Nitrogen-containing heterocyclic compound and use thereof

Abstract

Disclosed in the present invention are a nitrogen-containing heterocyclic compound and use thereof. The compound has a structure represented by formula (I). The compound of the present invention has an excellent inhibitory effect on glutaminyl cyclase, can be used in treating a tumor, an immunological disease, a neurological disease, obesity, or aging, and has good application prospects.

Description

Nitrogen-containing heterocyclic compound and application thereof TECHNICAL FIELD

[0001] The present application relates to the field of chemical medicine, and relates to a nitrogen-containing heterocyclic compound and application thereof, in particular to a nitrogen-containing heterocyclic compound, application of the nitrogen-containing heterocyclic compound to inhibition of glutaminyl cyclase, a pharmaceutical composition containing the nitrogen-containing heterocyclic compound and application thereof. BACKGROUND

[0002] Tumor is an important cause of human death, and combating cancer is a severe challenge to human health. For many years, chemotherapy, radiotherapy, surgery and immunotherapy are common medical means for tumor treatment. Tumor immunotherapy is a treatment method for combating tumor by enhancing the natural immune defense of human body. In recent years, the rapid development of this method brings new hope for human treatment of tumor. Existing tumor immunotherapy drugs are mainly antibody drugs targeting immune checkpoints such as PD-1 / PD-L1 and CTLA-4 / B7, but such drugs have problems in clinical application, such as immune-related toxicity, poor pharmacokinetic properties, weak tumor treatment penetration ability and narrow application population. At the same time, tumor cells can realize immune escape by inducing immune suppression and reducing their own immunogenicity. For example, by highly expressing immune suppression signal molecules to interact with immune cells, such as the interaction of PD-L1 and PD1, CD47 and SIRPα, etc., expressing the “don't eat me” signal directly inhibits immune response and promotes tumor cells to escape immune surveillance.

[0003] Glutaminyl cyclase (EC 2.3.2.5) is an enzyme that can catalyze the intramolecular cyclization reaction of N-terminal glutamine residues of polypeptides, proteins and the like to generate pyroglutamic acid (pGlu*), and has important biological functions such as changing the N-terminal chemical structure of proteins, regulating activity, and enhancing stability.

[0004] Pyroglutamylation is a post-translational modification in which a glutamine or glutamic acid amino acid is converted into a pyroglutamic acid moiety. At present, it is known that two enzymes encoded by genes in the human body are involved in catalyzing this N-terminal pyroglutamylation reaction, including glutaminyl cyclase encoded by glutaminyl-peptide cyclotransferase gene (QPCT) and glutaminyl cyclase-like protein encoded by glutaminyl-peptide cyclotransferase like gene (QPCTL).

[0005] QPCT catalyzes the intramolecular cyclization of N-terminal glutamine residues to pyroglutamic acid (pGlu*) with liberation of ammonia. The gene encoding QPCT is located on chromosome 2p22.3. Human QPCT consists of 361 amino acids with an N-terminal secretion signal, QPCT was originally isolated from the latex of the tropical plant Carica papaya by Messer in 1963 (Messer, M. 1963, Nature 4874, 1299). 24 years later, the corresponding enzymatic activity was found in animal pituitaries (Busby, W. H. J. et al. 1987, J Biol Chem 262, 8532-8536; Fischer, W. H. and Spiess, J. 1987, Proc Natl Acad Sci USA 84, 3628-3632). For mammalian QPCT, the conversion of Gin to pGlu by QPCT can be demonstrated from the precursors of TRH and GnRH (Busby, W. H. J. et al. 1987, J Biol Chem 262, 8532-8536; Fischer, W. H. and Spiess, J. 1987, Proc Natl Acad Sci USA 84, 3628-3632). In addition, initial localization experiments of QPCT showed co-localization with its putative catalytic product in bovine pituitary, further supporting the proposed function in the synthesis of peptide hormones (Bockers, T. M. et al. 1995, J Neuroendocrinol 7, 445-453). It was demonstrated that both recombinant human QPCT and QPCT from brain extracts catalyze the cyclization of N-terminal glutamine as well as glutamic acid. Most surprisingly, it was found that the Glu- conversion catalyzed by the cyclase is favored around pH 6.0, while the Gin- conversion to pGlu-derivatives occurs at an optimal pH of about 8.0. Since inhibition of QPCT-activity of recombinant human QPCT and QPCT from pig pituitary extract inhibits the formation of pGlu-Aβ-related peptides, the enzyme QPCT is a target for drug development for the treatment of Alzheimer’s disease (J Med. Chem. 2017, 60, 2573-2590; Alzheimers Res Ther 2018, 10, 107).

[0006] Glutaminyl peptide cyclotransferase-like protein (QPCTL) also catalyzes the intramolecular cyclization of N-terminal glutamine residues to pyroglutamic acid (pGlu*), releasing ammonia. QPCTL is localized in the Golgi complex, and the gene encoding this protein is located on chromosome 19q13.32. Mammalian QPCTL was identified in 2008, including human QPCTL and murine QPCTL (J. Mol. Biol. 2008, 379, 966-80). Compared with QPCT, QPCTL has 2- to 15-fold lower catalytic activity for several synthetic substrates. In addition, QPCT has higher expression in neuronal tissues, while the expression of QPCTL does not differ significantly between different tissues and organs (FEBS J. 2009, 276, 6522-36). Among nine different mouse strains, the highest enzymatic QPCT / QPCTL activity is in the ventral brain, followed by the cortex and hippocampus. QPCT knockout significantly reduces QPCT activity in the mouse brain, especially in the hypothalamus and plasma, although activity can still be detected in peripheral organs such as the liver and spleen, which can be the result of QPCTL expression (Int. J. Dev. Neurosci. 2014, 36, 64-73). QPCTL protein contains 382 amino acid residues, including an active catalytic domain (Ser53-Leu382), a transmembrane domain (Leu35-Trp52), and an extracellular domain (Met1-Arg34) (J Biol Chem. 286, 14199-14208).

[0007] CD47 (Cluster of Differentiation 47), also known as integrin-associated protein, belongs to the immunoglobulin superfamily member, which can be expressed on the surface of a variety of cells, including normal cells (such as red blood cells) and a variety of tumor cells. CD47 and signal regulatory protein SIRPα (Signal Regulatory Protein α) bind to each other, thereby mediating a series of cascading reactions such as apoptosis, proliferation, immune response, etc. SIRPα is mainly expressed in mononuclear cells, most of the macrophages in tissue subpopulations, granulocytes and other cells, and its expression on macrophages is relatively stable and is not affected by factors such as inflammation. After SIRPα binds to the N-terminal domain of CD47, the tyrosine residues on the immunoreceptor tyrosine-based inhibitory motifs (ITIM) of SIRPα are phosphorylated, and phosphatases SHP-1 / SHP-2 are recruited and activated, thereby triggering the dephosphorylation process of downstream pathway molecules, releasing the "don't eat me" signal, and inhibiting the phagocytosis of macrophages. CD47 / SIRPα binding ultimately triggers a series of negative regulation of cells, including inhibition of phagocytosis and cytotoxicity of macrophages and neutrophils, thereby allowing tumor cells to escape immune surveillance.

[0008] Studies have found that blocking the interaction between CD47 / SIRPα can promote the phagocytosis of macrophages to tumor cells, thereby exerting an anti-tumor effect. Clinical data also shows that the expression of CD47 is closely related to the survival rate of cancer patients, and patients with high expression of CD47 often have poor survival rate and prognosis. Currently, there are several antibody drugs targeting CD47 in clinical research. CD47 antibodies can effectively inhibit tumor growth in solid tumors and hematological tumors, but such drugs can cause serious adverse reactions. This is because CD47 is also expressed in normal red blood cells in the human body, and CD47 antibodies can bind to CD47 on the surface of red blood cells in addition to tumor cells, thereby causing serious side effects such as red blood cell toxicity. In addition, due to the wide expression range of CD47, the antibody drug has an antigen silencing effect, and a higher dose or frequent administration of the antibody drug is required to achieve effective treatment. Therefore, there is an urgent need in the clinic to find new CD47 inhibition strategies to provide effective means for tumor immunotherapy.

[0009] Studies have shown that QPCTL can specifically regulate the CD47 / SIRPa signaling axis in various cells, and this regulatory effect depends on the QPCTL enzyme activity (Nat. Med. 2019, 25, 612-619; Cell Res. 2019, 29, 502-505). In addition, knocking out QPCTL in cells or using QPCTL chemical inhibitors can effectively inhibit the N-terminal pyroglutamination level of CD47 and the binding of CD47 / SIRPa, but has no significant effect on the expression of cell surface CD47. QPCTL regulates the binding of CD47 and SIRPa by catalyzing the formation of pyroglutamic acid at the 19th glutamine of CD47. In addition, the increase of antibody-opsonized cell phagocytosis in vitro and the increase of opsonized tumor cell clearance in vivo are proved to be the effects of blocking QPCTL activity or production (Nat. Med. 2019, 25, 612-619). In QPCTL knockout mice, the deletion of QPCTL promotes the development of macrophages in bone marrow (Cell Res. 2019, 29, 502-505), and enhances the neutrophil-mediated tumor cell killing effect (Nat. Med. 2019, 25, 612-619; Cancer Sci 2021, 112, 3029-3040). QPCTL is a Golgi-localized protein and is almost not expressed in mature red blood cells. Therefore, by inhibiting the function of QPCTL protein to block the CD47 / SIRPa pathway, it is possible to reduce the impact on the normal red blood cell CD47 function, thereby avoiding the serious side effects caused by CD47 antibody drugs. In summary, QPCTL is a potential target for tumor immunotherapy mediated by the CD47 / SIRPa pathway.

[0010] In addition to CD47, QPCT and QPCTL can also pyroglutamate other proteins. For example, beta amyloid protein known to be involved in Alzheimer's disease is pyroglutamated by QPCT (Pharmacological research, 2019 147, 104342), while C-C motif chemokine ligand 2 (CCL2) protein is pyroglutamated by QPCTL (EMBO Mol Med, 2011, 3, 510-512), in addition, the N-terminal of CX3CL1 can also be pyroglutamated by QPCT and QPCTL (Bioscience reports, 2017 37, BSR20170712). A recent study found that QPCTL can also pyroglutamate the N-terminal of the BTN (butyrophilin) family of proteins, particularly BTN2A1, BTN3A1, BTN3A2 and BTN3A3 (Cell Mol Immunol, 2024, 21, 362-373). However, due to the huge overlap of enzyme properties and substrate preferences, it cannot be ruled out that QPCT and QPCTL have some functional overlap in the pyroglutamylation of these targets.

[0011] However, there is no targeted drug on the market for QPCT or QPCTL inhibitors so far.

[0012] Therefore, it is of great practical significance to develop a new QPCT or QPCTL inhibitor to provide a new treatment method for tumors, immune diseases, neurological diseases, obesity or aging. SUMMARY

[0013] The present application provides a new QPCT or QPCTL inhibitor to provide a new treatment method for tumor treatment, specifically a nitrogen-containing heterocyclic compound, its application in inhibiting glutamine cyclotransferase, a pharmaceutical composition containing a nitrogen-containing heterocyclic compound and its application.

[0014] In order to achieve the above-mentioned purpose, the present application provides the following technical solutions:

[0015] The present application provides a nitrogen-containing heterocyclic compound as shown in formula (I) or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotopically labeled or prodrug:

[0016] Wherein:

[0017] represents a single bond or is absent;

[0018] m is any integer from 0 to 3, and n is any integer from 0 to 3;

[0019] X is a carbon atom or a nitrogen atom;

[0020] R1is a 5- to 10-membered heteroaryl group optionally substituted by one or more R7;

[0021] R2is a cyano group, a nitro group, -C(=O)N(R8)2, -NR8C(=O)R9, -S(=O)2R9or -NR8S(=O)2R9;

[0022] R3is a hydrogen atom, a halogen atom, a trifluoromethyl group, -NR8C(=O)R9or C 1-20 alkyl group;

[0023] R4is a 5- to 10-membered heteroaryl group optionally substituted by one or more C 1-20 alkyl groups;

[0024] R5is a hydrogen atom, a halogen atom, a hydroxy group, a C 1-20 alkyl group or a C 1-20 alkoxy group; optionally, when R5is a C 1-20 alkyl group, any carbon atom of R5and any ring atom of R4are linked to form a 5- to 10-membered cyclic structure;

[0025] R6is a hydrogen atom or -NR8C(=O)R9;

[0026] Each R7is independently a halogen atom, a C 3-10 cycloalkyl group optionally substituted by C 1-20 alkyl groups, a C 3-10 cycloalkyl group optionally substituted by C 1-20 alkyl groups, a C 1-20 cycloalkyl group optionally substituted by C 3-10 alkyl groups or a C

[0027] Each R8is independently a hydrogen atom or a C 1-20 alkyl group;

[0028] Each R9is independently a hydrogen atom, a C 1-20 alkyl group, a C 1-20 haloalkyl group, -NHC 1-20 alkyl group, -C 1-20 alkylene-C 1-20 alkoxy group, a C 3-10 cycloalkyl group, a 5- to 10-membered heterocycloalkyl group, a 5- to 10-membered heteroaryl group or a C 6-10 aryl group; the C 3-10 cycloalkyl group, a 5- to 10-membered heterocycloalkyl group, a 5- to 10-membered heteroaryl group or a C 6-10 aryl group is each independently optionally substituted by one or more halogen atoms, C 1-20 alkyl groups or -C(=O)OC 1-20 alkyl groups; or, R8and R9are linked to form a 5- to 10-membered cyclic structure.

[0029] In some preferred embodiments, in formula (I):

[0030] m is 0 or 1, and n is 0 or 1;

[0031] X is a carbon atom or a nitrogen atom;

[0032] R1is a 5-10 membered nitrogen-containing heteroaryl group optionally substituted with one or more R7;

[0033] R2is a cyano group, a nitro group, -C(=O)N(R8)2, -NR8C(=O)R9, -S(=O)2R9, or -NR8S(=O)2R9;

[0034] R3is a hydrogen atom, a halogen atom, a trifluoromethyl group, -NR8C(=O)R9, or C 1-10 alkyl group;

[0035] R4is a 5-10 membered nitrogen-containing heteroaryl group optionally substituted with one or more C 1-10 alkyl groups;

[0036] R5is a hydrogen atom, a halogen atom, a hydroxy group, a C 1-10 alkyl group, or a C 1-10 alkoxy group; optionally, when R5is a C 1-10 alkyl group, any carbon atom of R5and any ring atom of R4are linked to form a 5-6 membered cyclic structure;

[0037] R6is a hydrogen atom or -NR8C(=O)R9;

[0038] each R7is independently a halogen atom, a C 1-10 alkyl group, a C 3-6 cycloalkyl group optionally substituted with a C 1-10 alkyl group, a C 3-6 cycloalkyl group optionally substituted with a C 1-10 alkyl group, or a C 1-10 cycloalkyloxy group optionally substituted with a C 3-6 alkyl group;

[0039] each R8is independently a hydrogen atom or a C 1-10 alkyl group;

[0040] each R9is independently a hydrogen atom, a C 1-10 alkyl group, a C 1-10 haloalkyl group, -NHC 1-10 alkyl group, -C 1-10 alkylene-C 1-10 alkoxy group, a C 3-6 cycloalkyl group, a 5-6 membered heterocycloalkyl group, a 5-10 membered heteroaryl group, or a C 6-10 aryl group; the C 3-6cycloalkyl, 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl or C 6-10 each aryl group is independently optionally substituted by one or more halogen atom, C 1-10 alkyl or -C(=O)OC 1-10 alkyl; or, R8and R9are linked to form a 5-6 membered ring structure.

[0041] In some more preferred embodiments, in formula (I):

[0042] m is 0 or 1, n is 0 or 1, and m and n are not simultaneously 0;

[0043] X is a carbon atom or a nitrogen atom;

[0044] R1is pyridyl optionally substituted by one or more R7;

[0045] R2is cyano, nitro, -C(=O)N(R8)2, -NR8C(=O)R9, -S(=O)2R9or -NR8S(=O)2R9;

[0046] R3is hydrogen atom, halogen atom, trifluoromethyl, -NR8C(=O)R9or C 1-10 alkoxy;

[0047] R4is the following group optionally substituted by one or more C 1-10 alkyl: wherein, represents a bond site;

[0048] R5is hydrogen atom, halogen atom, hydroxy or C 1-10 alkyl; optionally, when R5is C 1-10 alkyl, any carbon atom of R5and any ring atom of R4are linked to form a 5-6 membered ring structure;

[0049] R6is hydrogen atom or -NR8C(=O)R9;

[0050] each R7is independently methyl, methoxy, cyclopropyl-substituted methoxy, halogen atom;

[0051] each R8is independently hydrogen atom or C 1-10 alkyl;

[0052] each R9is independently hydrogen atom, C 1-10 alkyl, C 1-10 haloalkyl, -NHC 1-10 alkyl, -C 1-10 alkylene-C 1-10 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl or C6-10 Aryl; the C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl or C 6-10 Each aryl group is independently and optionally bonded by one or more halogen atoms, C 1-10 Alkyl or -C(=O)OC 1-10 Alkyl substitution; or, R8 and R9 linked together to form a five-membered ring structure.

[0053] In some embodiments, the compound is as shown in formula (II):

[0054] Wherein, m, n, X, R1, R2, R3, R4, R5 and R6 have the definitions described in equation (I).

[0055] In some embodiments, the compound is as shown in formula (III):

[0056] Wherein, m, n, X, R1, R2, R3 and R6 have the definitions described in equation (I);

[0057] p is any integer from 0 to 3, preferably 1 or 2.

[0058] In other embodiments, the compound is as shown in formula (IV):

[0059] Wherein, m, n, X, R1, R2, R3, R4, R5 and R6 have the definitions described in equation (I).

[0060] In other embodiments, the compound is as shown in formula (V):

[0061] In some preferred embodiments, the compound is as shown in formula (VI) or (VII):

[0062] Wherein, m, n, X, R1, R4, R5, R8 and R9 have the definitions described in equation (I);

[0063] Preferably, R4 is arbitrarily determined by one or two Cs. 1-10 Alkyl-substituted groups include the following: in, Indicates the combination of keys;

[0064] Preferably, R5 is a hydrogen atom or a halogen atom. In some preferred embodiments, the compound is as shown in formula (VIII):

[0065] Wherein, m, n, X, R1, R2, R3, R5 and R6 have the definitions described in equation (I);

[0066] Z represents a hydrogen atom or a nitrogen atom;

[0067] R 10 For hydrogen atoms, C 1-10 Alkyl or C 1-10 Alkoxy-substituted benzyl; optionally, R5 and R 10 They connect to form a 5-10 element ring structure;

[0068] R 11 For hydrogen atoms, C 1-10 Alkyl or amino groups.

[0069] Preferably, R 10 C 1-10 Alkyl group. More preferably, R 10 C 1-2 Alkyl group. Wherein, C 1-2 Alkyl groups include methyl, ethyl, and -CD3.

[0070] Preferably, R 11 For hydrogen atoms, C 1-5 Alkyl or amino.

[0071] In some preferred embodiments, R4 is Among them, Z and R 10 R 11 It has the definition described in equation (VIII).

[0072] In some preferred embodiments, R1 is one of the following groups:

[0073] in, Indicates the combination of keys;

[0074] Each R 12 Each is an independent halogen atom;

[0075] R 13 The methoxy or halogen atom is substituted with methyl, methoxy, or cyclopropyl groups;

[0076] Each R 14 Each independently is C 1-10 alkyl.

[0077] In some specific embodiments, the specific structural formula of the nitrogen-containing heterocyclic compound of the present invention is as follows:

[0078] The present invention also provides a pharmaceutical composition in which the above-mentioned nitrogen-containing heterocyclic compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug is used as the active ingredient. In some embodiments, the pharmaceutical composition contains at least one pharmaceutically acceptable carrier. Those skilled in the art can select the pharmaceutical composition according to actual needs to ensure that the active ingredient therein exerts its full effect.

[0079] This invention also provides a drug combination formulation comprising the above-described nitrogen-containing heterocyclic compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug, or the above-described pharmaceutical composition, and an antibody. In some embodiments, the antibody is a PD-1 / PD-L1 antibody or a CD47 antibody.

[0080] The present invention also provides the application of the above-mentioned nitrogen-containing heterocyclic compounds or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, isotope-labeled substances or prodrugs, or the above-mentioned pharmaceutical compositions, or the above-mentioned drug combinations, in the inhibition of glutamine cyclase. The above-mentioned nitrogen-containing heterocyclic compounds or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, isotope-labeled substances or prodrugs, or the above-mentioned pharmaceutical compositions, or the above-mentioned drug combinations, can act as glutamine cyclase inhibitors, capable of inhibiting glutamine cyclotransferase-like (QPCTL) enzymes and / or glutamine acyltransferase (QPCT), that is, capable of inhibiting, reducing or blocking the activity of QPCTL or QPCT.

[0081] In addition, the present invention also provides the use of the above-mentioned nitrogen-containing heterocyclic compounds or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, isotope labels or prodrugs, or the above-mentioned pharmaceutical compositions, or the above-mentioned drug combinations in the preparation of medicaments for the prevention and / or treatment of tumors, immune diseases, neurological diseases, obesity or aging.

[0082] In some embodiments, the tumor is selected from at least one of colorectal cancer, lung cancer, gastric cancer, melanoma, myeloma, breast cancer, adenocarcinoma, bladder cancer, and hematologic malignancy.

[0083] In some embodiments, the immune disease is selected from at least one of eczema, alopecia areata, psoriasis, vitiligo, rheumatoid arthritis, lupus syndrome, acne, and hidradenitis suppurativa.

[0084] In some embodiments, the neurological disease is selected from at least one of Alzheimer's disease, Huntington's disease, neurodegeneration of Down syndrome, depression, anxiety disorder, psychosis, and multiple sclerosis.

[0085] The above technical solution is only one feasible technical solution of the present invention. The scope of protection of the present invention is not limited thereto. Those skilled in the art can reasonably adjust the specific design according to actual needs.

[0086] The QPCTL / QPCT activity mentioned above refers to the cyclization of the N-terminal glutamine residue into pyroglutamic acid (pGlu*) or the intramolecular cyclization of the N-terminal L-high glutamine or L-β-high glutamine into cyclopyroglutamine derivatives when ammonia is released.

[0087] EC includes QPCT and QPCTL as the activity of glutamate cyclase (EC), which is further defined as EC activity.

[0088] QPCT inhibitors and glutamine acyl cyclase inhibitors are well known to those skilled in the art, specifically enzyme inhibitors that inhibit the catalytic activity of glutamine acyl cyclase (QPCT) or the activity of its glutamine cyclase (EC).

[0089] QPCTL inhibitors and glutamine cyclotransferase-like protein inhibitors are well known to those skilled in the art, specifically enzyme inhibitors that inhibit the catalytic activity of glutamine cyclotransferase-like protein (QPCTL) or its glutamine cyclase (EC) activity.

[0090] Glutamine cyclase inhibitors include QPCT inhibitors and / or QPCTL inhibitors, which inhibit QPCT / QPCTL and have the same or similar pharmacological effects.

[0091] The effectiveness of QPCTL suppression: In view of the relationship with QPCTL suppression, in the preferred embodiment, the IC of QPCTL suppression is... 50 The concentration is 10 μM or less, preferably 1 μM or less, even more preferably 0.1 μM or less, or 0.01 μM or less, or most preferably 0.001 μM or less. Therefore, although the active substance is described herein as a QPCTL inhibitor for convenience, it should be understood that such nomenclature is not intended to limit the subject matter of the invention to a specific mechanism of action.

[0092] The present invention has the following advantages or beneficial effects:

[0093] This invention provides a novel nitrogen-containing heterocyclic compound that exhibits excellent inhibitory effects on glutamine cyclases (especially QPCTL and QPCT enzymes), and has promising applications in the treatment of tumors, immune diseases, neurological diseases, obesity, or aging. Detailed Implementation

[0094] The present invention will be further described below with reference to specific embodiments, but these are not intended to limit the invention.

[0095] Example 1

[0096] 3-(6-Fluoropyridin-3-yl)-2-[4-(Thiazolyl-5-yl)piperidin-1-yl]-benzyl-1-carboxylonitrile (Compound 1)

[0097] 3-(6-fluoropyridin-3-yl)-2-(4-(thiazol-5-yl)piperidin-1-yl)benzonitrile

[0098] The synthetic route for compound 1 is shown in the figure above.

[0099] Step a: Compound MC1 (111 mg, 0.36 mmol, 1.5 eq), compound MC2 (39 mg, 0.24 mmol, 1.0 eq), and Na2CO3 (51 mg, 0.48 mmol, 2.0 eq) were dissolved in a mixed solvent of 1,4-dioxane (2 mL) and H2O (0.2 mL). Under argon protection, Pd(dppf)Cl2 (18 mg, 0.024 mmol, 0.1 eq) was added, and the system was heated to 90 °C and reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, extracted with water and EA, and the organic phase was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain a yellow oily compound MC3 (90 mg, 94.0% yield). 1 H NMR (400MHz, CDCl3) δ8.54 (s, 1H), 7.65 (s, 1H), 5.96 (brs, 1H), 3.99-3.96 (m, 2H), 3.54 (t, J = 5.6Hz, 2H), 2.45-2.41 (m, 2H), 1.38 (s, 9H).

[0100] Step b: Intermediate MC3 (1.47 g, 1.0 eq) was dissolved in MeOH (20 mL), and Pd / C (10%, 200 mg) was added under argon protection. The system was purged with hydrogen three times at room temperature, and the reaction was carried out overnight at 45 °C. After the reaction was completed, the mixture was filtered, and the organic phase was concentrated to obtain compound MC4 (1.2 g). 1 HNMR(400MHz, CDCl3)δ8.62(s,1H),7.58(s,1H),4.16-4.11(m,2H),3.03-2.95(m ,1H),2.79(t,J=13.2Hz,2H),1.95-1.91(m,2H),1.63-1.51(m,2H),1.41(s,9H).

[0101] Step c: After removing the Boc protecting group from intermediate MC4, the crude 5-(piperidin-4-yl)thiazole product (0.20 g, 1.21 mmol, 1.0 eq) was dissolved in DMSO (4 mL). Then, 3-bromo-2-fluorobenzonitrile (MC5) (0.29 g, 1.45 mmol, 1.2 eq) and anhydrous potassium carbonate (0.25 g, 1.82 mmol, 1.5 eq) were added sequentially, and the mixture was heated and stirred at 100 °C for 16 hours. After the reaction was completed by TLC monitoring, dichloromethane and water were added for extraction, followed by extraction again with saturated brine and dichloromethane. The organic phase was collected and purified using a SepaBean machine T200 to finally obtain 0.15 g of intermediate MC6.

[0102] In step d, intermediate MC6 (35 mg, 0.10 mmol, 1.0 eq), sodium carbonate (21 mg, 0.2 mmol, 2.0 eq), and 4-fluoro-3-pyridineboronic acid (34 mg, 0.15 mmol, 1.5 eq) were dissolved in a mixed solvent of 2 mL dioxane and 0.2 mL water. Under nitrogen protection, Pd(dppf)Cl2 (7 mg, 0.01 mmol, 0.1 eq) was added, and the reaction was carried out at 90°C for 10 hours. After cooling to room temperature, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was concentrated and separated by HPLC to obtain a white solid product.

[0103] The data for compound 1 were obtained as follows: 1 H NMR(400MHz,MeOD-d4)δ9.03(s,1H),8.26(d,J=2.5Hz,1H),8.07-7.92(m,1H),7.83-7.63(m,2H),7.54(dd,J=7.7,1.6Hz,1H),7.31(t,J =7.7Hz,1H),7.20(dd,J=8.5,2.6Hz,1H),3.26-3.20(m,1H),3.18-2.98(m,2H),2.07-1.89(m,2H),1.76-1.49(m,2H),1.35-1.28(m,2H). LRMS(ESI)[M+H] + ,found:365.2.

[0104] Example 2

[0105] 3-(6-Fluoropyridin-3-yl)-2-[4-(1-Methyl-1H-1,2,3-triazol-4-yl)piperidin-1-yl]-benzyl-1-carboxylonitrile (Compound 2)

[0106] 3-(6-fluoropyridin-3-yl)-2-(4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-1-yl)benzonitrile

[0107] The synthetic route for compound 2 is shown in the figure above.

[0108] Step a: Compound MC7 (1.05 g, 5.00 mmol, 1.0 eq), trimethylsilyl azidosilane (636 mg, 5.5 mmol, 1.1 eq), and CuI (48 mg, 0.25 mmol, 0.05 equiv) were dissolved in DMF (9 mL) and MeOH (1 mL) under argon protection. The reaction mixture was heated to 100 °C and stirred for 8 h. After the reaction was complete, EA (50 mL) was added for dilution, followed by washing with water (50 mL) and brine (50 mL). The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain intermediate MC8 (600 mg, 47.6% yield). 1 H NMR (400MHz, CDCl3) δ7.47(s,1H),4.17-4.15(m,2H),2.97-2.82(m,3H),1.99-1.94(m,2H),1.68-1.56(m,2H),1.44(s,9H).

[0109] Step b: Under argon protection at 0°C, intermediate MC8 (30 mg, 0.12 mmol, 1.0 eq) and potassium carbonate (33 mg, 0.24 mmol, 2.0 eq) were dissolved in DMF (2 mL). Iodomethane (25 mg, 0.18 mmol, 1.5 eq) was slowly added to the system, and the mixture was stirred overnight at room temperature. After the reaction was complete, EA (50 mL) was added for dilution, followed by washing with H2O (50 mL) and saline solution (50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain intermediate MC9 (22 mg, 70.5% yield). ¹H NMR (600 MHz, CDCl₃) δ 7.33 (s, 1H), 4.13–4.10 (m, 5H), 2.88–2.81 (m, 3H), 1.95–1.91 (m, 2H), 1.65–1.57 (m, 2H), 1.45 (s, 9H).

[0110] Steps c and d: Using intermediate MC9, react as in step c of Example 1 to generate intermediate MC10, and then as in step d of Example 1, to obtain the data for compound 2: 1H NMR (400MHz, MeOD-d4) δ8.24(dd,J=2.1,1.1Hz,1H),8.07-7.95(m,1H),7.69(dd,J=7.8,1.7Hz,1H),7.53(dd,J=7.7,1.7Hz,1H),7.43(s,1H),7.29(t, J=7.7Hz,1H),7.19(dd,J=8.4,2.6Hz,1H),4.09(s,3H),3.26-3.15(m,2H), 3.15-3.02(m,2H),2.83-2.66(m,1H),1.92-1.81(m,2H),1.70-1.53(m,2H). LRMS(ESI)[M+H] + ,found:363.2.

[0111] Example 3

[0112] 2-[4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]-3-(6-fluoropyridin-3-yl)benzyl-1-carboxylonitrile (Compound 3)

[0113] 2-(4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0114] The synthetic route of compound 3 is shown in the figure above.

[0115] Step a: Under argon protection at 0°C, compound MC12 (500 mg, 7.24 mmol, 1.0 eq) was dissolved in DMF (5 mL), and then NaH (320 mg, 60% mmol, 8.0 mmol, 1.1 eq) was slowly added. The reaction was slowly heated to room temperature and stirred for 2 hours. Then, compound MC11 (2.4 g, 8.69 mmol, 1.2 eq) was added to the system, and the system was heated to 60°C and stirred overnight. After the reaction was completed, EA (50 mL) was added for dilution, followed by washing with H2O (50 mL) and brine (50 mL). The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain intermediate MC13 (900 mg, 49.3% yield). 1H NMR(400MHz, CDCl3)δ7.49(brs,1H),7.45-7.43(m,1H),4.48-4.39(m,1H),4.00(d,J =13.6Hz,2H),2.80-2.74(m,2H),1.97-1.92(m,2H),1.80-1.69(m,2H),1.23(s,9H).

[0116] Steps b and c: Using intermediate MC13, react as in step c of Example 1 to generate intermediate MC14, and then as in step d of Example 1, to obtain the data for compound 3 as follows: 1 H NMR (400MHz, MeOD-d4) δ8.27(dd,J=2.1,1.2Hz,1H),8.10-7.98(m,2H),7.78(d,J=1.2Hz,1H),7.72(dd,J=7.7,1.6Hz,1H),7.56(dd,J=7.7, 1.7Hz,1H),7.33(t,J=7.7Hz,1H),7.22(dd,J=8.5,2.7Hz,1H),4.71-4.53(m,1H),3.30-3.27(m,2H),3.26-3.08(m,2H),2.17-1.98(m,4H). LRMS(ESI)[M+H] + ,found:349.2.

[0117] Example 4

[0118] 2-[4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl]-3-(6-fluoropyridin-3-yl)benzyl-1-carboxylonitrile (Compound 4)

[0119] 2-(4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0120] The synthesis method is the same as in Example 3, as shown in the route above. The data for compound 4 are as follows: 1H NMR (400MHz, MeOD-d4) δ8.95(d,J=15.8Hz,1H),8.03(td,J=8.0,2.5Hz,1H),7.72(dd,J=7.7,1.7Hz,1H),7.56(dd,J=7.7,1.7Hz,1 H),7.33(t,J=7.7Hz,1H),7.21(dd,J=8.5,2.5Hz,1H),4.56-4.36(m,1H),3.30-3.26(m,2H),3.24-3.06(m,2H),2.14-1.98(m,4H). LRMS(ESI)[M+H] + ,found:349.2.

[0121] Example 5

[0122] 2-[4-(2H-1,2,3-triazol-2-yl)piperidin-1-yl]-3-(6-fluoropyridin-3-yl)benzyl-1-carboxylonitrile (Compound 5)

[0123] 2-(4-(2H-1,2,3-triazol-2-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0124] The synthesis method is the same as in Example 3, as shown in the route above. The data for compound 5 are as follows: 1 H NMR (400MHz, DMSO) δ8.28 (d, J=2.5Hz, 1H), 8.05 (td, J=8.2, 2.5Hz, 1H), 7.86-7.73 (m, 3H), 7.56 (dd, J=7.6, 1.7Hz,1H),7.37-7.24(m,2H),4.68-4.48(m,1H),3.26-3.13(m,2H),3.13-2.95(m,2H),2.09-1.84(m,4H). LRMS(ESI)[M+H] + ,found:349.2.

[0125] Example 6

[0126] 2-[4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(6-fluoropyridin-3-yl)benzyl-1-carboxylonitrile (Compound 6)

[0127] 2-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0128] The synthesis method is the same as in Example 1, and the synthetic route is shown in the figure above. The data for compound 6 are as follows: 1 H NMR (400MHz, MeOD-d4) δ8.28(d,J=2.4Hz,1H),8.04(td,J=8.0,2.8Hz,1H),7.75(dd,J=8.0,2.0Hz,1H),7.58(dd,J=7.6,2.0Hz,1H),7.35(t,J=7.6Hz,1 H),7.22(dd,J=8.4,2.8Hz,1H),3.74(s,3H),3.30-3.28(m,2H),3.17-3.07 (m,3H),2.62(s,3H),1.97-1.93(m,2H),1.87-1.77(m,2H).LRMS(ESI)[M+H] + ,found:377.4.

[0129] Example 7

[0130] 3-(6-Fluoropyridin-3-yl)-2-(4-(4-isopropyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzyl-1-carboxylonitrile (Compound 7)

[0131] 3-(6-fluoropyridin-3-yl)-2-(4-(4-isopropyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0132] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 7 are as follows: 1 H NMR (400MHz, MeOD-d4) δ9.47(s,1H),8.56(d,J=2.8Hz,1H),8.52(s,1H),7.82-7.76(m,2H),7.61(dd,J=7.6,1.6Hz,1H),7.37(t, J=8.0Hz,1H),4.82-4.74(m,1H),3.27-3.19(m,4H),1.99-1.94(m,2H),1.89-1.57(m,2H),1.58(d,J=6.8Hz,6H).LRMS(ESI)[M+H]+ ,found:391.3.

[0133] Example 8

[0134] 2-(4-(1H-imidazol-5-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzyl-1-carboxylonitrile (Compound 8)

[0135] 2-(4-(1H-imidazol-5-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0136] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 8 are as follows: 1 H NMR (400MHz, MeOD-d4) δ8.83 (s, 1H), 8.29 (d, J = 2.4Hz, 1H), 8.02 (td, J = 8.0, 2.4Hz,1H),7.74(dd,J=8.0,1.6Hz,1H),7.57(dd,J=7.6,1.6Hz,1H),7.36-7 .32(m,2H),7.21(dd,J=8.4,2.4Hz,1H),3.29-3.24(m,2H),3.16-3.11(m,2H ),2.88-2.79(m,1H),1.98-1.93(m,2H),1.69-1.65(m,2H).LRMS(ESI)[M+H] + ,found:348.2.

[0137] Example 9

[0138] 2-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzyl-1-carboxylonitrile (compound)

[0139] 2-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0140] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 9 are as follows: 1H NMR(600MHz,MeOD-d4)δ9.34(s,1H),8.26(s,1H),8.02(t,J=7.8Hz,1H),7.73(d ,J=7.8Hz,1H),7.56(d,J=7.8Hz,1H),7.33(t,J=7.8Hz,1H),7.21(dd,J=8.4,2. 4Hz,1H),4.27(q,J=7.2Hz,2H),3.25-3.20(m,2H),3.28(brs,2H),3.21-3.15(m ,1H),1.97-1.93(m,2H),1.85(brs,2H),1.54(t,J=7.2Hz,3H).LRMS(ESI)calcd for C 21 H 22 FN6[M+H] + 377.2, found: 377.3.

[0141] Example 10

[0142] 3-(6-Fluoropyridin-3-yl)-2-(4-(1-methyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)benzyl-1-carboxylonitrile (compound)

[0143] 3-(6-fluoropyridin-3-yl)-2-(4-(1-methyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)benzonitrile

[0144] The synthetic route of compound 10 is shown in the figure above:

[0145] Step a: Compound MC32 (251 mg, 1.2 mmol, 1.2 eq), CuSO4·5H2O (3 mg, 0.01 mmol, 0.01 eq), (+)-sodium ascorbate (10 mg, 0.05 mmol, 0.05 eq), and urea (2 mg, 0.02 mmol, 0.02 eq) were dissolved in MeOH / H2O (2 mL / 2 mL). Benzyl azide (133 mg, 1.0 mmol, 1.0 eq) was then added to the system, and the reaction was continued at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with EA (50 mL), washed with H2O (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain intermediate MC33 (100 mg, 29.2% yield). 1H NMR (600MHz, CDCl3) δ7.39-7.32(m,3H),7.27-7.23(m,2H),7.16(s,1H),5.48(s,2H),4 .13-4.09(m,2H),2.93-2.83(m,3H),2.00-1.96(m,2H),1.59-1.51(m,2H),1.44(s,9H).

[0146] Step b: Intermediate MC33 (40 mg, 0.12 mmol, 1.0 eq) was dissolved in MeCN (2 mL), and then methyl iodide (103 mg, 0.72 mmol, 6.0 eq) was added. The reaction system was heated to 60 °C and reacted overnight. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate MC34 (50 mg, crude). 1 H NMR(400MHz, CDCl3)δ8.96(s,1H),7.60-7.56(m,2H),7.40-7.37(m,3H),5.90(s,2H),4.38(s, 3H),4.18-4.07(m,2H),3.41-3.32(m,1H),2.92-2.80(m,2H),2.06-1.92(m,4H),1.41(s,9H).

[0147] In step c, intermediate MC34 (50 mg, 1.0 mmol, 1.0 eq) and t-BuOK (29 mg, 2.5 mmol, 2.5 eq) were dissolved in MeCN (10 mL) under argon protection at 0 °C, and the mixture was slowly heated to room temperature and reacted overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate MC35 (20 mg, 74.9% yield). 1 H NMR(600MHz, CDCl3)δ7.44(s,1H),4.00(s,3H),2.84-2.72(m,3H),1.88(d,J=13.8Hz,2H),1.72(brs,2H),1.63-1.54(m,2H),1.47(s,9H).LRMS(ESI)calcd for C 13 H 23 N4O2[M+H] + 267.2, found:267.3.

[0148] After removing the Boc protecting group using compound MC35 in steps d and e, the synthesis method is the same as step c in Example 1 to obtain intermediate MC36. The data for compound 10 obtained is the same as step d in Example 1. 1 H NMR (400MHz, MeOD-)d4 )δ8.26(d,J=2.4Hz,1H),8.04-7.99(m,1H),7.71(dd,J=8.0,1.6Hz,1H),7.61(s,1H),7.55(dd,J=8.4,1.6Hz,1H),7.31(t,J=7.6Hz ,1H),7.23-7.19(m,1H),4.03(s,3H),3.26-3.14(m,4H),2.92-2.84(m,1H),1.88-1.84(m,2H),1.63-1.59(m,2H).LRMS(ESI)calcd for C 20 H 20 FN6[M+H] + 363.2, found: 363.3.

[0149] Example 11

[0150] 3-(6-Fluoropyridin-3-yl)-2-(4-(3-methyl-4H-1,2,4-triazol-4-yl)piperidin-1-yl)benzyl-1-carboxylonitrile (Compound 11)

[0151] 3-(6-fluoropyridin-3-yl)-2-(4-(3-methyl-4H-1,2,4-triazol-4-yl)piperidin-1-yl)benzonitrile

[0152] The synthetic route of compound 11 is shown in the figure above:

[0153] Step a: Compound MC37 (814 mg, 11.0 mmol, 1.0 eq) was dissolved in acetonitrile (5 mL), and then DMFDMA (1.35 g, 11.0 mmol, 1.0 eq) was added to the system. The mixture was heated to 50 °C and stirred for 1 hour. Then, compound MC38 (1.0 g, 5.5 mmol, 0.5 eq) and HOAc (1 mL) were added to the system, and the mixture was heated to 100 °C and stirred for 18 hours. After the reaction was completed, the reaction system was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain intermediate MC39 (1.5 g, 52.0% yield). 1 H NMR(600MHz, CDCl3)δ8.00(s,1H),4.19(brs,2H),3.93-3.87(m,1H),2.77-2 .73(m,2H),2.34(s,3H),1.92-1.88(m,2H),1.71-1.63(m,2H),1.35(s,9H).

[0154] Steps b and c: Using intermediate MC39, react as in step c of Example 1 to generate intermediate MC40, and then as in step d of Example 1, synthesize compound 11. The data are as follows: 1 H NMR (600MHz, MeOD-d4) δ9.23(s,1H),8.28(s,1H),8.02(t,J=6.6Hz,1H),7.74(d,J=7.8Hz,1H),7.56(d,J=7.8Hz,1H),7.35(t,J=7.8Hz,1H),7. 21(dd,J=9.0,2.4Hz,1H),4.43-4.37(m,1H),3.33(brs,2H),3.18(br,2H),2.72(s,3H),2.10-2.06(m,2H),1.99-1.96(m,2H).LRMS(ESI)calcd for C 20 H 20 FN6[M+H] + 363.2, found: 363.3.

[0155] Example 12

[0156] 2-(4-(1-ethyl-1H-imidazol-5-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzyl-1-carboxylonitrile (Compound 12)

[0157] 2-(4-(1-ethyl-1H-imidazol-5-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0158] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 12 are as follows: 1H NMR (400MHz, MeOD-d4) δ8.87 (s, 1H), 8.28 (d, J = 2.4Hz, 1H), 8.01 (td, J = 8.0, 2.4Hz, 1H), 7. 72(dd,J=7.6,1.6Hz,1H),7.55(dd,J=7.6,1.6Hz,1H),7.36(s,1H),7.32(t,J=7.6Hz,1H), 7.21(dd,J=8.4,2.4Hz,1H),4.23(q,J=7.2Hz,2H),3.27-3.23(m,2H),3.15(brs,2H),2.89 -2.81(m,1H),1.92-1.87(m,2H),1.65-1.61(m,2H),1.53(t,J=7.2Hz,3H).LRMS(ESI)calcd for C 22 H 23 FN5[M+H] + 376.2, found: 376.3.

[0159] Example 13

[0160] 3-(6-Fluoropyridin-3-yl)-2-(4-(4-methylpyridin-3-yl)piperidin-1-yl)benzyl-1-carboxylonitrile (Compound 13)

[0161] 3-(6-fluoropyridin-3-yl)-2-(4-(4-methylpyridin-3-yl)piperidin-1-yl)benzonitrile

[0162] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 13 are as follows: 1 H NMR (400MHz, MeOD-d4) δ8.57-8.53(m,2H),8.31(s,1H),8.04(t,J=8.0Hz,1H),7.88(d,J=6.0Hz,1H),7.73(d,J=8.0Hz,1H),7.57(d,J=8.0Hz, 1H),7.33(t,J=8.0Hz,1H),7.23(dd,J=8.4,2.4Hz,1H),3.29-3.18(m,4H),3.09-3.02(m,1H),2.67(s,3H),1.84-1.70(m,4H).LRMS(ESI)calcd for C 23 H 22 FN4[M+H] + 373.2, found: 373.3.

[0163] Example 14

[0164] 3-(6-Fluoropyridin-3-yl)-2-(4-(3-methylpyridin-4-yl)piperidin-1-yl)benzyl-1-carboxylonitrile (Compound 14)

[0165] 3-(6-fluoropyridin-3-yl)-2-(4-(3-methylpyridin-4-yl)piperidin-1-yl)benzonitrile

[0166] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 14 are as follows: 1 H NMR (400MHz, MeOD-d4) δ8.64-8.62(m,2H),8.31(s,1H),8.04(t,J=8.0Hz,1H),7.88(d,J=6.0Hz,1H),7.73(d,J=7.6Hz,1H),7.56(d, J=7.6Hz,1H),7.33(t,J=7.6Hz,1H),7.24(dd,J=8.4,2.0Hz,1H),3.30-3.08(m,5H),2.55(s,3H),1.80-1.76(m,4H).LRMS(ESI)calcd for C 23 H 22 FN4[M+H] + 373.2, found: 373.3.

[0167] Example 15

[0168] 3-(6-Fluoropyridin-3-yl)-2-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile (Compound 15)

[0169] 3-(6-fluoropyridin-3-yl)-2-(4-methyl-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0170] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 15 are as follows: 1H NMR (600MHz, MeOD-d4) δ9.09 (s, 1H), 8.25 (d, J = 2.4Hz, 1H), 8.00 (td, J = 7.8, 2.4Hz,1H),7.73(dd,J=7.8,1.8Hz,1H),7.58(dd,J=7.8,1.8Hz,1H),7.35(t ,J=7.8Hz,1H),7.19(dd,J=9.0,2.4Hz,1H),3.98(s,3H),3.22(brs,2H),3.1 1(brs,2H),2.28(brs,2H),1.86-1.84(m,2H),1.48(s,3H).LRMS(ESI)[M+H] + ,found:377.2.

[0171] Example 16

[0172] 2-(4-fluoro-4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile (Compound 16)

[0173] 2-(4-Fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0174] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 16 are as follows: 1 H NMR (600MHz, MeOD-d4) δ8.75(s,1H),8.27(d,J=2.4Hz,1H),8.06(td,J=7.8,2.4Hz,1H),7.76(dd,J=7.8,1.2Hz,1H),7.58(dd,J=7.8,1.2Hz ,1H),7.36(t,J=7.8Hz,1H),7.22(dd,J=8.4,2.4Hz,1H),3.90(s,3H),3.40(brs,2H),3.20-3.17(m,2H),2.30-2.23(m,4H).LRMS(ESI)[M+H] + ,found:381.2.

[0175] Example 17

[0176] 3-(6-Fluoropyridin-3-yl)-2-(6-(4-methyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-yl)benzonitrile (Compound 17)

[0177] 3-(6-Fluoropyridin-3-yl)-2-(6-(4-methyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)benzonitrile

[0178] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 17 are as follows: 1 H NMR (600MHz, MeOD-d4) δ8.96(s,1H),8.24(d,J=2.4Hz,1H),7.96(td,J=7.8,2 .4Hz,1H),7.76(dd,J=7.8,1.8Hz,1H),7.59(dd,J=7.8,1.2Hz,1H),7.38(t,J =7.8Hz,1H),7.24(dd,J=8.4,3.6Hz,1H),3.89(s,3H),3.52(d,J=9.6Hz,2H), 3.38(d,J=9.0Hz,2H),2.41-2.39(m,1H),2.27-2.25(m,2H).LRMS(ESI)[M+H] + ,found:361.4.

[0179] Example 18

[0180] 5-Fluoro-3-(6-Fluoropyridin-3-yl)-2-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile (Compound 18)

[0181] 5-fluoro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0182] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 18 are as follows: 1H NMR (600MHz, MeOD-d4) δ9.10(s,1H),8.43(s,1H),8.20-8.16(m,1H),7.46-7.43(m,1H),7.41-7.39(m,1H),7.25-7.22( m,1H),3.96-3.92(m,5H),3.32-3.28(m,1H),3.06-3.01(m,2H),2.21-2.17(m,2H),2.06-2.01(m,2H).LRMS(ESI)[M+H] + ,found:381.4.

[0183] Example 19

[0184] 3-(6-Fluoropyridin-3-yl)-2-(3-(4-methyl-4H-1,2,4-triazol-3-yl)pyrrolo-1-yl)benzonitrile (Compound 19)

[0185] 3-(6-fluoropyridin-3-yl)-2-(3-(4-methyl-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)benzonitrile

[0186] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 19 are as follows: 1 H NMR (400MHz, MeOD-d4) δ9.42 (s, 1H), 8.21 (d, J = 2.4Hz, 1H), 8.01-7.96 (m, 1 H),7.69(dd,J=8.0,1.6Hz,1H),7.35(dd,J=7.6,1.6Hz,1H),7.30(t,J=7.6H z,1H),7.17-7.13(m,1H),3.88(s,3H),3.85-3.78(m,2H),3.60-3.53(m,1H ),3.43-3.30(m,2H),2.49-2.39(m,1H),2.32-2.23(m,1H).LRMS(ESI)calcd for C 19 H 18 FN6[M+H] + 349.2, found:349.3.

[0187] Example 20

[0188] 3-(6-Fluoropyridin-3-yl)-2-(3-(4-methyl-4H-1,2,4-triazol-3-yl)azacyclopropane-1-yl)benzonitrile (Compound 20)

[0189] 3-(6-fluoropyridin-3-yl)-2-(3-(4-methyl-4H-1,2,4-triazol-3-yl)azetidin-1-yl)benzonitrile

[0190] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 20 are as follows: 1 H NMR(400MHz,MeOD-d4)δ9.05(s,1H),8.24(d,J=2.4Hz,1H),8.01-7.95(m,1H),7.58(dd,J=7.6,2.0Hz,1H),7.35(dd,J=7.6,1.6H z,1H),7.15(dd,J=8.4,2.8Hz,1H),6.97(t,J=8.0Hz,1H),4.35(t,J=8.0Hz,2H),4.17-4.07(m,3H),3.70(s,3H).LRMS(ESI)calcd for C 18 H 16 FN6[M+H] + 335.1, found: 335.3.

[0191] Example 21

[0192] 2-(6',7'-dihydro-5'H-spiro[piperidin-4,8'-[1,2,4]triazolo[4,3-a]pyridin]-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile (compound 21)

[0193] 2-(6',7'-dihydro-5'H-spiro[piperidine-4,8'-[1,2,4]triazolo[4,3-a]pyridin]-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0194] The synthetic route of compound 21 is shown in the figure above:

[0195] Step a: Compound MC60 (536 mg, 2.0 mmol, 1.0 eq) and Lawesson's reagent (409 mg, 2.1 mmol, 1.05 eq) were dissolved in toluene (20 mL). The reaction mixture was heated to reflux and stirred overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate MC61 (290 mg, 51.1% yield). 1H NMR (400MHz, CDCl3) δ8.31 (s, 1H), 4.01 (brs, 2H), 3.34 (brs, 2H), 2.90 (t, J = 11.6H z,2H),2.54(t,J=12.4Hz,2H),1.88(brs,4H),1.52-1.44(m,11H).LRMS(ESI)calcd for C 14 H 25 N₂O₂S[M+H] + 285.2, found:285.3.

[0196] In step b, intermediate MC61 (284 mg, 1.0 mmol, 1.0 eq) and compound MC62 (72 mg, 1.2 mmol, 1.2 eq) were dissolved in DCM (5 mL), followed by the addition of AgOBz (460 mg, 2.0 mmol, 2.0 eq) and HOAc (0.17 mL). The reaction mixture was heated to reflux and stirred overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate MC63 (170 mg, 58.0% yield). 1 H NMR (400MHz, CDCl3) δ8.08 (s, 1H), 4.01 (t, J = 6.0Hz, 2H), 3.84 (brs, 2H), 3.61 (brs, 2H) ,2.07-1.98(m,4H),1.88-1.85(m,2H),1.63-1.57(m,2H),1.47(s,9H).LRMS(ESI)calcd for C 15 H 25 N4O2[M+H] + 293.2, found:293.3.

[0197] After removing the Boc protecting group using intermediate MC63 in steps c and d, intermediate MC64 is obtained as in step c of the synthetic route in Example 1. Following step d of the synthetic route in Example 1, the data for compound 21 are as follows: 1H NMR(400MHz,MeOD-d4)δ9.21(s,1H),8.29(d,J=2.4Hz,1H),8.08-8.02(m,1H),7.74(dd,J=8.0,1.6Hz,1H),7.57(dd,J=8.0,2.0Hz,1H),7.3 4(t,J=7.6Hz,1H),7.23(dd,J=8.4,2.4Hz,1H),4.23(t,J=6.4Hz,2H),3.25(brs,4H),2.14-2.00(m,6H),1.81-1.75(m,2H).LRMS(ESI)calcd for C 22 H 22 FN6[M+H] + 389.2, found: 389.3.

[0198] Example 22

[0199] 2-(5',6'-dihydrospiro[piperidine-4,7'-pyrrolo[2,1-c][1,2,4]triazol]-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile (compound 22)

[0200] 2-(5',6'-dihydrospiro[piperidine-4,7'-pyrrolo[2,1-c][1,2,4]triazol]-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0201] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 21. The data for compound 22 are as follows: 1 H NMR (400MHz, MeOD-d4) δ9.23 (s, 1H), 8.29 (d, J = 2.4Hz, 1H), 8.06 (td, J = 8.0, 2.4Hz, 1H), 7.75 (dd, J = 7.6, 1.6Hz, 1H), 7.57 (dd, J = 7.6, 1.6Hz, 1H), 7. 34(t,J=7.6Hz,1H),7.24(dd,J=8.4,2.4Hz,1H),4.33(t,J=7.2Hz,2H),3.20-3.14(m,2H),2.72(t,J=7.2Hz,4H),1.94-1.84(m,4H).LRMS(ESI)calcd for C 21 H 20 FN6[M+H] + 375.2, found:375.2.

[0202] Example 23

[0203] 2-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoropiperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile (compound 23)

[0204] 2-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoropiperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0205] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 16. The data for compound 23 are as follows: 1 H NMR (600MHz, MeOD-d4) δ9.34(s,1H),8.26(s,1H),8.02(t,J=7.8Hz,1H),7.73(d,J=7.8Hz,1H),7.56(d,J=7.8Hz,1H),7.33(t,J=7.8Hz,1H),7.21 (dd,J=8.4,2.4Hz,1H),4.27(q,J=10.8Hz,2H),3.44-3.34(m,2H),3.18-3.15(m,2H),2.25-2.18(m,4H),1.54(t,J=10.8Hz,3H).LRMS(ESI)calcd for C 21 H 21 F2N6[M+H] + 395.2, found: 395.3.

[0206] Example 24

[0207] 3-(6-Fluoropyridin-3-yl)-2-(4-hydroxy-4-(1-methyl-1H-imidazol-5-yl)piperidin-1-yl)benzonitrile (Compound 24)

[0208] 3-(6-fluoropyridin-3-yl)-2-(4-hydroxy-4-(1-methyl-1H-imidazol-5-yl)piperidin-1-yl)benzonitrile

[0209] The synthetic route of compound 24 is shown in the figure above:

[0210] Step a: Dissolve MC71 (1.32 g, 16.0 mmol, 1.0 eq) in THF (30 mL). Under argon protection, cool the system to 78 °C, slowly add n-BuLi (10 mL, 1.6 M, 1.0 eq), and continue stirring for 1 hour. Then add triethylchlorosilane (2.4 g, 16.0 mmol, 1.0 eq), slowly heat to room temperature, then cool again to -78 °C, slowly add n-BuLi (10 mL, 1.6 M, 1.0 eq), and continue stirring for 1 hour. Then heat the system to -15 °C and cool again to -78 °C. Add a THF (10 mL) solution of MC72 (3.0 g, 15.0 mmol, 0.94 equiv) to the system. Heat the system to room temperature and continue stirring overnight. After the reaction was complete, the system was diluted with EA (50 mL), washed successively with H2O (50 mL) and saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The intermediate MC73 (1130 mg, 25.0% yield) was obtained by silica gel column chromatography. 1 H NMR (400MHz, CDCl3): δ7.20(s,1H),6.69(s,1H),3.86(brs,2H),3.79(s,3H),3.27(brs,2H),1.95-1.86(m,4H),1.45(s,9H).

[0211] After removing the Boc protecting group using intermediate MC73 in steps b and c, intermediate MC74 is obtained as in step c of the synthetic route in Example 1, and the data for compound 24 obtained as in step d of the synthetic route in Example 1 are as follows: 1 H NMR (400MHz, MeOD-d4) δ8.81(s,1H),8.27(d,J=2.4Hz,1H),8.01(td,J=8.0,2.4Hz,1H),7.72(dd,J=8.0,1.6Hz,1H),7.54(dd,J=7.6,1.6Hz,1H) ,7.43(d,J=7.6Hz,1H),7.31(t,J=7.6Hz,1H),7.20(dd,J=8.4,2.4Hz,1H),3.42(brs,2H),3.06-3.00(m,2H),1.99-1.95(m,4H).LRMS(ESI)calcd for C 21 H 21 FN5O[M+H] + 378.2, found:378.2.

[0212] Example 25

[0213] 3-(6-Fluoropyridin-3-yl)-2-(4-methoxy-4-(1-methyl-1H-imidazol-5-yl)piperidin-1-yl)benzonitrile (Compound 25)

[0214] 3-(6-fluoropyridin-3-yl)-2-(4-methoxy-4-(1-methyl-1H-imidazol-5-yl)piperidin-1-yl)benzonitrile

[0215] The synthetic route of compound 25 is shown in the figure above:

[0216] Step a: Intermediate MC73 (300 mg, 1.07 mmol, 1.0 eq) was dissolved in DMF (10 mL). NaH (85 mg, 60%, 2.14 mmol, 2.0 eq) was added under argon protection at 0 °C. The system was heated to room temperature and stirred for 2 hours. Then, iodomethane (303 mg, 2.14 mmol, 2.0 eq) was added, and the system was heated to reflux and stirred overnight. After the reaction was complete, the system was cooled to room temperature, diluted with EA (20 mL), washed once with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain intermediate MC74 (305 mg, 96.8% yield). 1 H NMR(400MHz, CDCl3)δ7.41(s,1H),6.89(s,1H),3.95-3.83(m,2H),3.75(s,3H),3 .23-3.12(m,2H),3.00(s,3H),2.15-2.10(m,2H),1.88-1.80(m,2H),1.47(s,9H).

[0217] After removing the Boc protecting group using intermediate MC74 in steps b and c, intermediate MC75 is obtained as in step c of the synthetic route in Example 1, and the data for compound 25 obtained as in step d of the synthetic route in Example 1 are as follows: 1H NMR(400MHz,MeOD-d4)δ8.88(s,1H),8.26(d,J=2.0Hz,1H),8.01(td,J=8.0,2.4Hz, 1H),7.72(dd,J=7.6,1.6Hz,1H),7.55(dd,J=8.0,1.6Hz,1H),7.52(d,J=1.6Hz,1H) ,7.32(t,J=8.0Hz,1H),7.19(dd,J=8.4,2.4Hz,1H),4.00(s,3H),3.35(brs,2H),3. 07(s,3H),3.05-3.00(m,2H),2.24-2.19(m,2H),1.94-1.90(m,2H).LRMS(ESI)calcd for C 22 H 23 FN5O[M+H] + 392.2, found: 392.3.

[0218] Example 26

[0219] 3-(6-Fluoropyridin-3-yl)-2-(4-hydroxy-4-(1-methyl-1H-imidazol-4-yl)piperidin-1-yl)benzonitrile (Compound 26)

[0220] 3-(6-fluoropyridin-3-yl)-2-(4-hydroxy-4-(1-methyl-1H-imidazol-4-yl)piperidin-1-yl)benzonitrile

[0221] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 24. The data for compound 26 are as follows: 1 H NMR(600MHz,MeOD-d4)δ8.28(s,1H),8.03-7.99(m,1H),7.74(dd,J=7.8,1.8Hz,1 H),7.56(dd,J=7.2,1.2Hz,1H),7.50(d,J=1.8Hz,1H),7.44(d,J=2.4Hz,1H),7.3 4(t,J=7.2Hz,1H),7.21(dd,J=8.4,2.4Hz,1H),4.06(s,3H),3.47-3.42(m,2H),3 .07(d,J=12.0Hz,2H),2.13-2.03(m,2H),1.94(d,J=11.4Hz,2H).LRMS(ESI)calcd for C 21 H 21 FN5O[M+H]+ 378.2, found: 378.3.

[0222] Example 27

[0223] 3-(6-Fluoropyridin-3-yl)-2-(4-methoxy-4-(1-methyl-1H-imidazol-4-yl)piperidin-1-yl)benzonitrile (Compound 27)

[0224] 3-(6-fluoropyridin-3-yl)-2-(4-methoxy-4-(1-methyl-1H-imidazol-4-yl)piperidin-1-yl)benzonitrile

[0225] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 25. The data for compound 27 are as follows: 1 H NMR(600MHz,MeOD-d4)δ8.26(d,J=2.4Hz,1H),8.04-7.99(m,1H),7.74(dd,J=7.8,1. 8Hz,1H),7.59(d,J=1.8Hz,1H),7.57(dd,J=7.8,1.8Hz,1H),7.53(d,J=2.4Hz,1H),7. 35(t,J=7.2Hz,1H),7.2(dd,J=8.4,2.4Hz,1H),4.04(s,3H),3.43-3.34(m,2H),3.14( s,3H),3.06(d,J=13.8Hz,2H),2.30-2.26(m,2H),2.04-1.98(m,2H).LRMS(ESI)calcd for C 22 H 23 FN5O[M+H] + 392.2, found: 392.3.

[0226] Example 28

[0227] 3-(6-Fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzylamine (Compound 28)

[0228] 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzamide

[0229] The synthetic route of compound 28 is shown in the figure above: QP5020 (10 mg, 0.028 mmol, 1.0 eq) and K2CO3 (1.0 mg, 0.0072 mmol, 0.25 eq) were dissolved in DMSO (1.0 mL), and H2O2 (3 μL) was added at room temperature. The reaction system was heated to 50 °C and stirred for 2 h. After the reaction was completed, the system was concentrated under reduced pressure and then purified by prep-HPLC (10% to 100% MeCN in H2O containing 0.1% TFA over 90 min) to obtain compound 28 (2 mg, 20% yield). The data for compound 28 are as follows: 1 H NMR (400MHz, MeOD-d4) δ9.13(s,1H),8.30(s,1H),8.08-8.03(m,1H),7.45(d,J=7.6Hz,1H),7.35(d,J=7.6Hz,1H),7.27(t ,J=7.6Hz,1H),7.17(d,J=8.4Hz,1H),3.86(s,3H),3.16-3.03(m,5H),1.87-1.83(m,2H),1.60(brs,2H).LRMS(ESI)calcd for C 20 H 22 FN6O[M+H] + 381.2, found: 381.3.

[0230] Example 29

[0231] 2-(4-fluoro-4-(1-methyl-1H-imidazol-5-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile (Compound 29)

[0232] 2-(4-fluoro-4-(1-methyl-1H-imidazol-5-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0233] The synthetic route of compound 29 is shown in the figure above:

[0234] Step a: Intermediate MC74 (10 mg, 0.027 mmol, 1.0 eq) was dissolved in DCM (2 ml). DAST (18 mg, 0.11 mmol, 4.0 eq) was added to the system at 0 °C, and the mixture was stirred at room temperature for 4 h. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure. Intermediate MC80 was obtained as a white oily liquid (7 mg, 71.6% yield) by silica gel column chromatography.1 H NMR (400MHz, CDCl3) δ7.78 (dd, J=8.0, 1.6Hz, 1H), 7.55 (dd, J=8.0, 1.6Hz, 1H), 7.43 (s, 1H), 7.05-6.99(m,2H),3.85-3.76(m,5H),3.26-3.22(m,2H),2.40-2.28(m,4H).LRMS(ESI)calcd for C 16 H 17 BrFN4[M+H] + 363.1, found:363.1.

[0235] Step b, the same as step d in Example 1, yielded the following data for compound 29: 1 H NMR (600MHz, MeOD-d4) δ8.91 (s, 1H), 8.28 (d, J = 2.4Hz, 1H), 8.01 (td, J = 7.8, 2. 4Hz,1H),7.75(dd,J=7.8,2.4Hz,1H),7.65(s,1H),7.57(dd,J=7.2,1.8Hz,1H) ,7.35(t,J=7.8Hz,1H),7.20(dd,J=8.4,2.4Hz,1H),4.01(s,3H),3.43-3.34(m ,2H),3.16-3.13(m,2H),2.29-2.25(m,2H),2.18-2.01(m,2H).LRMS(ESI)calcd for C 21 H 20 F2N5[M+H] + 380.2, found: 380.3.

[0236] Example 30

[0237] N-(2-cyano-4-(6-fluoropyridin-3-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)butyramide (compound 30)

[0238] N-(2-cyano-4-(6-fluoropyridin-3-yl)-3-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)butyramide

[0239] The synthesis method of compound 30 is shown above:

[0240] Step a: Compound MC81 (500 mg, 2.325 mmol, 1.0 eq), butyryl chloride (250 mg, 2.325 mmol, 1.0 eq), and DIPEA (460 μL, 1.2 eq) were dissolved in DCM (10 mL) and stirred overnight at room temperature. After the reaction was complete, the mixture was cooled to room temperature, and water and EA were added for extraction. The organic phase was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain a yellow oily compound MC82 (410 mg, 62.4% yield). 1 H NMR (400MHz, CDCl3) δ8.22(d,J=9.2Hz,1H),7.73(t,J=8.0Hz,1H),7.64(s,1H),7.23( dd,J=8.4,2.4Hz,1H),2.45(t,J=7.2Hz,2H),1.83-1.73(m,2H),1.03(t,J=7.2Hz,3H).

[0241] Step b: After removing the Cbz protecting group from intermediate MC83, the crude product (0.20 g, 1.21 mmol, 1.0 eq) was dissolved in DMSO (4 mL). Then, intermediate 3 (0.41 g, 1.45 mmol, 1.2 eq) and anhydrous potassium carbonate (0.25 g, 1.82 mmol, 1.5 eq) were added sequentially, and the mixture was heated and stirred at 100 °C for 16 hours. After the reaction was completed by TLC monitoring, dichloromethane and water were added for extraction, followed by extraction again with saturated brine and dichloromethane. The organic phase was collected and purified using a SepaBean machine T200, finally yielding 0.15 g of intermediate 5. 1 H NMR (400MHz, MeOD-d4) δ8.09-8.04(m,2H),7.71(d,J=9.2Hz,1H),7.59(s,1H),3.70(s,3H),3.50-3.43(m,2H),2.96-2.88( m,1H),2.43(t,J=7.2Hz,2H),2.33-2.29(m,2H),1.81-1.75(m,2H),1.64(s,2H),1.31-1.24(m,2H),1.03(t,J=7.2Hz,3H).

[0242] Step c: Intermediate MC84 (43 mg, 0.10 mmol, 1.0 eq), sodium carbonate (21 mg, 0.2 mmol, 2.0 eq), and 4-fluoro-3-pyridineboronic acid (34 mg, 0.15 mmol, 1.5 eq) were dissolved in a mixed solvent of 2 mL dioxane and 0.2 mL water. Under nitrogen protection, Pd(dppf)Cl2 (7 mg, 0.01 mmol, 0.1 eq) was added, and the reaction was carried out at 90°C for 10 hours. After cooling to room temperature, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was concentrated and separated by HPLC to obtain a white solid product. The data for compound 30 are as follows: 1 H NMR (400MHz, MeOD-d4) δ9.09(s,1H),8.27(s,1H),8.03(t,J=8.0Hz,1H),7.54(d,J=8.4Hz,1H),7.41(d,J=8.4Hz,1H),7.23(dd,J=8 .4,2.4Hz,1H),3.88(s,3H),3.16-3.14(m,2H),2.47(t,J=7.2Hz,2H),1.98-1.75(m,6H),1.36-1.31(m,3H),1.08(t,J=7.2Hz,3H). LRMS(ESI)[M+H] + ,found:448.1.

[0243] Example 31

[0244] 2-Fluoro-5-(2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(methanesulfonyl)phenyl)pyridine (compound 31)

[0245] 2-fluoro-5-(2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(methylsulfonyl)phenyl)pyridine

[0246] The synthetic route of compound 31 is shown in the figure above:

[0247] Step a: 1-Bromo-2-fluorobenzene MC85 (1.75 g, 10.0 mmol, 10.0 eq) was dissolved in tetrahydrofuran (30 mL) under argon protection. After cooling the system to -78 °C, LDA (6 mL, 2 M, 1.2 eq) was added dropwise over 1 h while maintaining the temperature at -78 °C. Then, DMSO (1.1 mL, 13.0 mmol, 1.3 eq) was added to the system, and the reaction was stirred at -78 °C for 2 h. After the reaction was completed, the reaction was terminated with H2O (20 mL), then extracted with EA (50 mL) and H2O (50 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (PE:EA 20:1–6:1) to obtain compound MC86 (1.4 g, 63.6% yield). 1 H NMR (400MHz, CDCl3) δ7.35 (t, J = 6.8 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 3.82 (s, 3H).

[0248] Step b: MC86 (1.40 g, 6.4 mmol, 1.0 equiv) was dissolved in DCM (30 mL) under argon protection. After the reaction system was cooled to 0 °C, m-CPBA (2.2 g, 30.0 mmol, 2.2 eq) was slowly added. The system was slowly warmed to room temperature to continue the reaction. After the reaction was completed, DCM (70 mL) was added to dilute the system, and then the mixture was washed with saturated NaHCO3aq (500 mL) and brine (50 mL). The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain a white solid compound MC87 (600 mg, 37.4% yield). 1 H NMR (400MHz, CDCl3) δ7.94-7.90(m,1H),7.88-7.83(m,1H),7.27-7.22(m,1H),3.25(s,3H).

[0249] Step c: Using intermediate MC87 and compound MC83, MC88 (105 mg, 21.7% yield) was obtained via the synthetic route step c in Example 1. 1H NMR (400MHz, CDCl3) δ8.07-8.04(m,2H),7.77(dd,J=8.0,2.4Hz,1H),7.25(t,J=8.0Hz,1H),3.89-3.82(m, 2H),3.68(s,3H),3.58(s,3H),3.16-3.11(m,2H),2.87-2.80(m,1H),2.30-2.18(m,2H),2.03-1.97(m,2H).

[0250] Step d: Using intermediate MC88, as in step d of the synthetic route in Example 1, the data for compound 31 are as follows: 1 H NMR(400MHz,MeOD-d4)δ9.07(s,1H),8.25(d,J=2.4Hz,1H),8.18(dd,J=7.2,2.4Hz,1H),7.98(td,J=8.0,2.4Hz,1H),7.54-7.48(m,2H),7.24(dd ,J=8.4,2.4Hz,1H),3.82(s,3H),3.41-3.34(m,5H),2.95-2.88(m,1H),2.66-2.59(m,2H),2.12-2.01(m,2H),1.92-1.88(m,2H).LRMS(ESI)calcd for C 20 H 23 FN5O2S[M+H] + 416.2, found: 416.3.

[0251] Example 32

[0252] 2-Fluoro-5-(2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-nitrobenzene)pyridine (compound 32)

[0253] 2-fluoro-5-(2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-nitrophenyl)pyridine

[0254] The synthesis route is shown in the figure above:

[0255] Step a: After removing the Cbz protecting group from compound MC83, 4-(4-methyl-4H-[1,2,4]triazol-3-yl)-piperidine (1.0 g, 6.02 mmol, 1.0 eq) was dissolved in DMSO (15 mL). Potassium carbonate (2.5 g, 18.06 mmol, 3.0 eq) and 1-bromo-2-fluoro-3-nitrobenzene (MC89) (2.6 g, 12.04 mmol, 2 eq) were added to the system. The mixture was heated to 60 °C and reacted with stirring for 4 hours. After cooling to room temperature, the mixture was filtered, and the solution was concentrated under pressure. The solution was then washed with DCM and water, and the organic phase was concentrated under reduced pressure. After purification by silica gel column chromatography, 0.65 g of intermediate MC90 (30% yield) was obtained. 1 H NMR(400MHz,MeOD-d4)δ8.40(s,1H),7.91(d,J=7.6Hz,1H),7.66(dd,J=7.6,2.4Hz,1H),7.16(t,J=7.6Hz,1H) ,3.79(s,3H),3.63-3.56(m,2H),3.43-3.32(m,2H),3.17-3.08(m,1H),2.26-2.15(m,2H),2.10-2.05(m,2H).

[0256] Step b: Intermediate 1-(2-bromo-6-nitrobenzene)-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine (0.65 g, 1.78 mmol, 1.0 eq), Na₂CO₃ (0.38 g, 3.56 mmol, 2.0 eq), and pinacol ester of 2-fluoropyridine 5-borate (0.6 g, 2.67 mmol, 1.5 eq) were dissolved in a mixed solvent of 1,4-dioxane (9 mL) and H₂O (1 mL). After purging the reaction system with nitrogen, Pd(dppf)Cl₂ (0.13 g, 0.18 mmol, 0.1 eq) was added. The system was heated to 90 °C and stirred for 12 hours under nitrogen protection. After cooling to room temperature, the system was diluted with water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by column chromatography to give compound 32 in a total of 0.45 g (yield 66%). 1H NMR (400MHz, MeOD-d4) δ9.03(s,1H),8.35(d,J=2.4Hz,1H),8.12(d,J=8.0,2.8Hz,1H),7.71(dd,J=8.0,1.6Hz,1H),7.53(dd,J=7.6,1.6 Hz,1H),7.37(t,J=8.0Hz,1H),7.23-7.20(m,1H),3.83(s,3H),3.14-3.01(m,5H),1.85-1.80(m,2H),1.63-1.53(m,2H).LRMS(ESI)calcd for C 19 H 20 FN6O2[M+H] + 383.2, found:383.2.

[0257] Example 33

[0258] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)formamide (compound 33)

[0259] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)formamide

[0260] The synthetic route of compound 33 is shown in the figure above:

[0261] In step a), compound 33 (0.6 g, 1.57 mmol, 1.0 eq) and reduced iron powder (0.88 g, 15.7 mmol, 10.0 eq) were dissolved in a mixed solvent of EtOH (9 mL) and H2O (1 mL), and then NH4Cl (0.83 g, 15.7 mmol, 10.0 eq) was added. The reaction system was heated to 70 °C and stirred for 3 h. After the reaction was completed, DCM (20 mL) was added to dilute the system, and the mixture was filtered and concentrated under reduced pressure to obtain the crude product MC91 (500 mg).

[0262] Step b: At room temperature, MC91 (25 mg, 0.071 mmol, 1.0 eq) was dissolved in Ac2O (0.1 mL) and HCOOH (0.3 mL) solutions. The system was heated to 60 °C and stirred for 2 hours. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, and compound 33 was purified by prep-HPLC to obtain a white solid (14 mg, 51.7% yield). 1H NMR(400MHz,MeOD-d4)δ9.18-9.11(m,1H),8.50(s,1H),8.26-8.20(m,1H),7.99-7.91(m,1H),7.26-7.17(m,2 H),7.04-6.90(m,1H),3.85(s,3H),3.09-2.94(m,3H),2.65-2.61(m,2H),2.12-1.91(m,4H).LRMS(ESI)calcd for C 20 H 22 FN6O[M+H] + 381.2, found:381.2.

[0263] Example 34

[0264] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)acetamide (compound 34)

[0265] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)acetamide

[0266] The synthetic route of compound 34 is shown in the figure above: MC91 (25 mg, 0.071 mmol, 1.0 eq) was dissolved in DCM (2.0 mL) at 0 °C. AcCl (8 mg, 0.102 mmol, 1.3 eq) and TEA (10 mg, 0.102 mmol, 1.3 eq) were added to the system with stirring. The mixture was heated to room temperature and the reaction was continued for 2 hours. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, and then compound 35 was obtained as a white solid (10 mg, 35.6% yield) by prep-HPLC. 1 H NMR(400MHz,MeOD-d4)δ8.91(brs,1H),8.21(brs,1H),7.96(brs,1H),7.24-7.16(m,3H),6.99(brs,1H ),3.80(s,3H),3.06-2.95(m,3H),2.70-2.57(m,2H),2.24(s,3H),2.04-1.90(m,4H).LRMS(ESI)calcd for C 21 H 24 FN6O[M+H] + 395.2, found: 395.3.

[0267] Example 35

[0268] 1,1,1-Trifluoro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide (compound 35)

[0269] 1,1,1-trifluoro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesul fonamide

[0270] The synthetic route is shown in the figure above. The synthetic method is the same as that for compound 33. The data for compound 35 are as follows: 1 H NMR(400MHz,MeOD-d4)δ9.11(s,1H),8.26(brs,1H),8.01(brs,1H),7.39-7.17(m,4H ),3.86(s,3H),3.21-2.99(m,4H),2.66(brs,1H),2.22-1.85(m,4H).LRMS(ESI)calcd for C 20 H 21 F4N6O2S[M+H] + 485.1, found: 485.2.

[0271] Example 36

[0272] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide (compound 36)

[0273] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide

[0274] The synthetic route for compound 36 is shown in the figure above. The crude MC91 product obtained above (30 mg, 0.09 mmol, 1.0 eq) was dissolved in DCM (2.0 mL), and methanesulfonyl chloride (16 mg, 0.14 mmol, 1.5 eq) and TEA (18 mg, 0.18 mmol, 1.5 eq) were added at 0 °C. The reaction was heated to room temperature and stirred for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the product was purified by prep-HPLC to obtain compound 36 as a yellow solid product (20 mg, yield 54%). 1 H NMR(400MHz,MeOD-d4)δ9.12(s,1H),8.22(s,1H),7.97(brs,1H),7.55-7.46(m,1H),7.26(t,J=8.0Hz,1H),7.20-7.17(m ,1H),6.95(brs,1H),3.87(s,3H),3.16(s,3H),3.10-2.99(m,3H),2.69-2.64(m,2H),2.04-1.94(m,4H).LRMS(ESI)calcd for C 20 H 24 FN6O2S[M+H] + 431.2,found:431.2.

[0275] Example 37

[0276] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)cyclopropylsulfonamide (compound 37)

[0277] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)cyclopropanesulfonamide

[0278] The synthesis method was the same as in Example 33, and the data for compound 37 were as follows: 1H NMR(600MHz,MeOD-d4)δ8.98(s,1H),8.22(s,1H),7.97(brs,1H),7.71-7.46(m,1H),7.25(t,J=7.8Hz,1H),7.18(d,J=8.4Hz, 1H),6.94(brs,1H),3.81(s,3H),3.10-2.96(m,3H),2.75-2.65(m,3H),2.04-1.93(m,4H),1.16-1.07(m,4H).LRMS(ESI)calcd for C 22 H 26 FN6O2S[M+H] + 457.2, found: 457.3.

[0279] Example 38

[0280] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)ethylsulfonamide (compound 38)

[0281] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)ethanesulfonamide

[0282] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33, and compound 38 was obtained as a white solid (8 mg, 17% yield). The structural characterization data are as follows: 1 H NMR(600MHz,MeOD-d4)δ9.11(s,1H),8.21(s,1H),7.95(brs,1H),7.56(brs,1H),7.25(t,J=7.8Hz,1H),7.19(d,J=7.8Hz,1H),6.9 2(brs,1H),3.85(s,3H),3.31-3.26(m,2H),3.09-2.99(m,3H),2.65(brs,2H),1.99-1.93(m,4H),1.39(brs,3H).LRMS(ESI)calcd for C 21 H 26 FN6O2S[M+H] + 445.2, found: 445.3.

[0283] Example 39

[0284] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)propane-1-sulfonamide (compound 39)

[0285] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 39 are as follows: 1 H NMR(600MHz,MeOD-d4)δ9.03(s,1H),8.21(s,1H),7.95(brs,1H),7.56(brs,1H),7.25(t,J=7.8Hz,1H),7.19(d,J=8.4Hz,1H),6.92 (brs,1H),3.83(s,3H),3.27(brs,2H),3.08-2.96(m,3H),2.64(brs,2H),1.98-1.87(m,6H),1.08(t,J=7.2Hz,3H).LRMS(ESI)calcd for C 22 H 28 FN6O2S[M+H] + 459.2, found:459.3.

[0286] Example 40

[0287] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)pyridine-2-sulfonamide (compound 40)

[0288] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)pyridine-2-sulfonamide

[0289] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 40 are as follows: 1H NMR(600MHz,MeOD-d4)δ9.15(s,1H),8.96(s,1H),8.82-8.80(m,1H),8.25-7.88(m,3H),7.66-7. 44(m,2H),7.17-7.01(m,3H),3.87(s,3H),3.32-2.54(m,5H),2.04-1.88(m,4H).LRMS(ESI)calcd for C 24 H 25 FN7O2S[M+H] + 494.2, found: 494.3.

[0290] Example 41

[0291] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-2-methylpropane-1-sulfonamide (compound 41)

[0292] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 41 are as follows: 1 H NMR(600MHz,MeOD-d4)δ9.11(s,1H),8.21(s,1H),7.95(brs,1H),7.55(brs,1H),7.26(t,J=7.8Hz,1H),7.19(d,J=8.4Hz,1H),6.92(brs,1H ),3.85(s,3H),3.20(brs,2H),3.08-2.98(m,3H),2.64(brs,2H),2.29(brs,1H),1.98-1.93(m,4H),1.12(d,J=7.2Hz,6H).LRMS(ESI)calcd for C 23 H 30 FN6O2S[M+H] + 473.2, found: 473.3.

[0293] Example 42

[0294] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)butyl-1-sulfonamide (compound 42)

[0295] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)butane-1-sulfonamide

[0296] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 42 are as follows: 1 H NMR(600MHz,MeOD-d4)δ9.10(s,1H),8.21(s,1H),7.96(brs,1H),7.57(brs,1H),7.26(t,J=7.8Hz,1H),7.19(d,J=7.8Hz,1H),6.92(brs, 1H),3.85(s,3H),3.31-3.26(m,2H),3.09-2.98(m,3H),2.65(brs,2H),1.99-1.81(m,6H),1.49(brs,2H),0.95(brs,3H).LRMS(ESI)calcd for C 23 H 30 FN6O2S[M+H] + 473.2, found: 473.3.

[0297] Example 43

[0298] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)propyl-2-sulfonamide (compound 43)

[0299] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)propane-2-sulfonamide

[0300] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 43 are as follows: 1H NMR(600MHz,MeOD-d4)δ9.07-8.96(m,1H),8.21(s,1H),7.96-7.93(m,1H),7.60(brs,1H),7.24(t,J=7.8Hz,1H),7.21-7.18(m,1H),6. 90(brs,1H),3.81(s,3H),3.50(brs,1H),3.09-2.94(m,3H),2.69-2.63(m,2H),1.98-1.89(m,4H),1.43-1.41(m,6H).LRMS(ESI)calcd for C 22 H 28 FN6O2S[M+H] + 459.2, found:459.3.

[0301] Example 44

[0302] 3-Chloro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)propyl-1-sulfonamide (Compound 44)

[0303] 3-chloro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)propane-1-sulfonamide

[0304] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 44 are as follows: 1 H NMR(600MHz,MeOD-d4)δ9.02(s,1H),8.22(s,1H),7.95(brs,1H),7.56(brs,1H),7.26(t,J=7.8Hz,1H),7.19(d,J=8.4Hz,1H),6.94( LRMS(ESI)calcd for C 22 H 27 ClFN6O2S[M+H] + 493.2, found: 493.3.

[0305] Example 45

[0306] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-N-methylmethanesulfonamide (compound 45)

[0307] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-N-methylmethanesulfonamide

[0308] The synthetic method is shown in the figure above. Compound 36 (20 mg, 0.05 mmol, 1.0 eq) was dissolved in THF (2.0 mL), and potassium carbonate (14 mg, 0.10 mmol, 2.0 eq) and methyl iodide (14 mg, 0.10 mmol, 2.0 eq) were added at room temperature. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the product was separated and purified by prep-HPLC to obtain compound 45 as a white solid product (8 mg, yield 40%). The data for compound 45 are as follows: 1 H NMR(400MHz,MeOD-d4)δ9.11(s,1H),8.29(s,1H),8.05(brs,1H),7.50-7.45(m,1H),7.29-7.26(m,2H ),7.19-7.15(m,1H),3.86(s,3H),3.33(s,3H),3.09-2.96(m,7H),2.04-1.66(m,5H).LRMS(ESI)calcd for C 21 H 26 FN6O2S[M+H] + 445.2, found: 445.3.

[0309] Example 46

[0310] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)thiophene-2-sulfonamide (compound 46)

[0311] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)thiophene-2-sulfonamide

[0312] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 46 are as follows: 1 H NMR(600MHz,MeOD-d4)δ9.02(s,1H),8.13(brs,1H),7.89-7.79(m,2H),7.63(brs,2H), 7.26-6.92(m,4H),3.82(s,3H),3.03-2.53(m,5H),1.91-1.88(m,4H).LRMS(ESI)calcd for C 23 H 24 FN6O2S2[M+H] + 499.1, found: 499.3.

[0313] Example 47

[0314] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methylamino-1-sulfonamide (compound 47)

[0315] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methylamino-1-sulfonamide

[0316] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 47 are as follows: 1 H NMR(600MHz,MeOD-d4)δ9.09(s,1H),8.20(s,1H),7.94(brs,1H),7.54(d,J=7.2Hz,1H),7.25(t,J=7.8Hz,1H),7.19(d ,J=8.4Hz,1H),6.86(brs,1H),3.85(s,3H),3.09-2.96(m,3H),2.80-2.65(m,5H),2.04-1.93(m,4H).LRMS(ESI)calcd for C 20 H 25 FN7O2S[M+H] + 446.2, found:446.3.

[0317] Example 48

[0318] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-4-methylbenzenesulfonamide (Compound 48)

[0319] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-4-methylbenzenesulfonamide

[0320] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 48 are as follows: 1 H NMR(400MHz,MeOD-d4)δ9.16(s,1H),8.10(brs,1H),7.85(brs,1H),7.72(d,J=7.6Hz,2H),7.56(brs,1H),7.36(d,J=8.0H z,2H),7.16-7.13(m,2H),6.88(brs,1H),3.86(s,3H),3.00-2.49(m,5H),2.41(s,3H),1.93-1.89(m,4H).LRMS(ESI)calcd for C 26 H 28 FN6O2S[M+H] + 507.2, found:507.2.

[0321] Example 49

[0322] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-2-methoxyethyl-1-sulfonamide (compound 49)

[0323] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-2-methoxyethane-1-sulfonamide

[0324] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 49 are as follows: 1H NMR(600MHz,MeOD-d4)δ9.15(s,1H),8.20(s,1H),7.95(brs,1H),7.61(brs,1H),7.25(t,J=7.8Hz,1H),7.18(d,J=8.4Hz,1H),6.90(br s,1H),3.86(s,3H),3.84(brs,2H),3.55(brs,2H),3.27(s,3H),3.08-2.98(m,3H),2.63(brs,2H),1.99-1.93(m,4H).LRMS(ESI)calcd for C 22 H 28 FN6O3S[M+H] + 475.2, found:475.2.

[0325] Example 55

[0326] N-(3-(5-(cyclopropylmethoxy)-6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide (compound 55)

[0327] N-(3-(5-(cyclopropylmethoxy)-6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide

[0328] The synthetic route is shown in the figure above: Step a, compound 90 (365 mg, 1.0 mmol, 1.0 eq) and reduced iron powder (560 mg, 10.0 mmol, 10.0 eq) were dissolved in a mixed solvent of EtOH (20 mL) and H2O (2 mL), and then NH4Cl (560 g, 10.0 mmol, 10.0 eq) was added. The reaction system was heated to 50 °C and stirred for 3 h. After the reaction was completed, DCM (200 mL) was added to dilute the system, and the mixture was filtered and concentrated under reduced pressure to obtain crude product (500 mg). The crude product (33 mg, 0.09 mmol, 1.0 eq) was dissolved in DCM (2.0 mL), and methanesulfonyl chloride (16 mg, 0.14 mmol, 1.5 eq) and TEA (18 mg, 0.18 mmol, 1.5 eq) were added at 0 °C. The reaction was heated to room temperature and stirred for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the product was separated and purified by silica gel chromatography to obtain compound 92 as a yellow solid product (20 mg, yield 54%).1 H NMR(400MHz,MeOD-d4)δ8.58(s,1H),8.41(s,1H),8.07(s,1H),3.68(s,3H),3.64-3.5 7(m,2H),3.29-3.14(m,5H),2.94-2.88(m,1H),2.23-2.13(m,2H),2.04-1.99(m,2H).

[0329] In step b, intermediates N-(3-bromo-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide (0.735 g, 1.78 mmol, 1.0 eq), Na2CO3 (0.38 g, 3.56 mmol, 2.0 eq) and 3-(cyclopropylmethoxy)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)pyridine (0.6 g, 2.67 mmol, 1.5 eq) were dissolved in a mixed solvent of 1,4-dioxane (9 mL) and H2O (1 mL). After purging the reaction system with nitrogen, Pd(dppf)Cl2 (0.13 g, 0.18 mmol, 0.1 eq) was added. The system was heated to 90 °C and stirred for 12 hours under nitrogen protection. After cooling to room temperature, the system was diluted with water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by column chromatography to give 0.587 g of compound 32 (66% yield). 1 H NMR(400MHz,MeOD-d4)δ9.08(s,1H),7.76-7.68(m,2H),7.55-7.46(m,1H),7.26(t,J=8.0Hz,1H),7.20-7.17(m,1H),3.98(s,3H),3.93(d,J=7.2H z,1H),3.86(s,3H),3.10-2.99(m,3H),2.69-2.64(m,2H),2.04-1.94(m,4H),1.28(brs,4H)0.71-0.66(m,2H),0.41-0.36(m,2H).LRMS(ESI)calcd for C 24 H 30 FN6O3S[M+H] + 500.2, found: 501.3.

[0330] Example 57

[0331] N-(3-(2-(tert-butyl)-2H-pyrazolo[3,4-b]pyridin-5-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide (compound 57)

[0332] N-(3-(2-(tert-butyl)-2H-pyrazolo[3,4-b]pyridin-5-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide

[0333] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 55. The data for compound 57 are as follows: 1 H NMR(400MHz,MeOD-d4)δ9.13(s,1H),8.98(s,1H),8.51(brs,1H),8.04(s,1H),7.26(t,J=8.0Hz,1H),7.20-7.17(m,1H),6.9 5(brs,1H),3.87(s,3H),3.16(s,3H),3.10-2.97(m,3H),2.68-2.65(m,2H),2.05-1.95(m,4H),1.20(s,9H).LRMS(ESI)calcd for C 25 H 33 FN8O2S[M+H] + 508.2, found: 509.3.

[0334] Example 65

[0335] N-(2-(4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)butane-1-sulfonamide (compound 65)

[0336] N-(2-(4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)butane-1-sulfonamide

[0337] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 65 are: LRMS(ESI)calcd for C 23 H 29 F2N6O2S[M+H] + 491.2, found: 491.3.

[0338] Example 67

[0339] 3-Chloro-N-(2-(4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)propane-1-sulfonamide (Compound 67)

[0340] 3-chloro-N-(2-(4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)propane-1-sulfonamide

[0341] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 67 are: LRMS(ESI)calcd for C 22 H 26 ClF2N6O2S[M+H] + 511.1, found: 511.2.

[0342] Example 68

[0343] N-(2-(4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)thiophene-2-sulfonamide (compound 68)

[0344] N-(2-(4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)thiophene-2-sulfonamide

[0345] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 68 are: LRMS(ESI)calcd for C 23 H 23 ClF2N6O2S2[M+H] + 517.1, found: 517.2.

[0346] Example 75

[0347] 3,3,3-Trifluoro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)propane-1-sulfonamide (Compound 75)

[0348] 3,3,3-trifluoro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)propane-1-sulfonamide

[0349] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 75 are: LRMS(ESI)calcd for C 22 H 25 F4N6O2S[M+H] + 513.2, found: 513.3.

[0350] Example 76

[0351] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)tetrahydro-2H-pyran-4-sulfonamide (compound 76)

[0352] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)tetrahydro-2H-pyran-4-sulfonamide

[0353] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 76 are: LRMS(ESI)calcd for C 24 H 30 FN6O3S[M+H] + 501.2, found: 501.4.

[0354] Example 77

[0355] 4-(N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)sulfanilyl)methyl benzoate (compound 77)

[0356] methyl

[0357] 4-(N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)sulfamoyl)benzoate

[0358] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 77 are as follows: 1 H NMR(400MHz,MeOD-d4)δ9.00(s,1H),8.20-8.17(m,6H),7.53(brs,1H),7.16-7.13(m, 3H),3.94(s,3H),3.82(s,3H),3.15-2.51(m,5H),1.89-1.86(m,4H).LRMS(ESI)calcd for C 27 H 28 FN6O4S[M+H] + 551.2,found:551.2.

[0359] Example 78

[0360] 4-Fluoro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)benzenesulfonamide (Compound 78)

[0361] 4-fluoro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)benzenesulfonamide

[0362] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 78 are as follows: 1 H NMR(400MHz,MeOD-d4)δ9.03(s,1H),8.12-7.91(m,4H),7.55(brs,1H),7.32-7.29(m,2H ),7.19-7.14(m,3H),3.83(s,3H),3.03-2.52(m,5H),2.03-1.30(m,4H).LRMS(ESI)calcd for C 25 H 25 F2N6O2S[M+H] + 511.2, found:511.2.

[0363] Example 79

[0364] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-6-methylpyridin-3-sulfonamide (compound 79)

[0365] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-6-methylpyridine-3-sulfonamide

[0366] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 79 are as follows: 1 H NMR(400MHz,MeOD-d4)δ9.15(s,1H),8.81(brs,1H),8.24-8.12(m,2H),7.92(brs,1H),7.53-7.3 5(m,1H),7.22-7.15(m,4H),3.87(s,3H),3.15-2.56(m,8H),2.03-1.59(m,4H).LRMS(ESI)calcd for C 25 H 27 FN7O2S[M+H] + 508.2, found:508.2.

[0367] Example 80

[0368] 2-(4-fluoro-4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile (Compound 80)

[0369] 2-(4-fluoro-4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0370] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 80 are as follows: 1H NMR (600MHz, MeOD-d4) δ8.76(s,1H),8.28(d,J=2.4Hz,1H),8.06(td,J=7.8,2.4Hz,1H),7.75(dd,J=7.8,1.2Hz,1H),7.58(dd,J=7.8, 1.2Hz,1H),7.36(t,J=7.8Hz,1H),7.22(dd,J=8.4,2.4Hz,1H),3.41(brs,2H),3.22-3.14(m,2H),2.30-2.23(m,4H).LRMS(ESI)calcd for C 20 H 16 D3F2N6[M+H] + 384.2, found:384.2.

[0371] Example 81

[0372] N-(2-(4-fluoro-4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)methanesulfonamide (compound 81)

[0373] N-(2-(4-fluoro-4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)methanesulfonamide

[0374] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 81 are as follows: 1 H NMR(400MHz,MeOD-d4)δ8.53(s,1H),8.20(d,J=1.6Hz,1H),7.97(brs,1H),7.55(brs,1H),7.26(t,J=5.2Hz,1H), 7.17(brs,1H),6.98(brs,1H),3.17(s,3H),3.06-2.70(m,4H),2.40(brs,2H),2.22-2.17(m,2H).LRMS(ESI)calcd for C 20 H 20 F2N6O2S[M+H] + 452.2, found:452.2.

[0375] Example 83

[0376] 3-(6-Fluoropyridin-3-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile (Compound 83)

[0377] 3-(6-fluoropyridin-3-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0378] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 83 are as follows: 1 H NMR (400MHz, MeOD-) d4 )δ9.01(s,1H),8.26(d,J=2.4Hz,1H),8.02(td,J=8.4,2.4Hz,1H),7.73(dd,J=8.0,1.6Hz,1H),7.56(dd,J=8.0,1.6Hz,1H), 7.33(t,J=8.0Hz,1H),7.20(dd,J=8.4,2.4Hz,1H),3.27(brs,2H),3.17-3.08(m,3H),1.97-1.93(m,2H),1.83-1.79(m,2H). 13 C NMR (150MHz, MeOD-) d4 )δ164.4(d,J=238.4Hz),159.1,154.2,148.5(d,J=14.3Hz),145.8,144.1(d,J=8.3Hz),137.6,136.9,135.9,1 35.1(d,J=2.7Hz),126.0,119.5,111.2,110.5(d,J=37.1Hz),52.5,32.8,32.6-31.9(m),30.8.HRMS(ESI)calcd for C 20 H 17 D3FN6[M+H] + :366.1916,found:366.1918.

[0379] Example 84

[0380] 3-(5,6-Difluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile (Compound 84)

[0381] 3-(5,6-difluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0382] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 84 are as follows: 1 H NMR(400MHz,MeOD)δ9.02(s,1H),8.05(s,1H),8.01-7.89(m,1H),7.75(dd,J=7.6,1.6Hz,1H),7.58(dd,J=8.0,2.0Hz, 1H),7.34(t,J=8.0Hz,1H),3.85(s,3H),3.25-3.07(m,4H),1.97(d,J=12.4Hz,2H),1.89-1.72(m,2H).LRMS(ESI)calcd for C 20 H 19 F2N6[M+H] + 381.2, found: 381.3.

[0383] Example 85

[0384] 3-(6-chloro-5-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile (Compound 85)

[0385] 3-(6-chloro-5-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0386] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 85 are as follows: 1 H NMR (600MHz, MeOD) δ9.00 (s, 1H), 8.23-8.10 (m, 2H), 7.75 (d, J = 7.2Hz, 1H), 7.59 (d, J = 7.2Hz, 1H), 7. 35(t,J=7.8Hz,1H),3.85(s,3H),3.26-3.05(m,4H),2.03-1.90(m,2H),1.80(s,2H).LRMS(ESI)calcd for C 20 H 19 FClN6[M+H]+ 397.1, found: 397.2.

[0387] Example 86

[0388] 3-(6-fluoro-5-methoxypyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile (Compound 86)

[0389] 3-(6-fluoro-5-methoxypyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0390] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 86 are as follows: 1 H NMR(400MHz,MeOD)δ9.08(s,1H),7.76-7.68(m,2H),7.63(dd,J=9.6,2.0Hz,1H),7.56(dd,J=7.6,1.6Hz,1H),7.31(t,J=7.6H z,1H),3.98(s,3H),3.86(s,3H),3.36(s,2H),3.22-3.07(m,2H),1.97(d,J=11.6Hz,2H),1.92-1.76(m,2H).LRMS(ESI)calcd for C 21 H 22 FN6O[M+H] + 393.2, found:393.2.

[0391] Example 87

[0392] 3-(6-fluoro-5-methylpyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile (Compound 87)

[0393] 3-(6-fluoro-5-methylpyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0394] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 87 are as follows: 1H NMR(600MHz,MeOD)δ9.02(s,1H),8.07(s,1H),7.88(d,J=9.6Hz,1H),7.73(dd,J=7.8,1.8Hz,1H),7.59-7.54(m,1H),7. 34(t,J=7.8Hz,1H),3.86(s,3H),3.28-3.06(m,4H),2.39(s,3H),1.96(d,J=12.6Hz,2H),1.83(s,2H).LRMS(ESI)calcd for C 21 H 22 FN6[M+H] + 377.3, found: 377.4.

[0395] Example 88

[0396] 3-(6-fluoro-4-methylpyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile (Compound 88)

[0397] 3-(6-fluoro-4-methylpyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0398] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 88 are as follows: 1 H NMR (400MHz, MeOD) δ9.08 (s, 1H), 7.99 (s, 1H), 7.75 (dd, J = 8.0, 2.0Hz, 1H), 7.45 ( dd,J=7.6,1.6Hz,1H),7.34(t,J=8.0Hz,1H),7.11(s,1H),3.84(s,3H),3.43-3.3 4(m,2H),3.22-3.05(m,2H),2.99-2.86(m,1H),2.25(s,3H),1.97(d,J=13.2Hz,1 H),1.88(d,J=13.2Hz,1H),1.81-1.69(m,1H),1.70-1.46(m,1H).LRMS(ESI)calcd for C 21 H 22 FN6[M+H] + 377.3, found:377.3.

[0399] Example 89

[0400] N-(3-cyano-5-(6-fluoropyridin-3-yl)-4-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-1-methylpiperidin-4-carboxamide (Compound 89)

[0401] N-(3-cyano-5-(6-fluoropyridin-3-yl)-4-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-1-methylpiperidine-4-carboxamide

[0402] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 89 are: LRMS(ESI)calcd for C 27 H 32 FN8O[M+H] + 503.2, found: 503.4.

[0403] Example 90

[0404] 3-(6-Fluoropyridin-3-yl)-2-(4-(4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile (Compound 90)

[0405] 3-(6-fluoropyridin-3-yl)-2-(4-(4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0406] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 1. The data for compound 90 are as follows: 1 H NMR (600MHz, CDCl3) δ8.47(s,1H),8.16(s,1H),7.92(t,J=8.4Hz,1H),7.63(d,J=8.4Hz,1H),7.43(d,J=7.2Hz,1H),7.25-7.23(m,1H),7.11 -7.09(m,3H),6.93(d,J=7.2Hz,2H),5.10(s,2H),3.82(s,3H),3.22-3.12(m,4H),2.83(t,J=12.0Hz,1H),1.86(brs,2H),1.73-1.70(m,2H). 13C NMR (125MHz, MeOD-) d4 )δ164.4(d,J=238.3Hz),161.9,159.1,154.2,148.5(d,J=14.1Hz),145.1,144.1(d,J=8.0Hz),137.6,136.9,135.9,135.1( d,J=3.3Hz),131.0,126.4,126.0,119.4,115.8,111.2,110.5(d,J=36.9Hz),55.9,52.6,50.2,33.3,31.3.HRMS(ESI)calcd for C 27 H 26 FN6O[M+H] + :469.2147,found:469.2149.

[0407] Example 91

[0408] 2-(4-(4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile (Compound 91)

[0409] 2-(4-(4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0410] The synthetic route is shown in the figure above. Compound 90 (24 mg, 0.05 mmol, 1.0 equiv) was dissolved in TFA (2 mL), and the reaction was heated to 50 °C and stirred for 4 h. After cooling to room temperature, the solvent was removed by rotary evaporation. The crude product was purified by preparative liquid chromatography, and the data for compound 91 were as follows: 1 H NMR (600MHz, MeOD-) d4 )δ8.53(brs,1H),8.25(s,1H),8.02(t,J=7.8Hz,1H),7.72(d,J=7.8Hz,1H),7.55(d,J=7.8Hz,1H),7.32(t,J=7.8Hz,1 H),7.21(d,J=8.4Hz,1H),3.27-3.24(m,2H),3.13(brs,2H),2.98-2.93(m,1H),1.98-1.94(m,2H),1.81-1.74(m,2H). 13 C NMR (125MHz, MeOD-) d4)δ164.4(d,J=238.4Hz),161.5,154.3,148.4(d,J=14.1Hz),146.0,144.2(d,J=8.3Hz),137.6,136.8,1 35.9,135.1(d,J=5.3Hz),125.9,119.5,111.1,110.4(d,J=36.9Hz),52.6,34.8,31.5.HRMS(ESI)calcd for C 19 H 18 FN6[M+H] + :349.1571,found:349.1572.

[0411] Example 92

[0412] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide (compound 92)

[0413] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide

[0414] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 92 are as follows: 1 H NMR(600MHz,MeOD-d4)δ8.92(s,1H),8.22(s,1H),7.96(s,1H),7.56(s,1H),7.26(t,J=7.9Hz,1H),7.19(d,J =7.7Hz,1H),6.94(s,1H),3.17(s,3H),3.07(m,2H),2.96(m,1H),2.63(m,2H),1.94(m,4H).LRMS(ESI)calcd for C 20 H 21 D3FN6O2S[M+H] + 434.2, found: 434.2.

[0415] Example 93

[0416] N-(2-(4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)methanesulfonamide (compound 93)

[0417] N-(2-(4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)methanesulfonamide

[0418] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 93 are as follows: 1 H NMR(600MHz,MeOD-d4)δ8.43(s,1H),8.20(s,1H),7.97(s,1H),7.55(brs,1H),7.26(t,J=7.8Hz,1H),7.18-7.16( m,1H),6.98(s,1H),3.81(s,3H),3.17(s,3H),2.92(brs,4H),2.40(brs,2H),2.22-1.91(m,2H).LRMS(ESI)calcd for C 20 H 24 FN6O2S[M+H] + 449.2, found: 449.2.

[0419] Example 94

[0420] N-(6'-fluoro-4-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[3,3'-bipyridine]-5-yl)methanesulfonamide (compound 94)

[0421] N-(6'-fluoro-4-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[3,3'-bipyridin]-5-yl)methanesulfonamide

[0422] The synthetic route of compound 94 is shown in the figure above:

[0423] Step a: MC53 (500 mg, 3.01 mmol, 1 eq), MC104 (1.07 g, 4.52 mmol, 1.5 eq), and potassium carbonate (541 mg, 3.91 mmol) were dissolved in DMSO (5 mL), and the reaction was carried out at 50 °C for 2 h. The reaction was quenched with water, and then extracted with EA and water. The organic phase was distilled under reduced pressure, and the concentrate was purified by silica gel column chromatography using DCM:MeOH (40:1-10:1) to obtain a pale yellow oily liquid compound MC105 (580 mg, 53% yield). 1 H NMR (600MHz, CDCl3) δ8.73(s,2H),8.07(s,1H),3.68(s,3H),3.46(m,2H),3.16(t,J= 13.6Hz, 2H), 2.95 (tt, J=11.7, 3.7Hz, 1H), 2.31 (qd, J=11.9, 4.0Hz, 2H), 2.01 (m, 2H).

[0424] In step b, MC105 (142 mg, 0.39 mmol, 1 eq), Fe (219 mg, 3.9 mmol, 10 eq), and NH4Cl (211 mg, 3.9 mmol, 10 eq) were dissolved in ethanol (5 mL) and water (1 mL). The temperature was raised to 70 °C, and the mixture was stirred for 2 h. After the reaction was complete, the mixture was filtered while hot, concentrated under reduced pressure, and the concentrate was dissolved in DCM and filtered to remove salt. The filtrate was concentrated under reduced pressure to obtain a grayish-white solid, crude MC106.

[0425] Step c: MC106 (131 mg, 0.39 mmol, 1 eq), methanesulfonyl chloride (89 mg, 0.78 mmol, 2 eq), and pyridine (62 mg, 0.78 mmol, 2 eq) were dissolved in DCM (5 mL), the temperature was raised to 50 °C, and the reaction was stirred for 12 h. The mixture was quenched with water, extracted with EA and water, and the organic phase was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography using DCM:MeOH (40:1-10:1) to obtain brown oily liquid compound MC107 (138 mg, 88%). 1 HNMR(400MHz, CDCl3)δ8.58(s,1H),8.41(s,1H),8.07(s,1H),3.68(s,3H),3 .57(m,2H),3.14(s,3H),2.91(m,1H),2.18(m,2H),2.01(m,2H),1.83(m,2H).

[0426] In step d, MC108 (162 mg, 0.39 mmol, 1 eq), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (132 mg, 0.59 mmol, 1.5 eq), and sodium carbonate (100 mg, 0.78 mmol, 2 eq) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). Pd(dppf)Cl2 was added under argon protection. The temperature was raised to 85 °C, and the reaction was stirred for 12 h. The reaction solution was concentrated under reduced pressure, and the concentrate was purified by prep-HPLC to obtain a yellow solid compound 94. The data for compound 94 are as follows: 1 H NMR(600MHz,MeOD)δ8.99(s,1H),8.56(s,1H),8.39(d,J=2.8Hz,1H),8.31(s,1H),8.13(td,J=7.6,2.7Hz,1H),7.29(dd,J=8 .4,2.6Hz,1H),3.82(s,3H),3.57(m,2H),3.26(m,2H),3.21(s,1H),3.19(s,3H),1.92(m,2H),1.84(m,2H).LRMS(ESI)calcd for C 19 H 23 FN6O2S[M+H] + 432.2, found: 432.2.

[0427] Example 95

[0428] N-(5-fluoro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide (compound 95)

[0429] N-(5-fluoro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide

[0430] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 95 are: LRMS(ESI)calcd for C 20 H 23 F2N6O2S[M+H] + 449.1, found: 449.2.

[0431] Example 96

[0432] N-(5-chloro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide (compound 96)

[0433] N-(5-chloro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide

[0434] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 96 are: LRMS(ESI)calcd for C 20 H 23 ClFN6O2S[M+H] + 465.1, found: 465.2.

[0435] Example 97

[0436] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-5-(trifluoromethyl)phenyl)methanesulfonamide (compound 97)

[0437] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-5-(trifluoromethyl)phenyl)methanesulfonamide

[0438] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 97 are as follows: 1 H NMR(600MHz,MeOD-d4)δ9.08(s,1H),8.27(d,J=2.4Hz,1H),8.01(brs,1H),7.76(brs,1H),7.33(brs,1H),7 .22(dd,J=8.4,2.4Hz,1H),3.84(s,3H),3.19(s,3H),3.14-2.52(m,5H),2.04-1.92(m,4H).LRMS(ESI)calcd for C 21 H 23 F4N6O2S[M+H] +499.1, found: 499.2.

[0439] Example 98

[0440] N-(3-(6-fluoropyridin-3-yl)-5-methoxy-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide (compound 98)

[0441] N-(3-(6-fluoropyridin-3-yl)-5-methoxy-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide

[0442] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 98 are: LRMS(ESI)calcd for C 21 H 26 FN6O3S[M+H] + 461.2, found:461.2.

[0443] Example 99

[0444] N-(3-(6-fluoropyridin-3-yl)-2-((1R,5S)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-8-azabicyclo[3.2.1]octane-8-yl)phenyl)methanesulfonamide (compound 99)

[0445] N-(3-(6-fluoropyridin-3-yl)-2-((1R,5S)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)methanesulfonamide

[0446] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 99 are as follows: 1H NMR(600MHz,MeOD-d4)δ9.10(s,1H),8.23(s,1H),7.40-7.38(m,1H),7.13-7.07(m,3H),3.99(brs,2 H),3.93(s,3H),3.52-3.45(m,1H),3.18(s,3H),1.90(brs,2H),1.78-1.73(m,6H).LRMS(ESI)calcd for C 22 H 26 FN6O2S[M+H] + 457.2, found:457.2.

[0447] Example 100

[0448] N-(2-(4-(5-amino-4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)methanesulfonamide (compound 100)

[0449] N-(2-(4-(5-amino-4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)methanesulfonamide

[0450] The synthetic route for compound 100 is shown in the figure above.

[0451] Step a: Compound MC89 (1.18 g, 5.0 mmol, 1.0 eq), compound MC1 (1.43 g, 10.0 mmol, 2.0 eq), and K3PO4 (2.12 g, 10.0 mmol, 2.0 eq) were dissolved in a mixed solvent of DMSO (10 mL). The system was heated to 80 °C and reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, extracted with water and EA, and the organic phase was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain a yellow oily compound MC2 (1.6 g, 93.3% yield). 1 H NMR (400MHz, CDCl3) δ7.78 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 8. 0Hz,1H),3.73(s,3H),3.18-2.96(m,4H),2.51-2.47(m,1H),1.97-1.93(m,4H).

[0452] In step b, compound MC2 (1.6 g, 4.66 mmol, 1.0 eq) and reduced iron powder (2.8 g, 10.0 mmol, 50.0 eq) were dissolved in a mixed solvent of EtOH (20 mL) and H2O (2 mL), and then NH4Cl (2.8 g, 10.0 mmol, 50.0 eq) was added. The reaction system was heated to 50 °C and stirred for 3 h. After the reaction was completed, DCM (200 mL) was added to dilute the system, and the mixture was filtered and concentrated under reduced pressure to obtain crude product MC3 (2.0 g). 1 H NMR(400MHz, CDCl3)δ6.81-6.78(m,2H),6.66(dd,J=6.4,2.8Hz,1H),4.36(brs,3H),3.71(s,3H) ,3.59-3.52(m,2H),2.91-2.85(m,2H),2.48-2.39(m,1H),2.03-1.99(m,2H),1.81-1.70(m,2H).

[0453] Step c: Dissolve crude product MC3 (2.0 g) in DCM (20.0 mL), and add methanesulfonyl chloride (773 mg, 6.75 mmol, 1.5 eq) and pyridine (712 mg, 9 mmol, 2.0 eq) at 0 °C. The reaction mixture is heated to 50 °C and stirred for 2 hours. After the reaction is complete, the solvent is removed under reduced pressure, and the product is purified by silica gel chromatography to obtain compound MC4 as a yellow solid (1.76 g, 99% yield). 1 HNMR(400MHz,MeOD-d4)δ7.50(d,J=8.0Hz,1H),7.22(d,J=8.0Hz,1H),7.06(t,J=8.0Hz,1H),3.72-3 .63(m,5H),3.03(s,3H),2.83-2.79(m,2H),2.48-2.40(m,1H),2.12-2.06(m,2H),1.84-1.73(m,2H).

[0454] Step d: The crude product MC4 (1.76 g, 4.5 mmol, 1.0 eq) was dissolved in EtOH (20.0 mL), and hydrazine hydrate (3 mL) was added. The reaction was heated to 90 °C and stirred for 16 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the product was separated and purified by silica gel chromatography to obtain compound MC5 as a white solid product (1.24 g, yield 71%). 1H NMR (400MHz, DMSO-d6) δ9.02(brs,1H),8.48(brs,1H),7.44(d,J=8.0Hz,1H),7.29(d,J=7.2Hz,1H),7.15(t,J=8.0Hz,1H), 4.19(brs,2H),3.52-3.45(m,2H),3.17(s,3H),2.79-2.75(m,2H),2.22-2.15(m,1H),1.87-1.77(m,2H),1.72-1.61(m,2H).

[0455] Step e: Dissolve MC5 (610 mg, 1.56 mmol, 1.0 eq) in dioxane (10 mL) and water (1 mL), and add CNBr (497 mg, 4.69 mmol, 3.0 eq) and NaHCO3 (524 mg, 6.24 mmol, 4.0 eq). After stirring at room temperature for 2 hours, the reaction mixture was quenched with 10% NaHCO3 solution (20 mL). The precipitated solid was obtained by filtration and washed with water (20 mL). The resulting solid was further dried under vacuum to give MC6 (530 mg, 78.8%) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ7.45(d,J=8.0Hz,1H),7.33(d,J=7.6Hz,1H),7.17(t,J=8.0 Hz,1H),3.62-3.56(m,2H),3.22-3.18(m,4H),2.89-2.85(m,2H),2.05-1.86(m,4H).

[0456] Step f: Add N-dimethylformamide dimethyl acetal (0.33 mL, 2.5 mmol, 2.0 eq) to a solution of MC6 (530 mg, 1.23 mmol, 1.0 eq) in dioxane (4 mL) at room temperature. Stir the reaction mixture at 100 °C for 2 h. After complete consumption of the starting material as monitored by TLC, concentrate the mixture under reduced pressure to obtain MC7 (600 mg, crude) as a yellow solid. The crude product itself is used in the next step without any further purification.

[0457] Step g: Add a solution of 600 mg (crude) of dioxane (6 mL) to a sealing tube, along with methylamine (25% MeOH solution, 6 mL) and AcOH (0.220 mL). Stir the reaction mixture at 110 °C for 16 hours. After the reaction is complete, remove the solvent under reduced pressure, and purify the product by silica gel chromatography to obtain compound MC8 as a white solid (230 mg, two-step yield 43.6%). LRMS(ESI)calcd for C 15 H 22 BrN6O2S[M+H] + 429.2, found:429.1.

[0458] In step h, intermediate MC8 (85 mg, 0.20 mmol, 1.0 eq), sodium carbonate (64 mg, 0.6 mmol, 3.0 eq), and 4-fluoro-3-pyridineboronic acid (89 mg, 0.4 mmol, 2.0 eq) were dissolved in a mixed solvent of 4 mL dioxane and 0.4 mL water. Under nitrogen protection, Pd(dppf)Cl2 (15 mg, 0.02 mmol, 0.1 eq) was added, and the reaction was carried out at 90°C for 10 hours. After cooling to room temperature, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was concentrated and separated by HPLC to obtain a white solid product. The data for compound 100 are as follows: 1 H NMR (400MHz, MeOD-d4) δ8.95 (s, 1H), 8.63-8.29 (m, 2H), 7.58-7.42 (m, 2H), 7.30 (t, J = 7.4Hz, 1H), 7. 01(brs,1H),3.78(s,3H),3.17-3.10(m,6H),2.92-2.68(m,2H),1.96-1.85(m,4H).LRMS(ESI)calcd for C 20 H 25 FN7O2S[M+H] + 446.2, found:446.2.

[0459] Example 101

[0460] N-(2-(4-(5-amino-4-methyl-4H-1,2,4-triazol-3-yl)-4-fluoropiperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)methanesulfonamide (chemical)

[0461] Compound 101)

[0462] N-(2-(4-(5-amino-4-methyl-4H-1,2,4-triazol-3-yl)-4-fluoropiperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)methanesulfonamide

[0463] The synthetic route for compound 101 is shown in the figure above. The data for compound 101 are: LRMS(ESI)calcd for C 20 H 24 F2N7O2S[M+H] + 464.2, found:464.2.

[0464] Example 102

[0465] N-(2-(4-(5-amino-4-methyl-4H-1,2,4-triazol-3-yl)-4-methylpiperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)methanesulfonamide (compound 102)

[0466] N-(2-(4-(5-amino-4-methyl-4H-1,2,4-triazol-3-yl)-4-methylpiperidin-1-yl)-3-(6-fluoropyridin-3-yl)phenyl)methanesulfonamide

[0467] The synthetic route for compound 102 is shown in the figure above. The data for compound 102 are: LRMS(ESI)calcd for C 21 H 27 FN7O2S[M+H] + 460.2, found:460.3.

[0468] Example 103

[0469] 2-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)isothiazolidin-1,1-dioxide (compound 103)

[0470] 2-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)isothiazolidine 1,1-dioxide

[0471] The synthetic route for compound 103 is shown in the figure above. The data for compound 103 are: LRMS(ESI)calcd for C 22 H 26 FN6O2S[M+H] + 457.2, found: 457.3.

[0472] Example 106

[0473] 3-Fluoro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)propane-1-sulfonamide (Compound 106)

[0474] 3-fluoro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)propane-1-sulfonamide

[0475] The synthetic route for compound 106 is shown in the figure above. The data for compound 106 are: LRMS(ESI)calcd for C 22 H 27 F2N6O2S[M+H] + 477.2, found:477.2.

[0476] Example 107

[0477] 4-Chloro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)butane-1-sulfonamide (Compound 107)

[0478] 4-chloro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)butane-1-sulfonamide

[0479] The synthetic route for compound 107 is shown in the figure above. The data for compound 107 are: LRMS(ESI)calcd for C 23 H 29 FClN6O2S[M+H]+ 507.2, found:507.2.

[0480] Example 108

[0481] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-3-methylbutane-1-sulfonamide (compound 108)

[0482] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-3-methylbutane-1-sulfonamide

[0483] The synthetic route for compound 108 is shown in the figure above. The data for compound 108 are: LRMS(ESI)calcd for C 24 H 32 FN6O2S[M+H] + 487.2, found: 487.3.

[0484] Example 109

[0485] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)benzenesulfonamide (compound 109)

[0486] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)benzenesulfonamide

[0487] The synthetic route for compound 109 is shown in the figure above. The data for compound 109 are: LRMS(ESI)calcd for C 25 H 26 FN6O2S[M+H] + 493.2, found:493.2.

[0488] Example 110

[0489] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)pentane-1-sulfonamide (compound 110)

[0490] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)pentane-1-sulfonamide

[0491] The synthetic route for compound 110 is shown in the figure above. The data for compound 110 are: LRMS(ESI)calcd for C 24 H 32 FN6O2S[M+H] + 487.2, found: 487.3.

[0492] Example 111

[0493] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)hexane-1-sulfonamide (compound 111)

[0494] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)hexane-1-sulfonamide

[0495] The synthetic route for compound 111 is shown in the figure above. The data for compound 111 are: LRMS(ESI)calcd for C 25 H 34 FN6O2S[M+H] + 501.2, found: 501.3.

[0496] Example 112

[0497] 4-Chloro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)benzenesulfonamide (compound 112)

[0498] 4-chloro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)benzenesulfonamide

[0499] The synthetic route for compound 112 is shown in the figure above. The data for compound 112 are: LRMS(ESI)calcd for C 25 H 25 ClFN6O2S[M+H] + 527.1, found:526.8.

[0500] Example 113

[0501] 4-Chloro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)butane-1-sulfonamide (compound 113)

[0502] 4-chloro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)butane-1-sulfonamide

[0503] The synthetic route for compound 113 is shown in the figure above. The data for compound 113 are: LRMS(ESI)calcd for C 23 H 29 ClFN6O2S[M+H] + 507.2, found:507.2.

[0504] Example 114

[0505] 3-Chloro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)benzenesulfonamide (compound 114)

[0506] 3-chloro-N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)benzenesulfonamide

[0507] The synthetic route for compound 114 is shown in the figure above. The data for compound 114 are: LRMS(ESI)calcd for C 25 H 25 ClFN6O2S[M+H] + 527.1, found: 527.2.

[0508] Example 115

[0509] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-3-hydroxypropane-1-sulfonamide (compound 115)

[0510] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-3-hydroxypropane-1-sulfonamide

[0511] The synthetic route of compound 115 is shown in the figure above:

[0512] Step a: 3-Bromopropanol MC123 (1 g, 7.2 mmol, 1 eq) and DMAP were dissolved in pyridine (15 mL). After the system temperature was lowered to 0 °C, p-methyl tert-butyryl chloride (955 mg, 7.92 mmol, 1.1 eq) was added dropwise. The temperature was then raised to room temperature, and the reaction was stirred for 30 min. The reaction was quenched with saturated NH4Cl aqueous solution, then extracted with EA (50 mL) and H2O (50 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a colorless oily liquid compound MC124 (1.38 g, 86% yield). 1 H NMR (600MHz, CDCl3) δ4.19 (t, J = 6.0 Hz, 2H), 3.46 (t, J = 6.6 Hz, 2H), 2.18 (p, J = 6.3 Hz, 2H), 1.20 (s, 9H).

[0513] Step b: MC124 (1.38 g, 6.2 mmol, 1 eq) and thiourea (567 mg, 7.44 mmol, 1.2 eq) were dissolved in ethanol (7 ml). The mixture was heated to 80 °C and stirred for 2 h. The solvent was then removed by concentration under reduced pressure. The concentrate was dissolved in DCM, filtered to remove thiourea, and the solvent was removed by rotary evaporation under reduced pressure. The concentrate was then washed with diethyl ether to remove excess MC125, and the filtered product was a white solid crude product MC125 (1.33 g, 98% yield).

[0514] Step c: Crude MC125 was dissolved in water (0.9 mL) and acetonitrile (15 mL), the temperature was lowered to 0 °C, tert-butyl hypochlorite was added dropwise, and the reaction was stirred for 30 min. Extracted with ethyl acetate and water, the organic phase was concentrated under reduced pressure to obtain a pale yellow solid crude product MC126 (1.32 g, 88% yield).

[0515] In step d, MC91 (40 mg, 0.12 mmol, 1 eq), crude MC126 (88 mg, 0.36 mmol, 3 eq), and pyridine (28 mg, 0.36 mmol, 3 eq) were dissolved in DCM. The temperature was raised to 50 °C, and the reaction was stirred for 12 h. The solvent was then removed by rotary evaporation under reduced pressure. The resulting concentrate was purified by silica gel column chromatography using DCM:MeOH (20:1–10:1) to obtain a brown oily liquid compound MC127 (25 mg, 37% yield). [M+H] + 559.2, found: 559.2.

[0516] In step e, MC127 (25 mg, 0.045 mmol, 1 eq), NaOH (20 mg, 0.45 mmol, 10 eq), and tetrabutylammonium hydrogen sulfate (8 mg, 0.023 mmol, 0.5 eq) were dissolved in tetrahydrofuran and reacted with the solution at room temperature for 3 h. The solution was concentrated under reduced pressure, and the concentrate was purified by prep-HPLC to obtain a brownish-yellow solid compound 115. 1 H NMR (400MHz, MeOD-d4) δ9.00(brs,1H),8.22(brs,1H),7.96(brs,1H),7.57(brs,1H),7.25(t,J=7.9Hz,1H),7.19(d,J=7.3Hz,1H),6.93(b rs,1H),3.82(s,3H),3.67(m,2H),3.37(m2H),3.08(d,J=11.4Hz,2H),2.99(s,1H),2.64(m,2H),2.03(m,2H),1.96(m,4H).LRMS(ESI)calcd for C 22 H 28 FN6O3S[M+H] + 475.2, found: 475.3.

[0517] Example 116

[0518] 4-(N-(3-(6-fluoropyridin-3-yl)-2-(5-(4-methyl-4H-1,2,4-triazol-3-yl)-1,2-oxazin-2-yl)phenyl)sulfanyl)butyric acid

[0519] 4-(N-(3-(6-fluoropyridin-3-yl)-2-(5-(4-methyl-4H-1,2,4-triazol-3-yl)-1,2-oxazinan-2-yl)phenyl)sulfamoyl)butanoic acid

[0520] The synthetic route for compound 116 is shown in the figure above. The synthetic method is the same as that for compound 115. The data for compound 116 are as follows: 1 H NMR(400MHz,MeOD-d4)δ9.02(brs,1H),8.22(brs,1H),7.96(brs,1H),7.58(brs,1H),7.26(t,J=7.8Hz,1H),7.19(d,J=8.6Hz,1H),6. 93(brs,1H),3.83(s,3H),3.32(m,4H),3.11(m,2H),3.00(s,1H),2.64(m,2H),2.51(m,2H),2.10(m,2H),1.97(m,2H).LRMS(ESI)calcd for C 23 H 28 FN6O4S[M+H] + 503.2, found: 503.2.

[0521] Example 117

[0522] 6-(N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)sulfanyl)hexanoic acid (compound 119)

[0523] 6-(N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)sulfamoyl)hexanoic acid

[0524] The synthetic route for compound 117 is shown in the figure above. The synthetic method is the same as that for compound 115. The data for compound 117 are as follows: 1H NMR(600MHz,MeOD-d4)δ8.92(brs,1H),8.22(brs,1H),7.97(brs,1H),7.58(b rs,1H),7.26(t,J=7.8Hz,1H),7.19(d,J=6.4Hz,1H),6.92(brs,1H),3.81(br s,3H),3.32(brs,4H),3.07(m,J=12.5Hz,2H),2.95(s,1H),2.65(m,2H),2.27 (m,2H),1.97(m,2H),1.85(m,2H),1.61(m,2H),1.50(m,2H).LRMS(ESI)calcd for C 25 H 31 FN6O4S[M+H] + 503.2, found: 503.2.

[0525] Example 118

[0526] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-1H-pyrazole-4-sulfonamide (compound 118)

[0527] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-1H-pyrazole-4-sulfonamide

[0528] The synthetic route for compound 118 is shown in the figure above. The synthetic method is the same as that for compound 115. The data for compound 118 are as follows: 1 H NMR(600MHz,MeOD-d4)δ9.02(brs,1H),8.16(brs,1H),7.95(m,J=54.3Hz,3H),7.65(brs,1H),7.24(brs,1H),7.18(br s,J=8.3,2.7Hz,1H),6.93(brs,1H),3.84(s,3H),2.94(s,1H),2.78(m,2H),2.57(m,2H),1.94(m,4H).LRMS(ESI)calcd for C 22 H 24 FN8O2S[M+H] + 483.2, found: 483.2.

[0529] Example 119

[0530] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide

[0531] The synthetic route for compound 119 is shown in the figure above. The crude MC91 obtained above (50 mg, 0.14 mmol, 1.0 eq) was dissolved in DCM (2.0 mL), and 1-methyl-1H-pyrazole-4-sulfonyl chloride (38 mg, 0.21 mmol, 1.5 eq) and Py (17 mg, 0.21 mmol, 1.5 eq) were added at 0 °C. The reaction was heated to 50 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the product was purified by prep-HPLC to obtain compound 101 as a white solid product (30 mg, yield 43%). 1 H NMR(400MHz,MeOD-d4)δ8.99(brs,1H),8.16(m,2H),7.91(brs,1H),7.72(brs,1H),7.61(brs,1H),7.22(brs,1H),7.16(brs,J =8.4,2.3Hz,1H),6.91(s,1H),3.91(s,3H),3.82(s,3H),2.92(s,1H),2.79(m,2H),2.55(m,2H),1.92(m,4H).LRMS(ESI)calcd for C 23 H 26 FN6O4S[M+H] + 497.2, found: 497.2.

[0532] Example 120

[0533] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)thiophene-3-sulfonamide (compound 120)

[0534] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)thiophene-3-sulfonamide

[0535] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 120 are as follows: 1 H NMR(400MHz,MeOD-d4)δ9.17(s,1H),8.13-7.88(m,2H),7.61(brs,2H),7.32-6 .92(m,4H),3.86(s,3H),2.98-2.53(m,5H),2.03-1.30(m,4H).LRMS(ESI)calcd for C 23 H 24 FN6O2S2[M+H] + 499.1, found: 499.2.

[0536] Example 121

[0537] 9-(N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)sulfanyl)-N-hydroxynonanoamide

[0538] 9-(N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)sulfamoyl)-N-hydroxynonanamide

[0539] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 121 are: LRMS(ESI)calcd for C 28 H 39 FN7O4S[M+H] + 588.3, ​​found: 589.3.

[0540] Example 122

[0541] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 122 are as follows: 1H NMR(600MHz,MeOD)δ8.97(s,1H),8.24(s,1H),7.98(s,1H),7.59(s,1H),7.28(t,J=7.9Hz,1H),7.21(s,1H),6.94(s,1H),3.8 4(s,3H),3.09(d,J=11.8Hz,2H),2.68(s,2H),2.32(s,1H),2.12(s,2H),1.99(s,6H),1.58(d,J=85.4Hz,6H).LRMS(ESI)calcd for C 26 H 35 FN7O4S[M+H] + 546.2, found: 546.3.

[0542] Example 123

[0543] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 123 are as follows: 1 H NMR(600MHz,MeOD)δ9.03(brs,1H),8.22(brs,1H),7.96(brs,1H),7.59(brs,1H),7.26(t,J=7.9Hz,1H),7.20(brs,1H),6 .93(brs,1H),3.85(s,3H),3.32(m,4H),3.08(m,3H),2.64(m,2H),2.29(m,2H),2.13(m,2H),1.99(m,2H).LRMS(ESI)calcd for C 23 H 29 FN7O4S[M+H] + 518.2, found: 518.2.

[0544] Example 124

[0545] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methylamino-1-sulfonamide (compound 124)

[0546] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methylamino-1-sulfonamide

[0547] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 124 are: LRMS(ESI)calcd for C 23 H 27 D3FN6O2S[M+H] + 476.2, found:476.3.

[0548] Example 125

[0549] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)thiophene-2-sulfonamide (compound 125)

[0550] N-(3-(6-fluoropyridin-3-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)thiophene-2-sulfonamide

[0551] The synthetic route is shown in the figure above. The synthetic method is the same as in Example 33. The data for compound 125 are: LRMS(ESI)calcd for C 23 H 21 D3FN6O2S2[M+H] + 502.1, found: 502.2.

[0552] Example 1

[0553] The method for testing the QPCTL enzyme (also known as gQC or isoQC) inhibitory activity of the compound is as follows: The reaction system consists of QPCTL protease, the fluorescent substrate glutamine 7-amino-4-methylcoumarin (Gln-AMC), the compound, and pyroglutamyl aminopeptidase I (PGPEP I). The reaction is carried out in a black 384-well plate. First, 12.5 μL of QPCTL protease (concentration 5.7 ng / μL) and 2.5 μL of the compound at different concentrations are mixed and reacted in a shaker at 37°C and 100 rpm for 10 minutes. Then, 10 μL of the fluorescent substrate Gln-AMC (final concentration 200 μM) is added and reacted in a shaker at 37°C and 100 rpm for 20 minutes. Finally, 25 μL of PGPEP I (final concentration 3.97 ng / μL) is added to the system and reacted in a shaker at 37°C and 100 rpm for 30 minutes. The fluorescence intensity of the microplates was read using a TECAN Infinite 200Pro microplate reader at excitation / emission wavelengths of 380 / 460 nm. The obtained fluorescence signal values ​​were analyzed using GraphPad Prism 8.0 to obtain the inhibition rate and IC50 of the compounds. 50 A≤10nM, 10nM <B≤100nM,100nM<C≤1000nM,D> The activity data at 1000 nM are shown in Table 1 below:

[0554] Table 1. QPCTL activity data for representative compounds

[0555] Based on the above experimental results, it can be seen that the compound of the present invention has excellent QPCTL enzyme inhibitory activity and can be used as a glutamine cyclase inhibitor. Further research can be conducted on its anti-tumor and other therapeutic effects.

[0556] Example 2

[0557] The test method for the QPCT enzyme (also known as sQC) inhibitory activity of the compound is as follows: The reaction system consists of QPCT protease, the fluorescent substrate Glutamine 7-amino-4-methylcoumarin (Gln-AMC), the compound, and pyroglutamyl aminopeptidase I (PGPEP I). The reaction is carried out in a black 384-well plate. First, 12.5 μL of QPCT protease (concentration 3.82 ng / μL) and 2.5 μL of the compound at different concentrations are mixed and reacted at 37 °C and 100 rpm in a shaker for 10 minutes. Then, 10 μL of the fluorescent substrate Gln-AMC (final concentration 200 μM) is added and reacted at 37 °C and 100 rpm in a shaker for 20 minutes. Then, 25 μL of PGPEP I (final concentration 3.97 ng / μL) is added to the system and reacted at 37 °C and 100 rpm in a shaker for 30 minutes. The fluorescence intensity of the microplate is read using a TECAN infinite 200Pro microplate reader at excitation / emission wavelengths of 380 / 460 nm respectively. The obtained fluorescence signal values are analyzed by GraphPad Prism 8.0 to obtain the inhibition rate and IC 50 , A ≤ 10 nM, 10 nM < B ≤ 100 nM, 100 nM < C ≤ 1000 nM. The activity data are shown in Table 2 below:

[0558] Table 2. QPCT activity data of representative compounds

[0559] According to the above experimental results, the compounds of the present invention have excellent QPCT enzyme inhibitory activity, can be used as glutamine cyclase inhibitors, and further study their effects in treating diseases such as Alzheimer's disease and anti-tumor.

[0560] Effect Example 3

[0561] The test method for the cell activity of the compound is as follows:

[0562] The inhibitory activity of the compounds against N-terminal pyroglutamate modification (pGlu-CD47) of CD47 cells was detected as follows: 293T cells were seeded at a density of 10,000 / well in 48-well plates. After treatment with different concentrations of the compounds for 48 hours, the in vitro activity of the compounds was tested using flow cytometry (FACS). The level of N-terminal pyroglutamate modification (pGlu-CD47) of CD47 on the cell surface was detected using the CD47 flow cytometry antibody CC2C6. After treatment with the compounds, the cells were washed with PBS and resuspended in 100 μL of FACS buffer. Then, 1 μL of the cell flow cytometry antibody was added, and the cells were incubated on ice in the dark for 30 minutes. After washing with FACS buffer, the cells were resuspended in 200 μL of FACS buffer. The cells were analyzed by flow cytometry, and the mean fluorescence intensity (MFI) was analyzed using GraphPad Prism 8.0 to calculate the pGlu-CD47 inhibition rate of the compounds. The activity data of representative compounds are shown in Table 3 below.

[0563] Table 3. Cell activity data representing compounds

[0564] Experimental results show that the compound of the present invention has a good inhibitory effect on the N-terminal pyroglutamate modification of CD47 on the surface of 293T cells and has extremely high cell activity.

[0565] PQ912 (CAS: 1276021-65-8) and SEN177 (CAS: 2117405-13-5) are both known glutamine acyl cyclase inhibitors. As positive control drugs, they demonstrate that the compounds of the present invention have better enzyme inhibitory activity and antitumor activity, and demonstrate that the compounds of the present invention have better drug development potential.

[0566] Those skilled in the art should understand that variations can be implemented by combining existing technology with the above embodiments, which will not be elaborated here. Such variations do not affect the essence of the present invention, and will not be elaborated here either.

[0567] The preferred embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and the devices and structures not described in detail should be understood as being implemented in a conventional manner in the art. Any person skilled in the art can make many possible variations and modifications to the technical solutions of the present invention using the methods and techniques disclosed above, or modify them into equivalent embodiments with equivalent changes, without departing from the scope of the present invention. This does not affect the essential content of the present invention. Therefore, any simple modifications, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the present invention's technical solutions still fall within the protection scope of the present invention.

Claims

1. A nitrogen-containing heterocyclic compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug thereof: in: Indicates a single key or that the key does not exist; m is any integer between 0 and 3, and n is any integer between 0 and 3; X is a carbon atom or a nitrogen atom; R1 is a 5-10 heteroaryl group optionally substituted with one or more R7s; R2 is cyano, nitro, -C(=O)N(R8)2, -NR8C(=O)R9, -S(=O)2R9 or -NR8S(=O)2R9; R3 can be a hydrogen atom, a halogen atom, a trifluoromethyl group, -NR8C(=O)R9, or C. 1-20 Alkoxy; R4 is arbitrarily assigned to one or more Cs 1-20 Alkyl or amino-substituted 5-10 membered heteroaryl groups; R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, or a carbon atom. 1-20 Alkyl or C 1-20 Alkoxy; optionally, when R5 is C 1-20 In the case of alkyl groups, any carbon atom of R5 is connected to any ring atom of R4 to form a 5-10 membered ring structure; R6 represents a hydrogen atom or -NR8C(=O)R9; Each R7 is independently composed of a halogen atom and a carbon atom. 1-20 Alkyl, optionally C 3-10 Cycloalkyl-substituted C 1-20 Alkyl, optionally C 3-10 Cycloalkyl-substituted C 1-20 Alkoxy or optionally C 1-20 Alkyl-substituted C 3-10 Cycloalkyloxy; Each R8 atom is independently either a hydrogen atom or a carbon atom. 1-20 alkyl; Each R9 atom is independently composed of hydrogen and carbon atoms. 1-20 Alkyl, C 1-20 Halogenated alkyl groups, -NHC 1-20 Alkyl, -C 1-20 Alkylene, -C 1-20 Alkoxy, C 3-10 Cycloalkyl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl; the C 1-10 Alkyl, C 3-10 Cycloalkyl, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl or C 6-10 Each aryl group is independently and optionally bonded by one or more halogen atoms, C 1-20 Alkyl or -C(=O)OC 1-20 Alkyl, carboxyl, and hydroxyl substitutions; Alternatively, R8 and R9 can be connected to form a 5-10 element ring structure.

2. The compound according to claim 1, or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug, characterized in that, m is 0 or 1, n is 0 or 1; X is a carbon atom or a nitrogen atom; R1 is a 5-10 nitrogen-containing heteroaryl group optionally substituted with one or more R7s; R2 is cyano, nitro, -C(=O)N(R8)2, -NR8C(=O)R9, -S(=O)2R9 or -NR8S(=O)2R9; R3 can be a hydrogen atom, a halogen atom, a trifluoromethyl group, -NR8C(=O)R9, or C. 1-10 Alkoxy R4 is arbitrarily assigned to one or more Cs 1-10 Alkyl or amino-substituted 5-10 nitrogen-containing heteroaryl groups; R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, or a carbon atom. 1-10 Alkyl or C 1-10 Alkoxy; optionally, when R5 is C 1-10 In the case of alkyl groups, any carbon atom of R5 is connected to any ring atom of R4 to form a 5-6 membered ring structure; R6 represents a hydrogen atom or -NR8C(=O)R9; Each R7 is independently composed of a halogen atom and a carbon atom. 1-10 Alkyl, optionally C 3-6 Cycloalkyl-substituted C 1-10 Alkyl, optionally C 3-6 Cycloalkyl-substituted C 1-10 Alkoxy or optionally C 1-10 Alkyl-substituted C 3-6 Cycloalkyloxy; Each R8 atom is independently either a hydrogen atom or a carbon atom. 1-10 alkyl; Each R9 atom is independently composed of hydrogen and carbon atoms. 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -NHC 1-10 Alkyl, -C 1-10 Alkylene-C 1-10 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl; the C 1-10 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl or C 6-10 Each aryl group is independently and optionally bonded by one or more halogen atoms, C 1-10 Alkyl or -C(=O)OC 1-10 Alkyl, carboxyl, and hydroxyl substitutions; Alternatively, R8 and R9 can be connected to form a 5-6 element ring structure.

3. The compound according to claim 2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug thereof, characterized in that, m is 0 or 1, n is 0 or 1, and m and n are not both 0 at the same time; X is a carbon atom or a nitrogen atom; R1 is a pyridinyl group optionally substituted with one or more R7 groups; R2 is cyano, nitro, -C(=O)N(R8)2, -NR8C(=O)R9, -S(=O)2R9 or -NR8S(=O)2R9; R3 can be a hydrogen atom, a halogen atom, a trifluoromethyl atom, -NR8C(=O)R9, or a methoxy atom; R4 is arbitrarily assigned to one or more Cs 1-10 The following groups are substituted with alkyl or amino groups: in, Indicates the combination of keys; R5 is a hydrogen atom, a halogen atom, a hydroxyl group, or a carbon atom. 1-10 Alkyl; optionally, when R5 is C 1-10 In the case of alkyl groups, any carbon atom of R5 is connected to any ring atom of R4 to form a 5-6 membered ring structure; R6 represents a hydrogen atom or -NR8C(=O)R9; Each R7 is independently substituted with a methyl, methoxy, or cyclopropyl methoxy or halogen atom; Each R8 atom is independently either a hydrogen atom or a carbon atom. 1-10 alkyl; Each R9 atom is independently composed of hydrogen and carbon atoms. 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -NHC 1-10 Alkyl, -C 1-10 Alkylene-C 1-10 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl; the C 1-10 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl or C 6-10 Each aryl group is independently and optionally bonded by one or more halogen atoms, C 1-10 Alkyl or -C(=O)OC 1-10 Alkyl, carboxyl, and hydroxyl substitutions; Alternatively, R8 and R9 can be connected to form a five-element ring structure.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug thereof, characterized in that, The compound is shown in formula (II): Wherein, m, n, X, R1, R2, R3, R4, R5 and R6 have the definitions as described in any one of claims 1-3.

5. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug thereof, characterized in that, The compound is shown in formula (III): Wherein, m, n, X, R1, R2, R3 and R6 have the definitions as described in any one of claims 1-3; p is any integer from 0 to 3, preferably 1 or 2.

6. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug thereof, characterized in that, The compound is shown in formula (IV): Wherein, m, n, X, R1, R2, R3, R4, R5 and R6 have the definitions as described in any one of claims 1-3.

7. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug thereof, characterized in that, The compound is shown in formula (V): Wherein, X, R1, R2, R3, R4, R5 and R6 have the definitions as described in any one of claims 1-3.

8. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug thereof, characterized in that, The compounds are shown in formula (VI) or (VII): Wherein, m, n, X, R1, R4, R5, R8 and R9 have the definitions as described in any one of claims 1-3; Preferably, R4 is arbitrarily determined by one or two Cs. 1-10 The following groups are substituted with alkyl or amino groups: in, Indicates the combination of keys; Preferably, R5 is a hydrogen atom or a halogen atom.

9. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug thereof, characterized in that, The compound is shown in formula (VIII): Wherein, m, n, X, R1, R2, R3, R5 and R6 have the definitions as described in any one of claims 1-3; Z represents a carbon atom or a nitrogen atom; R 10 For hydrogen atoms, C 1-10 Alkyl or C 1-10 Alkoxy-substituted benzyl; optionally, R5 and R 10 They connect to form a 5-10 element ring structure; R 11 For hydrogen atoms, C 1-10 Alkyl or amino groups.

10. The compound according to claim 9, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug thereof, characterized in that, R1 is one of the following groups: in, Indicates the combination of keys; Each R 12 Each is an independent halogen atom; R 13 The methoxy or halogen atom is substituted with methyl, methoxy, or cyclopropyl groups; Each R 14 Each independently is C 1-10 alkyl.

11. The following nitrogen-containing heterocyclic compounds or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, isotope-labeled substances, or prodrugs:

12. A pharmaceutical composition comprising, as an active ingredient, a nitrogen-containing heterocyclic compound according to any one of claims 1-11 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug thereof; preferably, the pharmaceutical composition contains at least one pharmaceutically acceptable carrier.

13. A combination of drugs comprising a nitrogen-containing heterocyclic compound according to any one of claims 1-11 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label or prodrug or a pharmaceutical composition according to claim 12, and an antibody; preferably, the antibody is a PD-1 / PD-L1 antibody or a CD47 antibody.

14. The use of a nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug according to any one of claims 1-11, or the pharmaceutical composition according to claim 12, or the combination of drugs according to claim 10, in the inhibition of glutamine cyclase.

15. The use of the nitrogen-containing heterocyclic compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope label, or prodrug thereof, or the pharmaceutical composition according to claim 12, or the combination of drugs according to claim 10, in the preparation of a medicament for the prevention and / or treatment of tumors, immune diseases, neurological diseases, obesity, or aging; Preferably, the tumor is selected from at least one of colorectal cancer, lung cancer, gastric cancer, melanoma, myeloma, breast cancer, adenocarcinoma, bladder cancer, and hematologic malignancy; Preferably, the immune disease is selected from at least one of eczema, alopecia areata, psoriasis, vitiligo, rheumatoid arthritis, lupus erythematosus syndrome, acne, and hidradenitis suppurativa; Preferably, the neurological disease is selected from at least one of Alzheimer's disease, Huntington's disease, Down syndrome, depression, anxiety disorder, psychosis, and multiple sclerosis.

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