (318 mg, 80% yield) as a pale yellow solid. ESI-MS m / z: 199.1 [M+H] + .

[0236] Subsequently, a similar synthesis method as in Preparation Example 1 was used to obtain intermediate 31.

[0237] Using a similar synthetic method as in Preparation Example 20, intermediate 32-33 can be obtained.

[0238] Preparation Example 21: Synthesis of N-((4-amino-1,5-dimethyl-1H-pyrazol-3-yl)methyl)acetamide (Intermediate 34)

[0239] Step 1: Synthesis of Intermediate 34-1

[0240] (1,5-Dimethyl-1H-pyrazol-3-yl)methanamine (300 mg, 2.40 mmol) and TEA (485 mg, 4.80 mmol) were dissolved in DCM (20 mL). A solution of acetyl chloride (198 mg, 2.52 mmol) in DCM was added at 0°C. The reaction was stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. Extraction with DCM (30 mL x 3) was performed, and the organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 3 / 1) to afford Intermediate 34-1 (353 mg, 88% yield) as a yellow solid. ESI-MS m / z: 168.1 [M+H] + .

[0241] Subsequently, a similar synthesis method as in Preparation Example 1 was used to obtain intermediate 34.

[0242] Preparation Example 22: Synthesis of 3-(2-fluoroethyl)-1,5-dimethylpyrazol-4-amine (Intermediate 35)

[0243] Step 1: Synthesis of Intermediate 35-1

[0244] Intermediate 12-1 (2 g, 13.89 mmol) was dissolved in ACN (50 mL). TMSCN (2.76 g, 27.78 mmol) and TBAF (1 M, 27.78 mL) were added at room temperature. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. Extraction was performed with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford Intermediate 35-1 (1.1 g, 59% yield) as a yellow solid. ESI-MS m / z: 136.1 [M+H] + .

[0245] Step 2: Synthesis of Intermediate 35-2

[0246] Intermediate 35-1 (1.1 g, 8.15 mmol) was dissolved in EtOH (20 mL), and HCl / EtOH (2 M, 20.4 mL) was added. The reaction was stirred at 80°C and monitored by LC-MS. The reaction was complete. The ethanol was removed by concentration, and the mixture was neutralized to a weak base with saturated sodium bicarbonate. The mixture was extracted with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford Intermediate 35-2 (1.15 g, 78% yield) as a pale yellow solid. ESI-MS m / z: 183.1 [M+H] + .

[0247] Step 3: Synthesis of Intermediate 35-3

[0248] Intermediate 35-2 (1.15 g, 6.32 mmol) was dissolved in THF (20 mL). LiAlH4 (360 mg, 9.48 mmol) was slowly added in an ice bath. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. The mixture was quenched with saturated ammonium chloride, filtered, and extracted with EA (30 mL x 3). The organic phases were combined, dried, and concentrated to afford Intermediate 35-3 (580 mg, 66% yield) as a pale yellow liquid. ESI-MS m / z: 141.1 [M+H] + .

[0249] Step 4: Synthesis of Intermediate 35-4

[0250] Intermediate 35-3 (580 mg, 4.14 mmol) was dissolved in DCM (20 mL). DAST (1.00 g, 6.21 mmol) was added in an ice bath and stirred at room temperature. LC-MS monitoring confirmed the complete reaction. Extraction with DCM (30 mL x 3) was performed, and the organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 35-4 (260 mg, 44% yield) as a pale yellow liquid. ESI-MS m / z: 143.1 [M+H] + .

[0251] Subsequently, a similar synthesis method as in Preparation Example 1 was used to obtain intermediate 35.

[0252] Preparation Example 23: Synthesis of 3-(2,2-difluoroethyl)-1,5-dimethylpyrazol-4-amine (Intermediate 36)

[0253] Step 1: Synthesis of Intermediate 36-1

[0254] Intermediate 17-1 (1 g, 4.41 mmol) was dissolved in DCM (20 mL). DIBAL-H (1 M, 8.82 mL) was added at -78°C and the reaction was stirred at -78°C. LC-MS monitoring indicated that the reaction was complete. The reaction was quenched with saturated ammonium chloride and extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford Intermediate 36-1 (610 mg, 76% yield) as a pale yellow liquid. ESI-MS m / z: 184.1 [M+H] + .

[0255] Subsequently, a similar synthetic method as in Preparation Example 14 was used to obtain intermediate 36.

[0256] Preparation Example 24: Synthesis of tert-butyl 8-bromo-3,4-dihydrobenzo[4,5]thieno[3,2-c]pyridine-2(1H)-carboxylate (Intermediate 37) and tert-butyl 6-bromo-3,4-dihydrobenzo[4,5]thieno[2,3-c]pyridine-2(1H)-carboxylate (Intermediate 38)

[0257] Step 1: Synthesis of Intermediate 37-1 and Intermediate 38-1

[0258] 4-Bromothiophenol (5 g, 26.46 mmol) was dissolved in methanol (80 mL), and NaOH (1.06 g, 26.46 mmol) and tert-butyl 7-oxo-3-azabicyclo[4.1.0]heptane-3-carboxylate (5.27 g, 26.46 mmol) were added. The reaction was stirred at 70°C. LC-MS monitoring indicated that the reaction was complete. Extraction was performed with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford Intermediate 37-1 (8.0 g, 78% yield) as a colorless oil. ESI-MS m / z: 388.0 [M+H] + Colorless oil intermediate 38-1 (1.6 g, yield 16%), ESI-MS m / z: 388.0 [M+H] + .

[0259] Step 2: Synthesis of Intermediate 37-2

[0260] Intermediate 37-1 (8 g, 20.62 mmol) was dissolved in DCM (100 mL) and Dess-Martin reagent (11.37 g, 26.80 mmol) was added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. The mixture was quenched with saturated sodium sulfite and extracted with DCM (50 mL x 3). The organic phases were combined, dried, and concentrated to afford Intermediate 37-2 (7.5 g, 94% yield) as a light yellow oil. ESI-MS m / z: 386.0 [M+H] + .

[0261] Step 3: Synthesis of Intermediate 37

[0262] Intermediate 37-2 (7 g, 18.13 mmol) was dissolved in polyphosphoric acid (50 mL) and stirred at 130°C. LC-MS monitoring indicated that the reaction was complete. THF and methanol were added for dilution, and the mixture was neutralized to a weak base with 50% sodium hydroxide. Boc2O (7.91 g, 36.26 mmol) was added and stirred at room temperature for 1 h. Extraction was performed with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 37 (1.4 g, 21% yield) as a yellow solid. ESI-MS m / z: 368.0 [M+H] + .

[0263] The same synthetic method can be used to obtain intermediate 38.

[0264] Preparation Example 25: Synthesis of tert-butyl 8-bromo-3,4-dihydrobenzofurano[3,2-c]pyridine-2(1H)-carboxylate (Intermediate 39)

[0265] Step 1: Synthesis of Intermediate 39-1

[0266] Ethyl acetohydroxamate (526 mg, 5.10 mmol) was dissolved in DMF (30 mL), and potassium tert-butoxide (572 mg, 5.10 mmol) was added. The mixture was stirred at room temperature for 5 minutes, followed by the addition of bis(4-bromophenyl)iodonium trifluoromethanesulfonate (2 g, 3.40 mmol). The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. Extraction was performed with EA (50 mL x 3), and the organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford Intermediate 39-1 (700 mg, 80% yield) as a colorless oil. ESI-MS m / z: 258.0 [M+H] + .

[0267] Step 2: Synthesis of Intermediate 39-2

[0268] Intermediate 39-1 (700 mg, 2.72 mmol) was dissolved in DCM (20 mL), and HCl / Dioxane (4 M, 5 mL) was added at 0°C. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. The mixture was directly concentrated to give Intermediate 39-2 (505 mg, yield 99%) as a white solid. ESI-MS m / z: 188.0 [M+H] + .

[0269] Step 3: Synthesis of Intermediate 39

[0270] Intermediate 39-2 (505 mg, 2.70 mmol) was dissolved in acetic acid / concentrated sulfuric acid (10 / 2 mL) and stirred at 110°C. LC-MS monitoring confirmed the completion of the reaction. The mixture was concentrated directly and neutralized to a weak base with saturated sodium bicarbonate. The mixture was extracted with EA (30 mL*3). The organic phases were combined, dried, and concentrated. The concentrated product was dissolved in MeOH (20 mL). K2CO3 (745 mg, 5.40 mmol) and Boc2O (1.18 g, 5.40 mmol) were added. The mixture was stirred at room temperature for 1 h. The mixture was extracted with EA (50 mL*3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford Intermediate 39 (768 mg, 81% yield) as a yellow oil. ESI-MS m / z: 352.0 [M+H] + .

[0271] Preparation Example 26: Synthesis of tert-butyl 9-bromo-3,4-dihydropyrazolo[1,5-a:4,3-c']bipyridine-2(1H)-carboxylate (Intermediate 40)

[0272] Step 1: Synthesis of Intermediate 40-1

[0273] 2,4-Dibromopyridine (15.00 g, 63.30 mmol) and 3-butyn-1-ol (4.40 g, 63.30 mmol) were dissolved in THF (150 mL). Pd(PPh3)2Cl2 (2.22 g, 3.17 mmol), CuI (1.21 g, 6.33 mmol), and TEA (12.83 g, 127.00 mmol) were added. The reaction was stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. Extraction was performed with EA (100 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 5 / 1 to 0 / 1) to afford Intermediate 40-1 (12.00 g, 85% yield) as a yellow solid. ESI-MS m / z: 226.0 [M+H] + .

[0274] Step 2: Synthesis of Intermediate 40-2

[0275] Intermediate 40-1 (7.00 g, 30.95 mmol) was dissolved in DCM (120 mL). 2,4,6-Trimethylbenzenesulfonylhydroxylamine (17.50 g, 81.51 mmol) was added at 0°C and the reaction was stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. Extraction was performed with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 5 / 1 to 0 / 1) to afford Intermediate 40-2 (5.50 g, 74% yield) as a yellow solid. ESI-MS m / z: 241.0 [M+H] + .

[0276] Step 3: Synthesis of Intermediate 40-3

[0277] Intermediate 40-2 (4.00 g, 16.60 mmol) and phthalimide (2.90 g, 19.90 mmol) were dissolved in THF (100 mL). DIAD (4.00 g, 19.90 mmol) and PPh3 (5.20 g, 19.90 mmol) were added and the reaction was stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. Extraction was performed with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 5 / 1 to 0 / 1) to afford Intermediate 40-3 (5.20 g, 85% yield) as a yellow solid. ESI-MS m / z: 370.0 [M+H] + .

[0278] Step 4: Synthesis of Intermediate 40-4

[0279] Intermediate 40-3 (5.20 g, 14.09 mmol) was dissolved in EtOH (100 mL), and hydrazine hydrate (4.09 g, 85%) was added. The reaction was stirred at 90°C and monitored by LC-MS. The reaction was complete. The mixture was filtered and extracted with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH = 20 / 1 to 10 / 1) to afford intermediate 40-4 (2.53 g, 75% yield), a yellow liquid. ESI-MS m / z: 240.0 [M+H] + .

[0280] Step 5: Synthesis of Intermediate 40-5

[0281] Intermediate 40-4 (1.05 g, 4.37 mmol) was dissolved in AcOH (20 mL), and paraformaldehyde (787 mg, 8.75 mmol) was added. The reaction was stirred at room temperature. LC-MS monitoring showed that the reaction was complete. The reaction was directly concentrated to give white solid intermediate 40-5 (1.85 g, crude product). ESI-MS m / z: 252.0 [M+H] + .

[0282] Step 6: Synthesis of Intermediate 40

[0283] Intermediate 49-5 (1.85 g, 4.37 mmol) was dissolved in DCM (30 mL), and TEA (2.21 g, 21.85 mmol) and Boc2O (1.91 g, 8.74 mmol) were added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. Extraction was performed with DCM (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford Intermediate 40 (936 mg, 61% yield) as a white solid. ESI-MS m / z: 352.1 [M+H] + .

[0284] Preparation Example 27: Synthesis of tert-butyl 9-bromo-3,4-dihydropyrazino[1,2-b]indazole-2(1H)-carboxylate (Intermediate 41)

[0285] Step 1: Synthesis of Intermediate 41-1

[0286] 5-Bromoindazole-3-carboxylic acid (2.20 g, 9.20 mmol) and 2-(4-methoxybenzylamino)ethanol (2.00 g, 11.04 mmol) were dissolved in DMF (30 mL). DIEA (7.10 g, 54.76 mmol) and HATU (3.50 g, 9.2 mmol) were added and stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. Extraction with EA (50 mL x 3) was performed, and the organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 41-1 (2.50 g, 67% yield) as a yellow solid. ESI-MS m / z: 404.1 [M+H] + .

[0287] Step 2: Synthesis of Intermediate 41-2

[0288] Intermediate 41-1 (2.45 g, 6.26 mmol) was dissolved in THF (50 mL), and DIAD (1.58 g, 9.10 mmol) and PPh3 (2.39 g, 9.10 mmol) were added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. Extraction was performed with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 5 / 1 to 1 / 1) to afford Intermediate 41-2 (2.10 g, 88% yield) as a white solid. ESI-MS m / z: 386.0 [M+H] + .

[0289] Step 3: Synthesis of Intermediate 41-3

[0290] Intermediate 41-2 (2.10 g, 5.45 mmol) was dissolved in THF (40 mL), and LiAlH4 (412 mg, 10.91 mmol) was added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. The mixture was quenched with saturated ammonium chloride, filtered, and extracted with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 41-3 (1.52 g, 75% yield) as a yellow liquid. ESI-MS m / z: 372.1 [M+H] + .

[0291] Step 4: Synthesis of Intermediate 41-4

[0292] Intermediate 41-3 (1.52 g, 4.10 mmol) was dissolved in DCM (20 mL), TFA (5 mL) was added, and the reaction was stirred at room temperature. LC-MS monitoring showed that the reaction of the starting material was complete. Direct concentration gave intermediate 41-4 (1.65 g, crude product) as a yellow oil. ESI-MS m / z: 252.0 [M+H] + .

[0293] Step 6: Synthesis of Intermediate 41

[0294] Intermediate 41-4 (1.65 g, 4.10 mmol) was dissolved in DCM (30 mL), and TEA (1.24 g, 12.30 mmol) and Boc2O (1.79 g, 8.20 mmol) were added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. Extraction was performed with DCM (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford Intermediate 41 (750 mg, 52% yield) as a white solid. ESI-MS m / z: 352.1 [M+H] + .

[0295] Preparation Example 28: Synthesis of (S)-tert-butyl 9-bromo-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (Intermediate 42)

[0296] Step 1: Synthesis of Intermediate 42-1

[0297] S-1-Boc-3-hydroxymethylpiperazine (5.00 g, 23.15 mmol) was dissolved in ACN (50 mL), and TEA (1.54 g, 15.28 mmol) and ethyl trifluoroacetate (3.29 g, 23.15 mmol) were added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. Extraction was performed with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 3 / 1) to afford Intermediate 42-1 (6.50 g, 90% yield) as a yellow oil. ESI-MS m / z: 313.1 [M+H] + .

[0298] Step 2: Synthesis of Intermediate 42-2

[0299] Intermediate 42-1 (6.50 g, 20.83 mmol) and 2,4-dibromophenol (5.25 g, 20.83 mmol) were dissolved in THF (80 mL). DIAD (8.42 g, 41.66 mmol) and PPh3 (10.91 g, 41.66 mmol) were added and stirred at 60°C. LC-MS monitoring indicated that the reaction was complete. Extraction was performed with EA (100 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 3 / 1) to afford Intermediate 42-2 (8.64 g, 76% yield) as a yellow solid. ESI-MS m / z: 547.0 [M+H] + .

[0300] Step 3: Synthesis of Intermediate 42-3

[0301] Intermediate 42-2 (8.64 g, 15.82 mmol) was dissolved in methanol / water (100 / 20 mL), and K2CO3 (6.55 g, 47.46 mmol) was added. The mixture was stirred at 60°C and monitored by LC-MS. The reaction was complete. Extraction was performed with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 42-3 (6.48 g, 91% yield) as a yellow solid. ESI-MS m / z: 451.0 [M+H] + .

[0302] Step 6: Synthesis of Intermediate 42

[0303] Intermediate 42-3 (6.48 g, 14.40 mmol) was dissolved in toluene (100 mL), and Pd(OAc)2 (323 mg, 1.44 mmol), BINAP (1.79 g, 2.88 mmol), and Cs2CO3 (9.38 g, 28.80 mmol) were added. The reaction was stirred at 100°C. LC-MS monitoring indicated that the reaction was complete. Extraction was performed with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 42 (1.32 g, 25% yield) as a yellow solid. ESI-MS m / z: 369.1 [M+H] + .

[0304] Using a similar synthetic method as in Preparation 28, intermediate 43 can be obtained.

[0305] Preparation Example 29: Synthesis of tert-butyl 3,4,6,7,8,9-hexahydrothiophene[3,2-c:4,5-c']dipyridine-2(1H)-carboxylate (Intermediate 44)

[0306] Step 1: Synthesis of Intermediate 44-1

[0307] 2-Bromo-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (20.00 g, 62.85 mmol) and DMF (9.20 g, 125.70 mmol) were dissolved in THF (300 mL) and added at -78°C. n- BuLi (2.5M, 38 mL) was slowly heated to room temperature with stirring. LC-MS monitoring indicated that the starting material was more than half reacted. The reaction was quenched with saturated ammonium chloride and extracted with EA (100 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford intermediate 44-1 (12.00 g, 71% yield) as a yellow solid. ESI-MS m / z: 268.1 [M+H] + .

[0308] Step 2: Synthesis of Intermediate 44-2

[0309] Intermediate 44-1 (12.00 g, 44.94 mmol) was dissolved in DCM (120 mL), TFA (20 mL) was added, and the reaction was stirred at room temperature. LC-MS monitoring showed that the reaction was complete. The reaction was directly concentrated to give intermediate 44-2 (10.15 g, yield exceeding 100%) as a yellow oil. ESI-MS m / z: 168.0 [M+H] + .

[0310] Step 3: Synthesis of Intermediate 44-3

[0311] Intermediate 44-2 (10.15 g, 44.94 mmol) was dissolved in DMF (100 mL), and K2CO3 (18.61 g, 134.82 mmol) was added. The reaction was stirred at 60°C and monitored by LC-MS. The reaction was complete. Extraction was performed with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford Intermediate 44-3 (9.82 g, 85% yield) as a yellow oil. ESI-MS m / z: 258.1 [M+H] + .

[0312] Step 4: Synthesis of Intermediate 44-4

[0313] Intermediate 44-3 (5.00 g, 19.46 mmol) was dissolved in MeOH (50 mL), and NaBH4 (1.47 g, 38.91 mmol) was added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. The mixture was quenched with saturated ammonium chloride, filtered, and extracted with EA (50 mL x 3). The organic phases were combined, dried, and concentrated to give a yellow liquid intermediate 44-4 (4.84 g, yield 96%). ESI-MS m / z: 260.1 [M+H] + .

[0314] Step 5: Synthesis of Intermediate 44-5

[0315] Intermediate 44-4 (4.84 g, 18.69 mmol) was dissolved in DCM (50 mL), and thionyl chloride (3.33 g, 28.03 mmol) was slowly added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. The reaction was concentrated to give Intermediate 44-5 (5.13 g, 99%) as a white solid. ESI-MS m / z: 278.1 [M+H] + .

[0316] Step 6: Synthesis of Intermediate 44-6

[0317] Intermediate 44-5 (5.13 g, 18.52 mmol) was dissolved in ACN (80 mL), and TMSCN (3.67 g, 37.04 mmol) and TBAF (9.68 g, 37.04 mmol) were added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. Extraction was performed with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 5 / 1) to afford Intermediate 44-6 (3.92 g, 79% yield) as a pale yellow solid. ESI-MS m / z: 269.1 [M+H] + .

[0318] Step 7: Synthesis of Intermediate 44-7

[0319] Intermediate 44-6 (3.92 g, 14.63 mmol) was dissolved in EtOH (50 mL), and concentrated sulfuric acid (5 mL) was slowly added.

[0320] The reaction was stirred at 80°C and monitored by LC-MS. The reaction was complete. The mixture was poured into ice water and neutralized to a weak base with saturated sodium bicarbonate. The mixture was extracted with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 3 / 1) to afford Intermediate 44-7 (4.06 g, 88% yield) as a pale yellow oil. ESI-MS m / z: 316.1 [M+H] + .

[0321] Step 8: Synthesis of Intermediate 44-8

[0322] Intermediate 44-7 (4.06 g, 12.89 mmol) was dissolved in THF (40 mL), and LiAlH4 (731 mg, 19.33 mmol) was added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. The mixture was quenched with saturated ammonium chloride, filtered, and extracted with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 44-8 (2.64 g, 75% yield) as a yellow liquid. ESI-MS m / z: 274.1 [M+H] + .

[0323] Step 9: Synthesis of Intermediate 44-9

[0324] Intermediate 44-8 (2.64 g, 9.67 mmol) and phthalimide (1.42 g, 9.67 mmol) were dissolved in THF (50 mL). DIAD (3.91 g, 19.34 mmol) and PPh3 (5.07 g, 19.34 mmol) were added and the reaction was stirred at room temperature. LC-MS monitoring indicated that the reaction was complete. Extraction was performed with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 5 / 1 to 1 / 1) to afford Intermediate 44-9 (3.34 g, 86% yield) as a white solid. ESI-MS m / z: 403.1 [M+H] + .

[0325] Step 10: Synthesis of Intermediate 44-10

[0326] Intermediate 44-9 (3.92 g, 8.31 mmol) was dissolved in DCE (50 mL), and 1-chloroethyl chloroformate (4.75 g, 33.24 mmol) was added. The reaction was stirred at 70°C and monitored by LC-MS. The reaction was complete. The mixture was neutralized with saturated sodium bicarbonate until weakly alkaline, and extracted with EA (50 mL x 3). The organic phases were combined, dried, and concentrated to afford Intermediate 44-10 (2.33 g, 90% yield) as a pale yellow oil. ESI-MS m / z: 313.1 [M+H]+.

[0327] Step 11: Synthesis of Intermediate 44-11

[0328] Intermediate 44-10 (2.33 g, 7.47 mmol) was dissolved in DCM (30 mL), and TEA (2.26 g, 22.40 mmol) and Boc2O (3.26 g, 14.94 mmol) were added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. Extraction was performed with DCM (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 3 / 1) to afford Intermediate 44-11 (2.43 g, 79% yield) as a white solid. ESI-MS m / z: 413.1 [M+H] + .

[0329] Subsequently, a similar synthesis method as in Preparation Example 26 was used to obtain intermediate 44, ESI-MS m / z: 295.1 [M+H] + .

[0330] Using a similar synthetic method as in Preparation 29, intermediate 45 can be obtained.

[0331] Preparation Example 30: Synthesis of 2-(4-methoxybenzyl)-1,2,3,4,7,8,9,10-octahydropyridine[4',3':3,4]pyrazolo[1,5-a]pyrazine (Intermediate 46)

[0332] Using a similar synthetic method as in Preparation Example 27, intermediate 46-5 was obtained, ESI-MS m / z: 275.1 [M+H] + Step 1: Synthesis of Intermediate 46-6

[0333] Intermediate 46-5 (1.00 g, 3.65 mmol) and PMBCl (572 mg, 3.65 mmol) were dissolved in THF (20 mL) and stirred at 80°C. LC-MS monitoring showed that the reaction of the starting material was complete. The mixture was directly concentrated to give yellow solid intermediate 46-6 (1.65 g, crude product). ESI-MS m / z: 396.2 [M+H]+ .

[0334] Step 2: Synthesis of Intermediate 46-7

[0335] Intermediate 46-6 (1.65 g, 3.65 mmol) was dissolved in MeOH (30 mL), and NaBH4 (414 mg, 10.95 mmol) was added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. Extraction was performed with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 5 / 1 to 0 / 1) to afford Intermediate 46-7 (799 mg, 55% yield) as a yellow solid. ESI-MS m / z: 399.2 [M+H] + .

[0336] Step 3: Synthesis of Intermediate 46

[0337] Intermediate 46-7 (799 mg, 2.01 mmol) was dissolved in DCM (20 mL) and HCl / Dioxane (4 M, 5 mL) was added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. The mixture was concentrated to give Intermediate 46 (740 mg, yield exceeding 100%) as a white solid. ESI-MS m / z: 299.2 [M+H] + .

[0338] Example 1: Synthesis of 2,6-dichloro-4-(1,2,3,4-tetrahydrobenzo[4,5]thieno[3,2-c]pyridin-8-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide (Compound 1)

[0339] Step 1: Synthesis of 1-1

[0340] Intermediate 37 (1 g, 2.72 mmol) was dissolved in dioxane (20 mL), and bis(pinacol) borate (690 mg, 2.72 mmol), Pd(PPh3)4 (312 mg, 0.27 mmol), and AcOK (530 mg, 5.44 mmol) were added. The reaction was stirred at 110°C. LC-MS monitoring confirmed the complete reaction. Extraction was performed with EA (30 mL x 3). The combined organic phases were dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 3 / 1) to afford 1-1 (1.00 g, 89% yield) as a colorless oil. ESI-MS m / z: 416.2 [M+H] + .

[0341] Step 2: Synthesis of 1-2

[0342] 1,3,5-Trimethyl-pyrazol-4-amine (1 g, 7.99 mmol) was dissolved in pyridine (20 mL), and 4-bromo-2,6-dichlorobenzenesulfonyl chloride (2.59 g, 7.99 mmol) was added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. The pyridine was removed by concentration, and water (30 mL) was added. The mixture was extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 3 / 1) to afford 1-2 as a pale yellow solid (3.00 g, 91% yield). ESI-MS m / z: 411.9 [M+H] + .

[0343] Step 3: Synthesis of 1-3

[0344] 1-2 (100 mg, 0.24 mmol) and 1-1 (100 mg, 0.24 mmol) were dissolved in DMF / H2O (5 / 0.5 mL). Pd(PPh3)4 (28 mg, 0.02 mmol) and K3PO4 (102 mg, 0.48 mmol) were added. The reaction was stirred at 60°C. LC-MS monitoring indicated that the reaction was complete. Water (30 mL) was added and the mixture was extracted with EA (30 mL*3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to afford 1-3 (90 mg, 60% yield) as a yellow solid. ESI-MS m / z: 621.1 [M+H] + .

[0345] Step 4: 1 Synthesis

[0346] 1-3 (90 mg, 0.14 mmol) was dissolved in DCM (5 mL) and HCl / Dioxane (4 M, 1 mL) was added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. The mixture was neutralized with saturated sodium bicarbonate until weakly alkaline. The mixture was extracted with EA (20 mL x 3). The organic phases were combined, dried, and concentrated to afford 1 (51 mg, 68% yield) as a yellow solid.

[0347] 1 H NMR (400MHz, DMSO-d6): δ8.24(s,1H),8.12(s,1H),8.07(s,2H),8.03(d,J=8.4Hz,1H),7.77(dd,J=8.4,1.6Hz ,1H),4.09(s,2H),3.57(s,3H),3.12(t,J=5.4Hz,2H),2.85(d,J=5.5Hz,2H),1.96(s,3H),1.75(s,3H); ESI-MS m / z:521.1[M+H] + .

[0348] Example 2-35: Synthesis of Compound 2-35

[0349] Intermediate 1-34 is used as a starting material, subjected to substitution reaction with corresponding substituted benzenesulfonyl chloride, and then coupled with 1-1. A similar synthetic method as in Example 1 is used to obtain the target compound 2-35.

[0350] Examples 36-44: Synthesis of Compounds 36-44

[0351] Intermediate 2 is reacted with the corresponding substituted benzenesulfonyl chloride, and then coupled with 1-1. A similar synthetic method as in Example 1 is used to obtain the target compound 36-44.

[0352] Example 45-62: Synthesis of Compound 45-62

[0353] Using 1,3,5-trimethyl-pyrazol-4-amine, intermediate 1, and intermediate 2 as raw materials, a substitution reaction is carried out with the corresponding substituted benzenesulfonyl chloride, and then coupled with the boronic acid or boric acid ester corresponding to intermediate 38-43. Using a similar synthetic method as in Example 1, the target compounds 45-62 can be obtained.

[0354] Example 63: Synthesis of 2,6-dichloro-4-(3,4,6,7,8,9-hexahydrothiophene[3,2-c:4,5-c']dipyridin-2(1H)-yl)-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)benzenesulfonamide (Compound 63)

[0355] Using a similar synthesis method as in Example 1, intermediate 63-1 was obtained, ESI-MS m / z: 454.0 [M+H] + .

[0356] Step 1: Synthesis of 63-2

[0357] 63-1 (200 mg, 0.44 mmol) and intermediate 44 (130 mg, 0.44 mmol) were dissolved in toluene (20 mL). Pd(OAc)2 (10 mg, 0.04 mmol), BINAP (56 mg, 0.09 mmol), and Cs2CO3 (287 mg, 0.88 mmol) were added. The reaction was stirred at 100°C. LC-MS monitoring confirmed the complete reaction. Water (30 mL) was added and the mixture was extracted with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford 63-2 (91 mg, 31% yield) as a yellow solid. ESI-MS m / z: 668.2 [M+H] + .

[0358] Step 2: Synthesis of 63

[0359] 63-2 (91 mg, 0.14 mmol) was dissolved in DCM (5 mL) and HCl / Dioxane (4 M, 1 mL) was added. The reaction was stirred at room temperature and monitored by LC-MS. The reaction was complete. The mixture was neutralized with saturated sodium bicarbonate until weakly alkaline, and extracted with EA (20 mL x 3). The organic phases were combined, dried, and concentrated to afford 63 (47 mg, 61% yield) as a yellow solid.

[0360] 1 H NMR (400MHz, DMSO-d6): δ7.35(s,1H),7.16(s,2H),4.30-4.25(m,2H),3.84-3.80(m,2H),3.75-3.70(m,2H),3.60-3.57(m,3H) ,3.08-3.04(m,2H),2.85-2.79(m,2H),2.74-2.68(m,2H),1.99-1.95(m,5H),1.79-1.73(m,1H),0.71(d,J=6.7Hz,6H); ESI-MS m / z:568.1[M+H] + .

[0361] Examples 64-71: Synthesis of Compounds 64-71

[0362] Using 1,3,5-trimethyl-pyrazol-4-amine, intermediate 1, and intermediate 2 as raw materials, a substitution reaction is carried out with the corresponding substituted benzenesulfonyl chloride, and then coupled with intermediates 44-46. A similar synthetic method as in Example 63 is used to obtain the target compounds 64-71.

[0363] Example 72: Synthesis of 2,6-dichloro-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-4-(2-methyl-1,2,3,4-tetrahydrobenzo[4,5]thieno[3,2-c]pyridin-8-yl)benzenesulfonamide (Compound 72)

[0364] Step 1: Synthesis of 72

[0365] 3 (50 mg, 0.09 mmol) was dissolved in DCM (5 mL), and paraformaldehyde (13 mg, 0.44 mmol), AcOH (5 mg, 303 μmol), and NaBH3CN (28 mg, 0.44 mmol) were added. The reaction was stirred at room temperature. LC-MS monitoring confirmed the complete reaction. Extraction with DCM (10 mL x 3) was performed, and the combined organic phases were dried and concentrated to afford 72 (30 mg, 58% yield) as a yellow solid.

[0366] 1 H NMR (400MHz, DMSO-d6): δ8.25(s,1H),8.11-8.07(m,3H),8.04(d,J=8.5Hz,1H),7.75(dd,J=8.5,1.7Hz,1H),4.10(s,2H),3.61(s,3H),3. 13(t,J=5.8Hz,2H),2.89-2.83(m,2H),2.24(s,3H),2.00(s,3H),1.95(d,J=7.2Hz,2H),1.77-1.68(m,1H),0.69(d,J=6.6Hz,6H); ESI-MS m / z:577.1[M+H] + .

[0367] Examples 73-79: Synthesis of Compounds 73-79

[0368] Using a similar synthetic method as in Example 72, target compounds 73-79 can be obtained.

[0369] Examples 80-137: Synthesis of Compounds B1-B34, B37-B45, B48-B56, B59-B64

[0370] Using 1,3,5-trimethyl-pyrazol-4-amine, intermediate 1, intermediate 2, intermediate 12, intermediate 16, intermediate 20, intermediate 35, and intermediate 36 as raw materials, a substitution reaction is carried out with the corresponding substituted benzenesulfonyl chloride, and then coupled with the boronic acid or boric acid ester corresponding to intermediates 37-39. Using a synthetic method similar to that in Example 1, the target compounds B1-B34, B37-B45, B48-B56, and B59-B64 can be obtained.

[0371] Examples 138-143: Synthesis of Compounds B35-B36, B46-B47, B57-B58

[0372] Intermediates 16, 35 and 36 were used as raw materials to undergo substitution reaction with corresponding substituted benzenesulfonyl chlorides, followed by coupling with intermediates 44-45. A similar synthesis method as in Example 63 was used to obtain target compounds B35-B36, B46-B47 and B57-B58.

[0373] Example 144: Screening of Compounds for NM1T Enzyme Catalytic Inhibitory Activity

[0374] This study evaluated the ability of the compounds of the present invention to inhibit the catalytic activity of NMT1 in vitro. This experiment used FI fluorescence intensity analysis to characterize NMT1 inhibitors in the presence of 1.25 μM myristoyCoA (myristyl CoA lithium salt, Sigma, M4414). In this experiment, a peptide HSPP60SRC (Nanjing Peptide Industry, NJP23953) with the sequence H-Gly-Ser-Asn-Lys-Ser-Lys-Pro-Lys-NH2 was synthesized as the reaction substrate. The final concentrations of NMT1 enzyme were 6 nM, CPM (reactive thiol fluorescent probe, Invitrogen, D346) were 1 μM, HSPP60 SRC were 20 μM, and DMSO were 0.5%.

[0375] Compounds were dissolved in DMSO to obtain a 10 mM stock solution. Dose gradient reactions were prepared with an endpoint compound concentration of 3 mM and then three-fold dilutions were performed in DMSO for a total of ten data points. Using an ECHO acoustic pipetting device (BECKMAN, ECHO 655 system), 0.05 μL of the diluted compound solution was transferred to a 384-well assay plate (Corning, CLS4514). 2.5 μL of NMT1 enzyme working solution was added to the 384-well assay plate and incubated at 25°C for 10 minutes. Then, 5 μL of CPM and myristoy COA working solution was added, and the reaction was centrifuged at 1000 rpm for 1 minute. Subsequently, 2.5 μL of HSPP60 SRC working solution was added and the reaction was incubated at 25°C for 45 minutes. FI signals (em: 320 nm; ex: 405 nm) were detected using an HTS high-throughput drug screening multi-function microplate reader (BMG, PHERA star FSX).

[0376] 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.

[0377] Example 145: Screening of antiproliferative activity of compounds against MV-4-11 cells

[0378] 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 treatment with NMT1 inhibitors. 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, NMT1 inhibitors were 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%.

[0379] MV-4-11 cells were seeded in a white 96-well plate with 80 μL of cell suspension per well, containing 6,000 MV-4-11 cells. The plate was incubated overnight in a CO2 incubator. Then, 20 μL of NMT1 inhibitor solution at varying concentrations was added to the plate, and the 96-well plate was incubated in the incubator for three days. A separate plate was prepared, and the signal value was read on the day of drug addition, which was used as the maximum value (Max value in the equation below) for data analysis. 25 μL of cell viability chemiluminescent detection reagent was added to each well of this plate, and the plate was incubated at room temperature for 10 minutes to stabilize the luminescent signal. The readings were read using a multilabel analyzer.

[0380] 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 (derived using the "log (inhibitor) vs. response -- Variable slope" mode in GraphPad Prism). Min: 0.5% DMSO-treated wells; Max: Day 0 wells. Table 1 provides the inhibitory activity of the compounds of the present invention on MV-4-11 cell proliferation.

[0381] Table 1: Inhibitory activity of compounds against NMT1 enzyme (IC 50 ) and antiproliferative activity against MV-4-11 cells (IC 50 )

[0382] “-” means no test was performed

[0383] “*” indicates the experimental results of two independent tests

[0384] The reference compound PCLX-001 is compound DDD86481 in patent WO2010026365A1.

[0385] From the data in the above table, it can be seen that the compound of the present invention has a stronger inhibitory effect on NMT1 enzyme catalytic activity than the control compound PCLX-001, and the compound also has a stronger anti-proliferation activity on MV-4-11 cells.

[0386] Example 146: Evaluation of blood drug concentration in mice after oral administration

[0387] This study evaluated the blood concentration of the compound of the present invention in mice. The experiment used ICR mice from Zhaoyan (Suzhou) New Drug Research Center Co., Ltd. At the start of dosing, the animals were 6-8 weeks old and weighed 18-25 grams. The animals were housed in transparent resin plastic cages (400mm*240mm*200mm). Fluorescent lighting was used, with 12 hours of lighting (07:00-19:00) and 12 hours of no lighting per day. The dark time can be intermittently interrupted due to the needs of research-related activities. The ambient temperature and relative humidity of the animal room should be controlled within the range of 20-26°C and 40-70%, respectively. The feed was qualified rodent feed, and the drinking water was filtered and sterilized by an ultrapure water machine. All animals had free access to water during the experiment. The animals were fasted for at least 12 hours before dosing, and food was resumed 4 hours after dosing.

[0388] Animal body weight was measured before administration. Healthy animals of similar weight were selected for inclusion in the experiment and randomly divided into groups of 3 per group. Compounds were prepared using a 0.5% CMC aqueous solution at a concentration of 10 mg / kg. A single oral dose was administered. At least 0.2 mL of venous blood was collected 1 and 4 hours after administration. Blood was collected using EDTA-K2 anticoagulant tubes and gently inverted to mix. After collection, the blood samples were placed in an ice-water bath and rapidly centrifuged to separate plasma at 4000 rpm for 10 minutes at 4°C. Plasma was then stored at -70°C until testing.

[0389] Plasma sample standard curve and quality control: Prepare standard curve working solution and quality control working solution using 80% methanol in water (Thermo Fisher) as the diluent. Add 45 μL of blank plasma to 5 μL of each working solution to prepare the plasma standard curve and quality control samples. Add 300 μL of internal standard (8 μg / mL tolbutamide, acetonitrile (Thermo Fisher)) to the prepared standard curve and quality control samples. Vortex mix for 1 minute, then centrifuge at 4°C, 15,400 g for 10 minutes using an Eppendorf, 5810 centrifuge. The supernatant is analyzed by liquid chromatography-mass spectrometry (AB Sciex, API5000).

[0390] Plasma sample pretreatment: After thawing at room temperature, 50 μL of plasma was added to 300 μL of internal standard (8 μg / mL tolbutamide, acetonitrile (Thermo Fisher)). After vortex mixing for 1 min, the sample was centrifuged at 4°C and 15,400 g for 10 min using an Eppendorf 5810 centrifuge. The supernatant was analyzed by liquid chromatography-mass spectrometry (AB Sciex, API5000).

[0391] Analyst 1.6.3 software was used to output the original spectra, concentration, accuracy and other data. Microsoft Excel 2007 software was used to calculate the mean and standard error. The compound concentration-time results in the plasma samples of each group of animals are shown in Table 2.

[0392] Table 2. Concentrations of the compounds of the present invention in plasma samples at different time points (Mean ± SEM)

[0393] It can be seen from the data in the above table that the compound of the present invention has good oral absorption characteristics in mice after oral administration, and the blood concentration of the compound is high.

[0394] Example 147: In vivo evaluation of the anti-tumor efficacy of the compounds of the present invention

[0395] To evaluate the effects of the compounds of the present invention on tumor growth, an MV-4-11 human myelomonocytic leukemia cell xenograft animal model was established. Female BALB / cnude mice, 6-7 weeks old and weighing 18-22 grams, were purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd. After purchase, the mice were housed in SPF-grade IVC cages, 2-6 mice per cage, with free access to food and water. The housing temperature was maintained between 20-26°C (68-79°F), the relative humidity was 40-70%, and the lighting conditions were 12 hours (05:00-17:00) of fluorescent light exposure and 12 hours of no light per day. The experiment was conducted after one week of adaptive breeding.

[0396] Human leukemia MV-4-11 cells (ATCC, CRL-9591) were cultured in suspension in IMDM (Gibco, 12440-053) supplemented with 10% heat-inactivated fetal bovine serum (FBS, Gibco, 10099-141C) at 37°C and 5% CO2. Cells were passaged 2-3 times per week. When cells reached the exponential growth phase, they were harvested, counted, and inoculated subcutaneously on the right dorsal flank of female nude mice. A 10-well plate containing 8 x 10 6A suspension of 100uL of MV-4-11 cells + 100uL of Matrigle (Corning, 354234) matrix gel was inoculated subcutaneously on the right dorsal side of nude mice. 13 days after inoculation, when the volume of the subcutaneous transplanted tumor of nude mice grew to 100-300mm3, tumor-bearing mice with suitable shape and uniform size were selected and randomly divided into groups according to the experimental plan, with 5 mice in each group. Oral administration (PO, OQ) was started once a day on the day of grouping. All compounds of the present invention were administered at a concentration of 30mg / kg. During the administration period, the tumor diameter was measured with a digital vernier caliper twice a week, and the mice were weighed; after stopping the administration, the tumor diameter was measured once a week during the observation period, and the mice were weighed. The formula for calculating the tumor volume is: V = 0.5a*b 2 , a and b represent the long diameter and short diameter of the tumor, respectively.

[0397] The tumor inhibition efficacy of the compound was evaluated by TGI (%), TGI (%) = [1-(TVi-TV0) / (TVVi-TVV0)] * 100% (TV0 is the average volume of the treatment group on day 0, TVV0 is the average volume of the control group on day 0; TVi is the average volume of the treatment group on day i, TVVi is the average volume of the control group on day i). Data were plotted using GraphPad Prism software, and tumor volume and body weight data were expressed as the mean plus or minus the standard error of the mean and plotted as a function of time.

[0398] The tumor volume results are shown in FIG2 . Daily oral administration of compounds 2, 3, 13 and 45 of the present invention can significantly inhibit the growth of MV-4-11 tumors and lead to tumor regression.

[0399] The body weight results are shown in Figure 1. Compound 2 caused a slight decrease in animal weight in the early stage of administration, which then returned to normal. Compound 45 caused a slight decrease in body weight in the later stage of administration, but it did not exceed 10%. Compounds 3 and 13 did not cause weight loss. Overall, the compounds of the present invention have good tolerability.

[0400] In summary, the compounds of the present invention have excellent tumor growth inhibition effects and are well tolerated.

[0401] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound having a structure as shown in formula (1), or an isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate thereof: In formula (1): A is selected from the following group: in, Dashed lines are chemical bonds or none; and It is an aromatic ring; X is selected from the group consisting of CH or N, and when X is N, the dashed line connected to X is absent; U is selected from the group consisting of CH or N; W is selected from the group consisting of CH or N; J is selected from the group consisting of O, S or NH; V is selected from the group consisting of CH or N; Y is selected from the group consisting of O, S, NH or N(C 1-3 alkyl); m is 1 or 2; n is 1 or 2; p is 1, 2, or 3; R 4 , R 5 , R 6 , R 7 , R 8 Each independently selected from the group consisting of H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl or C 1-6 Alkoxy; R 9 Selected from the following group: H or C 1-3 alkyl; j is 1, 2, 3, or 4; R 1 Selected from the following group: H, C 1-3 Alkyl or halogenated C 1-3 alkyl; R 2 is a 5-7 membered heteroaryl group, which may be further substituted by 1, 2 or 3 R 2a Replaced by R 2a Selected from the following group: cyano, NO2, -OR a 、-C(=O)R a 、-NR c R d 、-C(=O)NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl and heterocycloalkyl may be optionally substituted by one or more R 2b replace; R 2b Selected from the following group: halogen, CN, NO2, OH, SH, -OR a 、-NR c R d 、-C(=O)NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b S(=O)2R a 、-C(=O)R a 、-OC(=O)R a 、-C(=O)OR b 、-NR b C(=O)OR b 、-OC(=O)NR c R d , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl and heterocycloalkyl may be optionally substituted by one or more R; or two R on the same atom 2b Together they constitute = O; R a Independently selected from the following group: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl and heterocycloalkyl may be optionally substituted by one or more R; R b Independently selected from the following group: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl and heterocycloalkyl may be optionally substituted by one or more R; R c and R d Independently selected from the following group: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl and heterocycloalkyl may be optionally substituted by one or more R; or R c and R d Together with the atoms to which they are attached, they form a 4-7 membered heterocycloalkyl group, which may be optionally substituted with one or more R; Each R is independently selected from the group consisting of halogen, CN, OH, NH2, NHCH3, N(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl or C 3-6 Cycloalkyl; Each R 3 Independently selected from the group consisting of H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl or C 1-6 Alkoxy.

2. The compound according to claim 1, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: The compound of formula (1) has the structure shown in (2-1), (2-2) or (2-3): Wherein, the definitions of each group are as described in claim 1.

3. The compound according to claim 1-2, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: R 1 Selected from the group consisting of H, Me, Et, i- Pr, CHF2 or CH2CF3.

4. The compound according to claim 1-2, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: R 2 for Among them, R 10 Select from H or C 1-6 Alkyl, R 11 Select from H or C 1-6 Alkyl, R 12 Same definition as R in claim 1 2a .

5. The compound according to claim 1-2, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: R 2 for Among them, R 12 Same definition as R in claim 1 2a .

6. The compound according to claim 1-2, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: R 2 Select from the following group:

7. The compound according to claim 1-2, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Each is independently selected from the group consisting of H, halogen, cyano, Me, Et, CF3, cyclopropyl, OMe, OEt or OCF3.

8. The compound according to claim 1-2, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: R 9 Selected from the group consisting of H or Me.

9. The compound, its isomer, polymorph or pharmaceutically acceptable salt thereof according to claims 1-2, characterized in that: The compound has a structure selected from the group consisting of:

10. A pharmaceutical composition for treating, regulating and / or preventing diseases mediated by NMT, characterized in that: The pharmaceutical composition comprises a pharmaceutically acceptable excipient or carrier, and as an active ingredient, the compound according to any one of claims 1 to 9, or its isomers, polymorphs, pharmaceutically acceptable salts, hydrates or solvates.

11. Use of the compound according to any one of claims 1 to 9, or its isomers, polymorphs, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition according to claim 10, characterized in that: Used for preparing a pharmaceutical composition for treating, regulating and / or preventing diseases mediated by NMT.

12. 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 9, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition according to claim 10.

Images