Nav1.8 inhibitors, their manufacturing methods and uses

Abstract

This invention provides a Nav1.8 inhibitor represented by formula I, as well as a method for producing the same and its uses. The compounds of the present invention have excellent Nav1.8 selective inhibitory activity, good pharmacokinetic properties, and desirable drug-like properties. As Nav1.8 inhibitors, the compounds of the present invention can be used for the prevention and / or treatment of diseases associated with abnormal expression of Nav1.8 channel activity and have significant clinical application value. [Formula 1] JPEG2026514812000116.jpg55159

Description

[Technical Field]

[0001] The present invention relates to the synthetic technology of sodium channel inhibitors, and more particularly to Nav1.8 inhibitors, methods for producing the same, and their use in the manufacture of pharmaceuticals for the prevention and / or treatment of diseases associated with abnormal expression of Nav1.8 channel activity. [Background technology]

[0002] Voltage-gated sodium channels (VGSCs or Nav) mediate the selective permeable membrane transport of sodium ions and play a crucial role in the initiation, conduction, and transmission of action potentials in excitatory cells such as nerve cells (Catterall et al., Pharmacol Rev. 2005, 57(4):397-409). The Nav family consists of nine subtypes, namely Nav1.1 to Nav1.9, and by acting on Nav, they regulate a variety of important physiological and pathological processes in the human body (Black et al., Neuron. 2013, 80(2):280-91; Catterall et al., Annu Rev Pharmacol Toxicol. 2014, 54:317-38; Bennett et al., Physiol Rev. 2019, 99(2):1079-1151). Nav1.1, Nav1.2, Nav1.3, and Nav1.6 are expressed in both the central and peripheral nervous systems. Nav1.4 is mainly expressed in skeletal muscle, and Nav1.5 is mainly expressed in cardiomyocytes. On the other hand, Nav1.7, Nav1.8, and Nav1.9 are mainly expressed in the peripheral nervous system. These nine subtypes are functionally similar, but they differ in certain aspects of voltage-dependent and dynamic properties.

[0003] Nav1.8, a subtype of Nav, is primarily expressed in nerve cells that transmit pain signals in the dorsal root ganglia (DRGs) of the spinal cord. Nav1.8 channels have relatively high activation and inactivation potentials, which allows them to form the main current component in the rising phase of an action potential even when other Nav channel subtypes are inactive and non-functional (Goodwin et al., Nat Rev Neurosci. 2021,22(5):263-274).

[0004] Current research has demonstrated that Nav1.8, a member of the Nav family, is closely associated with the development of numerous diseases:

[0005] 1) Nav1.8 is involved in pain development: Due to its characteristic of slow inactivation and rapid reactivation, the Nav1.8 channel participates in physiological and pathological processes such as membrane potential depolarization and pain accompanied by high-frequency discharges of nerve cells (Alsaloum et al., Nat Rev Neurol. 2020,16(12):689-705.). Human genetic studies have confirmed that Nav1.8 gene mutations cause small fibrous neuralgia and erythematous pain (Faber et al., Proc Natl Acad Sci US A. 2012,109(47):19444-9; Kaluza et al., Pflugers Arch. 2018,470(12):1787-1801.). In rodents, knockout or knockdown of the Nav1.8 channel gene alleviates a variety of inflammatory and neuropathic pains, while administration of a Nav1.8 inhibitor (e.g., A-803467) effectively reduces the pain response (Jarvis et al., Proc Natl Acad Sci US A. 2007,104(20):8520-5). In a mouse model of diabetic neuropathy, methylglyoxal directly enhances Nav1.8 channel function, and knockout or knockdown of the Nav1.8 channel gene effectively alleviates methylglyoxal-induced neuropathy (Bierhaus et al., Nat Med. 2012,18(6):926-33). In a rat model of STZ-induced diabetic neuropathy, the Nav1.8 inhibitor A-803467, administered intraperitoneally or plantarly, dose-dependently reduced the animals' pain behavioral responses (Mert et al., J Am Assoc Lab Anim Sci. 2012, 51(5):579-85).

[0006] 2) Nav1.8 is involved in the development of multiple sclerosis: Multiple sclerosis (MS) is an inflammatory demyelinating disease originating in the central nervous system, and its exact pathogenesis remains unclear. Nav1.8 channels are not expressed in cerebellar Purkinje fibers of healthy individuals, but in patients with multiple sclerosis, Nav1.8 expression in the cerebellum is upregulated, and its expression level increases in a disease progression-dependent manner. Furthermore, single nucleotide polymorphisms (SNPs) in the Nav1.8 coding gene have also been shown to be associated with the severity of MS (Craner et al., J Neuropathol Exp Neurol. 2003, 62(9):968-75; Roostaei et al., Neurology. 2016, 86(5):410-7). Genetically modified mice (L7-1.8TG) in which Nav1.8 was forcibly expressed in cerebellar Purkinje fibers exhibited a multiple sclerosis-like behavioral phenotype, and administration of the Nav1.8 selective inhibitor PF-01247324 alleviated the MS-like behavior in these L7-1.8TG transgenic mice (Shields et al., Ann Neurol. 2012,71(2):186-94; Shields et al., PLoS One. 2015,10(3):e0119067).

[0007] 3) Nav1.8 is involved in the development of inflammation in osteoarthritis: Osteoarthritis is a degenerative joint disease characterized by cartilage wear and pain. Phosphorylated cAMP response element-binding protein (CREB) directly binds to the promoter of the Nav1.8 coding gene and promotes the transcription of the Nav1.8 protein, thereby upregulating the expression level of the Nav1.8 channel (Zhu et al., Elife. 2020,9:e57656).

[0008] 4) Nav1.8 is involved in the development of cardiovascular disease: In the cardiovascular system, Nav1.8 channels have been confirmed to be expressed in cardiac nerves such as Purkinje fibers. Some studies have also suggested expression in cardiomyocytes (Verkerk et al., Circ Res. 2012, 111(3):333-43). Human genetic studies have revealed that Nav1.8 gene mutations are associated with Brugada syndrome (Hu et al., J Am Coll Cardiol. 2014, 64(1):66-79). Since suppressing Nav1.8 channels improves cardiac remodeling, it is considered a potential therapeutic target for cardiovascular diseases such as arrhythmias, atrial fibrillation, and heart failure (Dybkova et al., Cardiovasc Res. 2018, 114(13):1728-1737).

[0009] 5) Nav1.8 is involved in the development of pathological cough: The Nav1.8 channel is expressed in the vagus plexus associated with cough, and its phosphorylation level and expression increase during the process of pathological cough, indicating its involvement in the cough reflex (Muroi et al., Lung. 2014, 192(1):15-20).

[0010] 6) Nav1.8 is involved in the expression of pruritic behavior: In mammalian pruritus perception, pruritic substances such as histamine released from lymphocytes and mast cells activate the Nav1.8 channel. In Nav1.8 knockout mice, histamine and endothelin-induced pruritic behavior is significantly suppressed (Riol-Blanco et al., Nature. 2014, 510(7503):157-61.).

[0011] 7) Other related diseases: Furthermore, congenital mutations in human Nav1.8 have been reported to cause diseases such as epilepsy and seizures (Kambouris et al., Ann Clin Transl Neurol. 2016,4(1):26-35).

[0012] As described above, Nav1.8 shows a very high correlation in the treatment of pain (such as small fibrous neuralgia, erythematous pain, and diabetic neuropathy) and other related diseases (such as multiple sclerosis, osteoarthritis, arrhythmias, atrial fibrillation, heart failure, pruritus, epilepsy, seizures, and pathological cough). Therefore, Nav1.8 channel inhibitors are considered useful for the treatment, prevention, or management of diseases associated with the involvement or dysfunction of the Nav1.8 channel.

[0013] Currently, specific Nav1.8-targeted inhibitors in clinical research include VX-548 (Phase III), HRS-4800 (Phase II), VX-150 (Phase I), and JMKX-000623 (Phase I), but none of these products are currently on the market. Therefore, the development of novel Nav1.8 inhibitors has extremely important scientific and clinical value for the treatment of diseases related to Nav1.8 expression dysregulation. [Overview of the Initiative]

[0014] One object of the present invention is to provide a compound represented by formula I, or a tautomer, stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt having Nav1.8 selective inhibitory activity.

[0015] The second object of the present invention is to provide a method for producing the compound represented by formula I.

[0016] The third object of the present invention is to provide a pharmaceutical composition comprising a compound represented by formula I, or a tautomer, stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof.

[0017] The fourth object of the present invention is to provide the use of a compound represented by formula I, or its tautomers, stereoisomers, deuterated compounds thereof, or pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions, in the production of Nav1.8 inhibitors.

[0018] The fifth object of the present invention is to provide the use of a compound represented by formula I, or its tautomers, stereoisomers, deuterides, or pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions, in the manufacture of pharmaceuticals for preventing and / or treating diseases associated with abnormal expression of Nav1.8 channel activity.

[0019] In one embodiment, the present invention provides a compound represented by formula I, or a tautomer, stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof. [ka] Here, R0 is [ka] Ring A is selected from the group consisting of substituted or unsubstituted C6-C10 aryl rings and substituted or unsubstituted 5-10 member heteroaryl rings, where the substitution means that it is substituted with 1, 2, 3, or 4 substituents selected from the group consisting of: halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyloxy, halo-C1-C6 alkyloxy, C2-C6 alkenyl, halo-C2-C6 alkenyl, C2-C6 alkenyloxy, halo-C2-C6 alkenyloxy, C2-C6 alkynyl, halo-C2-C6 alkynyl, C2-C6 alkynyloxy, halo-C2-C6 alkynyloxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy; n1 is selected from the group consisting of 0, 1, 2, 3, or 4; n2 is selected from the group consisting of 0 or 1; m is selected from the group consisting of 0, 1, 2, 3, or 4; R5 is O, S, C=O, CR 5a R 5b or NR 5c Selected from the group consisting of, among them, R 5a and R 5b However, each is independently selected from the group consisting of hydrogen and halogens; the R 5cis selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl, wherein said substitution means being substituted with 1, 2 or 3 substituents selected from the group consisting of: halogen, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyloxy, halogen-substituted C1-C4 alkyloxy; R6 is selected from the group consisting of O, S, C=O, CR 6a R 6b or NR 6c selected from the group consisting of, wherein said R 6a and R 6b are each independently selected from the group consisting of hydrogen and halogen; or CR 6a R 6b together form a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted 3-8 member heterocyclyl (as one ring of an azaspiro ring, with the C atom to which R 6a and R 6b are both attached as the spiro atom), [substituted or unsubstituted C3-C6 cycloalkyl] fused to [substituted or unsubstituted phenyl], [substituted or unsubstituted C3-C6 cycloalkyl] fused to [substituted or unsubstituted 5-6 member heteroaryl], [substituted or unsubstituted 3-8 member heterocyclyl] fused to [substituted or unsubstituted phenyl], [substituted or unsubstituted 3-8 member heterocyclyl] fused to [substituted or unsubstituted 5-6 member heteroaryl], substituted or unsubstituted cyclopenta[substituted or unsubstituted phenyl], or substituted or unsubstituted cyclopenta[substituted or unsubstituted 5-6 member heteroaryl]; said R 6c is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl, wherein said substitution means being substituted with 1, 2 or 3 substituents selected from the group consisting of: halogen, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyloxy, halogen-substituted C1-C4 alkyloxy, X1 is selected from the group consisting of N or CR a X2 is selected from the group consisting of N or CR b X3 is selected from the group consisting of N or CR cSelected from the group consisting of, X4 is N or CR d From the group consisting of these, there are no more than two N such that X1, X2, X3 and X4 exist; R a , R b , R c and R d Each time it is expressed, it is independently selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyloxy, halo-C1-C6 alkyloxy, C2-C6 alkenyl, halo-C2-C6 alkenyl, C2-C6 alkenyloxy, halo-C2-C6 alkenyloxy, C2-C6 alkynyl, halo-C2-C6 alkynyl, C2-C6 alkynyloxy, halo-C2-C6 alkynyloxy, C3-C6 cycloalkyl, and C3-C6 cycloalkyloxy; in particular, R a However, it is hydrogen; R b However, selected from the group consisting of -CF3, methyl, cyclopropyl, isopropyl, or -Cl; R c However, selected from the group consisting of -Cl, -CF3, cyano, or ethynyl; R d However, selected from the group consisting of hydrogen, -Cl, and -F; One of X5 and X6 is CR1, and the other is N or CR e Selected from the group consisting of; R e Each time it is expressed, it is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyloxy, halo-C1-C6 alkyloxy, C2-C6 alkenyl, halo-C2-C6 alkenyl, C2-C6 alkenyloxy, halo-C2-C6 alkenyloxy, C2-C6 alkynyl, halo-C2-C6 alkynyl, C2-C6 alkynyloxy, halo-C2-C6 alkynyloxy, C3-C6 cycloalkyl, and C3-C6 cycloalkyloxy; preferably, selected from the group consisting of -Cl, -F, Br, hydrogen, methoxy, and methyl; R1 is [ka] Selected from the group consisting of; or R1 and R eHowever, together with the carbon atoms linked to them [ka] form; Among them, R 1a However, selected from the group consisting of hydrogen, -CN, -OH, and C1-C6 alkyloxy; R 1b , R 1c , R 1e and R 1d However, each is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; R2, R3, and R4 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkyloxy, and substituted or unsubstituted C3-C6 cycloalkyl, wherein the substitution means substitution with one, two, or three substituents selected from the group consisting of: C1-C4 alkyl, halogen, -CN, -NO2, or -NH2.

[0020] In some embodiments, R0 is [ka] The substituent is selected from the group consisting of substituted or unsubstituted indolinyl, substituted or unsubstituted isoindolinyl, substituted or unsubstituted 1,2,3,4-tetrahydroquinolinyl, substituted or unsubstituted tetrahydroisoquinolinyl, substituted or unsubstituted 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, and substituted or unsubstituted 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, wherein the substituted substituent is selected from the group consisting of halogens (fluorine, chlorine, bromine), C1-C4 alkyl, C1-C4 alkyloxy, phenyl, or halo-C1-C4 alkyl (trifluoromethyl).

[0021] In some embodiments, R0 is [ka] These are substituted or unsubstituted tetrahydropyrrole, substituted or unsubstituted piperidine, substituted or unsubstituted morpholine, substituted or unsubstituted thiomorpholine, substituted or unsubstituted piperazine, substituted or unsubstituted azepane, substituted or unsubstituted 1,4-oxaazepane, substituted or unsubstituted azaspiro[2,5]octane, substituted or unsubstituted spiro[indan-1,4′-piperidine]-yl( [ka] ), substituted or unsubstituted 4,5-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]yl ( [ka] ), substituted or unsubstituted 3H-spiro[isobenzofuran-1,4′-piperidine]-yl( [ka] A substituent is selected from the group consisting of ), and among these, the substituent is selected from the group consisting of halogens (fluorine, chlorine, bromine), C1-C4 alkyl, C1-C4 alkyloxy, phenyl, or halo-C1-C4 alkyl (trifluoromethyl).

[0022] Preferably, selected from the group consisting of the following groups: [ka] In some embodiments, the compound represented by formula I is selected from the group consisting of compounds represented by formulas I-a1, I-a2, I-b1, I-b2, I-c1, I-c2, and Id. [ka] Among them, X5 and X6 are N or CR e X1, X2, X3, X4, R0, R 1a , R 1b , R 1c , R 1d , R 1e R2, R3, R4, Re The definition is the same as described above.

[0023] In some embodiments, the compound represented by formula I is selected from the group consisting of the compounds represented by formula II below. [ka] Among them, X1 is C or N; m, R6, R b , R c , R d The definitions of R2, R3, R4, X5, and X6 are the same as those described above. In Equation II, [ka] The selection is the same as described above.

[0024] In some embodiments, the compound represented by formula II is selected from the group consisting of the compounds represented by formulas II-a1, II-a2, II-b1, II-b2, II-c1, II-c2, and II-d. [ka] Among them, X1, m, R6, R b , R c , R d R2, R3, R4, X5, X6, R 1a , R 1b , R 1c , R 1d , R 1e The definition is the same as described above. In equations II-a to II-d [ka] The selection is the same as described above.

[0025] In some embodiments, the compounds represented by formulas II-a1 and II-a2 are selected from the group consisting of compounds represented by formulas II-a1-1 or II-a2-1. [ka] Among them, R 1a However, it is selected from the group consisting of hydrogen, -CN, -OH, or C1-C6 alkyloxy, and is preferably -OH; R 1b and R 1c However, each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, preferably hydrogen; R6 is -CH2, -C=O, or -CF2; R b , R c and R d Each is independently selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyloxy, halo-C1-C6 alkyloxy, C2-C6 alkenyl, halo-C2-C6 alkenyl, C2-C6 alkenyloxy, halo-C2-C6 alkenyloxy, C2-C6 alkynyl, halo-C2-C6 alkynyl, C2-C6 alkynyloxy, halo-C2-C6 alkynyloxy, C3-C6 cycloalkyl, and C3-C6 cycloalkyloxy; preferably, R b , R c and R d Each of these is independently selected from the group consisting of hydrogen, chlorine, fluorine, C1-C4 alkyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and trifluoromethyl; X1 is N or CH; X5 and X6 are N or CR e And R e Each time it is expressed, it is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyloxy, halo-C1-C6 alkyloxy, C2-C6 alkenyl, halo-C2-C6 alkenyl, C2-C6 alkenyloxy, halo-C2-C6 alkenyloxy, C2-C6 alkynyl, halo-C2-C6 alkynyl, C2-C6 alkynyloxy, halo-C2-C6 alkynyloxy, C3-C6 cycloalkyl, and C3-C6 cycloalkyloxy; preferably, R e Each time it is expressed, it is selected from the group consisting of hydrogen, fluorine, chlorine, Br, methoxy, or methyl; R2, R3, and R4 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkyloxy, and substituted or unsubstituted C3-C6 cycloalkyl, wherein the substitution means substitution with one, two, or three substituents selected from the group consisting of: methyl, -F, -CN, -NO2, or -NH2.

[0026] In some preferred embodiments, the compound represented by formula II-a2-1 is selected from the group consisting of compounds represented by the following formula II-a2-1-A. [ka]

[0027] R e However, it is selected from the group consisting of hydrogen, F, Cl, Br, C1-C6 alkyl, or C1-C6 alkyloxy, preferably hydrogen, F, Cl, or Br, more preferably hydrogen or F, and particularly F; R6 is -CH2, -C=O, or -CF2; R b , R c and R d Each is independently selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyloxy, halo-C1-C6 alkyloxy, C2-C6 alkenyl, halo-C2-C6 alkenyl, C2-C6 alkenyloxy, halo-C2-C6 alkenyloxy, C2-C6 alkynyl, halo-C2-C6 alkynyl, C2-C6 alkynyloxy, halo-C2-C6 alkynyloxy, C3-C6 cycloalkyl, and C3-C6 cycloalkyloxy; preferably, R b , R c and R d Each of these is independently selected from the group consisting of hydrogen, chlorine, fluorine, C1-C4 alkyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and trifluoromethyl; X1 is N or CH; The definitions of R2, R3, and R4 are the same as those described above.

[0028] If you are skilled in the art, [ka] Because it is a tautomer, [ka] The present invention, comprising the structure, [ka] It is believed to include the structure of [the two structures], and therefore both are understood to be equivalent.

[0029] Similarly, [ka] They are equivalent; [ka] They are equivalent.

[0030] Typical compounds of the present invention include, but are not limited to, the following. [Table 1] JPEG2026514812000025.jpg225159JPEG2026514812000026.jpg228159JPEG2026514812000027.jpg236159JPEG2026514812000028.jpg77159

[0031] In this invention, terms are defined as follows: "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0032] "C1-C6 alkyl" refers to a chain-like alkyl group having 1 to 6 carbon atoms. Specific examples include, but are not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, 1-methylbutyl, 1-ethylbutyl, pentyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, and 2-ethylbutyl. The meaning of C1-C4 alkyl can be similarly inferred.

[0033] The aforementioned "haloC1-C6 alkyl" refers to a C1-C6 alkyl as defined above in which one or more hydrogen atoms are substituted with halogen atoms.

[0034] "C2-C6 alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms. Specific examples include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, and hexenyl.

[0035] The aforementioned "haloC2-C6 alkynyl" refers to a C2-C6 alkynyl as defined above in which one or more hydrogen atoms are substituted with halogen atoms.

[0036] "C1-C6 alkoxy" refers to RO-yl, where R is the C1-C6 alkyl group mentioned above. Specific examples of alkoxy include methoxy, ethoxy, n-propoxy, and isopropoxy. The meaning of C1-C4 alkoxyalkyl can be similarly inferred.

[0037] The aforementioned "haloC1-C6 alkoxy" refers to a group obtained by substituting at least one hydrogen atom of the above-mentioned alkoxy with a halogen atom. Specific examples include trifluoromethoxy.

[0038] The aforementioned "C2-C6 alkenyloxy" refers to RO-yl, where R is the C2-C6 alkenyl mentioned above. Specific examples of alkenyloxy include vinyloxy and allyloxy.

[0039] The aforementioned "haloC2-C6 alkenyloxy" refers to an alkenyloxy in which at least one hydrogen atom is substituted with a halogen atom.

[0040] The aforementioned "C2-C6 alkynyloxy" refers to RO-yl, where R is the C2-C6 alkynyl mentioned above. Specific examples of alkynyloxy include ethynyloxy and propargyloxy.

[0041] The aforementioned "haloC2-C6 alkynyloxy" refers to an alkynyloxy in which at least one hydrogen atom is substituted with a halogen atom.

[0042] The aforementioned "C3-C6 cycloalkyl" refers to a fully saturated monovalent cyclic hydrocarbon group containing 3 to 6 ring carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The meaning of C4-C8 cycloalkyl can be similarly inferred.

[0043] The aforementioned "C3-C6 cycloalkyloxy" refers to RO-yl, where R is the C3-C6 cycloalkyl mentioned above.

[0044] The aforementioned "3- to 8-membered heterocyclyl" refers to a 3- to 8-membered non-aromatic cyclic group containing 1 to 3 heteroatoms selected from N, O, and S in its ring skeleton. Specific examples include oxetanyl, tetrahydroimidazolyl, and tetrahydrofuryl. The meaning of 5- to 6-membered heterocyclyl can be similarly inferred.

[0045] The aforementioned "C6-C10 aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group having 6 to 10 carbon atoms. Specific examples include phenyl.

[0046] The aforementioned "5-10 membered heteroaryl" refers to an aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, S(=O), and S(=O)2 in its ring skeleton, resulting in a total of 5 to 10 ring atoms. Specific examples include pyridyl, pyridazinyl, pyrimidinyl, and pyrrolyl. The meaning of 5-6 membered heteroaryl can be similarly inferred.

[0047] "Deuterides" are compounds in which one or more hydrogen atoms are present in the compound structure. 1 H) is deuterium ( 2 This refers to a structure substituted with H / D. Here, the content of "deuterium" is 20% to 100%, preferably 90% to 100%.

[0048] A "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of a particular compound's free acid or base and does not exhibit any biologically harmful effects. Examples include acid (including organic and inorganic acids) addition salts or base (including organic and inorganic bases) addition salts. The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods from the original compound containing an acid group or a base. Generally, they are produced by reacting the original compound in the form of a free acid or base with a stoichiometrically appropriate amount of base or acid in water, an organic solvent, or a mixture thereof.

[0049] The compounds relating to this application, as well as their pharmaceutically acceptable salts, esters, and prodrugs, may have isomers such as stereoisomers, tautomers, and mixtures thereof, but are not limited thereto. These isomers are also included within the scope defined by the claims of this invention.

[0050] Another aspect of the present invention provides a method for producing the compound represented by formula I above. This method is achieved by the following reaction scheme.

[0051] Scheme 1: [ka] After converting III-a1 or III-a2 to a Pinner salt via the Pinner reaction, NR 1aand NR 1b R 1c It is reacted with to produce I-a1 or I-a2.

[0052] The definitions of each substituent are the same as those described above.

[0053] Specifically, this scheme is suitable for the production of Examples 1 to 36. In particular, in Example 3, cyanamide is added first, and after the reaction is complete, an ammonia / methanol system is added to obtain I-3.

[0054] Scheme 2: [ka] III-a1 or III-a2 is reacted with hydroxylamine or a salt of hydroxylamine (for example, in the presence of an anhydrous solvent and a base) to obtain I-a1 or I-a2.

[0055] Among them, R 1a OH is R 1b H is R 1c H is the substituent, and the definitions of the remaining substituents are the same as those above.

[0056] Among these, the anhydrous organic solvent includes, but is not limited to, anhydrous methanol, anhydrous ethanol, anhydrous propanol, anhydrous butanol, anhydrous tetrahydrofuran, anhydrous ethyl acetate, and one or more mixed solvents. The base is an organic base and includes, but is not limited to, anhydrous triethylamine, anhydrous N,N-dimethylethylamine, anhydrous 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, triethylenediamine, sodium methanol, potassium ethanol, tert-butoxypotassium, and the like. The salt of hydroxylamine includes, but is not limited to, hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine phosphate, and the like.

[0057] Scheme 3: [ka] III-a3 or III-a4 is hydrolyzed to obtain an acid, and then this acid is converted to an acid chloride by the action of thionyl chloride, oxalate chloride, or phosphorus trichloride, etc., and then condensed with guanidine to produce I-b1 or I-b2.

[0058] The definitions of each substituent are the same as those described above.

[0059] Scheme 4: [ka] I-c1 or I-c2 is produced by treating Key1 with SM-2e or SM-2f via an acid amide condensation reaction.

[0060] The definitions of each substituent are the same as those described above.

[0061] Scheme 5: [ka] Id is produced by treating Key1 and SM-3 through an acid amide condensation reaction.

[0062] The definitions of each substituent are the same as those described above.

[0063] Among these, the acid amide condensation reaction is one of the following two options.

[0064] Solution one: Key1 and the reactant (SM-2e or SM-2f, SM-3) are subjected to an acid amide condensation reaction in a solvent at a temperature of 0 to 100°C in the presence of a coupling agent and a base to obtain the product (I-c1 or I-c2, Id). Here, the coupling agent is HATU or HBTU, the base is triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc., and the solvent is acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc.

[0065] Solution 2: Key1 is converted to an acid chloride by the action of thionyl chloride, oxalate, or phosphorus trichloride. Then, the acid chloride is reacted with the reactant (SM-2e or SM-2f, SM-3) in a solvent in the presence of a base to obtain the product (I-c1 or I-c2, Id). Examples of the base include triethylamine, diisopropylethylamine, pyridine, potassium carbonate, and cesium carbonate, and examples of the solvent include dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide.

[0066] In some embodiments, the manufacturing schemes for III-a1, III-a2, III-a3, and III-a4 are as follows: [ka] Key1 and SM-2a, SM-2b, SM-2c, and SM-2d are used in an acid amide condensation reaction to produce III-a1, III-a2, III-a3, and III-a4.

[0067] The definitions of each substituent are the same as those described above.

[0068] The acid amide condensation reaction is carried out as described above. In some embodiments, the manufacturing method for intermediate Key1 is as follows: [ka]

[0069] Specifically, SM1 (wherein LG represents a halogen or a nucleophilic leaving group such as S(O)2Me, and Y represents an ester group or a cyano group), [ka] Key1 is obtained by nucleophilic substitution reaction of either or their salts in the presence of a base such as potassium carbonate or cesium carbonate, under heating conditions in a suitable solvent such as acetonitrile, tetrahydrofuran, N,N-dimethylformamide, or dimethyl sulfoxide, followed by hydrolysis. This reaction is usually carried out at temperatures in the range of 50°C to 140°C.

[0070] The definitions of other substituents are the same as those defined above.

[0071] In yet another aspect of the present invention, a pharmaceutical composition is provided comprising one or more compounds selected from those represented by formula I, their tautomers, stereoisomers, deuterides, and pharmaceutically acceptable salts, and optionally pharmaceutically acceptable additives.

[0072] The pharmaceutical composition of the present invention may be selected to include at least one pharmaceutically acceptable carrier selected from diluents, adjuvants, excipients, preservatives, fillers, binders, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, antibacterial agents, antifungal agents, lubricants, dispersants, temperature-responsive materials, adhesives, stabilizers, suspending agents, etc., depending on the route of administration and the properties of the dosage form.

[0073] In yet another aspect of the present invention, the use of a compound represented by formula I, its tautomers, stereoisomers, its deuteride, or a pharmaceutically acceptable salt, or the aforementioned pharmaceutical composition, in the production of a Nav1.8 inhibitor is provided.

[0074] In yet another aspect of the present invention, a method for inhibiting the Nav1.8 channel activity of an individual is provided, comprising administering to the individual one or more compounds represented by formula I, or tautomers, stereoisomers thereof, deuterides thereof, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical composition.

[0075] In yet another aspect of the present invention, the use of a compound represented by formula I, or its tautomers, stereoisomers, deuterides, or pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions, in the manufacture of a pharmaceutical for preventing and / or treating a disease associated with abnormal expression of Nav1.8 channel activity.

[0076] In yet another aspect of the present invention, a method is provided for preventing and / or treating a disease associated with abnormal expression of Nav1.8 channel activity, comprising administering to a subject having this need one or more compounds represented by formula I, or tautomers, stereoisomers, deuterides thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

[0077] Diseases associated with the abnormal expression of Nav1.8 channel activity include pain disorders, etc. Here, pain disorders include nociceptive pain, inflammatory pain (including but not limited to rheumatoid arthritis pain or vulvar pain), neuropathic pain (including but not limited to postherpetic neuralgia or idiopathic small fibrous neuralgia), musculoskeletal pain (including but not limited to osteoarthritis pain, lower back pain, cold sensitivity, burn pain or toothache), postoperative pain (including but not limited to post-bunion resection pain or abdominal wall reconstruction pain, etc.), and visceral pain, functional pain This includes, but is not limited to, pain associated with muscle or bone injury, pelvic pain, abdominal pain, thoracic pain, lumbosacral pain, preoperative pain, intraoperative pain, postoperative pain, bowel pain (including, but not limited to, inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis), acute or chronic pain, migraine, trigeminal neuralgia, pancreatitis, renal colic, cancer pain, pain resulting from chemotherapy or drug therapy, diabetic neuropathy, postherpetic neuralgia, low back pain, phantom limb pain, sciatica, small fibrous neuralgia, erythematous pain, etc. Diseases associated with abnormal expression of Nav1.8 channel activity further include pruritus, acute or chronic pruritus, asthma, multiple sclerosis, arrhythmia, atrial fibrillation, heart failure, Brugada syndrome, kidney stones, epilepsy, convulsions, Charcot-Marie-Tooth disease, incontinence, etc.

[0078] The present invention has the following beneficial effects: The compounds of the present invention possess excellent Nav1.8 selective inhibitory activity, good pharmacokinetic properties, and high pharmacovigilance. As Nav1.8 inhibitors, they can be used for the prevention and / or treatment of diseases associated with abnormal expression of Nav1.8 channel activity, and thus have significant clinical application value.

[0079] Although the present invention has already been described in detail, the above embodiments are essentially illustrative and do not limit the present invention. Furthermore, the present invention is not limited by any theory described in the prior art, the summary of the invention, or the following embodiments. [Modes for carrying out the invention]

[0080] The present invention will be described in more detail below with reference to examples, but it should be noted that the following examples are provided for illustrative purposes only and do not limit the scope of the claims of the present invention.

[0081] Reagents and consumables: Unless otherwise specified, all reagents used were commercially available. For purification column chromatography, silica gel manufactured by Qingdao Marine Chemical Plant (200-300 mesh) was used, and for purification thin-layer chromatography (TLC) silica gel plates (model number HSGF-254, thickness 0.15-0.2 mm) manufactured by Yantai Chemical Laboratory Plant was used.

[0082] Analytical equipment: Proton nuclear magnetic resonance spectroscopy ( 1 ¹H-NMR was recorded using a Bruker Avance III 600, Bruker Avance III 500, Bruker AM-400, or GEMINI-300 NMR spectrometer. Chemical shifts are expressed in δ (ppm), and proton coupling is shown as a single line (s), double line (d), triple line (t), quadruple line (q), multiline (m), or broad peak (br).

[0083] Mass spectrometry (MS) was recorded using a Finnigan / MAT-95 mass spectrometer or an Agilent 1200-6110 single-phase quadrupole LC-MS instrument.

[0084] Example 1: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-1) [ka]

[0085] Step 1: 4-oxoazepane-1-carboxylate tert-butyl (1-a) (10.8 g, 50.6 mmol) was dissolved in dichloromethane (60 mL) and cooled to 0°C. Under an inert gas atmosphere, diethylamino sulfur trifluoride (14.7 mL, 111.4 mmol) diluted with dichloromethane (20 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction was allowed to proceed at room temperature for 48 hours. After the reaction of 1-a was complete, the reaction mixture was poured into ice water, and saturated sodium bicarbonate aqueous solution was added to adjust the pH to 8-9. The mixture was extracted three times with dichloromethane, the combined organic layer was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 100:1~10:1, v / v) to obtain 9.043 g of 4,4-difluoroazepane-1-carboxylate tert-butyl(1-b) as a reddish-brown liquid. The yield was 75.9%. 1 H NMR (400MHz, CDCl3) δ: 3.48~3.30 (m, 4H), 2.16~1.97 (m, 4H), 1.83~1.74 (m, 2H), 1.44 (s, 9H).

[0086] Step 2: 4,4-difluoroazepane-1-carboxylate tert-butyl (1-b) (9.043 g, 38.4 mmol) was mixed with hydrochloric acid-dioxane solution (4N, 60 mL) and reacted at room temperature until the starting material disappeared. The reaction mixture was directly concentrated under reduced pressure to obtain 7.183 g of 4,4-difluoroazepane hydrochloride (1-c) as a white solid. The yield was 93.7%. 1 H NMR(400 MHz,CDCl3)δ:9.88(s,2H),3.39~3.29(m,4H),2.61~2.47(m,2H),2.36~2.21(m,2H),2.08~1.98(m,2H); MS(ESI)m / z [M+H] + = 136.2.

[0087] Step 3: 2-Chloro-6-methylnicotinic acid (1-d) (3 g, 17.5 mmol) was dissolved in dichloromethane (20 mL), a catalytic amount of N,N-dimethylformamide was added, and the mixture was cooled to 0°C. Under a nitrogen gas atmosphere, oxalic acid chloride (2.2 mL, 26.2 mmol) was slowly added dropwise, and after the addition was complete, the reaction was continued at room temperature until the starting material had disappeared. Methanol (7.1 mL, 175.0 mmol) was then added and the mixture was reacted for 1 hour. After the compound reaction was complete, the reaction mixture was concentrated, and the pH was adjusted to 8-9 by adding saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with dichloromethane, the combined organic layer was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 20:1, v / v) to obtain 2.472 g of methyl 2-chloro-6-methylnicotinate (1-e) as a colorless liquid. The yield was 71.4%. 1 H NMR(400MHz,CDCl3)δ:8.09(d,J=7.8Hz,1H),7.20~7.14(m,1H),3.94(s,3H),2.59(s,3H); MS(ESI)m / z [M+H] + = 186.0.

[0088] Fourth Step: Methyl 2-chloro-6-methylnicotinate (1-e) (3.7 g, 19.9 mmol), 4,4-difluoroazepane hydrochloride (1-c) (4.1 g, 23.9 mmol), and potassium carbonate (8.253 g, 59.8 mmol) were added to N,N-dimethylformamide (100 mL), and the mixture was reacted at 90 °C overnight. After the compound reaction was completed, 1N hydrochloric acid was added to adjust the pH to 5-6, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 30:1, v / v) to obtain 4.52 g of methyl 2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate (1-f) as a colorless liquid. The yield was 84.3%. 1 H NMR (400 MHz, CDCl3) δ: 7.81 (d, J = 7.8 Hz, 1H), 6.52 (d, J = 7.7 Hz, 1H), 3.85 (s, 3H), 3.76~3.69 (m, 2H), 3.30 (t, J = 5.6 Hz, 2H), 2.44~ 2.34 (m, 5H), 2.07~ 1.91 (m, 4H); MS (ESI) m / z [M+H] + = 285.2。

[0089] Fifth Step: Methyl 2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate (1-f) (200 mg, 0.703 mmol) and N-chlorosuccinimide (187.9 mg, 1.41 mmol) were dissolved in N,N-dimethylformamide (4 mL) and reacted at room temperature. After the compound reaction was completed, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 20:1, v / v) to obtain 127 mg of methyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate (1-g) as a pale yellow liquid. The yield was 56.6%. 1H NMR(400MHz,CDCl3)δ:7.84(s,1H),3.86(s,3H),3.74~3.67(m,2H),3.26(t,J=5.6Hz,2H),2.48(s,3H),2.44~2.29(m,2H),1.98~ 1.91(m,4H); MS(ESI)m / z [M+H] + = 319.9.

[0090] Step 6: Sodium hydroxide solid (4.34 g, 108.6 mmol) was dissolved in water (15 mL). This aqueous sodium hydroxide solution was added dropwise to a methanol (15 mL) solution of methyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate (1 g) (3.462 g, 10.86 mmol), and the reaction was carried out under reflux. After the compound reaction was complete, the excess methanol was removed by distillation, and 2N hydrochloric acid was added to adjust the pH to 5-6, causing a solid to precipitate. The precipitate was filtered, and 3.25 g of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (1 H) was obtained as a pale yellow solid. The yield was 98.2%. 1 H NMR(400MHz,CDCl3)δ:8.33(s,1H),3.50~3.43(m,2H),3.33(t,J=5.6Hz,2H),2.62(s,3H),2.52~2.37(m,2H),2.30~2.17(m,2H),2.07 ~2.00(m,2H); MS(ESI)m / z [M+H] + = 305.9.

[0091] Step 7: 5-Chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (1-h) (600 mg, 2.0 mmol) was dissolved in thionyl chloride (10 mL) and refluxed at 80°C until the starting material was completely converted to an acid chloride. The excess thionyl chloride was removed by distillation to obtain the residue. This residue was dissolved in dichloromethane (6 mL), and 5-amino-2-fluorobenzonitrile (268 mg, 2.0 mmol) and triethylamine (547 μL, 3.9 mmol) were added and the mixture was reacted at room temperature. After the compound reaction was complete, the dichloromethane was removed by distillation, water (40 mL) was added, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 10:1~1:1, v / v) to obtain 730 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (1-i) as a yellow solid. The yield was 87.7%. 1 H NMR(400MHz,CDCl3)δ:10.24(s,1H),8.16(s,1H),8.13~8.10(m,1H),7.79~7.72(m,1H),7.23(t,J=8.6Hz,1H), 3.61~3.54(m,2H),3.37(t,J=5.6Hz,2H),2.57(s,3H),2.47~2.36(m,2H),2.25~2.12(m,2H),1.98~1.89(m,2H); MS(ESI)m / z [M+H] + = 424.1.

[0092] Eighth Step: 5-Chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (1-i) (200 mg, 0.47 mmol) and hydroxylamine hydrochloride (66 mg, 0.95 mmol) were dissolved in absolute ethanol (5 mL), triethylamine (197 μL, 1.42 mmol) was added, and the reaction was carried out at 80 °C overnight. After the completion of the compound reaction, it was concentrated to obtain a crude product. This crude product was purified by silica gel (200 - 300 mesh) column chromatography (eluent: dichloromethane / methanol = 40:1, v / v) to obtain 138 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimidoyl)phenyl)-6-methylnicotinamide (I-1) as a white solid. The yield was 63.9%. 1 H NMR (600 MHz, DMSO-d6) δ: 10.47 (s, 1H), 9.61 (s, 1H), 7.80 (dd, J = 6.4, 2.8 Hz, 1H), 7.70~7.64 (m, 2H), 7.19 (t, J = 9.6 Hz, 1H), 5.77 (s, 2H), 3.60~3.55 (m, 2H), 3.38 (t, J = 6.0 Hz, 2H), 2.41 (s, 3H), 2.32~2.22 (m, 2H), 1.97~1.88 (m, 2H), 1.82~1.78 (m, 2H); MS (ESI) m / z [M+H] + = 457.2.

[0093] Example 2: Preparation of N-(3-carbamimidoyl-4-fluorophenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-2)

Chemical Structure

[0094] 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-1) (310 mg, 0.68 mmol) obtained in Example 1 was dissolved in acetic acid (3 mL), and acetic anhydride (70 μL, 1.35 mmol) was added. The mixture was reacted at room temperature for 30 minutes. Subsequently, triethylsilane (1085 μL, 6.8 mmol) and palladium(II) chloride (120 mg, 0.68 mmol) were added, and the mixture was reacted at 70°C to confirm the disappearance of the starting materials. After the compound reaction was complete, 2N sodium hydroxide aqueous solution was added to make the mixture alkaline, and after adding water (20 mL), the mixture was extracted three times with ethyl acetate. The combined organic layer was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: dichloromethane / methanol = 40:1~10:1, v / v) to obtain 30 mg of N-(3-carbamimidoyl-4-fluorophenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-2) as a white solid. The yield was 10.1%. 1 H NMR(800 MHz,Methanol-d4)δ:8.18(dd,J=6.0,2.8Hz,1H),7.87~7.83(m,1H),7.71(s,1H),7.39(t,J=9.4Hz,1H),3.72~ 3.68(m,2H),3.46(t,J=6.0Hz,2H),2.49(s,3H),2.36~2.30(m,2H),2.05~1.94(m,2H),1.94~1.89(m,2H); MS(ESI)m / z [M+H] + = 440.2.

[0095] Example 3: Preparation of 5-chloro-N-(3-(N′-cyanocarbamimidoyl)-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-3) [ka]

[0096] 5-Chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (1-i) (150 mg, 0.36 mmol) obtained in Example 1, absolute ethanol (42 μL, 0.71 mmol), and dry hydrogen chloride / ethyl acetate solution (5 mL) were placed in a sealed tube and reacted at room temperature to obtain the Pinner salt intermediate (3-a). After the reaction was completed, the reaction mixture was concentrated under reduced pressure. Absolute ethanol (3 mL), cyanamide (180 mg, 4.26 mmol), and triethylamine (99 μL, 0.71 mmol) were added to the residue, and the mixture was refluxed at 80 °C until the intermediate was completely converted. Subsequently, ammonia / methanol solution (3 mL) was added to the reaction mixture, and the reaction was continued until completion. After the reaction was completed, the organic solvent was distilled off under reduced pressure. Water (30 mL) was added, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by silica gel (200 - 300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 4:1 - 2:1, v / v) to obtain 32 mg of 5-chloro-N-(3-(N'-cyanocarbamimidoyl)-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-3) as a white solid. The yield was 19.4%. 1 H NMR (600 MHz, DMSO-d6) δ: 10.65 (s, 1H), 9.10 - 8.76 (m, 2H), 8.08 - 7.64 (m, 3H), 7.39 (s, 1H), 3.62 - 3.59 (m, 2H), 3.40 (t, J = 6.0 Hz, 2H), 2.45 (s, 3H), 2.37 - 2.26 (m, 2H), 2.02 - 1.94 (m, 2H), 1.87 - 1.81 (m, 2H); MS (ESI) m / z [M + H] + = 466.1.

[0097] Example 4: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-methoxycarbamimidoyl)phenyl)-6-methylnicotinamide (I-4) [Chemical]

[0098] First Step: 5-Chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (1-i) (150 mg, 0.36 mmol) obtained in Example 1, absolute ethanol (42 μL, 0.71 mmol), and dry hydrogen chloride / ethyl acetate solution (5 mL) were placed in a sealed tube and reacted at room temperature to form the Pinner salt intermediate (3-a).

[0099] Second Step: After the reaction was completed, the reaction mixture was concentrated under reduced pressure. Absolute ethanol (3 mL), methoxylamine hydrochloride (296 mg, 3.55 mmol), and triethylamine (49 μL, 3.55 mmol) were added to the residue, and the mixture was refluxed at 80 °C until the reaction was completed. After the reaction was completed, the organic solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by silica gel (200 - 300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 10:1 - 4:1, v / v) to obtain 43 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-methoxycarbamimidoyl)phenyl)-6-methylnicotinamide (I-4) as a white solid. The yield was 25.7%. 1 H NMR (600 MHz, CDCl3) δ: 9.62 (s, 1H), 7.91 (s, 1H), 7.87 - 7.82 (m, 1H), 7.76 (dd, J = 6.4, 2.8 Hz, 1H), 7.08 (dd, J = 10.8, 9.0 Hz, 1H), 5.09 (s, 2H), 3.86 (s, 3H), 3.57 - 3.52 (m, 2H), 3.35 (t, J = 6.0 Hz, 2H), 2.50 (s, 3H), 2.40 - 2.31 (m, 2H), 2.12 - 2.04 (m, 2H), 1.91 - 1.86 (m, 2H); MS (ESI) m / z [M+H] + = 470.8.

[0100] Example 5: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-chloro-3-(N′-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-5) [ka]

[0101] Step 1: Referring to the method of Step 7 of Example 1, 115 mg of 5-chloro-N-(3-cyano-4-chlorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (5-a) was obtained as a yellow solid from 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (5-a) from 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (5-a) (200 mg, 0.66 mmol) and 5-amino-2-chlorobenzonitrile (100 mg, 0.66 mmol). The yield was 39.9%. 1 H NMR(400 MHz, CDCl3)δ:10.25(s,1H),8.16(d,J=13.4Hz,2H),7.75~7.69(m,1H),7.50(d,J=7.8Hz,1H),3.63~3 .48(m,2H),3.46~3.31(m,2H),2.57(s,3H),2.49~2.36(m,2H),2.26~2.13(m,2H),1.97~1.89(m,2H); MS(ESI)m / z [M+H] + = 440.0.

[0102] Second step: Referring to the method of the eighth step in Example 1, 80 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-chloro-3-(N′-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-5) was obtained as a white solid from 5-chloro-N-(3-cyano-4-chlorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (5-a) as a starting material. The yield was 67.6%. 1H NMR(500 MHz,DMSO-d6)δ:10.59(s,1H),9.49(s,1H),7.76(d,J=2.6Hz,1H),7.75~7.72(m,2H),7.44(d,J=8.6Hz,1H),5.85( s,2H),3.62~3.59(m,2H),3.42~3.39(m,2H),2.44(s,3H),2.35~2.26(m,2H),2.01~1.92(m,2H),1.86~1.81(m,2H); MS(ESI)m / z [M+H] + = 472.9.

[0103] Example 6: Preparation of N-(3-carbamimidoyl-4-chlorophenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-6) [ka]

[0104] Referring to the method of Example 2, 430 mg, 0.91 mmol, of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-chloro-3-(N′-hydroxycarbamidoyl)phenyl)-6-methylnicotinamide (I-5) (I-5) was used as a starting material to obtain 40 mg of N-(3-carbamimidoyl-4-chlorophenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-6) as a white solid. The yield was 9.6%. 1 H NMR(500 MHz,Methanol-d4)δ:8.15(d,J=2.6Hz,1H),7.78(dd,J=8.8,2.6Hz,1H),7.70(s,1H),7.61(d,J=8.8Hz,1H),3 .72~3.66(m,2H),3.45(t,J=6.0Hz,2H),2.49(s,3H),2.38~2.29(m,2H),2.04~1.95(m,2H),1.93~1.88(m,2H); MS(ESI)m / z[M+H] + = 457.2.

[0105] Example 7: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-(N'-hydroxycarbamimioyl)-4-methylphenyl)-6-methylnicotinamide (I-7) [ka]

[0106] Step 1: Referring to the method of Step 7 of Example 1, 300 mg of 5-chloro-N-(3-cyano-4-methylphenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (7-a) was obtained as a white solid from 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (7-a) (1-h) (300 mg, 0.98 mmol) and 5-amino-2-methylbenzonitrile (130 mg, 0.98 mmol). The yield was 72.7%. 1 H NMR(400 MHz, CDCl3)δ:9.90(s,1H),8.09(s,1H),8.03(d,J=2.4Hz,1H),7.64(dd,J=8.4,2.4Hz,1H),7.31(d,J=8.4Hz,1H),3.61~3.5 4(m,2H),3.41~3.34(m,2H),2.55(s,3H),2.53(s,3H),2.46~2.34(m,2H),2.23~2.11(m,2H),1.97~1.88(m,2H);MS(ESI)m / z [M+H] + = 420.0.

[0107] Second step: Referring to the method of the eighth step in Example 1, 100 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-(N'-hydroxycarbamimioyl)-4-methylphenyl)-6-methylnicotinamide (I-7) was obtained as a white solid from 5-chloro-N-(3-cyano-4-methylphenyl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N'-hydroxycarbamimioyl)-4-methylphenyl)-6-methylnicotinamide (I-7) using 5-chloro-N-(3-cyano-4-methylphenyl)-2-(4,4-difluoroazepan-1-yl)-2-(3-(N'-hydroxycarbamimioyl)-4-methylphenyl)-6-methylnicotinamide (I-7) as a starting material. The yield was 30.9%. 1H NMR(500 MHz,DMSO-d6)δ:10.38(s,1H),9.31(s,1H),7.68(s,1H),7.60(d,J=9.8Hz,2H),7.17(d,J=8.0Hz,1H),5.71(s,2H) ),3.63~3.59(m,2H),3.43(t,J=6.0Hz,2H),2.44(s,3H),2.30~2.29(m,5H),2.02~1.93(m,2H),1.86~1.79(m,2H); MS(ESI)m / z [M+H] + = 453.2.

[0108] Example 8: Preparation of N-(3-carbamimidoyl-4-methylphenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-8)

[0109] Referring to the method of Example 2, 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-(N'-hydroxycarbamidoyl)-4-methylphenyl)-6-methylnicotinamide (I-7) (325 mg, 0.72 mmol) was used as a starting material to obtain 22 mg of N-(3-carbamimidoyl-4-methylphenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-8) as a white solid. The yield was 7.05%. 1 H NMR(500 MHz,Methanol-d4)δ:7.99(d,J=2.4Hz,1H),7.68(s,1H),7.66(dd,J=8.4,2.4Hz,1H),7.40(d,J=8.4Hz,1H),3.72~3. 66(m,2H),3.46(t,J=6.0Hz,2H),2.49(s,3H),2.44(s,3H),2.38~2.28(m,2H),2.05~1.94(m,2H),1.93~1.87(m,2H); MS(ESI)m / z [M+H] + = 436.9.

[0110] Example 9: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-(N'-hydroxycarbamimioyl)-4-methoxyphenyl)-6-methylnicotinamide (I-9) [Chem.]

[0111] First step: Referring to the method of the seventh step of Example 1, from 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (1-h) (300 mg, 0.98 mmol) and 5-amino-2-methoxybenzonitrile (146 mg, 0.98 mmol), 309 mg of 5-chloro-N-(3-cyano-4-methoxyphenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (9-a) was obtained as a yellow solid. The yield was 70.1%. 1 H NMR (400 MHz, CDCl3) δ: 9.84 (s, 1H), 8.07 (s, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.76 (dd, J = 9.0, 2.8 Hz, 1H), 6.99 (d, J = 9.0 Hz, 1H), 3.94 (s, 3H), 3.61~3.54 (m, 2H), 3.38 (t, J = 5.8 Hz, 2H), 2.55 (s, 3H), 2.47~2.32 (m, 2H), 2.23~2.09 (m, 2H), 1.97~1.88 (m, 2H); MS (ESI) m / z [M+H] + = 435.9.

[0112] Second step: Referring to the method of the eighth step of Example 1, using 5-chloro-N-(3-cyano-4-methoxyphenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (9-a) (200 mg, 0.46 mmol) as the raw material, 50 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-(N'-hydroxycarbamimidoyl)-4-methoxyphenyl)-6-methylnicotinamide (I-9) was obtained as a white solid. The yield was 23.3%. 1H NMR(500 MHz,DMSO-d6)δ:10.31(s,1H),9.41(s,1H),7.73(dd,J=2.7,1.0Hz,1H),7.67(d,J=9.4Hz,2H),7.05(d,J=9.0Hz,1H),5.61(s,2 H),3.78(s,3H),3.63~3.58(m,2H),3.42(t,J=6.0Hz,2H),2.44(s,3H),2.34~2.25(m,2H),2.02~1.92(m,2H),1.87~1.80(m,2H); MS(ESI)m / z [M+H] + = 468.8.

[0113] Example 10: Preparation of N-(3-carbamimidoyl-4-methoxyphenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-10) [ka]

[0114] Referring to the method of Example 2, 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-(N′-hydroxycarbamidoyl)-4-methoxyphenyl)-6-methylnicotinamide (I-9) (240 mg, 0.53 mmol) was used as a starting material to obtain 14 mg of N-(3-carbamimidoyl-4-methoxyphenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-10) as a white solid. The yield was 5.8%. 1 H NMR(500 MHz,Methanol-d4)δ:8.01(d,J=2.8Hz,1H),7.77(dd,J=9.0,2.8Hz,1H),7.69(s,1H),7.25(d,J=9.0Hz,1H),3.94(s,3H),3.72~ 3.66(m,2H),3.48(t,J=6.0Hz,2H),2.49(s,3H),2.38~2.27(m,2H),2.05~ 1.95(m,2H),1.94~1.87(m,2H); MS(ESI)m / z [M+H] + = 453.2.

[0115] Example 11: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-(N'-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-11) [ka]

[0116] Step 1: Referring to the method of Step 7 of Example 1, 51 mg of 5-chloro-N-(3-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (11-a) was obtained as a white solid from 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (11-a) (100 mg, 0.33 mmol) and m-aminobenzonitrile (39 mg, 0.33 mmol). The yield was 38.3%. 1 H NMR(400 MHz, CDCl3)δ:10.05(s,1H),8.12(s,2H),7.75(d,J=8.0Hz,1H),7.52~7.40(m,2H ),3.61~3.54(m,2H),3.38(t,J=5.8Hz,2H),2.56(s,3H),2.47~2.33(m,2H),2.25~ 2.10(m,2H),1.96 ~ 1.89(m,2H);MS(ESI)m / z [M+H] + = 406.0.

[0117] Second step: Referring to the method of the eighth step in Example 1, 5-chloro-N-(3-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (11-a) (100 mg, 0.25 mmol) was used as a starting material to obtain 50 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-(N'-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-11) as a white solid. The yield was 46.3%. 1H NMR(600 MHz,DMSO-d6)δ:10.46(s,1H),9.65(s,1H),8.01(s,1H),7.71(s,1H),7.68(d,J=7.8Hz,1H),7.39~7.32(m,2H),5.77( s,2H),3.63~3.60(m,2H),3.43(t,J=6.0Hz,2H),2.44(s,3H),2.34~2.27(m,2H),2.01~1.93(m,2H),1.86~1.82(m,2H); MS(ESI)m / z [M+H] + = 439.0.

[0118] Example 12: Preparation of N-(3-carbamimidoylphenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-12) [ka]

[0119] 5-chloro-N-(3-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (11-a) (100 mg, 0.247 mmol), anhydrous methanol (3 mL), and dried HCl / methyl acetate solution (10 N, 4 mL) prepared in Example 11 were placed in a sealed tube and reacted overnight at room temperature to obtain the Pinner salt. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and anhydrous methanol (2 mL), ammonia / methanol solution (3 mL), and ammonium chloride (26 mg, 0.49 mmol) were added to the residue and the reaction was carried out under reflux until the reaction was complete. After the reaction was complete, the reaction mixture was concentrated, water (20 mL) was added, the pH was adjusted to 8-9 with 2 N sodium hydroxide aqueous solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: dichloromethane / methanol = 20:1~10:1, v / v) to obtain 49 mg of N-(3-carbamimidoylphenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-12) as a white solid. The yield was 47.1%. 1 H NMR(600 MHz,Methanol-d4)δ:8.29(t,J=2.0Hz,1H),7.85(d,J=8.0Hz,1H),7.72(s,1H),7.61(t,J=8.0Hz,1H),7.55(d,J=7.8H) z,1H),3.73~3.68(m,2H),3.47(t,J=6.0Hz,2H),2.50(s,3H),2.39~2.29(m,2H),2.03~1.95(m,2H),1.93~1.90(m,2H); MS(ESI)m / z [M+H] + = 423.0.

[0120] Example 13: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-(N'-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-13) [ka]

[0121] Step 1: Referring to the method of Step 7 of Example 1, 90 mg of 5-chloro-N-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (13-a) was obtained as a yellow solid from 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (13-a) obtained in Example 1 from 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (13-a) (200 mg, 0.66 mmol) and 4-aminobenzonitrile (78 mg, 0.66 mmol). The yield was 33.8%. 1 H NMR(400 MHz, CDCl3)δ:10.26(s,1H),8.15(s,1H),7.81~7.74(m,2H),7.70~7.63(m,2H),3.61~3.54(m, 2H),3.40~3.33(m,2H),2.57(s,3H),2.49~2.34(m,2H),2.26~2.11(m,2H),1.97~1.87(m,2H); MS(ESI)m / z [M+H] + = 406.0.

[0122] Second step: Referring to the method of step eight in Example 1, 28 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-13) was obtained as a white solid from 5-chloro-N-(4,4-difluoroazepan-1-yl)-N-(4-(N′-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-13) using 5-chloro-N-(4,4-difluoroazepan-1-yl)-N-(4-(N′-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-13) as a starting material. The yield was 18.5%. 1 H NMR(600 MHz,DMSO-d6)δ:10.54(s,1H),9.59(s,1H),7.73(s,1H),7.68(d,J=8.6Hz,2H),7.64(d,J=8.6Hz,2H),5.82(s,2H) ),3.62~3.59(m,2H),3.42(t,J=6.0Hz,2H),2.44(s,3H),2.34~2.26(m,2H),2.01~1.94(m,2H),1.85~1.81(m,2H); MS(ESI)m / z [M+H] + = 439.2.

[0123] Example 14: Preparation of N-(4-carbamimidoylphenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-14) [ka]

[0124] Referring to the method of Example 12, 5-chloro-N-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (13-a) (150 mg, 0.37 mmol) obtained in Example 13 was used as a starting material to obtain 75 mg of N-(4-carbamimidoylphenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-14) as a white solid. The yield was 48.0%. 1 H NMR(600 MHz,Methanol-d4)δ:7.94(d,J=8.4Hz,2H),7.83(d,J=8.7Hz,2H),7.72(s,1H),3.71~ 3.67(m,2H),3.44(t,J=6.0Hz,2H),2.49(s,3H),2.37~2.29(m,2H),2.02~1.95(m,2H),1.92~1.88(m,2H); MS(ESI)m / z [M+H] + = 422.9.

[0125] Example 15: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(N'-hydroxycarbamimioylimino)pyridine-4-yl)-6-methylnicotinamide (I-15) [ka]

[0126] Step 1: Referring to the method of Step 7 of Example 1, 100 mg of 5-chloro-N-(6-cyanopyridine-3-yl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (15-a) was obtained as a yellow solid from 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (15-a) (250 mg, 0.82 mmol) and 4-amino-2-cyanopyridine (98 mg, 0.82 mmol). The yield was 30.0%. 1 H NMR(400 MHz, CDCl3)δ:10.72(s,1H),8.62(d,J=5.6Hz,1H),8.22~ 8.15(m,2H),7.66(dd,J=5.6,2.2Hz,1H),3.60~3.53(m,2H),3.38~3.31(m, 2H),2.59(s,3H),2.51~2.36(m,2H),2.28~2.16(m,2H),1.99~1.90(m,2H); MS(ESI)m / z [M+H] + = 407.1.

[0127] Step 2: Referring to the method of Step 8 of Example 1, 5-chloro-N-(6-cyanopyridine-3-yl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (15-a) (100 mg, 0.25 mmol) was used as a starting material to obtain 93 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(6-(N'-hydroxycarbamimioyl)pyridine-3-yl)-6-methylnicotinamide (I-15) as a white solid. The yield was 86.1%. 1 H NMR(600 MHz,DMSO-d6)δ:10.81(s,1H),9.89(s,1H),8.45(d,J=5.6Hz,1H),8.26(s,1H),7.80(s,1H),7.65(d,J=6.4Hz,1H),5. 81(s,2H),3.62~3.59(m,2H),3.38~3.36(m,2H),2.45(s,3H),2.33~2.27(m,2H),1.99~1.92(m,2H),1.87~1.80(m,2H); MS(ESI)m / z [M+H] + = 440.2.

[0128] Example 16: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)nicotinamide (I-16) [ka]

[0129] Step 1: Referring to the method of Step 4 of Example 1, 879 mg of 2-(4,4-difluoroazepan-1-yl)methyl nicotinate (16-b) was obtained as a colorless liquid from 2-methyl chloronicotinate (16-a) (1 g, 5.8 mmol) and 4,4-difluoroazepane hydrochloride (1-c) (1.2 g, 7.0 mmol). The yield was 55.8%. 1 H NMR(400 MHz, CDCl3)δ:8.23(dd,J=4.6,2.0Hz,1H),7.89(dd,J=7.6,2.0Hz,1H),6.66(dd,J=7.6,4.6Hz,1 H),3.88(s,3H),3.76~3.69(m,2H),3.30(t,J=5.6Hz,2H),2.45~2.31(m,2H),2.03~1.89(m,4H); MS(ESI)m / z [M+H] + = 271.0.

[0130] Step 2: Referring to the method of Step 5 of Example 1, 523 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)nicotinate methyl (16-b) (658 mg, 2.4 mmol) was used as a starting material to obtain 523 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)nicotinate methyl (16-c) as a colorless liquid. The yield was 70.5%. 1 H NMR(400 MHz, CDCl3)δ:8.16(d,J=2.6Hz,1H),7.86(d,J=2.6Hz,1H),3.88(s,3H),3.7 2~3.65(m,2H),3.25(t,J=5.6Hz,2H),2.42~2.27(m,2H),2.01~1.90(m,4H); MS(ESI)m / z [M+H] + = 305.9.

[0131] Third step: Referring to the method of the sixth step in Example 1, 5-chloro-2-(4,4-difluoroazepan-1-yl)nicotinate methyl (16-c) (460 mg, 1.5 mmol) was used as a starting material to obtain 385 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)nicotinic acid (16-d) as a white solid. The yield was 87.7%. 1 H NMR(400 MHz, CDCl3)δ:8.41(d,J=2.6Hz,1H),8.34(d,J=2.6Hz,1H),3.53~3.49(m,2H), 3.31(t,J=6.0Hz,2H),2.50~2.35(m,2H),2.26~2.11(m,2H),2.07~1.98(m,2H); MS(ESI)m / z [M+H] + = 291.8.

[0132] Fourth step: Referring to the method of the seventh step in Example 1, 352 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)nicotinamide (16-e) was obtained as a white solid from 5-chloro-2-(4,4-difluoroazepan-1-yl)nicotinamide (16-e) using 5-chloro-2-(4,4-difluoroazepan-1-yl)nicotinamide (16-e) as raw materials, with 5-chloro-2-(4,4-difluoroazepan-1-yl)nicotinamide (16-e) as the raw materials. The yield was 83.4%. 1 H NMR(400 MHz,DMSO-d6)δ:10.85(s,1H),8.26(d,J=2.6Hz,1H),8.18(dd,J=5.8,2.6Hz,1H),7.99~7.90(m,1H),7.87(d,J=2.6Hz,1H) ,7.56(t,J=9.1Hz,1H),3.64~3.57(m,2H),3.39(t,J=6.0Hz,2H),2.35~2.25(m,2H),2.03~1.90(m,2H),1.90~1.79(m,2H); MS(ESI)m / z [M+H] + = 409.9.

[0133] Step 5: Referring to the method of Step 8 of Example 1, 138 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)nicotinamide (I-16) was obtained as a white solid from 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)nicotinamide (I-16) using 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)nicotinamide (I-16) as a starting material. The yield was 63.9%. 1 H NMR(500 MHz,DMSO-d6)δ:10.59(s,1H),9.65(s,1H),8.24(d,J=2.6Hz,1H),7.84(dd,J=6.4,2.8Hz,1 H),7.81(d,J=2.6Hz,1H),7.74~7.68(m,1H),7.23(t,J=9.6Hz,1H),5.83~5.78(m,2H),3.64 ~3.60(m,2H),3.43(t,J=6.0Hz,2H),2.34~2.23(m,2H),2.01~1.92(m,2H),1.87~ 1.83(m,2H); MS(ESI)m / z [M+H] + = 442.9.

[0134] Example 17: Preparation of N-(3-(carbamimidoylcarbamoyl)-4-fluorophenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-17) [ka]

[0135] Step 1: Referring to the method of Step 7 of Example 1, 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (1-h) (500 mg, 1.64 mmol) and methyl 5-amino-2-fluorobenzoate (280 mg, 1.64 mmol) were used as raw materials to obtain 547 mg of [5-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide)-2-fluorophenyl]methyl benzoate (17-a) as a yellow solid. The yield was 73.1%. 1H NMR(400 MHz, CDCl3)δ:9.86(s,1H),8.10(s,1H),8.04(dd,J=6.2,2.8Hz,1H),7.99~7.93(m,1H),7.17(t,J=9.6Hz,1H),3.94 (s,3H),3.61~3.54(m,2H),3.42~3.35(m,2H),2.55(s,3H),2.48~2.33(m,2H),2.24~2.10(m,2H),1.98~1.87(m,2H); MS(ESI)m / z [M+H] + = 457.0.

[0136] Step 2: Referring to the method of Step 6 of Example 1, 5-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide)-2-fluorobenzoate methyl(17-a) (400 mg, 0.88 mol) was used as a starting material to obtain 380 mg of 5-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide)-2-fluorobenzoic acid(17-b) as a white solid. The yield was 98%. 1 H NMR(500 MHz,DMSO-d6)δ:10.61(s,1H),8.23(dd,J=6.6,2.8Hz,1H),7.92~7.86(m,1H),7.76(s,1H),7.33~7.26(m,1H), 3.63~3.57(m,2H),3.40(t,J=6.0Hz,2H),2.44(s,3H),2.35~2.25(m,2H),2.03~1.90(m,2H),1.88~1.77(m,2H); MS(ESI)m / z [M+H] + = 443.0.

[0137] Step 3: 5-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide)-2-fluorobenzoic acid (17-b) (200 mg, 0.45 mmol) was mixed with thionyl chloride (5 mL) and refluxed until the acid was completely converted to the acid chloride. The mixture was then concentrated under reduced pressure to obtain the crude acid chloride. This crude acid chloride product was dissolved in anhydrous tetrahydrofuran (5 mL). At 0°C, a solution of guanidine hydrochloride (216 mg, 2.26 mmol) dissolved in aqueous sodium hydroxide solution (2 N, 1.36 mL, 2.7 mmol) was added dropwise, and after the addition was complete, the mixture was allowed to react at room temperature for 30 minutes. The tetrahydrofuran was removed by distillation, water (30 mL) was added, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 4:1~1:1, v / v), and the resulting solid was washed with chloroform to obtain 30 mg of N-(3-(carbamimidoylcarbamoyl)-4-fluorophenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-17) as a white solid. The yield was 13.7%. 1 H NMR(500 MHz,DMSO-d6)δ:10.46(s,1H),7.98(dd,J=6.6,2.8Hz,1H),7.73~7.65(m,2H),7.12(dd,J=10.2,8.8Hz,1H),6.78(s, 2H),3.64~3.58(m,2H),3.42(t,J=6.0Hz,2H),2.44(s,3H),2.34~2.27(m,2H),2.01~1.92(m,2H),1.87~1.82(m,2H); MS(ESI)m / z [M+H] + = 483.9.

[0138] Example 18: Preparation of N-(3-(carbamimidoylcarbamoyl)phenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-18) [ka]

[0139] Step 1: Referring to the method of Step 7 of Example 1, 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (1-h) (500 mg, 1.64 mmol) and methyl 3-aminobenzoate (248 mg, 1.64 mmol) were used as raw materials to obtain 423 mg of methyl 3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide)methyl benzoate (18-a) as a yellow solid. The yield was 58.9%. 1 H NMR(400 MHz, CDCl3)δ:9.75(s,1H),8.16(s,1H),8.09(s,1H),7.98(d,J=8.4Hz,1H),7.86~7.80(m,1H),7.46(t,J=7.8Hz,1H),3.9 3(s,3H),3.62~3.56(m,2H),3.41(t,J=5.8Hz,2H),2.55(s,3H),2.47~2.35(m,2H),2.21~2.08(m,2H),1.96~1.87(m,2H); MS(ESI)m / z [M+H] + = 438.9.

[0140] Second step: Referring to the method of the sixth step in Example 1, 3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide)methyl benzoate (18-a) (300 mg, 0.69 mol) was used as a starting material to obtain 270 mg of 3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide)benzoic acid (18-b) as a white solid. The yield was 93.1%. 1 H NMR(400 MHz,DMSO-d6)δ:10.60(s,1H),8.34(t,J=2.0Hz,1H),7.94~7.88(m,1H),7.77(s,1H),7.71~7.64(m,1H),7.47(t,J=7.8 Hz,1H),3.65~3.58(m,2H),3.42(t,J=6.0Hz,2H),2.45(s,3H),2.37~2.25(m,2H),2.03~1.90(m,2H),1.88~1.80(m,2H); MS(ESI)m / z [M+H] += 425.0.

[0141] Third step: Following the method of the third step in Reference Example 17, 28 mg of N-(3-(carbamimidoylcarbamoyl)phenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-18) was obtained as a white solid from 3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-18)) using 3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-18)) as a starting material. The yield was 10.2%. 1 H NMR(500 MHz,DMSO-d6)δ:12.16(s,1H),10.74(s,1H),8.85(s,1H),8.67(s,2H),8.39(t,J=2.0Hz,1H),8.05(d,J=7.8Hz,1H),7.97(dd,J=8.0,2.1Hz,1H),7 .76(s,1H),7.55(t,J=8.0Hz,1H),3.64~3.59(m,2H),3.41(t,J=6.0Hz,2 H),2.44(s,3H),2.35~2.26(m,2H),2.01~1.91(m,2H),1.86~1.81(m,2H); MS(ESI)m / z[M+H] + = 466.0.

[0142] Example 19: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-guanidinophenyl)-6-methylnicotinamide (I-19) [ka]

[0143] Step 1: Referring to the method of Step 7 of Example 1, 290 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (1-h) (400 mg, 1.31 mmol) and 4-fluoro-3-nitroaniline (205 mg, 1.31 mmol) were used as raw materials to obtain 290 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-nitrophenyl)-6-methylnicotinamide (19-a) as a yellow solid. The yield was 49.9%.1 H NMR(400 MHz, CDCl3)δ:10.30(s,1H),8.45(dd,J=6.4,2.8Hz,1H),8.16(s,1H),7.92~7.84(m,1H),7.33~7.28(m,1H), 3.59~3.55(m,2H),3.38~3.35(m,2H),2.57(s,3H),2.49~2.34(m,2H),2.26~2.12(m,2H),1.97~1.89(m,2H); MS(ESI)m / z [M+H] + = 444.1.

[0144] Step 2: 5-Chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-nitrophenyl)-6-methylnicotinamide (19-a) (260 mg, 0.59 mmol) was dissolved in anhydrous ethanol (4 mL), zinc powder (92 mg, 2.94 mmol) and acetic acid (2 mL) were added, and the mixture was reacted at 80°C until the starting materials disappeared. After the reaction was complete, the ethanol was removed by distillation, and saturated sodium bicarbonate aqueous solution was added to adjust the pH to 8-9. The mixture was extracted three times with ethyl acetate, the combined organic layer was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 10:1~4:1, v / v) to obtain 227 mg of N-(3-amino-4-fluorophenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (19-b) as a yellow solid. The yield was 93.8%. 1 H NMR(400 MHz, CDCl3)δ:9.46(s,1H),8.04(s,1H),7.38(dd,J=8.0,2.6Hz,1H),6.99~6.90(m,1H),6.73~6.64(m,1H),3.82(s, 2H),3.61~3.53(m,2H),3.38(t,J=5.8Hz,2H),2.54(s,3H),2.47~2.31(m,2H),2.21~2.07(m,2H),1.96~1.87(m,2H); MS(ESI)m / z [M+H] + = 414.2.

[0145] Step 3: N-(3-amino-4-fluorophenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (19-b) (100 mg, 0.24 mmol) was dissolved in anhydrous ethanol (4 mL), and 50% cyanamide aqueous solution (0.2 mL, 9.7 mmol) and 4N hydrochloric acid (0.2 mL, 12.1 mmol) were added. The reaction was carried out in a sealed tube at 80°C. After the reaction was complete, the reaction mixture was concentrated and the pH was adjusted to 8-9 with sodium hydroxide aqueous solution. The mixture was extracted three times with ethyl acetate, the combined organic layer was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: dichloromethane / methanol = 40:1~10:1, v / v) to obtain 72 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-guanidinophenyl)-6-methylnicotinamide (I-19) as a white solid. The yield was 65.3%. 1 H NMR(500 MHz,Methanol-d4)δ:7.92~7.85(m,1H),7.69(s,1H),7.62~7.56(m,1H),7.29(t,J=9.4Hz,1H),3 .72~3.66(m,2H),3.46(t,J=6.0Hz,2H),2.48(s,3H),2.37~2.28(m,2H),2.05~1.94(m,2H),1.94 ~1.87(m,2H); MS(ESI)m / z [M+H] + = 456.2.

[0146] Example 20: Preparation of N-(3-carbamimidoylphenyl)-5-chloro-6-methyl-2-(pyrrolidine-1-yl)nicotinamide (I-20) [ka]

[0147] Step 1: Referring to the method of Step 7 of Example 1, 2-chloro-6-methylnicotinic acid (200 mg, 1.16 mmol) and m-aminobenzonitrile (138 mg, 1.16 mmol) were used as raw materials to obtain 214 mg of 2-chloro-N-(3-cyanophenyl)-6-methylnicotinamide (20-a) as a pale yellow solid. The yield was 67.5%. 1 H NMR(400 MHz,CDCl3)δ:8.56(s,1H),8.15~8.08(m,2H),7.84~7.80(m,1H),7.52~7.45(m,2H),7.28~7.27(m,1H),2.61(s,3H); MS(ESI)m / z [M+H] + = 273.0.

[0148] Second step: Referring to the method of the fourth step in Example 1, 400 mg of N-(3-cyanophenyl)-6-methylnicotinamide (20-a) (500 mg, 1.84 mmol) and pyrrolidine (307 μL, 3.68 mmol) were used as starting materials to obtain 400 mg of N-(3-cyanophenyl)-6-methyl-2-(pyrrolidine-1-yl)nicotinamide (20-b) as a white solid. The yield was 70.9%. 1 H NMR(400 MHz,DMSO-d6)δ:10.62(s,1H),8.19(d,J=2.4Hz,1H),7.97~7.90(m,1H),7. 60~7.50(m,3H),6.54(d,J=7.6Hz,1H),3.38~3.35(m,4H),2.35(s,3H),1.86 ~1.79(m,4H); MS(ESI)m / z [M+H] + = 307.0.

[0149] Third step: Referring to the method of the fifth step in Example 1, 66 mg of 5-chloro-N-(3-cyanophenyl)-6-methyl-2-(pyrrolidine-1-yl)nicotinamide (20-b) (75 mg, 0.24 mmol) was used as a starting material to obtain 66 mg of 5-chloro-N-(3-cyanophenyl)-6-methyl-2-(pyrrolidine-1-yl)nicotinamide (20-c) as a white solid. The yield was 83.4%. 1H NMR(400 MHz,CDCl3)δ:9.19(s,1H),8.06 ~8.01(m,1H),7.85~7.77(m,2H),7.50~7.38(m,2H),3.43~3.39(m,4H),2.49(s,3H),1.95~1.90(m,4H); MS(ESI)m / z [M+H] + =342.0.

[0150] Step 4: Referring to the method of Example 12, 15 mg of N-(3-carbamimidoylphenyl)-5-chloro-6-methyl-2-(pyrrolidine-1-yl)nicotinamide (I-20) was obtained as a white solid from 5-chloro-N-(3-cyanophenyl)-6-methyl-2-(pyrrolidine-1-yl)nicotinamide (20-c) as a starting material. The yield was 28.6%. 1 H NMR(500 MHz,DMSO-d6)δ:10.84(s,1H),9.35(s,3H),8.17(s,1H),8.01~7.96(m,1H),7.67(s ,1H),7.59(t,J=8.0Hz,1H),7.52~7.47(m,1H),3.38~3.35(m,4H),2.43(s,3H),1.86 ~1.83(m,4H); MS(ESI)m / z [M+H] + =359.0.

[0151] Example 21: Preparation of N-(3-carbamimidoylphenyl)-5-chloro-6-methyl-2-(piperidine-1-yl)nicotinamide (I-21) [ka]

[0152] Step 1: Referring to the method of Step 4 of Example 1, 2-chloro-N-(3-cyanophenyl)-6-methylnicotinamide (20-a) (100 mg, 0.37 mmol) and piperidine (72 μL, 0.74 mmol) were used as starting materials to obtain 95 mg of N-(3-cyanophenyl)-6-methyl-2-(piperidine-1-yl)nicotinamide (21-a) as a white solid. The yield was 80.51%. 1H NMR(400 MHz, CDCl3)δ:12.34(s,1H),8.38(d,J=7.9Hz,1H),8.21~ 8.19(m,1H),7.91~7.86(m,1H),7.47(t,J=7.9Hz,1H),7.43~7.36(m,1H),7.07(d,J =7.9Hz,1H),3.18~3.14(m,4H),2.54(s,3H),1.85~1.75(m,4H),1.72~1.65(m,2H); MS(ESI)m / z [M+H] + =321.0.

[0153] Second step: Referring to the method of the fifth step in Example 1, 5-chloro-N-(3-cyanophenyl)-6-methyl-2-(piperidine-1-yl)nicotinamide (21-a) (500 mg, 1.56 mmol) and 1,3-dichloro-5,5-dimethylhydantoin (277 mg, 1.4 mmol) were used as raw materials to obtain 319 mg of 5-chloro-N-(3-cyanophenyl)-6-methyl-2-(piperidine-1-yl)nicotinamide (21-b) as a yellow solid. The yield was 57.6%. 1 H NMR(400 MHz,DMSO-d6)δ:10.79(s,1H),8.20~ 8.19(m,1H),7.94~7.90(m,1H),7.79(s,1H),7.59~7.55(m,2H),3.70~3.53(m,4H),2.46(s,3H),1.54~1.49(m,6H); MS(ESI)m / z [M+H] + = 356.0.

[0154] Third step: Referring to the method of Example 12, 80 mg of N-(3-carbamimidoylphenyl)-5-chloro-6-methyl-2-(piperidine-1-yl)nicotinamide (I-21) was obtained as a white solid from 5-chloro-N-(3-cyanophenyl)-6-methyl-2-(piperidine-1-yl)nicotinamide (21-b) (300 mg, 0.85 mmol) as a starting material. The yield was 25.5%. 1H NMR(500 MHz,DMSO-d6)δ:10.87(s,1H),9.40(s,3H),8.25~8.22(m,1H),7.94(d,J=8.2Hz,1H),7.77(s,1 H),7.60(t,J=8.0Hz,1H),7.54~7.49(m,1H),3.31~3.27(m,4H),2.46(s,3H),1.54~1.52(m,6H); MS(ESI)m / z [M+H] + =373.0.

[0155] Example 22: Preparation of N-(3-carbamimidoylphenyl)-5-chloro-6-methyl-2-morpholino-nicotinamide (I-22) [ka]

[0156] Step 1: Referring to the method of Step 4 of Example 1, 2-chloro-N-(3-cyanophenyl)-6-methylnicotinamide (20-a) (100 mg, 0.37 mmol) and morpholine (65 μL, 0.74 mmol) were used as starting materials to obtain 61 mg of N-(3-cyanophenyl)-6-methyl-2-morpholino-nicotinamide (22-a) as a yellow solid. The yield was 51.3%. 1 H NMR(400 MHz,CDCl3)δ:11.59(s,1H),8.34(d,J=7.9Hz,1H),8.25~8.24(m,1H),7.86~7.82(m,1H),7.48(t,J=7.9Hz,1H),7.44 ~7.38(m,1H),7.09(d,J=7.9Hz,1H),3.95~3.88(m,4H),3.29~3.22(m,4H),2.55(s,3H); MS(ESI)m / z [M+H] + =323.0.

[0157] Second step: Referring to the method of the fifth step in Example 1, 477 mg of 5-chloro-N-(3-cyanophenyl)-6-methyl-2-morpholino-nicotinamide (22-b) was obtained as a yellow solid using N-(3-cyanophenyl)-6-methyl-2-morpholino-nicotinamide (22-a) (600 mg, 1.86 mmol) and 1,3-dichloro-5,5-dimethylhydantoin (330 mg, 1.68 mmol) as starting materials. The yield was 71.8%. 1 H NMR(400 MHz,CDCl3)δ:11.53(s,1H),8.37(s,1H),8.23~8.18(m,1H),7.86~7.82(m,1H),7.49(t,J=7.9Hz,1H),7.45~ 7.42(m,1H),3.93~3.89(m,4H),3.25~3.21(m,4H),2.62(s,3H); MS(ESI)m / z [M+H] + =358.0.

[0158] Third step: Referring to the method of Example 12, 120 mg of N-(3-carbamimidoylphenyl)-5-chloro-6-methyl-2-morpholino-nicotinamide (I-22) was obtained as a white solid from 5-chloro-N-(3-cyanophenyl)-6-methyl-2-morpholino-nicotinamide (22-b) (400 mg, 1.12 mmol) as a starting material. The yield was 28.6%. 1 H NMR(500 MHz,DMSO-d6)δ:10.90(s,1H),9.41(s,3H),8.22(d,J=2.2Hz,1H),7.97(d,J=8.0Hz,1H),7.81(s, 1H),7.60(t,J=8.0Hz,1H),7.55~7.50(m,1H),3.66~3.61(m,4H),3.34~3.28(m,4H),2.48(s,3H); MS(ESI)m / z [M+H] + =375.0.

[0159] Example 23: Preparation of 2-(azepan-1-yl)-N-(3-carbamimidoylphenyl)-5-chloro-6-methylnicotinamide (I-23) [ka]

[0160] Step 1: Referring to the method of Step 4 of Example 1, 2-chloro-N-(3-cyanophenyl)-6-methylnicotinamide (20-a) (100 mg, 0.37 mmol) and azepane (85 μL, 0.74 mmol) were used as raw materials to obtain 67 mg of 2-(azepan-1-yl)-N-(3-cyanophenyl)-6-methylnicotinamide (23-a) as a yellow solid. The yield was 54.5%. 1 H NMR(400 MHz,CDCl3)δ:11.27(s,1H),8.21(d,J=7.8Hz,1H),8.13(s,1H),7.83(d,J=8.2Hz,1H),7.46(t,J=7.8Hz,1H),7.43 ~ 7.37(m,1H),6.94(d,J=7.8Hz,1H),3.43~3.36(m,4H),2.51(s,3H),1.89~1.82(m,4H),1.74~1.70(m,4H); MS(ESI)m / z [M+H] + = 335.1.

[0161] Second step: Referring to the method of the fifth step in Example 1, 2-(azepan-1-yl)-N-(3-cyanophenyl)-6-methylnicotinamide (23-a) (450 mg, 1.35 mmol) and 1,3-dichloro-5,5-dimethylhydantoin (265 mg, 1.35 mmol) were used as raw materials to obtain 240 mg of 2-(azepan-1-yl)-5-chloro-N-(3-cyanophenyl)-6-methylnicotinamide (23-b) as a yellow solid. The yield was 48.4%. 1 H NMR(400 MHz, CDCl3)δ:10.98(s,1H),8.22~8.17(m,1H),8.09~8.06(m,1H),7.84~7.81(m,1H),7.47(t,J=7. 8Hz,1H),7.44~7.40(m,1H),3.42~3.35(m,4H),2.56(s,3H),1.86~1.84(m,4H),1.73~1.68(m,4H); MS(ESI)m / z [M+H] + =370.0.

[0162] Third step: Referring to the method of Example 12, 2-(azepan-1-yl)-5-chloro-N-(3-cyanophenyl)-6-methylnicotinamide (23-b) (200 mg, 0.54 mmol) was used as a starting material to obtain 20 mg of 2-(azepan-1-yl)-N-(3-carbamimidoylphenyl)-5-chloro-6-methylnicotinamide (I-23) as a white solid. The yield was 9.6%. 1 H NMR(500MHz,DMSO-d6)δ:10.85(s,1H),9.37(s,3H),8.16~8.15(m,1H),7.98(d,J=7.8Hz,1H),7.63(s,1H),7. 58(t,J=8.0Hz,1H),7.51~7.48(m,1H),3.51~3.46(m,4H),2.43(s,3H),1.75~1.70(m,4H),1.46~1.43(m,4H); MS(ESI)m / z [M+H] + =387.0.

[0163] Example 24: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-isopropylnicotinamide (I-24) [ka]

[0164] Step 1: Referring to the method of Step 7 of Example 1, 75 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-isopropylnicotinamide (24-b) was obtained as a white solid from 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-isopropylnicotinamide (24-b) using 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-isopropylnicotinamide (24-b) as raw materials. The yield was 41.7%. 1H NMR(400 MHz, CDCl3)δ:9.80(s,1H),8.09(s,1H),8.09~8.06(m,1H),7.78~7.73(m,1H),7.22(t,J=8.8Hz,1H),3.63~3.59(m,2H),3. 54~3.47(m,1H),3.39(t,J=5.8Hz,2H),2.48~2.34(m,2H),2.23~2.09(m,2H),1.99~1.88(m,2H),1.26(s,3H),1.25(s,3H); MS(ESI)m / z [M+H] + = 452.2.

[0165] Second step: Referring to the method of step eight of Example 1, 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-isopropylnicotinamide (24-b) (70 mg, 0.16 mmol) was used as a starting material to obtain 54 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-isopropylnicotinamide (I-24) as a white solid. The yield was 72%. 1 H NMR(500 MHz,DMSO-d6)δ:10.52(s,1H),9.64(s,1H),7.86~7.83(m,1H),7.72~7.68(m,2H),7.22(t,J =9.6Hz,1H),5.79(s,2H),3.66~3.62(m,2H),3.43(t,J=6.0Hz,2H),3.39~3.35(m,1H),2.35~ 2.27(m,2H),2.00~1.93(m,2H),1.88~1.83(m,2H),1.21(s,3H),1.19(s,3H); MS(ESI)m / z [M+H] + = 485.2.

[0166] Example 25: Preparation of 6-chloro-3-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)pyridazine-4-carboxamide (I-25) [ka]

[0167] Step 1: Referring to the method of Step 4 of Example 1, 3,6-dichloropyridazine-4-carboxylate methyl (25-a) (900 mg, 4.35 mmol) and 4,4-difluoroazepane hydrochloride (1-c) (896 mg, 5.22 mmol) were used as raw materials to obtain 560 mg of 6-chloro-3-(4,4-difluoroazepan-1-yl)pyridazine-4-carboxylate methyl (25-b) as a colorless liquid. The yield was 42.1%. 1 H NMR(400 MHz,CDCl3)δ:7.49(s,1H),3.93(s,3H),3.85~3.78(m,2H),3.35~3.30(m,2H),2.48~2.33(m,2H),2.06~1.98(m,4H); MS(ESI)m / z [M+H] + = 306.9.

[0168] Step 2: Referring to the method of Step 6 of Example 1, 515 mg of 6-chloro-3-(4,4-difluoroazepan-1-yl)pyridazine-4-carboxylic acid (25-c) was obtained as a white solid from methyl 6-chloro-3-(4,4-difluoroazepan-1-yl)pyridazine-4-carboxylic acid (25-b) (560 mg, 1.83 mmol) as a starting material. The yield was 96.4%. 1 H NMR(400 MHz,DMSO-d6)δ:7.72(s,1H),3.81~3.68(m,2H),3.39(t,J=5.8Hz,2H),2.42~2.30(m,2H),2.12~1.99(m,2H),1.95~1.88(m,2H); MS(ESI)m / z [M+H] + =293.0.

[0169] Third step: Referring to the method of the seventh step in Example 1, 177 mg of 6-chloro-N-(3-cyano-4-fluorophenyl)-3-(4,4-difluoroazepan-1-yl)pyridazin-4-carboxylic acid (25-c) (200 mg, 0.686 mmol) and 5-amino-2-fluorobenzonitrile (93 mg, 0.686 mmol) were used as raw materials to obtain 177 mg of 6-chloro-N-(3-cyano-4-fluorophenyl)-3-(4,4-difluoroazepan-1-yl)pyridazin-4-carboxamide (25-d) as a yellow solid. The yield was 63.0%. 1 H NMR(400 MHz,DMSO-d6)δ:11.10(s,1H),8.15(dd,J=5.8,2.8Hz,1H),7.95~7.90(m,1H),7.83~7.81(m,1H),7.59(t,J=9.2Hz,1H),3.76 ~3.69(m,2H),3.50(t,J=6.0Hz,2H),2.41~ 2.26(m,2H),2.11~1.98(m,2H),1.92~1.86(m,2H); MS(ESI)m / z [M+H] + = 410.9.

[0170] Step 4: Referring to the method of Step 8 of Example 1, 25 mg of 6-chloro-3-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)pyridazin-4-carboxamide (I-25) was obtained as a white solid from 6-chloro-N-(3-cyano-4-fluorophenyl)-3-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)pyridazin-4-carboxamide (I-25) using 6-chloro-N-(3-cyano-4-fluorophenyl)-3-(4,4-difluoroazepan-1-yl)-4-(4,4-difluoroazepan-1-yl)-4-carboxamide (I-25) as a starting material. The yield was 13.6%. 1 H NMR(500 MHz,DMSO-d6)δ:10.83(s,1H),9.67(s,1H),7.82(dd,J=6.4,2.8Hz,1H),7.78(s,1H),7.71~7.65(m,1H),7.26(t,J=9.6 Hz,1H),5.81(s,2H),3.76~3.71(m,2H),3.52(t,J=6.0Hz,2H),2.39~2.28(m,2H),2.07~1.98(m,2H),1.91~1.86(m,2H); MS(ESI)m / z [M+H] += 444.1.

[0171] Example 26: Preparation of 2-(4,4-difluoroazepan-1-yl)-5-ethynyl-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-26) [ka]

[0172] Step 1: 2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate methyl(1-f) (840 mg, 2.95 mmol) was dissolved in acetic acid (5 mL), N-iodosuccinimide (665 mg, 2.95 mmol) was added, and the reaction was carried out at room temperature. After the reaction was complete, the reaction mixture was poured into ice water, and appropriate amounts of sodium thiosulfate aqueous solution and saturated sodium bicarbonate aqueous solution were added to adjust the pH to 7-8. The mixture was extracted three times with ethyl acetate, the combined organic layer was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 30:1, v / v) to obtain 1.2 g of 5-iodo-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate methyl(26-a) as a brown liquid. The yield was 99%. 1 H NMR(400 MHz, CDCl3)δ:8.16(s,1H),3.85(s,3H),3.74~ 3.66(m,2H),3.25(t,J=5.8Hz,2H),2.58(s,3H),2.42~2.27(m,2H),1.99~1.90(m,4H); MS(ESI)m / z [M+H] + = 411.1.

[0173] Step two: Under the protection of an argon stream, methyl 5-iodo-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate (26-a) (300 mg, 0.73 mmol), copper(I) iodide (70 mg, 0.37 mmol), bis(triphenylphosphine)palladium(II) chloride (51.3 mg, 0.07 mmol), and trimethylsilylacetylene (620 μL, 4.4 mmol) were added to triethylamine (4 mL) and reacted at 90°C. After the reaction of the mixture was complete, the triethylamine was removed by distillation, and potassium carbonate (202 mg, 1.46 mmol) and methanol (3 mL) were added to remove the silyl protecting group at room temperature. After the reaction was complete, the reaction mixture was filtered, water was added to the filtrate, and it was extracted three times with ethyl acetate. The combined organic layers were washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 50:1, v / v) to obtain 143 mg of 2-(4,4-difluoroazepan-1-yl)-5-ethynyl-6-methylnicotinate methyl(26-b) as a brown liquid. The yield was 63.4%. 1 H NMR(400 MHz,CDCl3)δ:7.97(s,1H),3.85(s,3H),3.78~3.71(m,2H),3.30~3.26(m,2H),3.24(s,1H),2.53(s,3H),2.41~ 2.30(m,2H),1.99~1.90(m,4H); MS(ESI)m / z [M+H] + = 309.2.

[0174] Third step: Referring to the method of the sixth step in Example 1, 100 mg of 2-(4,4-difluoroazepan-1-yl)-5-ethynyl-6-methylnicotinate methyl(26-b) (110 mg, 0.36 mmol) was used as a starting material to obtain 100 mg of 2-(4,4-difluoroazepan-1-yl)-5-ethynyl-6-methylnicotinate (26-c) as a white solid. The yield was 95.2%. 1H NMR(400 MHz,CDCl3)δ:8.28(s,1H),3.67~ 3.60(m,2H),3.35~3.32(m,2H),3.32(s,1H),2.60(s,3H),2.48 ~2.31(m,2H),2.14~2.0(m,2H),2.05~1.95(m,2H); MS(ESI)m / z [M+H] + = 295.2.

[0175] Step 4: Referring to the method of Step 7 of Example 1, 2-(4,4-difluoroazepan-1-yl)-5-ethynyl-6-methylnicotinic acid (26-c) (100 mg, 0.34 mmol) and 5-amino-2-fluorobenzonitrile (46 mg, 0.34 mmol) were used as raw materials to obtain 20 mg of N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-5-ethynyl-6-methylnicotinamide (26-d) as a white solid. The yield was 14.3%. 1 H NMR(400 MHz, CDCl3)δ:8.87(s,1H),8.07~8.03(m,1H),8.00(s,1H),7.78~7.73(m,1H),7.22(t,J=8.6Hz,1H),3.71~3.64( m,2H),3.41(t,J=5.8Hz,2H),3.32(s,1H),2.59(s,3H),2.44~2.34(m,2H),2.10~1.99(m,2H),1.97~1.83(m,2H); MS(ESI)m / z [M+H] + = 413.2.

[0176] Step 5: Referring to the method of Step 8 of Example 1, 10 mg of 2-(4,4-difluoroazepan-1-yl)-5-ethynyl-6-methylnicotinamide (I-26) was obtained as a white solid from N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-5-ethynyl-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-26) using N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-5-ethynyl-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-26). The yield was 46.3%. 1H-NMR(500MHz,DMSO-d6)δ:10.51(s,1H),9.66(s,1H),7.85(dd,J=6.4,2.8Hz, 1H),7.74~7.69(m,2H),7.22(t,J=9.6Hz,1H),5.82(s,2H),4.31(s,1H),3.68~ 3.62(m,2H),3.44(t,J=6.0Hz,2H),2.48(s,3H),2.36~2.26(m,2H),2.00~1.92(m,2H),1.87~1.83(m,2H); MS(ESI)m / z [M+H] + = 446.2.

[0177] Example 27: Preparation of 2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-methyl-5-(trifluoromethyl)nicotinamide (I-27) [ka]

[0178] Step 1: Under protection of an argon stream, 5-iodo-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate methyl (26-a) (400 mg, 0.98 mmol) obtained in Example 26 was dissolved in N,N-dimethylformamide (8 mL), copper(I) iodide (371 mg, 1.95 mmol) and fluorosulfonyl difluoroacetate methyl (1.5 mL, 11.7 mmol) were added, and the mixture was reacted at 100 °C. After the compound reaction was complete, the reaction mixture was filtered, water (40 mL) was added to the filtrate, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 30:1~15:1, v / v) to obtain 330 mg of 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinate methyl (27-a) as a colorless liquid. The yield was 96.1%. 1H NMR(400 MHz, CDCl3)δ:8.10(s,1H),3.87(s,3H),3.80~3.77(m,2H),3.32~3.28(m,2H),2.54(s,3H),2.41~2.30(m,2H),2.00~1.93(m,4H); MS(ESI)m / z [M+H] + = 353.1.

[0179] Step 2: Referring to the method of Step 6 of Example 1, 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinate methyl (27-a) (330 mg, 0.94 mmol) was used as a starting material to obtain 296 mg of 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (27-b) as a white solid. The yield was 93.7%. 1 H NMR(400 MHz,CDCl3)δ:8.30(s,1H),3.83~3.77(m,2H),3.40~3.35(m,2H),2.58(s,3H),2.44~2.32(m,2H),2.03~1.96(m,4H); MS(ESI)m / z [M+H] + = 339.2.

[0180] Third step: Referring to the method of the seventh step in Example 1, 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (27-b) (296 mg, 0.88 mmol) and 5-amino-2-fluorobenzonitrile (119 mg, 0.875 mmol) were used as raw materials to obtain 250 mg of N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide (27-c) as a white solid. The yield was 62.6%. 1H NMR(400 MHz,DMSO-d6)δ:10.81(s,1H),8.18(dd,J=5.8,2.8Hz,1H),7.99~7.90(m,2H),7.55(t,J=9.2Hz,1H),3.74 ~3.66(m,2H),3.45(t,J=5.8Hz,2H),2.50(s,3H),2.38~2.28(m,2H),2.02~1.93(m,2H),1.90~1.85(m,2H); MS(ESI)m / z [M+H] + = 456.9.

[0181] Step 4: Referring to the method of Step 8 of Example 1, 20 mg of 2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)-6-methyl-5-(trifluoromethyl)nicotinamide (I-27) was obtained as a white solid from N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide (I-27) using N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)-6-methyl-5-(trifluoromethyl)nicotinamide (I-27) as a starting material. The yield was 18.7%. 1 H NMR(500 MHz,DMSO-d6)δ:10.57(s,1H),9.64(s,1H),7.88(s,1H),7.86~7.81(m,1H),7.74~7.69(m,1H),7.22(t,J=9.6Hz,1H),5.8 0(s,2H),3.72~3.69(m,2H),3.48(t,J=6.0Hz,2H),2.50(s,3H),2.37~2.29(m,2H),2.02~1.94(m,2H),1.90~1.85(m,2H); MS(ESI)m / z [M+H] + = 489.8.

[0182] Example 28: Preparation of 5-cyano-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-28) [ka]

[0183] Step 1: Under an argon atmosphere, 5-iodo-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate methyl (26-a) (500 mg, 1.22 mmol) obtained in Example 26 was dissolved in N,N-dimethylacetamide (10 mL), sodium carbonate (258 mg, 2.44 mmol) and potassium ferrocyanide trihydrate (984 mg, 3.66 mmol) were added, and the reaction was carried out at 100°C. After the reaction was complete, water (40 mL) was added, and the mixture was extracted three times with ethyl acetate. The combined organic layer was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 20:1, v / v) to obtain 300 mg of 5-cyano-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate methyl(28-a) as a colorless liquid. The yield was 79.6%. 1 H NMR(400 MHz, CDCl3)δ:8.08(s,1H),3.87(s,3H),3.80~3.76(m,2H),3.31(t,J=5.6Hz,2H),2.59(s,3H),2.41~2.26(m,2H),2.01~1.91(m,4H); MS(ESI)m / z [M+H] + = 310.2.

[0184] Second step: Referring to the method of the sixth step in Example 1, 360 mg of 5-cyano-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate methyl (28-a) (390 mg, 1.26 mmol) was used as a starting material to obtain 360 mg of 5-cyano-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (28-b) as a white solid. The yield was 96.7%. 1 H NMR(400 MHz,CDCl3)δ:8.27(s,1H),3.86~3.79(m,2H),3.39(t,J=5.8Hz,2H),2.62(s,3H),2.43~2.29(m,2H),2.04~1.94(m,4H); MS(ESI)m / z [M+H] + =296.1.

[0185] Third step: Referring to the method of the seventh step in Example 1, 380 mg of 5-cyano-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (28-c) was obtained as a white solid from 5-cyano-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (28-c) using 5-cyano-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (28-c) as raw materials. The yield was 69.6%. 1 H NMR(400 MHz,DMSO-d6)δ:10.81(s,1H),8.18(dd,J=5.8,2.8Hz,1H),8.13(s,1H),7.98~7.89(m,1H),7.56(t,J=9.0Hz,1H) ,3.75~3.68(m,2H),3.47(t,J=5.8Hz,2H),2.54(s,3H),2.38~2.27(m,2H),2.03~1.95(m,2H),1.93~1.85(m,2H); MS(ESI)m / z [M+H] + = 413.9.

[0186] Step 4: Referring to the method of Step 8 of Example 1, 47 mg of 5-cyano-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-28) was obtained as a white solid from 5-cyano-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (I-28) using 5-cyano-N-(3-(N'-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-28) as a starting material. The yield was 43.5%. 1 H NMR(400 MHz,DMSO-d6)δ:10.56(s,1H),9.65(s,1H),8.07(s,1H),7.83(dd,J=6.6,2.8Hz,1H),7.73~7.65(m,1H),7.26~7.20(m,1H), 5.82(s,2H),3.75~3.68(m,2H),3.48(t,J=6.0Hz,2H),2.53(s,3H),2.34~2.30(m,2H),2.02~1.94(m,2H),1.90~1.83(m,2H); MS(ESI)m / z [M+H] + = 447.2.

[0187] Example 29: Preparation of 2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-29) [ka]

[0188] Step 1: Referring to the method of Step 6 of Example 1, 2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate methyl(1-f) (400 mg, 1.41 mmol) was used as a starting material to obtain 309 mg of 2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (29-a) as a white solid. The yield was 81.3%. 1 H NMR(400 MHz, CDCl3)δ:8.35(d,J=7.9Hz,1H),7.12(d,J=7.9Hz,1H),3.46~3.39(m,2H),3.31(t ,J=5.8Hz,2H),2.56(s,3H),2.51~2.40(m,2H),2.35~2.20(m,2H),2.06~1.99(m,2H); MS(ESI)m / z [M+H] + = 270.9.

[0189] Second step: Referring to the method of the seventh step in Example 1, 160 mg of N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (29-a) (400 mg, 1.48 mmol) and 5-amino-2-fluorobenzonitrile (202 mg, 1.48 mmol) were used as raw materials to obtain 160 mg of N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (29-b) as a white solid. The yield was 27.8%. 1H NMR(400 MHz, CDCl3)δ:10.40(s,1H),8.17~8.10(m,2H),7.78~7.69(m,1H),7.21(t,J=8.8Hz,1H),6.93(d,J=7.8Hz,1H), 3.61~3.54(m,2H),3.37(t,J=5.8Hz,2H),2.50(s,3H),2.47~2.35(m,2H),2.26~2.12(m,2H),1.95~1.89(m,2H); MS(ESI)m / z [M+H] + = 388.9.

[0190] Third step: Referring to the method of the eighth step in Example 1, 27 mg of 2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-29) was obtained as a white solid from N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-29) using N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-29) as a starting material. The yield was 35.5%. 1 H NMR(600 MHz, CDCl3)δ:9.85(s,1H),8.02(d,J=7.8Hz,1H),7.88~7.79(m,2H),7.12(t,J=10.0Hz,1H),6.83(d,J=7.8Hz,1H),5.45 (s,2H),3.62~3.59(m,2H),3.41(t,J=5.8Hz,2H),2.48(s,3H),2.43~2.35(m,2H),2.21~2.07(m,2H),1.97~1.84(m,2H); MS(ESI)m / z [M+H] + = 421.9.

[0191] Example 30: Preparation of 2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)-6-(trifluoromethyl)nicotinamide (I-30) [ka]

[0192] Step 1: Under a nitrogen atmosphere, 2-chloro-6-(trifluoromethyl)nicotinic acid (30-a) (1 g, 4.4 mmol) was dissolved in dichloromethane (10 mL) and at 0°C, a catalytic amount of N,N-dimethylformamide was added, followed by the dropwise addition of oxalic acid chloride (750 μL, 8.9 mmol). The reaction was carried out at room temperature until the acid chloride was completely converted. Subsequently, methanol (1.8 mL, 44.3 mmol) was added, and the reaction was continued until the ester was completely converted. After the compound reaction was complete, the mixture was concentrated, and the pH was adjusted to 8-9 by adding saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with ethyl acetate, the combined organic layer was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 10:1, v / v) to obtain 831 mg of methyl 2-chloro-6-(trifluoromethyl)nicotinate (30-b) as a colorless liquid. The yield was 78.2%. 1 H NMR(400 MHz,CDCl3)δ:8.33(d,J=7.8Hz,1H),7.70(d,J=7.8Hz,1H),4.00(s,3H); MS(ESI)m / z [M+H] + = 240.9.

[0193] Second step: Referring to the method of the fourth step in Example 1, 2-chloro-6-(trifluoromethyl)nicotinate methyl (30-b) (825 mg, 3.4 mmol) and 4,4-difluoroazepane hydrochloride (1-c) (768 mg, 4.5 mmol) were used as raw materials to obtain 1.007 g of 2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)nicotinate methyl (30-c) as a colorless liquid. The yield was 86.4%. 1 H NMR(400 MHz, CDCl3)δ:8.00(d,J=7.8Hz,1H),6.99(d,J=7.8Hz,1H),3.91(s,3H),3 .78~3.71(m,2H),3.34~3.26(m,2H),2.44~2.30(m,2H),2.05~1.90(m,4H); MS(ESI)m / z [M+H] + = 338.9.

[0194] Third step: Referring to the method of the sixth step in Example 1, 2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)nicotinate methyl (30-c) (1 g, 3.0 mmol) was used as a starting material to obtain 867 mg of 2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)nicotinic acid (30-d) as a white solid. The yield was 90.4%. 1 H NMR(600 MHz, CDCl3)δ:8.26(d,J=7.8Hz,1H),7.10(d,J=7.8Hz,1H),3.78~3.73(m,2H),3.40~3.37(m,2H),2.45~2.35(m,2H),2.08~1.96(m,4H); MS(ESI)m / z [M+H] + = 324.9.

[0195] Step 4: Referring to the method of Step 7 of Example 1, 80 mg of N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)nicotinic acid (30-d) (1 g, 3.1 mmol) and 5-amino-2-fluorobenzonitrile (420 mg, 3.1 mmol) were used as raw materials to obtain 80 mg of N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)nicotinamide (30-e) as a white solid. The yield was 5.9%. 1 H NMR(400 MHz,DMSO-d6)δ:10.93(s,1H),8.20(dd,J=5.8,2.8Hz,1H),8.00~7.90(m,2H),7.56(t,J=9.0Hz,1H),7.20(d,J =7.6Hz,1H),3.68~3.61(m,2H),3.46(t,J=5.9Hz,2H),2.38~2.23(m,2H),2.04~1.92(m,2H),1.89~1.83(m,2H); MS(ESI)m / z [M+H] + = 442.8.

[0196] Step 5: Referring to the method of Step 8 of Example 1, 20 mg of 2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)-6-(trifluoromethyl)nicotinamide (I-30) was obtained as a white solid from N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)-6-(trifluoromethyl)nicotinamide (I-30) using N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)-6-(trifluoromethyl)nicotinamide (I-30) as a starting material. The yield was 31.0%. 1 H NMR(500 MHz,Methanol-d4)δ:7.90(d,J=7.6Hz,1H),7.84~7.75(m,2H),7.18(t,J=9.5Hz,1H),7.11(d,J=7.6Hz,1H),3.78~ 3.72(m,2H),3.54(t,J=5.8Hz,2H),2.38~ 2.29(m,2H),2.04~ 1.91(m,4H); MS(ESI)m / z [M+H] + = 476.1.

[0197] Example 31: Preparation of 2-chloro-6-(4,4-difluoroazepan-1-yl)-N-(1,1-dioxo-2,3-dihydrobenzoisothiazole-6-yl)-3-trifluoromethylbenzamide (I-31) [ka]

[0198] Step 1: 2,2,6,6-tetramethylpiperidine (19 g, 135.9 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL), and n-BuLi (2.4 M, 57 mL) was slowly added dropwise under ice bath cooling and nitrogen gas flow. After the addition was complete, the reaction was allowed to proceed for 1 hour under ice bath cooling, and then the reaction solution was cooled to -78°C. 2-chloro-4-fluorotrifluorotoluene (18 g, 91 mmol) was slowly added dropwise, and after the addition was complete, the reaction was allowed to proceed for 3 hours, then excess dry ice was added and the reaction was allowed to proceed for 2 hours. After allowing the temperature to rise naturally to room temperature, saturated ammonium chloride aqueous solution was added to stop the reaction, and the pH was adjusted to approximately 2 with dilute hydrochloric acid. The organic layer was extracted with ethyl acetate and water, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: dichloromethane / methanol = 40:1~20:1, v / v) to obtain 10 g of 2-chloro-6-fluoro-3-trifluoromethylbenzoic acid (31-a). The yield was 47%. 1 H NMR(400 MHz,DMSO-d6)δ 14.60(s,1H),8.03(dd,J=8.8,5.8Hz,1H),7.59(t,J=8.6Hz,1H); MS(ESI)m / z [M+H] + = 240.9.

[0199] Step 2: 2-chloro-6-fluoro-3-trifluoromethylbenzoic acid (31-a) (8.7 g, 36 mmol) was dissolved in anhydrous dichloromethane, and a catalytic amount of DMF was added. The reaction mixture was cooled in an ice bath under a nitrogen stream, and oxalic acid chloride (2 M, 22 mL) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature until the acid chloride was completely formed. The reaction mixture was concentrated, methanol (50 mL) and anhydrous triethylamine (11 g, 108 mmol) were added, and the reaction was allowed to proceed at room temperature until the conversion was complete. The reaction mixture was concentrated to obtain the crude product. This crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 20:1~10:1, v / v) to obtain 6.5 g of methyl 2-chloro-6-fluoro-3-trifluoromethylbenzoate (31-b). The yield was 70%. 1 H NMR(400 MHz,CDCl3)δ 7.77(dd,J=8.8,5.6Hz,1H),7.17(t,J=8.4Hz,1H),4.00(s,3H); MS(ESI)m / z [M+H] + =257.2

[0200] Third step: 2-chloro-6-fluoro-3-trifluoromethylbenzoate methyl (31-b) (0.5 g, 1.94 mmol) and 4,4-difluoroazepane hydrochloride (1-c) (0.49 g, 2.91 mmol) were dissolved in dimethyl sulfoxide, and DIPEA (0.7 g, 5.8 mmol) was added. The reaction mixture was heated to 90°C and allowed to react overnight. The reaction was extracted with ethyl acetate and water, the organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. This crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 10:1, v / v) to obtain 0.2 g of 2-chloro-6-(4,4-difluoroazepane-1-yl)-3-trifluoromethylbenzoate methyl (31-c). The yield was 28%. 1H NMR(400 MHz,CDCl3)δ 7.57(d,J=9.0Hz,1H),6.88(d,J=9.0Hz,1H),3.95(s,3H),3.36(ddd,J=15.1,8.9,4.2Hz,4H),2.29 ~2.09(m,4H),1.91(ddd,J=12.0,6.1,2.5Hz,2H); MS(ESI)m / z [M+H] + =372.0.

[0201] Step 4: Referring to the method of Step 6 of Example 1, 2-chloro-6-(4,4-difluoroazepan-1-yl)-3-trifluoromethylbenzoate methyl (31-c) (690 mg, 1.8 mmol) was used as a starting material to obtain 200 mg of 2-chloro-6-(4,4-difluoroazepan-1-yl)-3-trifluoromethylbenzoic acid (31-d). The yield was 30%. 1 H NMR(400 MHz,DMSO-d6)δ:12.05(s,1H),7.65(d,J=9.0Hz,1H),7.06(d,J=9.0Hz,1H),3.53~3.40 (m,4H),2.23(dd,J=15.2,5.0Hz,2H),2.16~2.06(m,2H),1.86(dd,J=11.8,6.0Hz,2H); MS(ESI)m / z [M+H] + = 355.9.

[0202] Step 5: 2-Chloro-6-(4,4-difluoroazepan-1-yl)-3-trifluoromethylbenzoic acid (31-d) (100 mg, 0.28 mmol) was dissolved in anhydrous DCM (5 mL), and the reaction mixture was cooled in an ice bath. A catalytic amount of DMF was added, and under a nitrogen stream, oxalic acid chloride (2 M, 0.2 mL) was added, and the reaction was carried out at room temperature. After the starting materials were completely converted, the excess oxalic acid chloride was removed by distillation to obtain an acid chloride. This acid chloride was dissolved in dichloromethane, and 6-amino-2,3-dihydrobenzoisothiazole 1,1-dioxide (31-f) (77 mg, 0.42 mmol) was added at 0°C, and anhydrous pyridine (3 mL) was added dropwise under ice bath cooling. After the reaction was complete, ethyl acetate and water were added and liquid-liquid-liquid was separated, the organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: dichloromethane / methanol = 20:1~10:1, v / v) to obtain 54 mg of 2-chloro-6-(4,4-difluoroazepan-1-yl)-N-(1,1-dioxide-2,3-dihydrobenzoisothiazole-6-yl)-3-trifluoromethylbenzamide (I-31). The yield was 37%. 1 H NMR(400MHz,DMSO-d6)δ:11.16(s,1H),8.22(s,1H),7.91(s,1H),7.79(d,J=8.4Hz,1H),7.74(d,J=9.0Hz,1H),7.57 (d,J=8.1Hz,1H),7.15(d,J=9.7Hz,1H),4.38(d,J=4.5Hz,2H),3.45(m,4H),2.18(m,2H),2.02(m,2H),1.79(m,2H); MS(ESI)m / z [M+H] + = 524.0.

[0203] Example 32: Preparation of 2-chloro-6-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-3-(trifluoromethyl)benzamide (I-32) [ka]

[0204] Step 1: Referring to the method of Step 7 of Example 1, 2-chloro-6-(4,4-difluoroazepan-1-yl)-3-trifluoromethylbenzoic acid (31-d) (188 mg, 0.53 mmol) and 5-amino-2-fluorobenzonitrile (83 mg, 0.61 mmol) were used as raw materials to obtain 63 mg of 2-chloro-N-(3-cyano-4-fluorophenyl)-6-(4,4-difluoroazepan-1-yl)-3-(trifluoromethyl)benzamide (32-a). The yield was 25%. 1 H NMR(400 MHz, CDCl3)δ:8.02(dd,J=5.2,2.6Hz,1H),7.80(dd,J=5.8,3.2Hz,1H),7.73(s,1H),7.62(d,J=8 .8Hz,1H),6.97(t,J=8.2Hz,1H),3.43(t,J=5.4Hz,4H),2.30~2.00(m,4H),1.89(d,J=5.4Hz,2H); MS(ESI)m / z [M+H] + = 476.1.

[0205] Second step: Referring to the method of step eight of Example 1, 2-chloro-N-(3-cyano-4-fluorophenyl)-6-(4,4-difluoroazepan-1-yl)-3-(trifluoromethyl)benzamide (32-a) was used as a starting material to obtain 34 mg of 2-chloro-6-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)-3-(trifluoromethyl)benzamide (I-32). The yield was 51%. 1 H NMR(400MHz,DMSO-d6)δ:10.82(s,1H),9.67(s,1H),7.85(dd,J=6.4,2.8Hz,1H),7.69(dd,J=11.8,6.6Hz,2H),7.29~7.18(m,1H) ),7.12(d,J=9.0Hz,1H),5.85(s,2H),3.46(dd,J=15.0,8.4Hz,4H),2.18(s,2H),2.03(s,2H),1.80(d,J=5.8Hz,2H);MS(ESI)m / z [M+H] + = 509.1.

[0206] Example 33: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-4-(trifluoromethyl)benzamide (I-33) [ka]

[0207] Step 1: Referring to the method of Step 1 in Example 31, 10 g of 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (33-a) was obtained using 2-chloro-5-fluorotrifluorotoluene (15 g, 75 mmol) as a starting material. The yield was 55%. 1 H NMR(400 MHz,DMSO)δ:14.35(s,1H),7.88(dd,J=9.0,5.0Hz,1H),7.76(t,J=8.8Hz,1H);MS(ESI)m / z [MH] - = 240.8.

[0208] Second step: Referring to the method of the second step in Example 31, 1.7 g of methyl 5-chloro-2-fluoro-4-(trifluoromethyl)benzoate (33-b) was obtained using 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (33-a) as a starting material. The yield was 32%. 1 H NMR(400 MHz,CDCl3)δ:8.09(d,J=6.0Hz,1H),7.53(d,J=10.0Hz,1H),4.00(s,3H); MS(ESI)m / z [M+H] + = 257.3.

[0209] Third step: 5-chloro-2-fluoro-4-(trifluoromethyl)methyl benzoate (33-b) (1.7g, 6.9 mmol) and 4,4-difluoroazepane hydrochloride (1-c) (1.7g, 10.3 mmol) were dissolved in dimethyl sulfoxide, and DIPEA (2.6g, 20.7 mmol) was added. The reaction system was then heated to 90°C and allowed to react until all the starting materials were consumed. The mixture was extracted with ethyl acetate and water, the organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 20:1~10:1, v / v) to obtain 0.5 g of 5-chloro-2-(4,4-difluoroazepane-1-yl)-4-(trifluoromethyl)methyl benzoate (33-c). The yield was 21%. 1 H NMR(400 MHz,CDCl3)δ 7.70(s,1H),7.28(s,1H),3.94(s,3H),3.43~3.38(m,2H),3.36~3.32(m,2H ),2.37~2.25(m,2H),2.17(m,2H),1.95(dt,J=11.8,6.0Hz,2H);MS(ESI)m / z [M+H] + =372.1.

[0210] Step 4: Referring to the method of Step 6 of Example 1, 0.5 g of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzoate methyl (33-c) (0.5 g, 1.4 mmol) was used as a starting material to obtain 0.5 g of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzoic acid (33-d). The yield was 99%. 1 H NMR(400 MHz,DMSO-d6)δ:13.78(s,1H),7.71(s,1H),7.35(s,1H),3.40(d,J=5.2Hz,2H),3.35~3.33(m,2H),2.38~2.21(m,2H),2.12(m,2H),1.88 ~1.79(m,2H); MS(ESI)m / z [M+H] + = 355.8.

[0211] Step 5: Referring to the method of Step 7 of Example 1, 124 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzoic acid (33-d) (0.2 g, 0.54 mmol) and 5-amino-2-fluorobenzonitrile (74 mg, 0.54 mmol) were used as raw materials to obtain 124 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamide (33-e). The yield was 48%. 1 1H NMR (400 MHz, DMSO-d6) δ: 1 H NMR(400 MHz,CDCl3)δ 11.84(s,1H),8.36(s,1H),8.23~8.10(m,1H),7.74(d,J=4.4Hz,1H),7.59(s,1H),3.38 ~3.29(m,2H),3.24(d,J=4.4Hz,2H),2.48(d,J=5.4Hz,2H),2.40 ~2.24(m,2H),1.97(s,2H). MS(ESI)m / z [M+H] + = 476.2.

[0212] Step 6: Referring to the method of Step 8 of Example 1, 46 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-4-(trifluoromethyl)benzamide (I-33) was obtained using 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamide (I-33) as a starting material. The yield was 35%. 1 H NMR(400 MHz,DMSO-d6)δ:10.66(s,1H),9.6(s,1H),7.87(dd,J=6.2,2.4Hz,1H),7.81~7.69(m,1H),7.66( s,1H),7.33(s,1H),7.26(t,J=9.6Hz,1H),5.87(s,2H),3.39(d,J=8.0Hz,4H),2.24(s,2H),2.12 ~ 2.01(m,2H),1.81(s,2H); MS(ESI)m / z [M+H] + = 509.2.

[0213] Example 34: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(sulfamoylamino)phenyl)-6-methylnicotinamide (I-34) [ka]

[0214] N-(3-amino-4-fluorophenyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (19-b) (139 mg, 0.34 mmol), prepared in the second step of Example 19, was dissolved in anhydrous tetrahydrofuran (20 mL), and triethylamine (0.18 mL, 1.35 mmol) was added, after which the mixture was cooled to around 0°C. Subsequently, chlorosulfonamide (77.8 mg, 0.67 mmol) was added, and the mixture was reacted under reflux until the starting materials were completely gone. The mixture was washed with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: dichloromethane / methanol = 40:1~4:1, v / v) to obtain 45 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(sulfamoylamino)phenyl)-6-methylnicotinamide (I-34). The yield was 27%. 1 H NMR(400MHz,DMSO-d6)δ:10.47(s,1H),9.09(s,1H),7.76(dd,J=7.2,2.4Hz,1H),7.69(s,1H),7.48~7.52(q,1H),7.19(t,J=9.2Hz,1 MS(ESI)m / z [M+H] +=492.1,493.9 (3:1).

[0215] Example 35: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(sulfamoylamino)phenyl)nicotinamide (I-35) [ka]

[0216] 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (1-h) (150 mg, 0.5 mmol) prepared in the sixth step of Example 1 was dissolved in anhydrous toluene (10 mL), thionyl chloride (2.0 mL) was added, and the mixture was reacted under reflux until it was completely converted to an acid chloride. Thionyl chloride and toluene were removed by distillation under reduced pressure to obtain the crude acid chloride. This crude acid chloride product was dissolved in anhydrous dichloromethane (10 mL) and cooled to 0°C. N-(3-aminophenyl)sulfamoylamide (93.0 mg, 0.5 mmol) and pyridine (2 mL) were slowly added, and the mixture was reacted at room temperature until the reaction was complete. The mixture was washed with 1N hydrochloric acid and extracted with dichloromethane. The organic layer was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: dichloromethane / methanol = 40:1~10:1, v / v) to obtain 30 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(sulfamoylamino)phenyl)nicotinamide (I-35) as a solid. The yield was 12.8%. 1H NMR(400 MHz,DMSO-d6)δ:10.39(s,1H),9.51(s,1H),7.66(s,1H),7.46(s,1H),7.29(d,J=7.6Hz,1H),7.20(t,J=8.0Hz,1H),7.03(s ,2H),6.95(d,J=7.6Hz,1H),3.59(s,2H),3.40(t,J=6.4Hz,2H),2.42(s,3H),2.31(brs,2H),1.96(brs,2H),1.81(brs,2H); MS(ESI)m / z [M+H] + =473.7,475.7 (3:1).

[0217] Example 36: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-(trifluoromethyl)nicotinamide (I-36) [ka]

[0218] Step 1: Referring to the method of Step 5 of Example 1, 120 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)nicotinamide (36-a) was obtained using N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)nicotinamide (36-a) as a starting material. The yield was 74%. 1 H NMR(400 MHz,DMSO-d6)δ:10.98(s,1H),8.18(dd,J=5.8,2.6Hz,1H),8.15(s,1H),7.98~7.92(m,1H),7.58(t ,J=9.2Hz,1H),3.65(s,2H),3.45(t,J=5.6Hz,2H),2.31(s,2H),2.00(s,2H),1.87(d,J=5.4Hz,2H); MS(ESI)m / z [M+H] + = 477.2.

[0219] Second step: Referring to the method of step eight in Example 1, 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)nicotinamide (36-a) (120 mg, 0.25 mmol) was used as a starting material to obtain 54 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)-6-(trifluoromethyl)nicotinamide (I-36). The yield was 42%. 1 H NMR(400 MHz,DMSO-d6)δ:10.72(s,1H),9.68(s,1H),8.10(s,1H),7.84(dd,J=6.4,2.8Hz,1H),7.75~7.67(m,1H),7.30~7.20(m,1H) ),5.84(s,2H),3.65(s,2H),3.47(t,J=5.8Hz,2H),2.31(s,2H),2.00(d,J=7.2Hz,2H),1.87(d,J=5.8Hz,2H);MS(ESI)m / z [M+H] + = 510.2.

[0220] Example 37: Preparation of 5-chloro-N-(3-(N′-cyanocarbamimidoyl)-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-trifluoromethylnicotinamide (I-37) [ka]

[0221] Referring to the method of Example 3, 15 mg of 5-chloro-N-(3-(N′-cyanocarbamimioyl)-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)nicotinamide (I-37) was obtained using 5-chloro-N-(3-(N′-cyanocarbamimioyl)-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-trifluoromethylnicotinamide (I-37) as a starting material, with reference to the method of Example 3. The yield was 10.2%. 1H NMR(400 MHz,DMSO-d6)δ:10.86(brs,1H),9.04(brs,1H),8.85(brs,1H),8.11(s,1H),7.83~7.96(brs,2H),7.42(s ,1H),3.65(brs,2H),3.46(brs,2H),2.28~2.34(t,2H),1.96~2.04(m,2H),1.86~1.90(m,2H);MS(ESI)m / z [M+H] + = 519.1, 521.1 (3:1).

[0222] Example 38: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-(difluoromethyl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)nicotinamide (I-38) [ka]

[0223] Step 1: Referring to the method of Step 4 of Example 1, 2-chloro-6-difluoromethylnicotinate methyl (368 mg, 16.6 mmol) and 1-c (428.0 mg, 24.9 mmol) were used as raw materials to obtain 320 mg of 2-(4,4-difluoroazepan-1-yl)-6-difluoromethylnicotinate methyl (38-a). The yield was 60%. 1 H NMR(400 MHz,DMSO-d6)δ:8.01(d,J=7.6Hz,1H),6.99(d,J=7.6Hz,1H),6.79(t,1H,CHF2),3.83 (s,3H),3.62(sq,2H),3.28(t,J=6.0Hz,2H),2.27~2.37(tq,2H),1.87~2.01(dq,4H); MS(ESI)m / z [M+H] + = 321.1.

[0224] Step 2: Referring to the method of Step 6 of Example 1, 2-(4,4-difluorocycloheptan-1-yl)-6-difluoromethylnicotinate methyl (38-a) (320 mg, 1.0 mmol) was used as a starting material to obtain 276 mg of 2-(4,4-difluoroazepan-1-yl)-6-(difluoromethyl)nicotinic acid (38-b). The yield was 90%. It was used directly in the next reaction. MS(ESI)m / z [M+H] + = 307.1.

[0225] Third step: Referring to the method of the seventh step in Example 1, 160 mg of N-(3-cyano-4-fluorophenyl)-2-(4,4-difluorocycloheptan-1-yl)-6-difluoromethylnicotinamide (38-c) was obtained using 2-(4,4-difluoroazepan-1-yl)-6-difluoromethylnicotinamide (38-c) as a starting material, with reference to the method of the seventh step in Example 1. The yield was 96.3%. 1 H NMR(400 MHz,DMSO-d6)δ:10.86(s,1H),8.19~8.21(q,J=2.8Hz,1H),7.91~7.97(q,1H),7.90(d,J=7.6Hz,1H),7.56(t,J=9.2Hz,1H), 7.03(d,J=7.6Hz,1H),6.89(t,1H,CHF2),3.64(sq,2H),4.33(t,J=6.0Hz,2H),2.33(t,2H),1.92~2.03(m,2H),1.85(m,2H); MS(ESI)m / z [M+H] + = 425.1.

[0226] Step 4: Referring to the method of Step 5 of Example 1, 100 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-difluoromethylnicotinamide (38-d) was obtained using N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-difluoromethylnicotinamide (38-d) as a starting material. The yield was 92.5%. 1H NMR(400 MHz,DMSO-d6)δ:10.92(s,1H),8.17~8.19(q,1H),8.03(s,1H),7.93~7.97(m,1H),7.58(t,J=9.2Hz,1H),7.06(t,1H, CHF2),3.64~3.66(sq,2H),3.44(t,J=6.0Hz,2H),2.28~2.37(t,J=6.0Hz,2H),1.98~2.02(q,2H),1.85~1.88(q,2H); MS(ESI)m / z [M+H] + =459.1,461.0 (3:1).

[0227] Step 5: 70.0 mg, 0.15 mmol of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-difluoromethylnicotinamide (38-d) and 10 eq of 40% aqueous hydroxylamine were added to dimethyl sulfoxide and reacted overnight at room temperature. After the compound reaction was complete, water was added to the reaction mixture, extracted with ethyl acetate, and concentrated to obtain the crude product. This crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: dichloromethane / methanol = 40:1, v / v) to obtain 70 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-difluoromethyl-N-(4-fluoro-3-(N′-hydroxycarbamimiol)phenyl)nicotinamide (I-38). The yield was 93.3%. 1 H NMR(400 MHz,DMSO-d6)δ:10.65(s,1H),9.65(s,1H),7.96(s,1H),7.82~7.85(q,1H),7.68~7.72(m,1H),7.24(t,J=9.6Hz,1H),7.05 (t,1H,CHF2),5.81(s,2H),3.65(sq,2H),3.46(t,2H),2.30~2.33(m,2H),1.98~2.03(m,2H),1.84~1.87(m,2H);MS(ESI)m / z [M+H] + =492.1,494.1 (3:1).

[0228] Example 39: Preparation of N-(3-carbamimidoyl-4-fluorophenyl)-5-chloro-2-(4,4-difluorocycloheptan-1-yl)-6-difluoromethylnicotinamide (I-39) [ka]

[0229] Referring to the method of Example 12, 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluorocycloheptan-1-yl)-6-difluoromethylnicotinamide (38-d) (560 mg, 1.22 mmol) was used as a starting material to obtain 260.0 mg of N-(3-carbamimidoyl-4-fluorophenyl)-5-chloro-2-(4,4-difluorocycloheptan-1-yl)-6-difluoromethylnicotinamide (I-39). The yield was 44.7%. 1 H NMR(400 MHz,DMSO-d6)δ:10.94(s,1H),9.38(brs,3H),8.01~03(sq,1H),7.92(s,1H),7.88~7.92(sq,1H),7.52 (t,J=9.6Hz,1H),7.07(t,1H,CHF2),3.66(q,2H),3.46(t,2H),2.33(t,2H),2.02(m,2H),1.87(m,2H); MS(ESI)m / z [M+H] + =475.8,477.8 (3:1).

[0230] Example 40: Preparation and separation of 5-chloro-2-(4,4-difluoro-3-methylpiperidine-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-(trifluoromethyl)nicotinamide (I-40) and its optical isomers (I-40-P1) and (I-40-P2). [ka]

[0231] Step 1: 2-chloro-6-trifluoromethylnicotinic acid (30-a) (450.0 mg, 2.0 mmol), racemic 4,4-difluoro-3-methylpiperidine hydrochloride (446.0 mg, 2.6 mmol), and potassium carbonate (830.0 mg, 6.0 mmol) were added to N,N-dimethylformamide (20.0 mL) and reacted at 90°C until the starting materials disappeared. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate, dried, and concentrated to obtain the crude product 2-(4,4-difluoro-3-methylpiperidine-1-yl)-6-(trifluoromethyl)nicotinic acid (40-a) 600.0 mg. This was used directly in the next reaction. MS(ESI)m / z [M+H] + = 325.1.

[0232] Second step: Referring to the method of the seventh step in Example 1, 2-(4,4-difluoro-3-methylpiperidine-1-yl)-6-(trifluoromethyl)nicotinic acid (40-a) (500.0 mg, 0.93 mmol) was used as a starting material to obtain 220.0 mg of N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoro-3-methylpiperidine-1-yl)-6-methylnicotinamide (40-b). The yield was 21.9%. 1 H NMR(400 MHz,DMSO-d6)δ:10.74(brs,1H),9.67(brs,1H),8.14(s,1H),7.85~7.87(sm,1H),7.68~7.72(sm,1H),7.27(t,J=10.0Hz,1H),5.83(brs,2H),3. 90(d,J=13.6Hz,1H),3.75(d,J=13.6Hz,1H),3.22(t,J=10.8Hz,1H),3.0 2(t,J=10.8Hz,1H),2.12~2.18(m,2H),1.98~2.01(m,1H),0.88(sd,3H); MS(ESI)m / z [M+H] + = 443.2.

[0233] Third step: Referring to the method of the fifth step in Example 1, 120.0 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoro-3-methylpiperidine-1-yl)-6-methylnicotinamide (40-b) (200.0 mg, 4.5 mmol) was used as a starting material to obtain 120.0 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoro-3-methylpiperidine-1-yl)-6-(trifluoromethyl)nicotinamide (40-c). The yield was 55.7%. 1 H NMR(400 MHz,DMSO-d6)δ:11.02(s,1H),8.20(m,1H),8.19(s,1H),7.93~7.97(m,1H),7.59(t,J=9.2Hz,1H),3.82~3.87(d,J=14.0Hz,1H),3.75(d,J=1 4.0Hz,1H),3.22(td,J=13.6,3.6Hz,1H),3.03(dd,J=13.6,3.6Hz,1H),2.11~2.18(m,2H),1.85~2.02(m,2H),0.90(s,1.5H),0.89(s,1.5H); MS(ESI)m / z [M+H] + =477.2,479.1 (3:1).

[0234] Step 4: Referring to the method of Step 5 in Example 38, 100.0 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoro-3-methylpiperidine-1-yl)-6-(trifluoromethyl)nicotinamide (40-c) (100.0 mg, 0.21 mmol) was used as a starting material to obtain 100.0 mg of 5-chloro-2-(4,4-difluoro-3-methylpiperidine-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)-6-(trifluoromethyl)nicotinamide (I-40). The yield was 92%. 1H NMR(400 MHz,DMSO-d6)δ:10.74(brs,1H),9.67(brs,1H),8.14(s,1H),7.85~7.87(sm,1H),7.68~7.72(sm,1H),7.27(t,J=10.0Hz,1H),5.83(brs,2H),3. 90(d,J=13.6Hz,1H),3.75(d,J=13.6Hz,1H),3.22(t,J=10.8Hz,1H),3.0 2(t,J=10.8Hz,1H),2.12~2.18(m,2H),1.98~2.01(m,1H),0.88(sd,3H); MS(ESI)m / z [M+H] + = 510.2, 512.1 (3:1).

[0235] Step 5: Optical resolution of 5-chloro-2-(4,4-difluoro-3-methylpiperidine-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-(trifluoromethyl)nicotinamide (I-40) I-40 has the following optical isomers: [ka]

[0236] Manufacturing conditions: [Equipment: Berger SFC Multigram II (Mettler-Toledo International Inc.); Chromatography column: Superchiral R-OJ (Chiralway Biotech Co.,ltd.), 2.1 cm ID * 25 cm Length, 5 μm; Column temperature: 40 °C; Mobile phase: CO2 / EtOH / DEA = 85 / 15 / 0.05 (v / v / v); Detection wavelength: 214 nm; Flow rate: 30 ml / min].

[0237] Analytical conditions: [Instrument: Berger analytical SFC (Mettler-Toledo International Inc.); Chromatography column: Superchiral R-OJ (Chiralway Biotech Co.,ltd.), 0.46 cm ID * 15 cm Length, 5 μm; Column temperature: 40 °C; Mobile phase: CO2 / EtOH / DEA = 85 / 15 / 0.05 (v / v / v); Detection wavelength: 214 nm; Flow rate: 3.0 ml / min].

[0238] Specific rotation measurement conditions: [equipment: SGW-1 (Shanghai INESA Physico-Optical Instrument Co., Ltd.); temperature: 20 °C; wavelength: 589.4 nm; solvent: methanol].

[0239] Compound I-40 was separated using the chiral separation column described above to obtain I-40-P1 (retention time 1.755 min, ee value 98%) and I-40-P2 (retention time 2.042 min, ee value 98%).

[0240] Example 41: Preparation and separation of 5-chloro-2-(4,4-difluoro-3-methylpiperidine-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-(methyl)nicotinamide (I-41) and its optical isomers (I-41-P1) and (I-41-P2). [ka]

[0241] Step 1: Referring to the method of Step 4 of Example 1, 300.0 mg of 2-(4,4-difluoro-3-methylpiperidine-1-yl)-6-methylnicotinate methyl (41-a) was obtained using 1-e (441.0 mg, 2.0 mmol) and racemic 4,4-difluoro-3-methylpiperidine hydrochloride (375.7 mg, 2.2 mmol) as starting materials. The yield was 35%. 1H NMR(400 MHz,DMSO-d6)δ:7.89(d,J=7.6Hz,1H),6.75(d,J=7.6Hz,1H),3.80(s,3H),3. 62~3.72(m,2H),3.08(t,J=11.2Hz,1H),2.87(t,J=11.2Hz,1H),2.37(s,3H); MS(ESI)m / z [M+H] + = 285.2.

[0242] Step 2: Referring to the method of Step 6 of Example 1, 2-(4,4-difluoro-3-methylpiperidine-1-yl)-6-methylnicotinate methyl (41-a) (280.0 mg, 1.0 mmol) was used as a starting material to obtain 250.0 mg of 2-(4,4-difluoro-3-methylpiperidine-1-yl)-6-methylnicotinate (41-b). The yield was 92.5%. MS(ESI)m / z [M+H] + = 271.2.

[0243] Third step: Referring to the method of the seventh step in Example 1, 2-(4,4-difluoro-3-methylpiperidine-1-yl)-6-methylnicotinic acid (41-b) (250.0 mg, 0.93 mmol) and 5-amino-2-fluorobenzonitrile (150 mg, 1.1 mmol) were used as raw materials to obtain 150.0 mg of N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoro-3-methylpiperidine-1-yl)-6-methylnicotinamide (41-c). The yield was 20.8%. 1 H NMR(400 MHz,DMSO-d6)δ:10.70(s,1H),8.27(s,1H),7.99(s,1H),7.74(d,J=7.6Hz,1H),7.56(t,J=8.8Hz,1H),6.86(d,J=7.6Hz,1H),3.65~3.74( m,2H),3.10(t,J=10.4Hz,1H),2.87(t,J=10.4Hz,1H),2.41(s,3H),2.09~2.18(m,2H),1.88~2.01(m,2H),0.91(s,1.5H),0.90(s,1.5H); MS(ESI)m / z [M+H] += 389.2.

[0244] Step 4: N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoro-3-methylpiperidine-1-yl)-6-methylnicotinamide (41-c) (140.0 mg, 3.6 mmol) and N-chlorosuccinimide (62.3 mg, 4.7 mmol) were reacted with acetonitrile to obtain 150.0 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoro-3-methylpiperidine-1-yl)-6-methylnicotinamide (41-d). The yield was 98.4%. 1 H NMR(400 MHz,DMSO-d6)δ:10.78(brs,1H),8.21(sq,J=6.0,2.8Hz,1H),7.96(sm,J=6. 0,2.8Hz,1H),7.85(s,1H),7.57(t,J=9.2Hz,1H),3.65~4.75(m,2H),3.09~3 .16(td,J=11.6,2.4Hz,1H),2.89(t,J=10.8Hz,1H),2.47(s,3H),2.05~2.15 (m,2H),1.95~2.02(m,1H),1.84~1.91(m,1H),0.91(s,1.5H),0.89(s,1.5H); MS(ESI)m / z [M+H] + =423.2,425.2 (3:1).

[0245] Fifth step: Referring to the method of the fifth step in Example 38, 120.0 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoro-3-methylpiperidine-1-yl)-6-methylnicotinamide (I-41) was obtained using 5-chloro-2-(4,4-difluoro-3-methylpiperidine-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)-6-methylnicotinamide (I-41) as a starting material. The yield was 86%. 1H NMR(400 MHz,DMSO-d6)δ:10.54(brs,1H),9.66(s,1H),7.88(dd,J=6.4,2.8Hz,1H),7.81(s,1H),7.69~7.73(m,1H),7.25(t,J=9.6Hz,1H),5.82 (brs,2H),3.77(d,J=13.6Hz,1H),3.68(dd,J=13.6Hz,1H),3.12(t,J=10.0Hz,1H),2.89(dd,J=10.0Hz,1H),2.48(s,3H),2.07~2.20(m ,2H),1.94~2.03(m,1H),0.90(sd,3H); MS(ESI)m / z [M+H] + =456.2,438.2 (3:1).

[0246] Step 6: Optical resolution of 5-chloro-2-(4,4-difluoro-3-methylpiperidine-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-(methyl)nicotinamide (I-41) I-41 has the following optical isomers: [ka]

[0247] Manufacturing conditions: [Equipment: Berger SFC Multigram II (Mettler-Toledo International Inc.); Chromatography column: Superchiral R-OJ (Chiralway Biotech Co.,ltd.), 2.1 cm ID * 25 cm Length, 5 μm; Column temperature: 40 °C; Mobile phase: CO2 / EtOH / DEA = 80 / 20 / 0.05 (v / v / v); Detection wavelength: 214 nm; Flow rate: 30 ml / min].

[0248] Analytical conditions: [Instrument: Berger analytical SFC (Mettler-Toledo International Inc.); Chromatography column: Superchiral R-OJ (Chiralway Biotech Co.,ltd.), 0.46 cm ID * 15 cm Length, 5 μm; Column temperature: 40 °C; Mobile phase: CO2 / EtOH / DEA = 80 / 20 / 0.05 (v / v / v); Detection wavelength: 214 nm; Flow rate: 3.0 ml / min].

[0249] Specific rotation measurement conditions: [Apparatus: SGW-1 (Shanghai INESA Physico-Optical Instrument Co., Ltd.; Temperature: 20 °C; Wavelength: 589.4 nm; Solvent: Methanol].

[0250] As a result of separating compound I-41 using the chiral separation column described above, I-41-P1 (retention time 1.650 min, ee value 98%) and I-41-P2 (retention time 1.911 min, ee value 98%) were obtained.

[0251] Example 42: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-triduteromethylnicotinamide (I-42) [ka]

[0252] Step 1: Under an N2 atmosphere, methyl 6-bromo-2-chloronicotinate (1.0 g, 5.0 mmol) and 1,3-bis(diphenylphosphin)propanedichloride nickel (Ni(dppp)Cl2) (100 mg, 0.16 mmol) were cooled to around 0°C and then slowly added dropwise with a stirring of triduteromethylmagnesium iodide (CD3MgI) solution (5.2 mL, 1.0 mol / L). After the addition was complete, the mixture was allowed to rise naturally to room temperature and reacted overnight. Saturated brine was slowly added to the reaction mixture, and the organic phase was obtained by extraction with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / dichloromethane = 1:1, v / v) to obtain 330.0 mg of methyl 6-triduteromethyl-2-chloronicotinate (42-a). The yield was 43.8%. 1 H NMR(400 MHz,DMSO-d6)δ:8.15(d,J=7.6Hz,1H),7.42(d,J=7.6Hz,1H),2.86(s,3H); MS(ESI)m / z [M+H] + =189.1,191.1 (3:1).

[0253] Second step: Referring to the method of the fourth step in Example 1, 200.0 mg of 2-(4,4-difluoroazepan-1-yl)-6-(triduteromethyl)nicotinate methyl (42-b) was obtained using 6-triduteromethyl-2-chloronicotinate methyl (42-a) (250 mg, 1.35 mmol) as a starting material. The yield was 43.5%.

[0254] Third step: Referring to the method of the fifth step in Example 1, 300 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-(triduteromethyl)nicotinate methyl (42-b) (450.0 mg, 1.57 mmol) was obtained using 2-(4,4-difluoroazepan-1-yl)-6-(triduteromethyl)nicotinate methyl (42-c) as a starting material. The yield was 59.6%.

[0255] Step 4: Referring to the method of Step 6 of Example 1, 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-(triduteromethyl)nicotinate methyl (42-c) (280.0 mg, 0.87 mmol) was used as a starting material to obtain 268.0 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-(triduteromethyl)nicotinic acid (42-d). The yield was 100%. It was used directly in the next reaction.

[0256] Step 5: Referring to the method of Step 7 of Example 1, 191.0 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-(triduteromethyl)nicotinic acid (42-d) (268.0 mg, 0.87 mmol) and 5-amino-2-fluorobenzonitrile (142.0 mg, 1.04 mmol) were used as raw materials to obtain 191.0 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-(triduteromethyl)nicotinamide (42-e). The yield was 51.5%. 1 H NMR(400 MHz,DMSO-d6)δ:10.76(brs,1H),8.17(dd,J=5.6,2.8Hz,1H),7.84(td,J=7.6,1.2Hz,1H),7.78(s,1H) ),7.54(t,J=7.6Hz,1H),3.61(sq,2H),3.38(t,J=5.6Hz,2H),2.24~2.36(tm,2H),1.91~2.01(m,2H); MS(ESI)m / z [M+H] + = 426.2.

[0257] Step 6: Referring to the method of Step 5 in Example 38, 120.0 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)-6-(triduteromethyl)nicotinamide (I-42) was obtained using 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)-6-(triduteromethyl)nicotinamide (I-42) as a starting material. The yield was 76.9%. 1H NMR(400 MHz,DMSO-d6)δ:10.50(brs,1H),9.64(brs,1H),7.84(dd,J=6.4,2.4Hz,1H),7.72(s,1H),7.70(dd, 1H),7.22(t,J=9.6Hz,1H),5.80(brs,2H),3.61(sq,2H),3.41(t,J=5.6Hz,2H),2.26~2.35(tm,2H); MS(ESI)m / z [M+H] + = 459.2.

[0258] Example 43: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-(dimethylamino)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)nicotinamide (I-43) [ka]

[0259] Step 1: 2,6-difluoronicotinic acid (43-a) (1.0 g, 6.29 mmol) and 4,4-difluoroazepane hydrochloride (1-c) (1.29 g, 7.5 mmol) were dissolved in N,N-dimethylformamide, and potassium carbonate (2.61 g, 18.9 mmol) was added. The reaction mixture was heated to 100°C and allowed to react overnight. After the reaction was complete, the mixture was diluted with 10 mL of water, and 6N hydrochloric acid was added to adjust the pH to 2-3, causing a solid to precipitate. The mixture was filtered to obtain 1.2 g of 2-(4,4-difluoroazepane)-6-fluoronicotinic acid (43-b). The yield was 70%. 1 H NMR(400MHz,DMSO-d6)δ:12.86(s,1H),8.08~7.99(m,1H),6.37(m,1H),3.56(m,2H),3.33~3.28(m,2H),2.29(m,2H),1.98(m,2H),1.88(m,2H); MS(ESI)m / z [MH] - = 273.1.

[0260] Step 2: 2-(4,4-difluoroazepane)-6-fluoronicotinic acid (43-b) (500 mg, 1.82 mmol) was dissolved in dichloromethane (20 mL), and a catalytic amount of DMF was added. The reaction mixture was cooled in an ice bath, and a 2 M solution of oxalic acid chloride in dichloromethane (1.82 mL, 3.64 mmol) was slowly added dropwise, and the mixture was reacted at room temperature for 2 hours. After concentration under reduced pressure, 5-amino-2-fluorobenzonitrile (298 mg, 2.18 mmol) was added under ice bath cooling, followed by the slow addition of anhydrous pyridine (6 mL), and the mixture was reacted at room temperature for 1 hour. After the reaction was complete, the reaction was stopped with ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bisulfite aqueous solution and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 370 mg of N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepane)-6-fluoronicotinamide (43-c) as a white solid. The yield was 52%. 1 H NMR(400MHz,DMSO-d6)δ:10.75(s,1H),8.21~8.16(m,1H),7.92(q,J=8.2Hz,2H),7.58~7.51(m,1H),6.47~6.42( m,1H),3.58(d,J=6.0Hz,2H),3.40(t,J=5.8Hz,2H),2.30(s,2H),1.95(d,J=14.0Hz,2H),1.85(d,J=6.4Hz,2H); MS(ESI)m / z [M+H] + =393.1.

[0261] Third step: N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepane)-6-fluoronicotinamide (43-c) (150 mg, 0.52 mmol) and N-chlorosuccinimide (17.2 mg, 0.52 mmol) were dissolved in N,N-dimethylacetamide (3 mL) and reacted at 100°C for 1 hour. After the compound reaction was complete, water (10 mL) was added and the mixture was extracted three times with ethyl acetate. The combined organic layer was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 20:1, v / v) to obtain 120 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepane)-6-fluoronicotinamide (43-d) as a pale yellow solid. The yield was 74%. 1 H NMR(400MHz,DMSO-d6)δ:10.82(s,1H),8.17(dd,J=5.8,2.6Hz,1H),8.11(d,J=9.2Hz,1H),7.97~ MS(ESI)m / z [M+H] + = 427.1.

[0262] Step 4: 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepane)-6-fluoronicotinamide (43-d) (27 mg, 0.063 mmol), potassium carbonate (44 mg, 0.315 mmol), and dimethylamine hydrochloride (16 mg, 0.19 mmol) were placed in a microwave reaction tube and reacted at 100°C under microwave irradiation for 1 hour. After confirming completion of the reaction by TLC, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1, v / v) to obtain 9 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepane)-6-(dimethylamino)nicotinamide (43-e) as a white solid. The yield was 31%. 1 H NMR(400 MHz,DMSO-d6)δ:10.53(s,1H),8.19~8.14(m,1H),7.92(m,1H),7.67(s,1H),7.52(t,J=9.2 Hz,1H),3.59(m,2H),3.37(m,2H),3.00(s,6H),2.3(s,2H),2.01~1.92(m,2H),1.83(m,2H); MS(ESI)m / z [M+H] + = 452.1.

[0263] Step 5: Referring to the experimental procedure for Step 5 of Example 38, 3 mg of 5-chloro-2-(4,4-difluoroazepane)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-(dimethylamino)nicotinamide (I-43) was obtained as a white solid from 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepane)-6-(dimethylamino)nicotinamide (I-43) (9 mg, 0.02 mmol) and an aqueous solution of hydroxylamine (50% wt, 15 μL, 0.2 mmol). The yield was 31%. 1H NMR(400 MHz, CDCl3)δ:9.62(s,1H),8.04(s,1H),7.86(s,1H),7.73(dd,J=6.3,2.8Hz,1H),7.12(dd,J=11.0,9.0Hz,1H),5.30(s,1H), 5.16(s,2H),3.58~3.51(m,2H),3.39(t,J=5.7Hz,2H),3.13(s,6H),2.44~2.33(m,2H),2.22~2.11(m,2H),1.94~1.89(m,2H); MS(ESI)m / z [M+H] + = 485.2.

[0264] Example 44: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-(fluoromethyl)nicotinamide (I-44) [ka]

[0265] Step 1: 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-hydroxymethylnicotinate methyl (43-c) (268.0 mg, 0.8 mmol) was dissolved in dichloromethane (10.0 mL) and cooled to 0°C. Diethylaminotrifluoride sulfur (DAST) (155.0 mg, 0.96 mmol) was slowly added dropwise, and the mixture was then allowed to rise naturally to room temperature to allow the reaction to proceed. After the reaction of 43-c was complete, the reaction mixture was poured into ice water and extracted three times with dichloromethane. The combined organic layers were washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 10:1~4:1, v / v) to obtain 200.0 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-(fluoromethyl)nicotinate methyl (44-a). The yield was 74.0%. 1H NMR(400 MHz,DMSO-d6)δ:7.96(s,1H),5.49(s,1H),5.37(s,1H),3.82(s,3H),3.62(sm,J=7.2Hz ,2H),3.24(t,J=5.2Hz,2H),2.72~2.36(td,2H),1.95~1.99(m,2H),1.84~1.92(m,2H); MS(ESI)m / z [M+H] + =337.2,339.2 (3:1).

[0266] Step 2: Referring to the method of Step 6 of Example 1, 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-(fluoromethyl)nicotinate methyl (44-a) (200.0 mg, 0.6 mmol) was used as a starting material to obtain 192 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-fluoromethylnicotinic acid (44-b). The yield was 100%. This was used directly in the next reaction.

[0267] Third step: Referring to the method of the seventh step in Example 1, 140.0 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-(fluoromethyl)nicotinamide (44-c) was obtained using 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-(fluoromethyl)nicotinamide (44-c) as a starting material. The yield was 53.4%. 1 H NMR(400 MHz,DMSO-d6)δ:10.87(s,1H),8.17~8.19(sq,J=8.0Hz,1H),7.93~7.95(m,1H),7.92(s,1H),7.56(t,J=9.2Hz,1H),5.50( s,1H),5.38(s,1H),3.62~3.64(sm,2H),3.417(d,J=6.0Hz,2H),2.26~2.37(tq,2H),1.94~2.03(m,2H),1.81~188(m,2H); MS(ESI)m / z [M+H] + =441.2,443.2 (3:1).

[0268] Step 4: Referring to the method of Step 5 in Example 38, 66.0 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)-6-(fluoromethyl)nicotinamide (I-44) was obtained using 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)-6-(fluoromethyl)nicotinamide (I-44) as a starting material. The yield was 61.4%. 1 H NMR(400 MHz,DMSO-d6)δ:10.62(brs,1H),9.68(brs,1H),7.87(s,1H),7.85(s,1H),7.71(s,1H),7.24(s,1H),5.86(br s,2H),5.50(s,1H),5.38(s,1H),3.64(s,2H),3.44(s,2H),2.30(s,2H),1.97(s,2H),1.85(s,2H),MS(ESI)m / z [M+H] + = 474.2.

[0269] Example 45: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-ethyl-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)nicotinamide (I-45) [ka]

[0270] Step 1: 2,6-Dichloronicotinic acid (45-a) (1.0 g, 4.85 mmol) and 4,4-Difluoroazepane hydrochloride (1-c) (1.0 g, 5.82 mmol) were dissolved in N,N-dimethylformamide (20 mL), potassium carbonate (2.0 g, 14.56 mmol) was added, and the mixture was reacted overnight at room temperature. After the reaction was complete, the mixture was diluted with water (10 mL) and the pH was adjusted to 2-3 with 6N hydrochloric acid. The mixture was extracted three times with ethyl acetate, the combined organic layer was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 20:1~10:1, v / v) to obtain 440.0 mg of 2-(4,4-Difluoroazepane)-6-chloronicotinic acid (45-b). The yield was 29.7%. MS(ESI)m / z [M+H] + =305.2,307.2(3:1).

[0271] Step 2: Under an N2 atmosphere at room temperature, 2-(4,4-difluoroazepane)-6-chloronicotinic acid (45-b) (500.0 mg, 1.6 mmol) and 1,3-bis(diphenylphosphino)propanedichloridenickel (Ni(dppp)Cl2) (28.4 mg, 0.05 mmol) were dissolved in anhydrous THF (30 mL). Ethyl magnesium bromide solution (1.6 mL, 2.0 mol / L) was slowly added dropwise with stirring. After the addition was complete, the mixture was allowed to rise naturally to room temperature and reacted overnight. The starting materials were not completely consumed. Saturated brine was slowly added to the reaction mixture, and the organic phase was obtained by extraction with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 20:1~10:1, v / v) to obtain 140.0 mg of 2-(4,4-difluoroazepan-1-yl)-6-ethylnicotinate methyl(45-c). The conversion rate was 60%, and the conversion yield was 47.8%. 1H NMR(400 MHz, CDCl3)δ:7.81(d,J=8.0Hz,1H),6.51(d,J=8.0Hz,1H),3.85(s,3H),3.74(st,J=8.8Hz,2H),3.29(t,J=5.6Hz,2H),2 .67(q,J=7.6Hz,2H),2.40(tt,J=9.2,4.4Hz,2H),1.98~2.01(q,2H),1.93~1.96(d,J=8.8Hz,2H),1.25(t,J=7.6Hz,3H); MS(ESI)m / z [M+H] + = 299.2.

[0272] Step 3: 2-(4,4-difluoroazepan-1-yl)-6-ethylnicotinate methyl (45-c) (140 mg, 0.47 mmol) and N-chlorosuccinimide (81.4 mg, 0.61 mmol) were dissolved in acetonitrile (3 mL) and reacted under reflux. After the reaction was complete, water (10 mL) was added and the mixture was extracted three times with ethyl acetate. The combined organic layer was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 30:1, v / v) to obtain 80.0 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-ethylnicotinate methyl (45-d) as an oily substance. The yield was 51.2%. 1 H NMR(600MHz,CDCl3)δ:7.84(s,1H),3.86(s,3H),3.72~3.74(q,2H),3.26(t,J=6.0Hz,2H) ,2.82(q,J=7.8Hz,2H),2.33~2.40(tq,2H),1.95~1.98(q,2H),1.92~1.94(q,2H),1.25(t, J=7.8Hz,3H); MS(ESI)m / z [M+H] + =333.2,335.2 (3:1).

[0273] Step 4: Referring to the method of Step 6 of Example 1, 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-ethylnicotinate methyl (45-d) (57.0 mg, 0.17 mmol) was used as a starting material to obtain 54 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-ethylnicotinic acid (45-e). The yield was 100%. It was used directly in the next reaction. MS(ESI)m / z [M+H] + =319.2,321.2 (3:1).

[0274] Step 5: Referring to the method of Step 7 of Example 1, 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-ethylnicotinic acid (45-e) (54.0 mg, 0.17 mmol) and 5-amino-2-fluorobenzonitrile (28.0 mg, 0.20 mmol) were used as raw materials to obtain 42.0 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-ethylnicotinamide (45-f). The yield was 56%. 1 H NMR(400 MHz,DMSO-d6)δ:10.76(s,1H),8.18(dd,J=5.6,2.4Hz,1H),7.92~7.96(m,1H),7.78(s,1H),7.54(t,J=9.2Hz,1H),3.62~3.64(brs ,2H),3.40(t,J=5.6Hz,2H),2.78(q,J=7.6Hz,2H),2.27~2.37(tq,2H),1.93~2.01(q,2H),1.85~1.91(q,2H),1.22(t,J=7.6Hz,3H ); MS(ESI)m / z [M+H] + =426.2,428.2 (3:1).

[0275] Step 6: Referring to the method of Step 5 in Example 38, 9.0 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)-6-ethylnicotinamide (I-45) was obtained using 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-ethylnicotinamide (I-45) as a starting material. The yield was 21%. 1 H NMR(400 MHz,DMSO-d6)δ:10.50(s,1H),9.64(s,1H),7.83(dd,J=9.2,2.4Hz,1H),7.71(s,1H),7.70(qt,J=8.8,2.4Hz,1H),7.20(dd,J=9.2,8.8Hz,1H),5 .80(brs,2H),3.62~3.64(sm,2H),3.42(t,J=6.0Hz,2H),2.77(q,J=7.6H z,2H),2.27~2.36(m,2H),1.95~2.01(m,2H),1.82~1.87(m,2H),1.22(t, J=7.6Hz,3H); MS(ESI)m / z [M+H] + =470.2,472.2 (3:1).

[0276] Example 46: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamioyl)phenyl)-6-(pyrrolidine-1-yl)nicotinamide (I-46) [ka]

[0277] Step 1: 5-Chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-fluoronicotinamide (43-c) (100 mg, 0.14 mmol), potassium carbonate (32 mg, 0.14 mmol), and pyrrolidine (20 μL, 0.14 mmol) were placed in a sealed tube and reacted at 50°C. After confirming completion of the reaction by TLC, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 10:1, v / v) to obtain 77 mg of 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepane)-6-(pyrrolidine-1-yl)nicotinamide (46-a) as a yellow solid. The yield was 55%. 1 H NMR(400 MHz,DMSO-d6)δ:10.45(s,1H),8.17(brs,1H),7.93(brs,1H),7.61(s,1H),7.51(t,J=9.2Hz,1H ),3.64(t,4H),3.56(brs,2H),3.36(m,2H),2.33(m,2H),1.93(m,2H),1.87(t,4H),1.82(s,2H); MS(ESI)m / z [M+H] + = 478.2.

[0278] Step 2: Referring to the method of Step 5 of Example 38, 27 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)-6-(pyrrolidine-1-yl)nicotinamide (I-46) was obtained as a white solid from 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6-(pyrrolidine-1-yl)nicotinamide (I-46) (77 mg, 0.16 mmol) and an aqueous solution of hydroxylamine (50% wt, 99 μL, 1.6 mmol). The yield was 33%. 1H NMR(400 MHz,DMSO-d6)δ:10.22(s,1H),9.62(s,1H),7.87~7.78(m,1H),7.73 ~7.66(m,1H),7.56(s,1H),7.19(t,J=9.7Hz,1H),5.79(s,2H),3.64(t,4H),3.6 1~3.57(m,2H),3.37(m,2H),2.33(m,2H),1.94(m,2H),1.88(t,4H),1.84(m,2H); MS(ESI)m / z [M+H] + = 511.2.

[0279] Example 47: Preparation of 4,5-dichloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N'-hydroxycarbamimioyl)phenyl)benzamide (I-47) [ka]

[0280] Step 1: 4,5-Dichloro-2-fluorobenzoic acid (47-a) (300 mg, 1.44 mmol) and 4,4-Difluoroazepane hydrochloride (1-c) (271 mg, 1.58 mmol) were dissolved in dimethyl sulfoxide, and potassium carbonate (793 mg, 5.76 mmol) was added. The reaction system was heated to 140°C and stirred overnight. After the reaction was complete, the mixture was diluted with water (10 mL) and the pH was adjusted to 2-3 with 6N hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate / acetic acid = 100:10:1, v / v / v) to obtain 154 mg of 4,5-dichloro-2-(4,4-difluoroazepane)benzoic acid (47-b). The yield was 37%. MS(ESI)m / z[MH] - =322.0.

[0281] Step 2: Referring to the method of Step 7 of Example 1, 4,5-dichloro-2-(4,4-difluoroazepan-1-yl)benzoic acid (47-b) (154 mg, 0.48 mmol) and 5-amino-2-fluorobenzonitrile (72 mg, 0.57 mmol) yielded 45 mg of 4,5-dichloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)benzamide (47-c) as a white solid. The yield was 21%. 1 H NMR(400 MHz,DMSO-d6)δ:10.83(s,1H),8.19(dd,J=5.8,2.7Hz,1H),8.00~7.94(m,1H),7.64(s,1H),7.60~ 7.53(m,1H),7.26(s,1H),3.57(m,2H),3.29(m,2H),2.23(m,2H),2.13~1.98(m,2H),1.78(m,2H); MS(ESI)m / z[M+H] + = 442.1.

[0282] Third step: Referring to the method of the fifth step in Example 38, 10 mg of 4,5-dichloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(N′-hydroxycarbamimioyl)phenyl)benzamide (I-47) was obtained as a white solid from 4,5-dichloro-N-(3-cyano-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)benzamide (47-c) (45 mg, 0.11 mmol) and aqueous hydroxylamine solution (50 wt%, 90 μL, 2.2 mmol). The yield was 21%. 1 H NMR(400 MHz,DMSO-d6)δ:10.58(s,1H),9.65(s,1H),7.86(dd,J=6.6,2.6Hz,1H),7.70(dd,J=8.6,4.2Hz,1H),7.59(s ,1H),7.30~7.16(m,2H),5.81(s,2H),3.36(m,2H),3.30(m,2H),2.22(m,2H),2.13~2.00(m,2H),1.78(m,2H); MS(ESI)m / z[M+H] + = 475.1.

[0283] Example 48: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-(N'-hydroxycarbamimioyl)phenyl)-4-trifluoromethylbenzamide (I-48) [ka]

[0284] Step 1: Referring to the method of Step 7 of Example 1, 30 mg of 5-chloro-N-(3-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-trifluoromethylbenzoic acid (33-d) (50 mg, 0.14 mmol) and 3-aminobenzonitrile (20 mg, 0.17 mmol) were used to obtain 30 mg of 5-chloro-N-(3-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-trifluoromethylbenzamide (48-a) as a white solid. The yield was 47%. 1 H NMR(400 MHz,DMSO-d6)δ:10.89(s,1H),8.17(s,1H),7.93(m,1H),7.72(s,1H),7.61(d,J=4.8 Hz,2H),7.36(s,1H),3.43~3.35(m,4H),2.24(m,2H),2.14~1.97(m,2H),1.81(m,2H); MS(ESI)m / z [M+H] + = 458.1.

[0285] Step 2: Referring to the method of Step 5 of Example 38, 10 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-trifluoromethylbenzamide (I-48) was obtained as a white solid from 5-chloro-N-(3-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-trifluoromethylbenzamide (48-a) (30 mg, 0.07 mmol) and an aqueous solution of hydroxylamine (50% wt, 80 μL, 1.4 mmol). The yield was 31%. 1H NMR(400 MHz,DMSO-d6)δ:10.60(s,1H),9.65(s,1H),8.05(d,J=2.1Hz,1H),7.67(d,J=7.5Hz,1H),7.64(s ,1H),7.41~7.31(m,3H),5.76(s,2H),3.43~3.27(m,4H),2.23(m,2H),2.05(m,2H),1.80(m,2H); MS(ESI)m / z [M+H] + = 491.1.

[0286] Example 49: Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-(N'-hydroxycarbamimioyl)phenyl)-6-(trifluoromethyl)benzamide (I-49) [ka]

[0287] Step 1: 2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)nicotinic acid (30-d) (90 mg, 0.28 mmol) was dissolved in dichloromethane (3 mL), and a catalytic amount of DMF was added. The reaction mixture was cooled in an ice bath, and oxalic acid chloride solution (32 μL, 0.42 mmol) was slowly added dropwise, and the mixture was reacted at room temperature for 2 hours. After concentration under reduced pressure, 3-aminobenzonitrile (36 mg, 0.33 mmol) was added under ice bath cooling, followed by the slow addition of anhydrous pyridine (2 mL), and the mixture was reacted at room temperature for 1 hour. After the reaction was complete, the reaction was stopped with ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bisulfite aqueous solution and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 70 mg of N-(3-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)nicotinamide (49-a) as a white solid. The yield was 59%. 1H NMR(400MHz,DMSO-d6)δ:10.89(s,1H),8.17(s,1H),7.98(d,J=7.6Hz,1H),7.95~7.88(m,1H),7.60(d,J=4.8H z,2H),7.24~7.19(m,1H),3.66(t,J=5.4Hz,2H),3.48(t,J=5.6Hz,2H),2.33(m,2H),1.96(m,2H),1.87(m,2H); MS(ESI)m / z [M+H] + = 425.1.

[0288] Step 2: N-(3-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)nicotinamide (49-a) (70 mg, 0.16 mmol) and N-chlorosuccinimide (22 mg, 0.16 mmol) were dissolved in N,N-dimethylacetamide (1 mL) and reacted at 100°C. After the reaction was complete, water (10 mL) was added and the mixture was extracted three times with ethyl acetate. The combined organic layer was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (200-300 mesh) column chromatography (eluent: petroleum ether / ethyl acetate = 20:1, v / v) to obtain 67 mg of 5-chloro-N-(3-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)nicotinamide (49-b) as a white solid. The yield was 89%. 1 H NMR(400 MHz,DMSO-d6)δ:10.94(s,1H),8.14(s,2H),7.95~7.87(m,1H),7.60(d,J=6.3Hz ,2H),3.64(m,2H),3.46(t,J=5.9Hz,2H),2.32(m,3H),1.97(m,2H),1.86(m,2H); MS(ESI)m / z [M+H]+=459.1.

[0289] Third step: Referring to the method of the fifth step in Example 38, 15 mg of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-(N′-hydroxycarbamimiol)phenyl)-6-(trifluoromethyl)benzamide (I-49) was obtained as a white solid from 5-chloro-N-(3-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N′-hydroxycarbamimiol)phenyl)-6-(trifluoromethyl)benzamide (I-49) using 5-chloro-N-(3-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N′-hydroxycarbamimiol)phenyl)-6-(trifluoromethyl)benzamide (I-49) as a white solid, using 5-chloro-N-(3-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N′-hydroxycarbamimiol)phenyl)-6-(trifluoromethyl)benzamide (I-49) as a starting material. The yield was 21%. δ: 1 H NMR(400 MHz,DMSO-d6)δ:10.65(s,1H),9.65(s,1H),8.06(s,1H),8.01(s,1H),7.67(d,J=7.6Hz,1H),7.447.33(m,2H),5.77(s,2H),3.65 m,2H),3.49(m,2H),2.31(m,2H),1.99(m,2H),1.86(m,2H); MS(ESI)m / z [M+H] + = 492.1.

[0290] Test Example 1: Biological Measurement Inhibitory activity of the compound of the present invention against sodium channel 1.8 (Nav1.8)

[0291] Measurement method: Effect of compounds on Nav1.8 channel current by whole-cell manual patch-clamp method.

[0292] 1. Preparation and analysis of the compounds under consideration

[0293] Control: Electrophysiological extracellular fluid containing 0.5% DMSO

[0294] Compound under investigation: A fixed amount of the compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a 20 mM DMSO stock solution. On the day of the test, the 20 mM compound stock solution was serially diluted with extracellular fluid to obtain the final detection concentration, ensuring that the DMSO content in the test drug solution did not exceed 0.5%. This concentration of DMSO does not affect the Nav1.8 channel current being tested. For example, when preparing 100 nM and 1 μM compound solutions, the serial dilution method is as follows: First, 5 μL of DMSO stock solution is added to 10 mL of extracellular fluid and uniformly dissolved to obtain a 10 μM compound solution. Next, 1 mL of the 10 μM compound solution is added to 9 mL of extracellular fluid and uniformly dissolved to obtain a 1 μM compound solution. Furthermore, 1 mL of the 1 μM compound solution is added to 9 mL of extracellular fluid and uniformly dissolved to obtain a 100 nM compound solution. VX-150 was used as the positive control for all positive controls in this experiment. The median inhibitory concentration of VX-150 was 33.45 ± 0.86 nM, which was consistent with the results reported in the original publication. The negative control used in this experiment was extracellular fluid containing 0.5% DMSO, and the change in channel current 10 minutes after administration was ≤5%.

[0295] 2.Cell culture

[0296] (1) Nav1.8 cell line: We used the HEK293 (Flp-In T-REx-293) cell line (gene sequence number: NM_001293306.2) which stably expresses the human Nav1.8 sodium channel.

[0297] (2) Culture and subculturing conditions and methods: Cell lines were cultured in an incubator at 37°C and 5% CO2. Nav1.8 stable expression cell lines were cultured in complete medium using 10% tetracycline-free fetal bovine serum (HyClone) and high-glucose DMEM medium (Gibco) supplemented with 100 μg / mL hygromycin B. Subculturing was performed the day before the experiment when the cell density reached approximately 90%. First, the medium was removed and the cells were washed with phosphate-buffered saline (PBS) preheated to 37°C. After removing the PBS, the cells were treated with trypsin, transferred to a centrifuge tube, and centrifuged at 800 rpm for 3 minutes. After removing the supernatant, the cells were resuspended in complete medium containing 1 μg / mL doxycycline and subculturised in a 6-well plate. After induction culture for 20 hours, the cells were subculturised again on poly-L-lysine coated coverslips and cultured for 1-2 hours before being subjected to electrophysiological recording experiments.

[0298] 3. Electrophysiological experiments

[0299] (1) The Nav1.8 sodium channel current was recorded under room temperature (23-25°C) conditions using the whole cell potential fixation method.

[0300] (2) For whole cell potential fixation recording, an Axon Patch 700B patch clamp amplifier (Molecular Devices) and a digital-to-analog converter Digidata 1440A (Molecular Devices) were used. Glass microelectrodes were fabricated using glass capillaries (World Precision Instruments) with an electrode pulling machine (P97, Sutter). The tip resistance after filling with the internal fluid was 1.5 to 2.5 MΩ. The glass microelectrodes were inserted into the amplifier probe and connected to the patch clamp amplifier. Potential fixation and data recording were performed under computer control using pClamp 10 software (Molecular Devices), with a sampling frequency of 20 kHz and a cutoff frequency of 2 kHz.

[0301] (3) Composition of extracellular and intracellular fluid used in electrophysiological experiments: Extracellular fluid composition (mM): 140 NaCl, 3 KCl, 1 CaCl2, 1 MgCl2, 10 HEPES, 20 Glucose, adjusted to pH 7.3 with NaOH. Intracellular fluid composition (mM): 140 CsF, 10 NaCl, 10 HEPES, 1.1 EGTA, 20 Glucose, and CsOH, adjusted to pH 7.3.

[0302] (4) Electrophysiological stimulation procedure: After whole-cell recording was achieved, the cells were held at a holding potential of -60 mV for 4-5 minutes to allow the electrode fluid and intracellular fluid to equilibrate, and then electrophysiological recording was started. Current stimulation and compound activity evaluation protocol: Cells were held at -60 mV, a 20 ms depolarization stimulus to +10 mV was applied, and then repolarized to -60 mV, with a stimulation frequency of 0.5 Hz. After the Nav1.8 sodium channel current stabilized (approximately 1 minute), the compound administration process was started, and recording was continued until the cell current stopped fluctuating (until compound inhibition reached a steady state). For each compound concentration, measurements were taken in at least 3 cells (n ≥ 3). After all compounds had been applied, 100 nM VX-150 was administered as a single concentration as a positive control.

[0303] 4. Data Analysis Data acquisition, analysis, and processing were performed using pClamp 10 (Molecular Devices), GraphPad Prism 5 (GraphPad Software), and Excel (Microsoft). All data are expressed as mean ± standard error (Mean ± SEM). The effect of compounds on current was calculated using the following formula: Suppression rate (%) = [1 - Current value after drug addition (I Drug ) / Current value before drug addition (I Control )] × 100.

[0304] The concentration-effect curve was analyzed by fitting it to the Hill equation: Y = Bottom + (Top - Bottom) / (1 + 10^( X - LogIC) 50)) Here, Bottom and Top represent the minimum and maximum values ​​of inhibition, respectively, X represents the logarithm of the compound concentration, and Y is I Drug / I Control The value is shown. IC 50 This indicates the drug concentration that shows a 50% inhibitory effect.

[0305] The results are shown in Tables 1, 2, 3, and 4. [Table 2] [Table 3] [Table 4] [Table 5]

[0306] Test Example 2: Pharmacokinetic Study In this study, rats were given a single intravenous or oral dose, and pharmacokinetic evaluations were performed.

[0307] 1. Test methods and conditions: Male SD rats were used and fasted overnight. After fasting, the test compound was administered as a single intravenous dose of 2 mg / kg or 1 mg / kg, respectively (intravenous solvent: 5% DMSO / 10% Solutol). R HS 15 / 10% EtOH / 75% physiological saline (Saline), administered at a volume of 5 mL / kg, and orally at 10 mg / kg or 5 mg / kg (administered as 0.5% CMC-Na, administered at a volume of 10 mL / kg).

[0308] 2. Blood sampling information: Approximately 0.2 mL of blood was collected from the orbital venous plexus before administration and at 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, and 24 hours after administration (an additional 5-minute blood sampling point was added for the intravenous administration group). The obtained blood samples were collected in test tubes containing EDTA-K2, and plasma was separated by centrifugation at 11,000 rpm for 5 minutes. The separated plasma was frozen and stored at -20°C.

[0309] 3. Measurement Information: Plasma concentrations of the unchanged compound were measured in rats after intravenous and oral administration using LC / MS / MS. Plasma pharmacokinetic parameters were calculated for both administration routes, and the bioavailability of each compound in rats was determined. The results are shown in Tables 5 and 6 below. [Table 6] [Table 7] [ka] This refers to the compound, and VX548 is a drug in Phase III clinical trials that targets Nav1.8, and its structural formula is [ka] Its CAS number is 2649467-58-1.

[0310] The above embodiments are intended to illustrate, and not limit, the technical solutions of the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art will understand the following: It is possible to modify the technical solutions described in the above embodiments, or to replace some or all of their technical features with equivalents, without departing from the spirit and substance limited by the claims of the present invention. And these modifications or replacements still fall within the scope limited by the claims of the present invention.

Claims

1. A compound represented by formula I, or its tautomers, stereoisomers, deuterides, or pharmaceutically acceptable salts thereof, 【Chemistry 1】 Here, R ０ but, 【Chemistry 2】 Selected from the group consisting of, Ring A is selected from the group consisting of substituted or unsubstituted C6-C10 aryls and substituted or unsubstituted 5-10 membered heteroaryls, wherein the substitution means that it is substituted with one, two, three, or four substituents selected from the group consisting of halogens, C1-C6 alkyls, halo-C1-C6 alkyls, C1-C6 alkyloxys, halo-C1-C6 alkyloxys, C2-C6 alkenyls, halo-C2-C6 alkenyls, C2-C6 alkenyloxys, halo-C2-C6 alkenyloxys, C2-C6 alkynyls, halo-C2-C6 alkynyls, C2-C6 alkynyloxys, halo-C2-C6 alkynyloxys, C3-C6 cycloalkyls, and C3-C6 cycloalkyloxys; n １ n is selected from the group consisting of 0, 1, 2, 3, or 4; ２ m is selected from the group consisting of 0 or 1; m is selected from the group consisting of 0, 1, 2, 3 or 4; R ５ is selected from the group consisting of O, S, C═O, CR ５ａ R ５ｂ or NR ５ｃ and among them, said R ５ａ and R ５ｂ are each independently selected from the group consisting of hydrogen and halogen; said R ５ｃ is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl, where said substitution means being substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyloxy, and halogen-substituted C1-C4 alkyloxy; R ６ is O, S, C=O, CR ６ａ R ６ｂ or NR ６ｃ Selected from the group consisting of, among them, R ６ａ and R ６ｂ However, each is independently selected from the group consisting of hydrogen and halogens; or CR ６ａ R ６ｂ However, together they form a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted 3-8 member heterocycline, a [substituted or unsubstituted C3-C6 cycloalkyl] condensation [substituted or unsubstituted phenyl], a [substituted or unsubstituted C3-C6 cycloalkyl] condensation [substituted or unsubstituted 5-6 member heteroaryl], a [substituted or unsubstituted 3-8 member heterocycline] condensation [substituted or unsubstituted phenyl], a [substituted or unsubstituted 3-8 member heterocycline] condensation [substituted or unsubstituted 5-6 member heteroaryl], a [substituted or unsubstituted cyclopentanyl] condensation [substituted or unsubstituted phenyl], or a [substituted or unsubstituted cyclopentanyl] condensation [substituted or unsubstituted 5-6 member heteroaryl]; the R ６ｃ However, the substituent is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl, where the substitution means that it is substituted with one, two, or three substituents selected from the group consisting of halogen, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyloxy, and halogen-substituted C1-C4 alkyloxy; X １ However, N or CR ａ Selected from the group consisting of X ２ However, N or CR ｂ Selected from the group consisting of X ３ However, N or CR ｃ Selected from the group consisting of X ４ However, N or CR ｄ Selected from the group consisting of X １ , X ２ , X ３ and X ４ Of these, there are no more than two N values; R ａ , R ｂ , R ｃ and R ｄ Each time it is expressed, it is independently selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyloxy, halo-C1-C6 alkyloxy, C2-C6 alkenyl, halo-C2-C6 alkenyl, C2-C6 alkenyloxy, halo-C2-C6 alkenyloxy, C2-C6 alkynyl, halo-C2-C6 alkynyl, C2-C6 alkynyloxy, halo-C2-C6 alkynyloxy, C3-C6 cycloalkyl, and C3-C6 cycloalkyloxy; in particular, R ａ However, it is hydrogen; R ｂ However, -CF ３ Selected from the group consisting of methyl, cyclopropyl, isopropyl, or -Cl; R ｃ However, -Cl, -CF ３ Selected from the group consisting of cyano or ethynyl; R ｄ However, selected from the group consisting of hydrogen, -Cl, and -F; X ５ and X ６ One of them is CR １ The other is N or CR ｅ Selected from the group consisting of; R ｅ Each time it is expressed, it is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyloxy, halo-C1-C6 alkyloxy, C2-C6 alkenyl, halo-C2-C6 alkenyl, C2-C6 alkenyloxy, halo-C2-C6 alkenyloxy, C2-C6 alkynyl, halo-C2-C6 alkynyl, C2-C6 alkynyloxy, halo-C2-C6 alkynyloxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy; preferably selected from the group consisting of -Cl, -F, Br, hydrogen, methoxy, methyl; R １ but, 【Transformation 3】 Selected from the group consisting of; or, R １ and R ｅ However, together with the carbon atoms linked to them 【Chemistry 4】 Forming; Among them, R １ａ However, selected from the group consisting of hydrogen, -CN, -OH, and C1-C6 alkyloxy; R １ｂ , R １ｃ , R １ｅ and R １ｄ However, each is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; R ２ , R ３ and R ４ Each is independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkyloxy, and substituted or unsubstituted C3-C6 cycloalkyl, where the substitutions are C1-C4 alkyl, halogen, -CN, and -NO ２ or -NH ２ This means that it is substituted with one, two, or three substituents selected from the group consisting of the following: Compounds, their tautomers, stereoisomers, deuterated compounds, or pharmaceutically acceptable salts.

2. R ０ but 【Transformation 5】 The compound is selected from the group consisting of substituted or unsubstituted indolinyl, substituted or unsubstituted isoindolinyl, substituted or unsubstituted 1,2,3,4-tetrahydroquinolinyl, substituted or unsubstituted tetrahydroisoquinolinyl, substituted or unsubstituted 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, and substituted or unsubstituted 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, wherein the substituted substituent is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkyloxy, phenyl, or halo-C1-C4 alkyl. The compound according to claim 1, or its tautomers, stereoisomers, deuterides, or pharmaceutically acceptable salts.

3. R ０ but 【Transformation 6】 The substituted substituent is selected from the group consisting of substituted or unsubstituted tetrahydropyrrole, substituted or unsubstituted piperidine, substituted or unsubstituted morpholine, substituted or unsubstituted thiomorpholine, substituted or unsubstituted piperazine, substituted or unsubstituted azepane, substituted or unsubstituted 1,4-oxaazepane, substituted or unsubstituted azaspiro[2.5]octane, substituted or unsubstituted spiro[indan-1,4'-piperidine]-yl, substituted or unsubstituted 4,5-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-yl, and substituted or unsubstituted 3H-spiro[isobenzofuran-1,4'-piperidine]-yl, wherein the substituted substituent is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkyloxy, phenyl, or haloC1-C4 alkyl; Preferably, selected from the group consisting of the following groups: 【Transformation 7】 The compound according to claim 1, or its tautomers, stereoisomers, deuterides, or pharmaceutically acceptable salts.

4. The compound represented by formula I is selected from the group consisting of the compounds represented by the following formulas: I-a1, I-a2, I-b1, I-b2, I-c1, I-c2, and I-d: 【Transformation 8】 Among them, X ５ and X ６ is N or CR ｅ X １ , X ２ , X ３ , X ４ , R ０ , R １ａ , R １ｂ , R １ｃ , R １ｄ , R １ｅ , R ２ , R ３ , R ４ , R ｅ The definition is the same as that of the corresponding claim. The compound according to claim 1, or its tautomers, stereoisomers, deuterides, or pharmaceutically acceptable salts.

5. The compound represented by formula I is selected from the group consisting of the compounds represented by formula II below: 【Chemistry 9】 Among them, X １ is C or N; m, R ６ , R ｂ , R ｃ , R ｄ , R ２ , R ３ , R ４ , X ５ , X ６ The definition is the same as that of the corresponding claim; Preferably, the compound represented by formula II is selected from the group consisting of the compounds represented by formulas II-a1, II-a2, II-b1, II-b2, II-c1, II-c2, and II-d: 【Chemistry 10】 Among them, X １ , m, R ６ , R ｂ , R ｃ , R ｄ , R ２ , R ３ , R ４ , X ５ , X ６ , R １ａ , R １ｂ , R １ｃ , R １ｄ , R １ｅ are the same as those in the corresponding claims; Preferably, the compounds represented by formulas II-a1 and II-a2 are selected from the group consisting of compounds represented by the following formulas II-a1-1 or II-a2-1: 【Chemistry 11】 Among them, R １ａ However, it is selected from the group consisting of hydrogen, -CN, -OH, or C1-C6 alkyloxy, and preferably -OH; R １ｂ and R １ｃ However, each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, preferably hydrogen; R ６ However, -CH ２ -C=O or -CF ２ And; R ｂ , R ｃ and R ｄ Each is independently selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyloxy, halo-C1-C6 alkyloxy, C2-C6 alkenyl, halo-C2-C6 alkenyl, C2-C6 alkenyloxy, halo-C2-C6 alkenyloxy, C2-C6 alkynyl, halo-C2-C6 alkynyl, C2-C6 alkynyloxy, halo-C2-C6 alkynyloxy, C3-C6 cycloalkyl, and C3-C6 cycloalkyloxy; preferably, R ｂ , R ｃ and R ｄ Each of these is independently selected from the group consisting of hydrogen, chlorine, fluorine, C1-C4 alkyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and trifluoromethyl; X １ is N or CH; X ５ and X ６ is N or CR ｅ And R ｅ Each time it is expressed, it is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyloxy, halo-C1-C6 alkyloxy, C2-C6 alkenyl, halo-C2-C6 alkenyl, C2-C6 alkenyloxy, halo-C2-C6 alkenyloxy, C2-C6 alkynyl, halo-C2-C6 alkynyl, C2-C6 alkynyloxy, halo-C2-C6 alkynyloxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy; preferably, R ｅ Each time it is expressed, it is selected from the group consisting of hydrogen, fluorine, chlorine, Br, methoxy, or methyl; R ２ , R ３ and R ４ Each of these is independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkyloxy, and substituted or unsubstituted C3-C6 cycloalkyl, where the substitutions are methyl, -F, -CN, and -NO. ２ or -NH ２ This means that the substituents are substituted with one, two, or three substituents selected from the group consisting of; Preferably, the compound represented by formula II-a2-1 is selected from the group consisting of the compounds represented by formula II-a2-1-A below: 【Chemistry 12】 R ｅ However, it is selected from the group consisting of hydrogen, F, Cl, Br, C1-C6 alkyl, or C1-C6 alkyloxy, preferably hydrogen, F, Cl, or Br, more preferably hydrogen or F, and particularly F; R ６ However, -CH ２ -C=O or -CF ２ And; R ｂ , R ｃ and R ｄ Each is independently selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkyloxy, halo-C1-C6 alkyloxy, C2-C6 alkenyl, halo-C2-C6 alkenyl, C2-C6 alkenyloxy, halo-C2-C6 alkenyloxy, C2-C6 alkynyl, halo-C2-C6 alkynyl, C2-C6 alkynyloxy, halo-C2-C6 alkynyloxy, C3-C6 cycloalkyl, and C3-C6 cycloalkyloxy; preferably, R ｂ , R ｃ and R ｄ Each of these is independently selected from the group consisting of hydrogen, chlorine, fluorine, C1-C4 alkyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and trifluoromethyl; X １ is N or CH; R ２ , R ３ and R ４ The definition is the same as that of the corresponding claim. A compound according to any one of claims 1 to 4, or a tautomer, stereoisomer thereof, a deuteride thereof, or a pharmaceutically acceptable salt thereof.

6. The compound represented by formula I is selected from the group consisting of the following compounds, according to any one of claims 1 to 4, or a tautomer, stereoisomer thereof, deuterated thereof, or a pharmaceutically acceptable salt thereof. Table 1

7. A method for producing the compound according to any one of claims 1 to 6, which is achieved by the following reaction scheme: Scheme 1: 【Chemistry 13】 After converting III-a1 or III-a2 to a Pinner salt via the Pinner reaction, NR １ａ and NR １ｂ R １ｃ By reacting with it, I-a1 or I-a2 is produced. Among them, the definition of each substituent is the same as that of the corresponding claim; Scheme 2: 【Chemistry 14】 III-a1 or III-a2 is reacted with hydroxylamine or a salt of hydroxylamine to obtain I-a1 or I-a2. Among them, R １ａ OH is R １ｂ H is R １ｃ H is H, and the definitions of the remaining substituents are the same as in the corresponding claims; Scheme 3: 【Chemistry 15】 III-a3 or III-a4 is hydrolyzed to produce an acid, and then this acid is converted into an acid chloride, which is then condensed with guanidine to produce I-b1 or I-b2. Among them, the definition of each substituent is the same as that of the corresponding claim; Scheme 4: 【Chemistry 16】 By treating Key1 and SM-2e or SM-2f with an acid amide condensation reaction, I-c1 or I-c2 is produced. Among them, the definition of each substituent is the same as that of the corresponding claim; Scheme Five: 【Chemistry 17】 Key1 and SM-3 are treated by an acid amide condensation reaction to produce I-d. Among these, the definition of each substituent is the same as that of the corresponding claim. method.

8. A pharmaceutical composition comprising one or more compounds selected from any one of claims 1 to 6, their tautomers, stereoisomers, deuterides, and pharmaceutically acceptable salts, and optionally a pharmaceutically acceptable additive.

9. Use of any compound according to claim 1 to 6, or a tautomer, stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the production of a Nav 1.8 inhibitor.

10. The use of a compound according to any one of claims 1 to 6, or a tautomer, stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the manufacture of a pharmaceutical product for preventing and / or treating a disease associated with abnormal expression of Nav1.8 channel activity, Preferably, diseases associated with abnormal expression of Nav1.8 channel activity include painful disorders, pruritus, acute or chronic pruritus, asthma, multiple sclerosis, arrhythmia, atrial fibrillation, heart failure, Brugada syndrome, kidney stones, epilepsy, convulsions, Charcot-Marie-Tooth disease, and incontinence. use.

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