Aromatic fused ring NAV1.8 inhibitors and uses thereof

Abstract

The present invention provides an aromatic fused ring compound that acts as a sodium channel blocker, and uses thereof. The aromatic fused ring compound has inhibitory activity against the sodium ion channel Nav1.8 and can be used as a drug for the treatment of a wide range of pain.

Description

[Technical field]

[0001] The present invention relates to aromatic fused ring compounds having inhibitory activity against voltage-gated sodium channel 1.8 (Nav1.8) and uses thereof. [Background technology]

[0002] Pain is a complex physiological and psychological activity and one of the most common clinical symptoms. Pain is originally a protective mechanism of the human body to warn people of potential danger, but abnormal pain can cause physiological disorders, especially chronic pain, which seriously affects people's quality of life. According to a 2019 report (http: / / news.medlive.cn / anes / info-progress / show-153086_201.html), the global prevalence of chronic pain has reached 12-30%. In the United States, the number of pain patients has exceeded the number of diabetes patients, heart disease patients and cancer patients, and the economic loss caused by pain has increased to $560-635 billion annually (https: / / www.physio-pedia.com / Epidemiology_of_Pain). According to China's 2015 statistics, the pain market has also reached 20.8 billion yuan (https: / / paindoctor.com / resources / chronic-pain-statistics / ). At present, commonly used analgesics such as opioid receptor agonists, cyclooxygenase inhibitors, GABA receptor agonists, etc. are far from meeting clinical needs because they may have side effects such as addiction, respiratory depression, gastrointestinal reactions, or cardiovascular events, central nervous system depression, etc. This shows that the pain market has great potential (Nora D. Volkow, A. Thomas McLellan. Opioid Abuse in Chronic Pain-Misconceptions and Mitigation Strategies. N Engl J Med, 2016, 374(13): 1253-63; Sheng HG, Shao JY, Kir Kland SC, et al. Inhibition of human colon Cancer cell growth by selective inhibition of cyclooxygenase-2. J Chm Invest, 1997, 99: 2254; Janette Brohan, Basavana G. Goudra. The Role of GABA Receptor Agonists in Anesthesia and Sedation. CNS Drugs, 2017).

[0003] Pain can be classified into various types based on the stimulus characteristics, such as mechanical pain, thermal pain, chemical pain, etc., according to the etiology of inflammation, it can be classified into inflammatory pain and non-inflammatory pain, according to the location of the nerve, it can be classified into central neuralgia, peripheral neuralgia, and autonomic neuralgia, and according to the course of onset, it can be classified into acute pain and chronic pain. Regardless of the type, all pain requires the involvement of voltage-gated sodium channels (Nav).

[0004] Human pain sensation arises from pain receptors at peripheral nerve endings throughout the body, which can transduce mechanical, heat, cold, and chemical stimuli into nerve impulses. These impulses are transmitted via afferent nerves to the dorsal root ganglion (DRG) and then via efferent nerves to the nerve center, causing the perception of pain (Bennett DL, Clark AJ, Huang J, et al. The Role of Voltage-Gated Sodium Channels in Pain Signaling. Physiol Rev, 2019, 99: 1079-1151). NaV plays a role in triggering and transmitting signals during nerve impulse signal transmission and is the main medium of the ascending branch of the action potential (i.e., nerve impulse) (Mark D. Baker, John N.Wood. Involvement of Na + channels in pain pathways. TRENDS in Pharmacological Sciences, 2001, 22(1): 27-31, Alan L Goldin. RESURGENCE OF SODIUM CHANNEL RESEARCH. Annu. Rev. Physiol. 2001. 63:871-894). Therefore, inhibiting Nav can help relieve and treat pain. However, existing Nav inhibitors such as lidocaine, carbamazepine, lamotrigine, etc. are non-selective for Nav, and therefore have the disadvantages of a narrow therapeutic window and significant side effects. For this reason, research into selective Nav inhibitors has been focused.

[0005] Nav is a type of transmembrane ion channel protein composed of an α subunit with a molecular weight of 260 kDa and a β subunit with a molecular weight of 30 to 40 kDa (Bennett DL, Clark AJ, Huang J, et al. The Role of Voltage-Gated Sodium Channels in Pain Signaling. Physiol Rev, 2019, 99: 1079-1151). Depending on the inhibitory activity of tetrodotoxin (TTX), Nav subtypes can be divided into two categories: TTX-sensitive type (TTX-S), which includes Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6 and Nav1.7, and TTX-resistant type (TTX-R), which includes Nav1.5, Nav1.8 and Nav1.9. Existing physiological and pharmacological studies (Bennett DL, Clark AJ, Huang J, et al. The Role of Voltage-Gated Sodium Channels in Pain Signaling. Physiol Rev, 2019, 99: 1079-1151, Alan L Goldin. RESURGENCE OF SODIUM CHANNEL RESEARCH. Annu. Rev. Physiol. 2001. 63:871-94, Laura Sole, Michael M. Tamkun. Trafficking mechanisms underlying Nav channel subcellular localization in neurons. Channels, 2020, 14(1), 1-17, Manuel de Lera Ruiz, Richard L. Kraus. Voltage-Gated Sodium Channels: Structure, Function, Pharmacology and Clinical Indications. J. Med. Chem., 2015, 58(18): According to the International Journal of Clinical Neuroscience (IJNSE) 2016, 7093-7118, as shown in Table 1, Nav1.1, Nav1.2 and Nav1.3 are mainly distributed in the CNS region and are associated with epilepsy, local anesthesia and other CNS diseases.Nav1.4 is distributed mainly in skeletal muscles, and its inhibitors are used as local anesthetics for myotonia. Nav1.5 is distributed mainly in cardiac myocytes, and its inhibitors are used to treat arrhythmias. Nav1.6 is involved in movement disorders. Currently, the main pain-related targets are Nav1.7, Nav1.8, and Nav1.9. Among them, Nav1.7 inhibitors are the most widely studied for their application in pain, but there have been no successful clinical trials to date. There are few studies on Nav1.9, and its mechanism of action on pain is not very clear, and there are no pain pharmacodynamic models of related inhibitors reported as evidence. Regarding the mechanism of action of Nav1.8, Dib-Hajj et al. (Bennett DL, Clark AJ, Huang J, et al. The Role of Voltage-Gated Sodium Channels in Pain Signaling. Physiol Rev, 2019, 99: 1079 - 1151) summarized existing research in a 2019 review and concluded that Nav1.8 is a major contributor to the ascending branch of the action potential. Its rapid onset supports high-frequency discharge, has a high activation threshold, and a slow dynamic process. Blocking Nav1.8 can block the generation of action potentials and the transmission of electrical signals. Blair and Bean's study (Blair NT, Bean BP.Roles of tetrodotoxin (TTX)-sensitive Na. + current, TTX-resistant Na + current, and Ca 2+current in the action potentials of nociceptive sensory neurons. J Neurosci 2002, 22: 10277-10290) suggests that although both Nav1.8 and Nav1.9 are expressed in the DRG, the contribution of Nav1.8 to the TTX-R current is the most important. In the acute phase of nerve injury, Nav1.8 is downregulated in the injured neurons but upregulated in the neighboring uninjured neurons, leading to an increase in spontaneous discharges. In the chronic phase, crosstalk is formed between the injured and uninjured neurons, leading to an upregulation of Nav1.8 in the injured neurons, leading to a further increase and maintenance of spontaneous discharges. In addition to mechanistic studies, the efficacy of Nav1.8 inhibitors in animal models of pain was also examined. For example, A-803467, developed by Abbott, showed analgesic effects of more than 50% in carrageenan model, complete Freund's adjuvant (CFA) model, chronic sciatic nerve compression pain (CCI) model, spinal nerve ligation pain (SNL) model, and acute mechanical pain model compared to the model groups (Michael F. Jarvis, Prisca Honore, et al. A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. PNAS, 2007, 104(20): 8520-8525). Additionally, systemically administered A-803467 was superior to lidocaine in a streptozotocin (STZ)-induced diabetic neuropathic heat pain model; both were comparable when administered by local plantar injection, but the efficacy of A-803467 lasted longer (Mert, Gunes Y. Antinociceptive activities of lidocaine and the nav1.8 blocker a803467 in diabetic rats. J Am Assoc Lab Anim Sci. 2012; 51(5):579-585).Pfizer's PF-01247324 also showed significant analgesic effects in CFA and SNL models (Payne CE, Brown AR, Theile JW, et al. A novel selective and orally bioavailable Nav 1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability. Br J Pharmacol. 2015; 172(10):2654-2670). Most importantly, VX150, a highly selective Nav1.8 inhibitor developed by Vertex, has been clinically successful in three pain-related Phase II clinical trials. Taken together, Nav1.8 is a promising target for the treatment of pain or pain-related disorders. Nav Subtype Overview [Table 1]

[0006] Currently, not many companies are reported to be developing Nav1.8 inhibitors. The main overseas companies are Abbott, Pfizer (WO2013114250A1), Gilead (AU2015224425A1), Sumitomo (WO2015008861A1), AbbVie (WO2016149169A1), Raqualia (WO2020138271A1), Merck Sharp & Dohme (WO2020092187A1), Lieber (WO2020014243A1) and Vertex (WO2019014352A1). In China, the main ones are Hengrui (WO2020151728A1) and Shanghai Jiyu Pharmaceutical (CN111808019A). The patents of these companies do not disclose specific inhibitory activity of Nav1.8, or the activity is insufficient. Only Pfizer's PF-04531083 and Vertex's VX-150 and VX-548 have entered Phase II clinical trials, and the development of PF-04531083 was discontinued because it did not show activity over placebo in postoperative dental pain. VX-150 was clinically successful in three Phase II clinical trials, namely inflammatory pain, postoperative acute pain, and neuropathic pain, and preliminarily verified the role of Nav1.8 in pain. However, according to Vertex's publication, the development of VX150 has been discontinued due to insufficient pharmacokinetics (PK). VX-548 is currently in Phase III clinical trials. Therefore, the development of new Nav1.8 inhibitors is still promising and necessary. Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide aromatic fused ring compounds having inhibitory activity against voltage-gated sodium channels, particularly Nav1.8, and uses thereof. [Means for solving the problem]

[0008] To achieve the above object, the present invention provides a compound of formula I, or a solvate, tautomer, or pharma- ceutically acceptable salt thereof, [ka] Formula I wherein X1, X2, Z1, and Z2 are independently selected from substituted or unsubstituted C or N; R1 is independently selected from hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino, -SO2R2, -S(O)(NH)R2, -COR2, -CONR2R3; wherein R2 and R3 are independently selected from hydrogen, -NH2, and -C1-C3 alkyl; Ring A is a substituted or unsubstituted benzene ring or a 6-membered aromatic heteroaryl; Ring B is a substituted or unsubstituted 3- to 10-membered aliphatic ring or aliphatic heterocyclic ring.

[0009] In some embodiments, at least one of X1 and X2 is N.

[0010] In some embodiments, X 1 and X 2 are both N.

[0011] In some embodiments, X 1 is N.

[0012] In some embodiments, X1 and X2 are simultaneously N, and Z1 and Z2 are C. In some embodiments, X1 is N, and X2, Z1, Z2 are C.

[0013] In some embodiments, R1 is selected from H, halogen. Preferably, R1 is H.

[0014] In some embodiments, R 1 is H.

[0015] In some embodiments, Ring A is selected from a 6-membered aryl or heteroaryl containing 0-3 nitrogen atoms, wherein said aryl or heteroaryl is optionally substituted with hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, carbonyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino, -SO2R2, -S(O)(NH)R2, -COR2, -CONR2R3, or -POR2R3, wherein R2 and R3 are independently selected from hydrogen, -NH2, -NHCH3, and -C1-C3 alkyl.

[0016] In some embodiments, ring A is a group represented by the following formula, wherein R4 is hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino, -SO2R2, -S(O)(NH)R2, -COR2, -CONR2R3, or -POR2R3, and R2 and R3 are independently selected from hydrogen, -NH2, -NHCH3, -C1-C3 alkyl, or R2 and R3 together with phosphorus form a 3-8 membered ring. [ka]

[0017] In some embodiments, ring A is a group represented by the following formula, wherein R4 is hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino, -SO2R2, -S(O)(NH)R2, -COR2, -CONR2R3, or -POR2R3, and R2 and R3 are independently selected from hydrogen, -NH2, -NHCH3, -C1-C3 alkyl, or R2 and R3 together with phosphorus form a 3-8 membered ring. [ka]

[0018] In some embodiments, ring A is a group represented by the following formula, wherein R4 is hydrogen, halogen, -SO2R2, -S(O)(NH)R2, -COR2, -CONR2R3, and wherein R2 and R3 are independently selected from hydrogen, -NH2, -NHCH3, and -C1-C3 alkyl. [ka]

[0019] In some embodiments, ring A is a group represented by the following formula, wherein R4 is hydrogen, halogen, -SO2R2, -S(O)(NH)R2, -COR2, -CONR2R3, and wherein R2 and R3 are independently selected from hydrogen, -NH2, -NHCH3, and -C1-C3 alkyl. [ka]

[0020] In some embodiments, ring A is selected from: [ka]

[0021] In some embodiments, Ring B is selected from a 3-10 membered aliphatic or aliphatic heterocyclic ring containing 0-3 heteroatoms selected from N, O, and S, and optionally the aliphatic or aliphatic heterocyclic ring is substituted with halogen, carbonyl, -NH, -CN, -OH, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino, -C3-C6 cycloalkyl, and -C3-C6 cycloheteroalkyl.

[0022] In some embodiments, Ring B is a group represented by the formula below, wherein Y is selected from CH or N, and Ring B is substituted with m R5, wherein R5 is hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino, and m is an integer from 0 to 2(n+3), and n is an integer from 0 to 6. [ka]

[0023] In some embodiments, n is an integer from 1 to 4.

[0024] In some embodiments, Y is N, n is 3, and R5 is hydrogen or halogen.

[0025] In some embodiments, Ring B is: [ka]

[0026] In some embodiments, the compounds of the present invention are represented by formula II: [ka] Formula II In the formula, X1 and X2 are independently selected from C or N, and at least X1 is N; R1 is independently selected from hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino, -SO2R2, -S(O)(NH)R2, -COR2, -CONR2R3, where R2 and R3 are independently selected from hydrogen, -NH2, and -C1-C3 alkyl; Y is selected from CH or N; R5 is selected from hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino; n is an integer from 0 to 6, Ring A is selected from 6-membered aryl or heteroaryl containing 0-3 nitrogen atoms, wherein said aryl or heteroaryl is optionally substituted by hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, carbonyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino, -SO2R2, -S(O)(NH)R2, -COR2, -CONR2R3, or -POR2R3, wherein R2 and R3 are independently selected from hydrogen, -NH2, -NHCH3, and -C1-C3 alkyl.

[0027] In some preferred embodiments, in the compound of formula II of the present invention, ring A is a group represented by the following formula: In the formula, R4 is hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino, -SO2R2, -S(O)(NH)R2, -COR2, -CONR2R3, or -POR2R3, where R2 and R3 are independently selected from hydrogen, -NH2, -NHCH3, -C1-C3 alkyl, or R2 and R3 together with phosphorus form a 3- to 8-membered ring. [ka]

[0028] In some embodiments, the compounds of the present invention are represented by formula III: [ka] Formula III wherein X1 and X2 are independently selected from C or N, and at least X1 is N; R1 is independently selected from hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino, -SO2R2, -S(O)(NH)R2, -COR2, -CONR2R3, where R2 and R3 are independently selected from hydrogen, -NH2, and -C1-C3 alkyl; T is CR6 or N; R6 is hydrogen, halogen or -C1-C6 alkyl; R9 is hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino, -SO2R2, -S(O)(NH)R2, -COR2, -CONR2R3, or -POR2R3; R2 and R3 are independently selected from hydrogen, -NH2, -NHCH3, -C1-C3 alkyl, or R2 and R3 together with phosphorus form a 3- to 8-membered ring; R5 is selected from hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino; n is an integer from 0 to 6.

[0029] In some preferred embodiments, in the compounds of formula III of the present invention, Y is N, and n is an integer from 1 to 4.

[0030] In some preferred embodiments, n is 3 in the compounds of formula III of the present invention.

[0031] In some embodiments, the compound of the present invention is represented by formula IV: [ka] Formula IV In the formula, R 10 and R 11 is independently selected from hydrogen or halogen; The other substituents are as defined above.

[0032] In some preferred embodiments, in the compounds of formula IV of the present invention, R1 is independently selected from hydrogen, halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy.

[0033] In some preferred embodiments, in compounds of formula IV of the present invention, R1 is independently selected from hydrogen, halogen, -CH3, or -OCH3.

[0034] In some preferred embodiments, in the compounds of formula IV of the present invention, R 1 is selected from hydrogen or halogen.

[0035] In some preferred embodiments, X1 is N and X2 is C in the compounds of formula IV of the present invention.

[0036] In some preferred embodiments, X1 is N and X2 is N in the compounds of formula IV of the present invention.

[0037] In some preferred embodiments, in the compounds of formula IV of the present invention, R6 is hydrogen or halogen.

[0038] In some preferred embodiments, in the compounds of formula IV of the present invention, R9 is -SO2R2, -S(O)(NH)R2, -COR2, or -CONR2R3, where R2 and R3 are independently selected from hydrogen, -NH2, -NHCH3, and -C 1-3 -alkyl.

[0039] In some embodiments, the compounds of the present invention are represented by formula V: [ka] Formula V In the formula, R7 and R8 are independently selected from hydrogen, halogen, -CH3, and -OCH3; R9 is selected from -SO2R2, -S(O)(NH)R2, -COR2, -CONR2R3; R2 and R3 are independently selected from hydrogen, -NH2, -NHCH3, -C1-C3 alkyl; T is CR6 or N; R 10 and R 11 is independently selected from hydrogen or halogen.

[0040] In some preferred embodiments, in the compound of formula V of the present invention, R9 is selected from -SO2NH2, -CONH2.

[0041] In some preferred embodiments, in compounds of formula V of the present invention, R9 is -SO2NH2.

[0042] In some preferred embodiments, in the compounds of formula V of the present invention, R7 and R8 are independently selected from hydrogen or halogen.

[0043] In some preferred embodiments, in the compounds of formula V of the present invention, R 10 and R 11 Both are halogens.

[0044] In some embodiments, the compounds of the present invention have the general structure VI: [ka] Equation VI wherein Ar1 is a substituted or unsubstituted 5- or 6-membered aryl or heteroaryl; Ar1 is a substituted or unsubstituted 6-membered aryl or benzene ring; X and Y are C or N.

[0045] In some preferred embodiments, the Ar1 is selected from 5- or 6-membered aryl or heteroaryl containing 0-3 N, O, S atoms, and the aryl or heteroaryl is optionally substituted by hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, carbonyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino, -SO2R2, -S(O)(NH)R2, -COR2, -CONR2R3, or -POR2R3, where R2 and R3 are independently selected from hydrogen, -NH2, -NHCH3, and -C1-C3 alkyl.

[0046] In some preferred embodiments, the Ar2 is selected from a 6-membered aryl or benzene ring containing 0-3 N atoms, and the aryl or benzene ring is optionally substituted by halogen, -NH2, -CN, -OH, -C1-C6 alkyl, carbonyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino.

[0047] In some embodiments, the compounds of the present invention have the general structure VII: [ka] Formula VII wherein Ar1 is a substituted or unsubstituted 5- or 6-membered aryl or heteroaryl; Ar1 is a substituted or unsubstituted 6-membered aryl or benzene ring; X and Y are C or N.

[0048] In some preferred embodiments, the Ar1 is selected from a 5- or 6-membered aryl or heteroaryl containing 0-3 N, O, S atoms, the aryl or heteroaryl being optionally substituted by hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, carbonyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino, -SO2R2, -S(O)(NH)R2, -COR2, -CONR2R3, or -POR2R3, where R2 and R3 are independently selected from hydrogen, -NH2, -NHCH3, and -C1-C6 alkyl. 1-3 is selected from alkyl.

[0049] In some preferred embodiments, the Ar2 is selected from a 6-membered aryl or benzene ring containing 0-3 N atoms, and the aryl or benzene ring is optionally substituted by halogen, -NH2, -CN, -OH, -C1-C6 alkyl, carbonyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino.

[0050] In some embodiments, the compounds of the present invention have the general structure VIII: [ka] Formula VIII wherein Ar1 is a substituted or unsubstituted 5- or 6-membered aryl or heteroaryl; Ar1 is a substituted or unsubstituted 6-membered aryl or benzene ring; X and Y are C or N; R1 is an aliphatic chain, an aliphatic ring, or an aryl.

[0051] In some preferred embodiments, the Ar1 is selected from a 5- or 6-membered aryl or heteroaryl containing 0-3 N, O, or S atoms, and the aryl or heteroaryl is optionally substituted by hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, carbonyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, or -C1-C6 alkylamino.

[0052] In some preferred embodiments, the Ar2 is selected from a 6-membered aryl or benzene ring containing 0-3 N atoms, and the aryl or benzene ring is optionally substituted by halogen, -NH2, -CN, -OH, -C1-C6 alkyl, carbonyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino.

[0053] In some preferred embodiments, R1 is hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, carbonyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, or -C1-C6 alkylamino.

[0054] In some embodiments, the compounds of the present invention have the general structure IX: [ka] Formula IX wherein Ar1 is a substituted or unsubstituted 5- or 6-membered aryl or heteroaryl; Ar1 is a substituted or unsubstituted 6-membered aryl or benzene ring; X and Y are C or N; R1 is an aliphatic chain, an aliphatic ring, or an aryl.

[0055] In some preferred embodiments, the Ar1 is selected from a 5- or 6-membered aryl or heteroaryl containing 0-3 N, O, or S atoms, and the aryl or heteroaryl is optionally substituted by hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, carbonyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, or -C1-C6 alkylamino.

[0056] In some preferred embodiments, the Ar2 is selected from a 6-membered aryl or benzene ring containing 0-3 N atoms, and the aryl or benzene ring is optionally substituted by halogen, -NH2, -CN, -OH, -C1-C6 alkyl, carbonyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino.

[0057] In some preferred embodiments, R1 is hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, or -C1-C6 alkylamino.

[0058] In some embodiments, the compounds of the present invention have the general structure X: [ka] formula wherein Ar1 is a substituted or unsubstituted 5- or 6-membered aryl or heteroaryl; Ar1 is a substituted or unsubstituted 6-membered aryl or benzene ring; X and Y are C or N; R1 is an aliphatic chain, an aliphatic ring, or an aryl.

[0059] In some preferred embodiments, the Ar1 is selected from a 5- or 6-membered aryl or heteroaryl containing 0-3 N, O, or S atoms, and the aryl or heteroaryl is optionally substituted by hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, carbonyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, or -C1-C6 alkylamino.

[0060] In some preferred embodiments, the Ar2 is selected from a 6-membered aryl or benzene ring containing 0-3 N atoms, and the aryl or benzene ring is optionally substituted by halogen, -NH2, -CN, -OH, -C1-C6 alkyl, carbonyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino.

[0061] In some preferred embodiments, R1 is hydrogen, -NH2, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, or -C1-C6 alkylamino.

[0062] In some embodiments, the compounds of the present invention have the general structure XI: [ka] Formula XI wherein Ar1 is a substituted or unsubstituted 5- or 6-membered aryl or heteroaryl; Ar1 is a substituted or unsubstituted 6-membered aryl or benzene ring; X and Y are C or N; R1 is an aliphatic chain, an aliphatic ring, or an aryl.

[0063] In some preferred embodiments, the Ar1 is selected from a 5- or 6-membered aryl or heteroaryl containing 0-3 N, O, or S atoms, and the aryl or heteroaryl is optionally substituted by hydrogen, halogen, -NH2, -CN, -OH, -C1-C6 alkyl, carbonyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, or -C1-C6 alkylamino.

[0064] In some preferred embodiments, the Ar2 is selected from a 6-membered aryl or benzene ring containing 0-3 N atoms, and the aryl or benzene ring is optionally substituted by halogen, -NH2, -CN, -OH, -C1-C6 alkyl, carbonyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, -C1-C6 alkylamino.

[0065] In some preferred embodiments, R1 is hydrogen, -NH2, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkoxy, -C1-C6 haloalkoxy, or -C1-C6 alkylamino.

[0066] In some embodiments, the compound of the present invention is selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0067] In some preferred embodiments, the compounds according to the present invention are selected from the following: [ka]

[0068] A second object of the present invention is to provide a pharmaceutical composition comprising a compound according to the first object of the present invention or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

[0069] A third object of the present invention is to provide the use of said compound or a pharma- ceutically acceptable salt thereof in the preparation of a medicament for treating pain.

[0070] A fourth object of the present invention is to provide a method for preventing or treating pain which comprises administering to a patient a compound according to the first object of the present invention or a pharma- ceutically acceptable salt thereof.

[0071] In some embodiments, the pain is selected from chronic pain, bowel pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, post-operative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or arrhythmia. [Brief description of the drawings]

[0072] [Figure 1]3 shows experimental voltage fluctuations in Method 2 of Example 33, in which -80 mV is the clamp voltage, at which the Nav1.8 channels of the cells are in a resting state, and 10 mV is the activation voltage, at which the Nav1.8 channels of the cells are in an activated state. [Diagram 2] 1 shows the results of the mechanical allodynia test of Example 36. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0073] definition As used herein, the term “alkyl” (unless otherwise stated) by itself or as part of another substituent refers to a straight or branched chain alkyl group having the specified number of carbon atoms (i.e., C 1-8 (meaning 1 to 8 carbons.) Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-amyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0074] As used herein, the term "heteroaryl" refers to groups having 5 to 10 heterocyclic atoms, preferably 5- or 6-membered monocyclic aromatic heterocycles or 8- to 10-membered bicyclic aromatic heterocycles, and having 1 to 3 heteroatoms in addition to carbon. A "heteroatom" is nitrogen, oxygen, or sulfur.

[0075] The term "aliphatic ring" refers to a monocyclic or polycyclic alkane having a saturated or unsaturated bond, preferably a saturated monocyclic alkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc. Polycyclic alkanes can be divided into helical rings and bridged rings according to the bonding mode.

[0076] The term "aliphatic heterocycle" refers to a monocyclic or polycyclic alkane having, in addition to carbon atoms, one or more saturated or unsaturated bonds of heteroatoms, such as nitrogen, oxygen, or sulfur.

[0077] The terms "substituted" and "substituted by" mean that any one or more hydrogen atoms bonded to a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, so long as the valence state of the particular atom is normal and the substituted compound is stable. The term "optionally substituted" means that a substituent may or may not be substituted, and unless otherwise specified, the type and number of substituents may be any that is chemically achievable.

[0078] In addition, even if the term "optionally substituted" does not appear, it should be understood that when optional substitution occurs on a ring (such as an aliphatic ring or an aryl), the positions and number of substituents are optional, so long as they are chemically achievable.

[0079] As used herein, the term "halogen" by itself or as part of another substituent (unless otherwise stated) means a fluorine, chlorine, bromine, or iodine atom. Additionally, the term "haloalkyl" is intended to include both monohaloalkyl and polyhaloalkyl groups. For example, the term "C 1-4 "Haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl and the like.

[0080] As used herein, "alkoxy" refers to an alkyl group as defined above with the specified number of carbon atoms connected through an oxygen bridge, unless otherwise specified, -C 1- A C6 alkoxy group includes C1, C2, C3, C4, C5 and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-amoxy and S-amoxy.

[0081] Unless otherwise specified, structures depicted herein are also intended to include all isomers of the structure (such as enantiomers, diastereomers, and geometric (or conformational) isomers), such as the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers and enantiomeric, diastereomeric, and geometric (or conformational) mixtures of these compounds are within the scope of the invention. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise specified, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium or the like. 13 C- or 14 Compounds having structures other than the replacement of carbons with C-enriched carbons are also included within the scope of this invention.

[0082] Unless otherwise specified, a structure described herein is also intended to include solvates of the structure, where solvates refer to a physical association of a compound of the present application with one or more solvent molecules. The physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvates" encompass both solution-phase and isolable solvates. Non-limiting examples of suitable solvents include, but are not limited to, isopropyl alcohol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine, and the like. "Hydrates" are solvates in which the solvent molecule is H2O.

[0083] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, and any product derived directly or indirectly from a combination of the specified ingredients in the specified amounts. The phrase "pharmaceutical acceptable" means that the carrier, diluent or excipient must be compatible with other ingredients in the formulation and not deleterious to the drug recipient thereof.

[0084] As used herein, the term "pharmaceutical acceptable salts" is intended to include salts prepared with active compounds from relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, alkali addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base in pure or suitable inert solvent. Examples of salts derived from pharmaceutical acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Salts derived from pharma- ceutically acceptable organic bases include salts of primary, secondary, and tertiary amines (including substituted amines, cyclic amines, naturally occurring amines, and the like), such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Pharmaceutically acceptable examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and the like, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginine, and organic acids such as glucuronic acid or galacturonic acid, etc.

[0085] The term "pharmaceutically acceptable carrier" refers to a representative carrier of any formulation or carrier medium capable of delivering an effective amount of an active agent of the present invention, does not interfere with the biological activity of the active agent, does not have toxic side effects on the host or patient, and includes water, oils, vegetable and mineral substances, paste bases, lotion bases, ointment bases, and the like. These bases include suspending agents, thickening agents, transdermal enhancers, and the like. Their formulations are well known to those skilled in the art of cosmetics or topical drugs.

[0086] The composition containing the compound of formula I is usually formulated according to standard pharmaceutical practice for pharmaceutical compositions.A typical preparation is prepared by mixing the compound of the present invention with a diluent, carrier, or excipient.The preparation may also contain one or more of buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, aromas, flavorings, thinners, and other known additives.

[0087] The compounds of the present invention may be applied in any convenient form for use, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional ingredients of pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0088] The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, pulmonary, intradermal, intrathecal and epidural, and intranasal, as well as intralesional administration where required for localized treatment. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, intracerebral, intraocular, topical, or subcutaneous administration.

[0089] "Pain" in the present invention means pain associated with abnormalities in voltage-gated sodium channels, specifically, the voltage-gated sodium channel is Nav1.8. Pain in the present invention includes, but is not limited to, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, and arrhythmia.

[0090] Among them, intestinal pain is, for example, inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain. Musculoskeletal pain is, for example, osteoarthritis pain, back pain, cold pain, burning pain or toothache. Inflammatory pain is, for example, rheumatoid arthritis pain or vulvodynia, idiopathic pain including fibromyalgia. Neuropathic pain is, for example, postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, amputation pain, hallucinatory pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal canal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, neuralgia due to drug therapy, neuralgia due to cancer chemotherapy, neuralgia due to antiretroviral therapy, pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy or trigeminal neuropathy.

[0091] The compounds of the present invention are named manually or by Chemdraw software; commercially available compounds adopt the supplier's catalogue name.

[0092] Compared with the prior art, the present invention has the following advantages: A series of structurally novel aromatic fused ring compounds are provided that have inhibitory activity against Nav1.8 and can be used as drugs to treat a wide range of pain.

[0093] The present invention will be described in more detail in connection with specific examples. It should be understood that these examples are merely for the purpose of illustrating the present invention and do not limit the scope of the present invention. In the following examples, the experimental methods for which no specific conditions are given are generally subject to conventional conditions or conditions recommended by the manufacturer. The chemical reactions described in the examples (preparation) can be easily modified to prepare many other compounds of the present invention, and alternative methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. Unless otherwise defined, the terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods or materials similar or equivalent to those described may be applied in the present invention.

[0094] The structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are 10 -6 The units are shown in ppm. Deuterated dimethylsulfone (DMSO-d6) or deuterated chloroform (CDCl3) was used as the solvent, and tetramethylsilane (TMS) was used as the internal standard. NMR was measured by a Bruker AVANCE III HD (400 MHz) or a Bruker NEO (400 MHz) nuclear magnetometer. MS was measured by a liquid mass spectrometry (LC-MS): LC-20AD / LCMS-2020 from Shimadzu or Agilent 1260 / 6125 from Agilent. High performance liquid chromatography (HPLC) analysis was performed by LC-20AD or LC-2030C from Shimadzu, or Agilent 1100 / 1200 from Agilent. Preparation and purification were performed by waters2767 or gilson GX281.

[0095] Example 1 Preparation of 3-(3-(4,4-difluoroazepan-1-yl)quinoxaline-2-formamide-pyridine-1-oxide (KH01) [ka] Step a): Preparation of ethyl 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylate [ka] 4,4-Difluoroazepane hydrochloride (4.3 g, 25.4 mmol) and DIEA (8.2 g, 63.5 mmol) were added to a solution of ethyl 3-quinoxaline-2-carboxylate (5 g, 21.2 mmol) in isopropyl alcohol (150 mL), and the reaction mixture was stirred at 50 °C for 16 h. After the reaction was cooled to room temperature, ethyl acetate was added to dilute it, water was added to separate the two phases, and the organic phase was then washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography to give ethyl 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylate (6.2 g, 73% yield) as a pale yellow solid. ESI-MS (m / z): 336.0 [M+H] + .

[0096] Step b): Preparation of 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid [ka] Lithium hydroxide (3.7 g, 89.2 mmol) was slowly added to a mixture of ethyl 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylate (6 g, 17.8 mmol) in water (20 mL) / methanol (60 mL) / tetrahydrofuran (5 mL) and reacted at 50° C. for 2.5 h. After the reaction was completed, it was quenched with ice water and 1M dilute hydrochloric acid was added to adjust the pH to about 7, after which the organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was spun dry, a yellow solid of 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid was obtained (4 g, 74% yield). 1H NMR (400MHz, DMSO-d6) δ7.81(d, J=8.2Hz, 1H), 7.67-7.55(m, 2H), 7.47-7.34(m, 1H), 3.78-3 .72(m, 2h), 3.64(t, J=6.0Hz, 2h), 2.36-2.34(m, 2h), 2.13-1.97(m, 2h), 1.94-1.83(m, 2h). ESI-MS(m / z):308.1[M+H] + .

[0097] Step c): Preparation of 3-(4,4-difluoroazepan-1-yl)-N-(pyridin-3-yl)quinoxaline-2-carboxamide [ka] 3-(4,4-Difluoroazepan-1-yl)quinoxaline-2-carboxylic acid (500mg, 1.6mmol) was dissolved in DMF (5mL), then DIEA (420.5mg, 3.2mmol) and HATU (928mg, 2.4mmol) were added and stirred at room temperature for 1h, followed by pyridin-3-amine (183.7mg, 1.9mmol) and the reaction continued for 2h. The reaction was quenched by adding 10mL of saturated aqueous NH4Cl solution, and the resulting mixture was extracted with dichloromethane (20mL*3), then the organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by normal phase preparative chromatography to give 3-(4,4-difluoroazepan-1-yl)-N-(pyridin-3-yl)quinoxaline-2-carboxamide (405 mg, 64.9% yield) as a yellow solid. ESI-MS (m / z): 382.1 [MH] - .

[0098] Step d): Preparation of 3-(3-(4,4-difluoroazepan-1-yl))quinoxaline-2-carboxamide)pyridine-1-oxide (KH01) [ka] m-Chloroperbenzoic acid (180.0 mg, 1.0 mmol) was added to a solution of 3-(4,4-difluoroazepan-1-yl)-N-(pyridin-3-yl)quinoxaline-2-carboxamide (200 mg, 0.5 mmol) in dichloromethane (3 mL), and the reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, 10 mL of saturated aqueous NaHCO3 was added, and the resulting mixture was extracted with dichloromethane (20 mL x 3), after which the organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by reverse phase preparative chromatography to give 3-(3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide)pyridine-1-oxide (56.42 mg, 27.0% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.40(s, 1H), 8.82(t, J=1.6Hz, 1H), 8.06(d, J=6.4Hz, 1H), 7.96(d, J=8.2Hz, 1H), 7.77-7.69(m, 2h ), 7.63(d, J=9.4Hz, 1h), 7.55-7.50(m, 1h), 7.45(dd, J=8.4, 6.4Hz, 1h), 3.83-3.73(m, 2h), 3.61(t, J=5.8Hz, 2H), 2.40(br s, 2H), 2.03(t, J=16.6Hz, 2H), 1.93(d, J=5.4Hz, 2H). ESI-MS(m / z):400.0[M+H] + .

[0099] Example 2 Preparation of N-(3-carbamoyl-4-fluorophenyl)-3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide (KH02) [ka] N-(3-carbamoyl-4-fluorophenyl)-3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide was synthesized in the same manner as steps a-c in Example 1, except that pyridine-3-amine in step c was replaced with 5-amino-2-fluorobenzamide, and white solid N-(3-carbamoyl-4-fluorophenyl)-3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide (67.41 mg, yield 35.9%) was obtained. 1 H NMR (400MHz, CDCl3) δ9.58 (s, 1H), 8.36-8.27 (m, 1H), 8.14 (dd, J=6.6, 2.9Hz, 1H), 7.92(dd, J=8.3, 0.8Hz, 1H), 7.74(d, J=7.7Hz, 1H), 7.71-7.63(m, 1H), 7.47-7.30( m, 1H), 7.21(dd, J=11.3, 9.0Hz, 1H), 6.76(d, J=11.3Hz, 1H), 5.95(s, 1H), 3.96-3. 84(m, 2H), 3.63(d, J=5.1Hz, 2H), 2.55-2.38(m, 2H), 2.02(dd, J=12.3, 8.2Hz, 4H). ESI-MS(m / z):444.1[M+H] + .

[0100] Example 3 Preparation of 3-(4,4-difluoroazepan-1-yl)-N-(2-carbonyl-1,2-dihydropyridin-4-yl)quinoxaline-2-carboxamide (KH03) [ka] 3-(4,4-difluoroazepan-1-yl)-N-(2-methoxypyridin-4-yl)quinoxaline-2-carboxamide is synthesized similarly to steps a to c in Example 1, except that pyridine-3-amine in step c is replaced with 2-methoxypyridin-4-amine.

[0101] Sodium iodide (181.5 mg, 1.21 mmol) and trimethylchlorosilane (131 mg, 1.21 mmol) were added to a solution of 3-(4,4-difluoroazepan-1-yl)-N-(2-methoxypyridin-4-yl)quinoxaline-2-carboxamide (190 mg, 0.605 mmol) in tetrahydrofuran (4 mL), and the resulting mixture was reacted at 50° C. for 16 h. After the reaction was completed, it was quenched with water and extracted with ethyl acetate. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by C18 reverse phase column under formic acid condition to obtain a pale yellow solid powder of 3-(4,4-difluoroazepan-1-yl)-N-(2-carbonyl-1,2-dihydropyridin-4-yl)quinoxaline-2-carboxamide (67.1 mg, yield 37%). 1 H NMR (400MHz, DMSO-d6) δ11.38(br s, 1H), 11.07(s, 1H), 7.95(d, J=8.2Hz, 1H), 7.71(d, J=3.5Hz, 2H), 7.56-7.45(m, 1H), 7 .38(d, J=7.1Hz, 1H), 6.87(s, 1H), 6.50(d, J=7.1Hz, 1H), 3.77(d, J=2.5Hz, 2H), 3.62(br s, 2H), 2.39(br s, 2H), 2.03(br s, 2H), 1.93(d, J=5.1Hz, 2H). ESI-MS(m / z):400.1[M+H] + .

[0102] Example 4 Preparation of 3-(4,4-difluoroazepan-1-yl)-N-(6-carbonyl-1,6-dihydropyridazin-4-yl)quinoxaline-2-carboxamide (KH04) [ka] Step a): Preparation of 6-methoxypyridazin-4-amine [ka] Sodium methylate (1.78 g, 32.9 mmol) was added to a solution of 6-chloro-pyridazin-4-amine (850 mg, 6.589 mmol) in methanol (20 mL) at 0° C. and stirred at 75° C. for 16 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was extracted and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 6-methoxypyridazin-4-amine (780 mg, 94% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.26 (d, J=1.5Hz, 1H), 6.33 (s, 2H), 5.97 (d, J=1.4Hz, 1H), 3.87 (s, 3H). ESI-MS(m / z):126.1[M+H] + .

[0103] Step b): Preparation of 3-(4,4-difluoroazepan-1-yl)-N-(6-methoxydrazine-4-yl)quinoxaline-2-carboxamide [ka] For the synthesis of 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid, see Example 1, steps a and b.

[0104] HATU (297 mg, 0.781 mmol) and DIEA (210 mg, 1.628 mmol) were added to a solution of 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid (200 mg, 0.651 mmol) in DMF (5 mL). After reacting at room temperature for 0.5 h, 6-methoxy-pyridazin-4-amine (163 mg, 1.302 mmol) was added and reacted at room temperature for 16 h. After the reaction was completed, water was added to quench the reaction, and the organic phase (20 mL) was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel plate (ethyl acetate / petroleum ether (v / v) = 1 / 1) to give 3-(4,4-difluoroazepan-1-yl)-N-(6-methoxy-pyridazin-4-yl)quinoxaline-2-carboxamide (55 mg, 20% yield) as a pale yellow oil. 1 H NMR (400MHz, DMSO-d6) δ11.65(s, 1H), 9.13(s, 1H), 7.95(s, 1H), 7.74(d, J=13.5Hz, 2H), 7.63(s, 1H), 7.52(s, 1H), 4.05(s, 3H), 3.77(br s, 2H), 3.58(t, J=5.6Hz, 2H), 2.39(br s, 2H), 2.00(d, J=12.4Hz, 2H), 1.92(d, J=4.7Hz, 2H). ESI-MS(m / z):415.1[M+H]+.

[0105] Step c): Preparation of 3-(4,4-difluoroazepan-1-yl)-N-(6-carbonyl-1,6-dihydropyridazin-4-yl)quinoxaline-2-carboxamide (KH04) [ka] Sodium iodide (50 mg, 0.332 mmol) and trimethylchlorosilane (36 mg, 0.332 mmol) were added to a solution of 3-(4,4-difluoroazepan-1-yl)-N-(6-methoxydiazin-4-yl)quinoxaline-2-carboxamide (55 mg, 0.133 mmol) in tetrahydrofuran (4 mL) and reacted at 50° C. for 16 hours. After the reaction was completed, water was added to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by C18 reverse phase column under formic acid condition to obtain a pale yellow solid powder of 3-(4,4-difluoroazepan-1-yl)-N-(6-carbonyl-1,6-dihydropyridazin-4-yl)quinoxaline-2-carboxamide (13.2 mg, yield 25%). 1 H NMR (400MHz, DMSO-d6) δ12.89(s, 1H), 11.45(s, 1H), 8.09(d, J=2.3Hz, 1H), 7.96(d, J=8.1Hz, 1H), 7. 73-7.72(m, 2H), 7.52(ddd, J=8.3, 5.6, 2.8Hz, 1H), 7.33(d, J=2.0Hz, 1H), 3.79-3.74(m, 2H), 3.57(br s, 2H), 2.40(br s, 2H), 2.05-2.00(m, 2H), 1.93(br s, 2H). ESI-MS(m / z):401.1[M+H] + .

[0106] Example 5 Preparation of N-(2-carbamoylpyridin-4-yl)-3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide (KH05) [ka] Step a): Preparation of 4-aminopyridine-2-carbonitrile [ka] Iron powder (1.88 g, 33.5 mmol) and ammonium chloride (1.78 g, 33.5 mmol) were added to a mixture of 2-cyano-4-nitropyridine (1 g, 6.7 mmol) in ethanol (100 mL) / water (10 mL) and stirred at 60° C. for 2 h. After cooling the reaction mixture to room temperature, it was filtered and the filtrate was quenched with water, after which the organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v)=1 / 40) to give 4-aminopyridine-2-carbonitrile (400 mg, 51% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.07 (d, J=5.7Hz, 1H), 6.95 (d, J=2.3Hz, 1H), 6.69 (dd, J=5.7, 2.3Hz, 1H), 6.60 (s, 2H). ESI-MS(m / z):120.2[M+H] + .

[0107] Step b): Preparation of 4-aminopyridine-2-carboxamide [ka] Cesium carbonate (1.65 g, 10.08 mmol) was added to a solution of 4-aminopyridine-2-carbonitrile (400 mg, 3.36 mmol) in dimethyl sulfoxide (10 mL), and 30% hydrogen peroxide (0.5 mL) was added slowly at 0° C. The reaction was carried out at room temperature for 4 h. After the reaction was completed, it was quenched with ice water, and the organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by reverse phase preparative chromatography to give 4-aminopyridine-2-carboxamide (300 mg, 65% yield). 1H NMR (400MHz, DMSO-d6) δ8.01(d, J=5.5Hz, 1H), 7.89(s, 1H), 7.39(s, 1H), 7.21(d, J=2.3Hz, 1H), 6.58(dd, J=5.5, 2.4Hz, 1H), 6.28(s, 2H). ESI-MS(m / z):308.1[M+H] + .

[0108] Step c): Preparation of N-(2-carbamoylpyridin-4-yl)-3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide (KH05) [ka] For the synthesis of 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid, see Example 1, steps a and b.

[0109] 2-(7-Azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (333 mg, 0.8795 mmol), N,N-diisopropylethylamine (188 mg, 1.459 mmol) were added to a solution of 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid (224 mg, 0.730 mmol) in N,N-dimethylformamide (5 mL), and the reaction mixture was reacted at room temperature for 0.5 h, and then 4-aminopyridine-2-carboxamide (110 mg, 0.803 mmol) was added, and the resulting mixture was reacted at room temperature for 16 h. After the reaction was completed, it was quenched with water, and the organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by preparative chromatography to obtain a pale yellow solid powder of N-(2-carbamoylpyridin-4-yl)-3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide (25.6 mg, yield 8.3%). 1H NMR (400MHz, DMSO-d6) δ11.55(s, 1H), 8.58(d, J=5.4Hz, 1H), 8.45(s, 1H), 8.13(s, 1H), 8.03-7.91(m, 2H) ), 7.77-7.71(m, 2H), 7.68(s, 1H), 7.55-7.48(m, 1H), 3.88-3.76(m, 2H), 3.63(t, J=5.7Hz, 2H), 2.40(br s, 2H), 2.10-2.01(m, 2H), 1.93(d, J=5.4Hz, 2H). ESI-MS(m / z):427.1[M+H] + .

[0110] Example 6 Preparation of 3-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)quinoxaline-2-carboxamide (KH06) [ka] Step a): Preparation of 2-benzylthio-4-bromopyridine [ka] A solution of benzylthiol (3 g, 24.1 mmol) in tetrahydrofuran (50 mL) was placed in an ice-water bath, and NaH (1.45 g, 60.4 mmol, 60%) was added in batches, after which the reaction was allowed to warm to room temperature and stirred for 1 h. 4-Bromo-2-fluoropyridine (4.5 g, 25.5 mmol) was then added and the reaction continued for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, 20 mL of saturated aqueous NH4Cl was added under ice-water bath conditions, the organic matter was extracted with dichloromethane (20 mL x 3), the organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by normal phase chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1) to give 2-benzylthioether-4-bromopyridine (5.8 g, 85.6% yield) as a colorless oil. ESI-MS(m / z):281.9[M+2] + .

[0111] Step b): Preparation of 4-bromopyridine-2-sulfonyl chloride [ka] Water (8 mL) and acetic acid (4 mL) were added to a solution of 2-benzylthio-4-bromopyridine (2 g, 7.1 mmol) in dichloromethane (28 mL) and the reaction was cooled to 0°C. 1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (4.22 g, 21.4 mmol) was added in batches, and then the reaction was allowed to warm to room temperature and stirred for 16 h. After the reaction was complete, the reaction was placed in an ice-water bath and 20 mL of saturated aqueous NaHCO3 was added to quench the reaction. The organics were extracted with dichloromethane (20 mL x 3), and the organic phase was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. After concentration under reduced pressure, a cream-colored semi-oily 4-bromopyridine-2-sulfonyl chloride (4.78 g, crude) was obtained. ESI-MS (m / z): 253.9 [M-Cl+MeO - +2] + .

[0112] Step c): Preparation of 4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridinesulfonamide [ka] 4-Bromopyridine-2-sulfonyl chloride (2 g, 7.8 mmol) was dissolved in dichloromethane (20 mL), DIEA (5.04 g, 38.9 mmol) was added under ice-water bath, followed by the batch addition of bis(2,4-dimethoxybenzyl)amine (3.71 g, 11.7 mmol). The reaction was then allowed to warm to room temperature and stirred for 4 h. After the reaction was complete, 20 mL of saturated aqueous NH4Cl was added to quench the reaction, and the organic phase was extracted with dichloromethane (25 mL x 3), separated, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting crude product was purified by normal phase chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1) to give light brown sugar-like 4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridinesulfonamide (860 mg, 20.5% yield). LCMS (ESI, m / z): 560.9 [M+Na+2] + . 1 H NMR (400MHz, DMSO-d6) δ8.51(d, J=5.2Hz, 1H), 7.86-7.82(m, 1H), 7.60(d, J=1.8Hz, 1H), 7.08(d, J=8 .4Hz, 2h), 6.45(dd, J=8.4, 2.3Hz, 2h), 6.35(d, J=2.3Hz, 2h), 4.43(s, 4h), 3.73(s, 6h), 3.61(s, 6h). ESI-MS(m / z):560.9[M+Na + +2] + .

[0113] Step d): Preparation of N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide [ka] 4-Bromo-N,N-bis(2,4-dimethoxybenzyl)pyridinesulfonamide (140 mg, 0.26 mmol) was dissolved in toluene (2 mL), then 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide (87.7 mg, 0.28 mmol) and Cs2CO3 (254.6 mg, 0.78 mmol) were added, followed by Ruphos Pd G2 (20.2 mg, 0.026 mmol). After the reaction was purged with nitrogen, the reaction was carried out at 110° C. for 16 h. After the reaction was completed, the reaction was cooled to room temperature and then concentrated under reduced pressure. 10 mL of saturated aqueous NH4Cl was added to the resulting residue and extracted with dichloromethane (25 mL×3). The organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting crude product was purified by normal phase chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to obtain a yellow solid, N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide (116.8 mg, 58.7% yield). ESI-MS ( + m / z):763.1[M+H].

[0114] Step e): Preparation of 3-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)quinoxaline-2-carboxamide (KH06) [ka] N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide (110 mg, 0.14 mmol) was dissolved in dichloromethane (2 mL), then trifluoroacetic acid (1 mL) was added, and the reaction was stirred at room temperature for 2 h after addition. After the reaction was complete, 10 mL of saturated aqueous NaHCO3 was added, and the reaction mixture was extracted with dichloromethane (25 mL x 3). The organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by reverse phase chromatography to give N-(2-aminosulfonylpyridin-4-yl)-3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxamide (31.17 mg, 46.7% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.71(s, 1H), 8.66(d, J=5.4Hz, 1H), 8.40(d, J=1.7Hz, 1H), 7.96(d, J=8.1Hz, 1H), 7.93(dd, J=5.5, 2.0Hz, 1H), 7.77-7.71(m, 2H), 7.55-7.51(m, 1H), 7.50(d, J=4.2Hz, 2H), 3.86-3.74(m, 2H), 3.61(t, J=5.7Hz, 2H), 2.40(br s, 2H), 2.05(d, J=19.4Hz, 2H), 1.93(d, J=5.4Hz, 2H). ESI-MS(m / z):463.0[M+H] + .

[0115] Step f): Preparation of 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide [ka] For the synthesis of 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid, see Example 1, steps a and b.

[0116] HATU (371.2 mg, 0.9 mmol) and DIEA (420.5 mg, 3.2 mmol) were added to a solution of 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid (200 mg, 0.6 mmol) in DMF (5 mL). After half an hour, NH4Cl (139.2 mg, 2.6 mmol) was added and stirred at room temperature for 2 h. Water (15 mL) was added to quench the reaction, and then the reaction was extracted using dichloromethane (20 mL x 3), the organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by normal phase chromatography (dichloromethane / methanol (v / v)=20 / 1) to obtain 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide (160 mg, yield 80.2%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.25(br s, 1H), 7.85(d, J=7.2Hz, 2H), 7.65(d, J=3.9Hz, 2H), 7.45-7.40(m, 1H), 3.843 .73(m, 2H), 3.68(2H, t, J=5.8Hz), 2.39(d, J=10.3Hz, 2h), 2.11-1.88(m, 4h). ESI-MS(m / z):306.9[M+H] + .

[0117] Example 7 Preparation of N-(3-carbamoylphenyl)-3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide (KH07) [ka] The procedure was the same as steps a to c in Example 1, except that pyridin-3-amine was replaced with 3-aminobenzamide. After the reaction, the mixture was extracted with ethyl acetate to obtain a white solid, N-(3-carbamoylphenyl)-3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide (50 mg, yield 12.1%). 1H NMR (400MHz, CDCl3) δ11.10(s, 1H), 8.24(s, 1H), 8.02(br s, 1H), 7.94(dd, J=16.2, 8.1Hz, 2H), 7.73(d, J=4.0Hz, 2H), 7.66(d, J=7.8Hz, 1H), 7.51-7.48(m, 2H), 7.42(br s, 1H), 3.89-3.76(m, 2H), 3.71(t, J=5.8Hz, 2H), 2.41-2.38(m, 2H), 2.132.04(m, 2H), 1.95-1.92(m, 2H). ESI-MS(m / z):425.9[M+H] + .

[0118] Example 8 Preparation of N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide (KH08) [ka] Step a): Preparation of 2-chloroquinoline-3-carboxylic acid [ka] NaClO 2( 11.8 g, 130.9 mmol) and Na2H2PO4 (18.5 g, 130.9 mmol) were dissolved in water (10 mL), and a solution of 2-chloroquinoline-3-formaldehyde (5 g, 26.1 mmol) in tert-butanol was added at 0°C and stirred at room temperature for 16 h. After the reaction was completed, water was added to dilute the mixture, and the pH of the reaction mixture was adjusted to 3-4 with 1 M HCl solution and filtered. The residue was washed to obtain a pale yellow solid of 2-chloroquinoline-3-carboxylic acid (2.8 g, 52% yield). H NMR (400 1 MHz, DMSO-d6)δ8.86(s, 1H), 8.16(d, J=8.0Hz, 1H), 8.00(d, J=8.4Hz, 1H), 7.92(dd, J=11.2, 4.1Hz, 1H), 7.72(t, J=7.5Hz, 1H). ESI-MS(m / z):208.1[M+H] + .

[0119] Step b): Preparation of ethyl 2-chloroquinoline-3-carboxylate [ka] K2CO3 (3.7 g, 27 mmol) and iodine ethane (4.2 g, 27 mmol) were added to a solution of 2-chloroquinoline-3-carboxylic acid (2.8 g, 13.5 mmol) in DMF (20 mL) and stirred at room temperature for 16 h. After the reaction was completed, water was added to dilute the reaction mixture, and the reaction was extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed three times with saturated brine, and the solvent was removed by vacuum rotary evaporation. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give ethyl 2-chloroquinoline-3-carboxylate (2.3 g, 72% yield) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ8.95-8.50(m, 1H), 8.07(t, J=13.4Hz, 1H), 7.90(d, J=8.2Hz, 1H ), 7.86-7.80(m, 1H), 7.68-7.55(m, 1H), 4.48(q, J=7.1Hz, 2H), 1.46(t, J=7.1Hz, 3H). ESI-MS(m / z):236.1[M+H] + .

[0120] Step c): Preparation of ethyl 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylate [ka] 4-Difluoroazepane hydrochloride (1.9 g, 11.64 mmol) and DIEA (3.75 g, 29.1 mmol) were added to a solution of 2-chloroquinoline-3-carboxylic acid (2.3 g, 9.7 mmol) in NMP (15 mL), respectively. The reaction mixture was stirred at 140° C. for 16 h. After the reaction was completed, it was cooled to room temperature and diluted with 100 mL of water. Then, the reaction mixture was extracted with ethyl acetate (100 mL×3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=5 / 1) to give ethyl 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylate (2 g, 61% yield) as a pale yellow oil. 1 H NMR (400MHz, CDCl3) δ8.31(s, 1H), 7.68(dd, J=10.6, 8.7Hz, 2H), 7.60-7.56(m, 1H), 7.25-7.21(m, 1H), 4.40(q, J=7.1H) z, 2H), 3.88-3.74(m, 2H), 3.48(2H, t, J=5.6Hz), 2.58-2.40(m, 2H), 1.98(dd, J=8.7, 4.1Hz, 4h), 1.42(t, J=7.1Hz, 3H). ESI-MS(m / z):335.0[M+H] + .

[0121] Step d): Preparation of 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid [ka] Lithium hydroxide (288 mg, 12 mmol) was added to a solution of 2-(4,4-difluoroazepan-1-yl)quinoline-3-ethyl carboxylate (2 g, 6.0 mmol) in methanol / water (10 mL / 2 mL) and reacted at room temperature for 16 h. After the reaction was completed, the pH of the reaction system was adjusted to 3-4 with 1 M HCl solution, and then extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a yellow solid 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid (1.4 g, 70% yield), which was used directly in the next step. ESI-MS ( + m / z): 306.9 [M+H].

[0122] Step e): Preparation of N-(2-methylformatopyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide [ka] Oxalyl chloride (621 mg, 4.89 mmol) and one drop of DMF were added to 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid (500 mg, 1.63 mmol) at 0° C. and reacted at room temperature for 1 H. The reaction mixture was concentrated under reduced pressure and the obtained crude product was dissolved in 4 mL of dichloromethane. Then, triethylamine (823 mg, 8.15 mmol) and methyl 4-aminopyridine-2-carboxylate (300 mg, 1.95 mmol) were added and reacted at room temperature for 16 h. After the reaction was completed, it was diluted with water and then extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid, N-(2-methylformatopyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide (300 mg, 41% yield), which was used directly in the next step. ESI-MS (m / z): 441.2 [M+H] + .

[0123] Step f): Preparation of N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide (KH08) [ka] N-(2-methylformatopyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide (300 mg, 0.68 mmol) was dissolved in 3 mL of acetonitrile. Ammonium chloride (6.3 mg, 0.12 mmol) and 1.8 mL of aqueous ammonia were added, and the resulting mixture was reacted at room temperature for 3 h. After the reaction was completed, the reaction system was concentrated, and the crude product was purified by Prep-HPLC to obtain white solid N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide (50 mg, 17.3% yield). 1 H NMR (400MHz, DMSO-d6) δ11.20(s, 1H), 8.56(d, J=5.5Hz, 1H), 8.48-8.33(m, 2H), 8.11(br s, 1H), 7.95-7.80(m, 2H), 7.65(d, J=3.6Hz, 3H), 7.32-7.30(m, 1H), 3.80-3.67(m, 2H) ), 3.57(2H, t, J=5.8Hz), 2.43-2.31(m, 2H), 2.01-1.98(m, 2H), 1.89(d, J=5.4Hz, 2H). ESI-MS(m / z):425.9[M+H] + .

[0124] Example 9 Preparation of N-(3-carbamoyl-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide (KH09) [ka] For the synthesis of 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid, see steps a to d in Example 8.

[0125] HATU (296 mg, 0.778 mmol), 5-amino-2-fluorobenzamide (92.2 mg, 0.598 mmol) and DIEA (231 mg, 1.796 mmol) were added to a solution of (4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid (200 mg, 0.598 mmol) in DMF (5 mL) and reacted at room temperature for 16 h. After the reaction was completed, water was added to quench the reaction, and the organic phase was extracted with ethyl acetate (20 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by Prep-HPLC to obtain N-(3-carbamoyl-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide (108.7 mg, 41% yield) as a white solid powder. 1 H NMR (400MHz, DMSO-d6) δ10.79(s, 1H), 8.32(s, 1H), 8.03(dd, J=6.4, 2.7Hz, 1H), 7.86(d, J=4.4Hz, 1H), 7.84(d, J=3.6Hz, 1H), 7.68(br s, 2H), 7.64(br s, 2H), 7.30(dd, J=11.9, 7.2Hz, 2H), 3.76(d, J=4.8Hz, 2H), 3.62(t, J=5.8Hz, 2H), 2.40(br s, 2H), 2.00(br s, 2H), 1.89(d, J=4.9Hz, 2H). ESI-MS(m / z):443.2[M+H] + .

[0126] Example 10 Preparation of N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxamide (KH10) [ka] Step a): Preparation of 2-chloro-6,7-difluoroquinoline-3-carboxylic acid [ka] Silver nitrate (1.2 g, 7.02 mmol) was dissolved in a premixed solution of NaOH (0.88 g, 22 mmol) in ethanol / water (12 mL / 3 mL) under ice-water bath, and a solution of 2-chloro-6,7-difluoroquinoline-3-carbaldehyde (1 g, 4.39 mmol) in ethanol (10 mL) was slowly added dropwise at room temperature and stirred for 16 h. After the reaction was completed, the reaction mixture was filtered, and the pH of the filtrate was adjusted to 6 with 1 M hydrochloric acid, and then the organic phase was extracted with ethyl acetate (50 mL x 3), washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. A white solid 2-chloro-6,7-difluoroquinoline-3-carboxylic acid (1.0 g, 93.46% yield) was obtained. ESI-MS (m / z): 244.0 [M+H] + .

[0127] Step b): Preparation of ethyl 2-chloro-6,7-difluoroquinoline-3-carboxylate [ka] 2-Chloro-6,7-difluoroquinoline-3-carboxylic acid (1.0 g, 4.10 mmol) was dissolved in DMF (20 mL), then iodine ethane (1.28 g, 8.21 mmol) and potassium carbonate (1.13 g, 8.21 mmol) were added and stirred at room temperature for 16 h. The reaction mixture was diluted by adding water (100 mL) and extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by normal phase silica gel column (petroleum ether / ethyl acetate (v / v) = 0% to 30%) to give ethyl 2-chloro-6,7-difluoroquinoline-3-carboxylate (1.0 g, 89.29% yield) as a white solid. ESI-MS (m / z): 281.2 [M+H] + .

[0128] Step c): Preparation of ethyl 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylate [ka] 4-Difluoroazepane hydrochloride (0.81 g, 4.79 mmol) and DIEA (1.42 g, 11.04 mmol) were added to a solution of ethyl 2-chloro-6,7-difluoroquinoline-3-carboxylate (1.0 g, 3.68 mmol) in NMP (13 mL) and stirred at 140 °C for 16 h. After the reaction was completed, the reaction was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by normal phase silica gel column (petroleum ether / ethyl acetate (v / v) = 0% to 25%) to give ethyl 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylate (900 mg, 65.93% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3)delta8.21(s, 1H), 7.49-7.32(m, 2H), 4.40(q, J=7.1Hz, 2H), 3.83-3.74 (m, 2H), 3.45(t, J=5.6Hz, 2H), 2.53-2.37(m, 2H), 2.04-1.92(m, 4h), 1.42(t, J=7.1Hz, 3H). ESI-MS(m / z):371.2[M+H] + .

[0129] Step d): Preparation of 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylic acid [ka] First, a mixture of methanol (10 mL), water (10 mL) and THF (10 mL) was prepared, and ethyl 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylate (900 mg, 2.43 mmol) was added to the prepared mixture. Lithium hydroxide (612.36 mg, 14.58 mmol) was then added and stirred at 50° C. for 3 h. The pH of the reaction mixture was adjusted to 6 with 1 M hydrochloric acid and extracted with ethyl acetate (15 mL×3), after which the combined organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a pale yellow solid 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylic acid (702.03 mg, 84.38% yield). 1 H NMR (400MHz, DMSO-d6) δ13.42(br s, 1H), 8.44(s, 1H), 7.93(dd, J=10.9, 9.2Hz, 1H), 7.53(dd, J=12.3, 7.6Hz, 1H), 3.75-3.67(m, 2H), 3.49(2H, t, J=5.8Hz), 2.46-2.33(m, 2H), 2.08-1.86(m, 4h). ESI-MS(m / z):343.2[M+H] + .

[0130] Step e): Preparation of methyl 4-(2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxamide)pyridinecarboxylate [ka] At room temperature, 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylic acid (300 mg, 0.88 mmol) was dissolved in dichloromethane (10 mL), then DMF (0.05 mL) was added, and oxalyl chloride (335.09 mg, 2.64 mmol) was slowly added. The resulting mixture was stirred at room temperature for 1 h. The solvent was removed by vacuum rotary evaporation, and the resulting residue was dissolved in dichloromethane (5 mL). Then methyl 4-aminopyridine-2-carboxylate (401.68 mg, 2.64 mmol) and triethylamine (445.23 mg, 4.40 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (30 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by normal phase silica gel column (petroleum ether / ethyl acetate (v / v) = 0% to 35%) to obtain a pale yellow solid, methyl 4-(2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxamide)pyridinecarboxylate (152 mg, 36.4% yield). ESI-MS (m / z): 476.8 [M+H] + .

[0131] Step f): Preparation of N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxamide (KH10) [ka] Solid ammonium chloride (5 mg, 0.09 mmol) and aqueous ammonia (5 mL) were added to a solution of methyl 4-(2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxamide)pyridinecarboxylate (150 mg, 0.315 mmol) in acetonitrile (5 mL) and reacted at 40° C. for 4 h, and water (20 mL) was added to dilute the reaction solution. The organic phase was extracted with ethyl acetate (35 mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The obtained crude product was purified by Prep-HPLC to obtain white solid N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxamide (53.77 mg, 37.0% yield). 1 H NMR (400MHz, DMSO-d6) δ11.26(s, 1H), 8.56(d, J=5.5Hz, 1H), 8.45-8.32(m, 2H), 8.11(d, J=2.2Hz, 1H), 7.977.85(m, 2H), 7.66(d, J=2.2H) z, 1H), 7.60(dd, J=12.2, 7.6Hz, 1H), 3.74-3.71(m, 2H), 3.55(t, J=5.8Hz, 2H), 2.39-2.38(m, 2H), 1.97-1.95(m, 2H), 1.88-1.86(m, 2H). ESI-MS(m / z):462.3[M+H] + .

[0132] Example 11 Preparation of N-(3-carbamoyl-4-fluorophenyl)-3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxamide (KH11) [ka] Step a): Preparation of 3-(4,4-difluoroazepan-1-yl)quinoline [ka] 4,4-Difluoroazepane hydrochloride (4.49 g, 26.4 mmol), Ruphos-Pd-G2 (0.513 g, 0.66 mmol) and potassium tert-butanol (7.4 g, 66 mmol) were added to a solution of 3-chloroquinoline (3.6 g, 22 mmol) in 1,4-dioxane (30 mL) and stirred at 105 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction was quenched with water (100 mL), extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20) to give 3-(4,4-difluoroazepan-1-yl)quinoline (3 g, 51.7% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.73(d, J=2.5Hz, 1H), 7.82(d, J=8.1Hz, 1H), 7.72(d, J=7.9Hz, 1H), 7.45-7.28(m, 3H), 3.68(d, J=4.9Hz, 2H), 3.60(2H, t, J=5.8Hz), 2.39-2.24(m, 2H), 2.17-2.02(m, 2H), 1.97-1.85(m, 2H). ESI-MS(m / z):263.2[M+H] + .

[0133] Step b): Preparation of 3-(4,4-difluoroazepan-1-yl)quinoline-oxide [ka] m-Chloroperoxybenzoic acid (3.4 g, 19.7 mmol) was slowly added to a solution of 3-(4,4-difluoroazepan-1-yl)quinoline (2.6 g, 9.88 mmol) in dichloromethane (40 mL) and reacted at 40 °C for 48 h. After the reaction was completed, the reaction was quenched with water (50 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed twice with 10% aqueous sodium thiosulfate solution, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 5) to give 3-(4,4-difluoroazepan-1-l)quinoline-1-oxide (1.5 g, 55.5% yield) as a white solid. ESI-MS (m / z): 279.3 [M+H] + .

[0134] Step c): Preparation of 2-bromo-3-(4,4-difluoroazepan-1-yl)quinoline [ka] N-bromosuccinimide (1.9 g, 10.7 mmol) and triphenylphosphine (2.83 g, 10.7 mmol) were added to a solution of 3-(4,4-difluoroazepan-1-yl)quinoline-1-oxide (1.5 g, 5.37 mmol) in toluene (20 mL) and reacted at 115 °C for 2 h. After the reaction was completed, the reaction was quenched with water (40 mL), extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 7) to give 2-bromo-3-(4,4-difluoroazepan-1-l)quinoline (100 mg, 5.4% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 7.95-7.85 (m, 2H), 7.61-7.55 (m, 3H), 3.29 (br s, 4H), 2.36-2.30 (m, 4H), 1.86 (br s, 2H). ESI-MS(m / z):341.2[M+H]+ .

[0135] Step d): Preparation of methyl 3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxylate [ka] Triethylamine (88.8 mg, 0.879 mmol) and Pd(dppf)Cl2 (23 mg, 0.0293 mmol) were added to a solution of 2-bromo-3-(4,4-difluoroazepan-1-yl)quinoline (100 mg, 0.293 mmol) in methanol (20 mL), the gas was replaced with carbon monoxide three times, and the reaction was reacted in an autoclave (4 atm) at 110 °C for 16 h. After the reaction was completed, the reaction was quenched with water (40 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v)=1 / 5) to give a yellow solid, methyl 3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxylate (55 mg, yield 58%). 1 H NMR (400MHz, DMSO-d6) δ7.98-7.84(m, 3H), 7.63-7.45(m, 2H), 3.939(s, 3H), 3.40-3.34(m, 4H), 2.33-2.23(m, 2H), 2.21-2.14(m, 2H), 1.91-1.83(m, 2H). ESI-MS(m / z):321.3[M+H] + .

[0136] Step e): Preparation of 3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxylic acid [ka] Lithium hydroxide (25 mg, 0.601 mmol) was slowly added to a mixture of methyl 3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxylate (55 mg, 0.178 mmol) in water (0.5 mL) and tetrahydrofuran (2 mL) and allowed to react at room temperature for 1 h. After completion of the reaction, the reaction was quenched with ice water and 1M dilute hydrochloric acid was added to adjust the pH to 7. It was then extracted with ethyl acetate (10 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxylic acid (40 mg, 76% yield) as a yellow solid. ESI-MS (m / z): 307.1 [M+H] + .

[0137] Step f): Preparation of N-(3-carbamoyl-4-fluorophenyl)-3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxamide (KH11) [ka] HATU (60 mg, 0.1302 mmol), 5-amino-2-fluorobenzamide (20 mg, 0.1302 mmol) and triethylamine (39 mg, 0.3908 mmol) were added to a solution of 3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxylic acid (40 mg, 0.1302 mmol) in dichloromethane (2 mL) and reacted at room temperature for 2 h. After completion of the reaction, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to give N-(3-carbamoyl-4-fluorophenyl)-3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxamide (3.10 mg, yield 5.3%) as a solid powder. 1H NMR (400MHz, MeOD) δ8.16 (dd, J=6.4, 2.7Hz, 1H), 8.05-7.97 (m, 2H), 7.96 (s, 1H), 7.86 (d, J=8.3Hz, 1H), 7.65 -7.55(m, 2H), 7.32-7.24(m, 1H), 3.49-3.43(m, 4h), 2.35-2.24(m, 2H), 2.17-2.01(m, 2H), 1.98-1.90(m, 2H). ESI-MS(m / z):443.2[M+H] + . Example 12

[0138] Preparation of N-(3-carbamoylphenyl)-2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxamide (KH12) [ka] 2-(4,4-Difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylic acid was prepared similarly to steps a-d of Example 10.

[0139] (4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylic acid (100 mg, 0.29 mmol) was dissolved in DMF (2 mL), then 3-aminobenzamide (43.75 mg, 0.32 mmol), HATU (113.3 mg, 0.35 mmol) and DIEA (113.27 mg, 0.87 mmol) were added and stirred at room temperature for 4 h. Water (20 mL) was added to dilute the reaction system, then it was extracted with ethyl acetate (10 ml x 3), washed with saturated brine (10 ml x 2), and the organic phase was dried over anhydrous sodium sulfate and concentrated. White solid N-(3-carbamoylphenyl)-2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxamide (3.2 mg, 2.37% yield) was prepared by Prep-HPLC. 1H NMR (400MHz, DMSO-d6) δ10.80(s, 1H), 8.31(s, 1H), 8.19(s, 1H), 8.01-7.88(m, 2H), 7.85(d, J=8.0Hz, 1H), 7. 62(d, J=7.8Hz, 2H), 7.43-7.40(m, 2H), 3.82-3.67(m, 2H), 3.61(2H, t, J=5.9Hz), 2.36-2.32(m, 2H), 2.00(br s, 2H), 1.89(br s, 2H). ESI-MS(m / z):461.3[M+H] + .

[0140] Example 13 Preparation of 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide (KH13) [ka] The preparation of 3-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide is similar to steps a-d of Example 8 and Example 6, except that 3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxylic acid in step f of Example 6 is replaced with 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid synthesized through steps a-d of Example 8, 4-bromo-2-fluoropyridine in step a of Example 6 is replaced with 4-bromo-2-fluorobenzene, and the room temperature in step e of Example 6 is changed to 80 ° C., and white solid 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide (22.12 mg, yield 30.56%) is obtained. 1H NMR (400MHz, DMSO-d6) δ10.96(s, 1H), 8.33(s, 2H), 7.93-7.75(m, 2H), 7.64(d, J=3.6Hz, 2H), 7.57(dd, J=8.0, 5.5Hz, 2H) , 7.42(s, 2H), 7.35-7.25(m, 1H), 3.83-3.70(m, 2H), 3.61(t, J=5.9Hz, 2H), 2.43-2.40(m, 2H), 2.00-1.95(m, 2H), 1.90(br s, 2H). ESI-MS(m / z):461.1[M+H]+.

[0141] Example 14 Preparation of 2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)quinoline-3-carboxamide (KH14) [ka] KH14 The preparation of 2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)quinoline-3-carboxamide is similar to steps a-d of Example 8 and Example 6, except that 3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxylic acid in step f of Example 6 is replaced with 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid synthesized through steps a-d of Example 8, and the room temperature in step e of Example 6 is changed to 80°C, and white solid 2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)quinoline-3-carboxamide (7.49 mg, yield 11.4%) is obtained. 1H NMR (400MHz, DMSO-d6) δ11.34(s, 1H), 8.63(d, J=5.4Hz, 1H), 8.41(s, 1H), 8.34(d, J=1.7Hz, 1H), 7.90-7.81(m, 2H), 7.65(d, J=3. 6Hz, 2H), 7.47(s, 2H), 7.37-7.27(m, 1H), 3.77-3.69(m, 2H), 3.55(t, J=5.9Hz, 2H), 2.43-2.40(m, 2H), 1.98-1.95(m, 2H), 1.89(br s, 2H). ESI-MS(m / z):462.1[M+H] + .

[0142] Example 15 Preparation of N-(2-carbamoylpyridin-4-yl)-3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxamide (KH15) [ka] Step a): Preparation of 3-chloro-2-methylquinoline [ka] A solution of benzyltriethylammonium chloride (1.74 g, 7.63 mmol) in chloroform (300 mL) was slowly added to a solution of 2-methyl-1H-indole (10 g, 76.3 mmol) in 50% KOH (32 mL) in an ice bath at 0 °C and stirred at room temperature for 16 h. After the reaction was completed, it was quenched with water (200 mL), extracted with dichloromethane (200 mL x 3), and the combined organic phase was washed with saturated brine (80 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20) to give 3-chloro-2-methylquinoline (2.1 g, 15% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ8.55(s, 1H), 8.06-7.94(m, 2H), 7.80-7.78(m, 1H), 7.71-7.56(m, 1H), 2.77(s, 3H). ESI-MS(m / z):178.1[M+H] + .

[0143] Step b): Preparation of 3-chloroquinoline-2-carbaldehyde [ka] Selenium dioxide (3.76 g, 33.8 mmol) was slowly added to a solution of 3-chloro-2-methylquinoline (2 g, 11.2 mmol) in 1,4-dioxane (40 mL) and reacted at 100° C. for 2 hours. After the reaction was completed, it was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure to give 3-chloroquinoline-2-carbaldehyde (2.1 g, 97% yield) as a white solid. ESI-MS (m / z): 192.1 [M+H] + .

[0144] Step c): Preparation of 3-chloroquinoline-2-carboxylic acid [ka] A mixed aqueous solution of sodium chlorite (4.7 g, 52.3 mmol) and disodium hydrogen phosphate (7.4 g, 52.3 mmol) was slowly added to a solution of 3-chloroquinoline-2-carbaldehyde (2 g, 10.47 mmol) in tert-butanol (20 mL) in an ice bath (36 mL) at 0° C. and stirred at room temperature for 16 h. After the reaction was completed, the pH was adjusted to neutral with 1 M aqueous hydrochloric acid, then the organic phase was extracted with ethyl acetate (100 mL×3), washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3-chloroquinoline-2-carboxylic acid (1.9 g, 88% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ8.79(s, 1H), 8.11(dd, J=19.2, 8.3Hz, 2H), 7.93(dd, J=11.2, 4.1Hz, 1H), 7.80(t, J=7.5Hz, 1H). ESI-MS(m / z):208.1[M+H] + .

[0145] Step d): Preparation of 3-chloroquinoline-2-carboxamide [ka] Ammonium chloride (231.5 mg, 4.33 mmol), HATU (657.7 mg, 1.73 mmol) and N,N-diisopropylethylamine (558 mg, 4.33 mmol) were added to a solution of 3-chloroquinoline-2-carboxylic acid (300 mg, 1.44 mmol) in DMF (3 mL) and reacted at room temperature for 4 h. After the reaction was completed, the reaction was quenched with water (20 mL), extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 10) to give 3-chloroquinoline-2-carboxamide (180 mg, 60% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.68(s, 1H), 8.17(s, 1H), 8.07(d, J=8.5Hz, 1H), 8.02(d, J=8.2Hz, 1H), 7.86(t, J=7.4Hz, 2H), 7.73(t, J=7.5Hz, 1H). ESI-MS(m / z):207.3[M+H] + .

[0146] Step e): Preparation of 3-chloroquinoline-2-carbonitrile [ka] Triethylamine (220 mg, 2.17 mmol) and trifluoroacetic anhydride (220 mg, 1.04 mmol) were added to a solution of 3-chloroquinoline-2-carboxamide (180 mg, 0.87 mmol) in tetrahydrofuran (5 mL) under ice bath at 0 °C and stirred continuously for 1 h under ice bath. After the reaction was completed, the reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10) to give 3-chloroquinoline-2-carbonitrile (100 mg, 61% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.93(s, 1H), 8.16(d, J=8.4Hz, 1H), 8.10(d, J=8.1Hz, 1H), 7.97(t, J=7.6Hz, 1H), 7.87(t, J=7.5Hz, 1H). ESI-MS(m / z):189.0[M+H] + .

[0147] Step f): Preparation of 3-(4,4-difluoroazepan-1-yl)quinoline-2-carbonitrile [ka] 4,4-Difluoroazepane hydrochloride (400 mg, 2.34 mmol), Ruphos-Pd-G2 (140 mg, 0.179 mmol) and cesium carbonate (1750 mg, 5.4 mmol) were added to a solution of 3-chloroquinoline-2-carbonitrile (340 mg, 1.80 mmol) in toluene (8 mL) and stirred at 110 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 5) to give 3-(4,4-difluoroazepan-1-yl)quinoline-2-carbonitrile (200 mg, 48% yield) as a yellow oil. ESI-MS(m / z):228.1[M+H] + .

[0148] Step g): Preparation of 3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxamide [ka] Cesium carbonate (437 mg, 1.315 mmol) was added to a solution of 3-(4,4-difluoroazepan-1-yl)quinoline-2-carbonitrile (200 mg, 0.877 mmol) in dimethyl sulfoxide (3 mL), and 30% hydrogen peroxide (0.5 mL) was added slowly at 0° C. The reaction was carried out under ice bath for 2 h. After the reaction was completed, the reaction was quenched by adding ice water (10 mL), extracted with ethyl acetate (10 mL×3), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxamide (120 mg, 45% yield) as a yellow solid. ESI-MS (m / z): 306.3 [M+H] + .

[0149] Step h): Preparation of N-(2-(bis(4-methoxybenzyl)carbamoyl)pyridin-4-yl)-3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxamide [ka] 3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxamide (120 mg, 0.393 mmol), Ruphos-Pd-G2 (30.6 mg, 0.0393 mmol) and cesium carbonate (320 mg, 2.5 mmol) were added to a solution of 4-bromo-N,N-bis(4-methoxybenzyl)pyridine-2-carboxamide (208.7 mg, 0.472 mmol) in 1,4-dioxane (4 mL) and stirred under nitrogen protection at 105° C. for 16 h. After the reaction was completed, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (15 mL×3), the combined organic phase was washed with saturated brine (10 mL×3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 1) to give a yellow solid, N-(2-(bis(4-methoxybenzyl)carbamoyl)pyridin-4-yl)-3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxamide (180 mg, 65% yield). ESI-MS (m / z): 666.5 [M+H] + .

[0150] Step i): Preparation of N-(2-carbamoylpyridin-4-yl)-3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxamide [ka] A solution of trifluoroacetic acid (5 mL) and one drop of trifluoromethanesulfonic acid was added to a solution of N-(2-(bis(4-methoxybenzyl)carbamoyl)pyridin-4-yl)-3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxamide (170 mg, 0.255 mmol) in 1,2-dichloroethane (3 mL) and reacted at 70° C. for 1 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the pH of the resulting mixture was adjusted to neutral with saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate (15 mL×3), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by Prep-HPLC to give N-(2-carbamoylpyridin-4-yl)-3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxamide (15 mg, 14% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.33(s, 1H), 8.58(d, J=5.5Hz, 1H), 8.44(d, J=1.9Hz, 1H), 8.12(s, 1H), 8.007.96(m, 1H), 7.96(d, J=2.3Hz, 1H), 7.95-7.9 3(m, 1H), 7.92(dd, J=4.6, 3.3Hz, 1H), 7.67(s, 1H), 7.64-7.57(m, 2H), 3. 43-3.38(m, 4h), 2.26-2.23(m, 2h), 2.13-2.09(m, 2h), 1.90-1.81(m, 2h). ESI-MS(m / z):426.4[M+H] + .

[0151] Step j): Preparation of 4-bromo-N,N-bis(4-methoxybenzyl)pyridine-2-carboxamide [ka] Bis-(4-methoxybenzyl)-amine (636 mg, 2.47 mmol), HATU (1130 mg, 2.97 mmol) and N,N-diisopropylethylamine (638 mg, 4.95 mmol) were added to a solution of 4-bromopyridinecarboxylic acid (500 mg, 2.47 mmol) in N,N-dimethylformamide (6 mL) and reacted at room temperature for 16 h. After the reaction was completed, the reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 4) to give 4-bromo-N,N-bis(4-methoxybenzyl)pyridine-2-carboxamide (500 mg, 45% yield) as a clear oil. 1 H NMR (400MHz, DMSO-d6) δ8.49(d, J=5.4Hz, 1H), 7.90(d, J=1.8Hz, 1H), 7.77(dd, J=5.3, 1.9Hz, 1H), 7.23(d, J=8.6Hz, 2H), 7.14(d, J=8.6Hz, 2H), 6.94(2H, t, J=5.7Hz), 6.89(d, J=8.7Hz, 2H), 4.48(s, 2H), 4.34(s, 2H), 3.76(s, 3H), 3.74(s, 3H). ESI-MS(m / z):443.1[M+H] + .

[0152] Example 16 Preparation of 2-(4,4-difluoroazepan-1-yl)-6,7-difluoro-N-(3-sulfamoylphenyl)quinoline-3-carboxamide (KH16) [ka] The preparation of 2-(4,4-difluoroazepan-1-yl)-6,7-difluoro-N-(3-sulfamoylphenyl)quinoline-3-carboxamide was carried out by changing 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid in step f of Example 6 to 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylic acid which can be synthesized by steps a to d of Example 10. The procedure was the same as steps a to d of Example 10 and Example 6, except that in step a of Example 6, 4-bromo-2-fluoropyridine was replaced with 4-bromo-2-fluorobenzene, and the room temperature in step e of Example 6 was changed to 80°C. A white solid of 2-(4,4-difluoroazepan-1-yl)-6,7-difluoro-N-(3-sulfamoylphenyl)quinoline-3-carboxamide (10.92 mg, yield 17.5%) was obtained. 1 H NMR (400MHz, MeOD) δ8.36(s, 1H), 8.26(s, 1H), 7.86(d, J=8.1Hz, 1H), 7.67(dd, J=19.6, 10.0Hz, 2H), 7.60-7. 43(m, 2H), 3.87-3.78(m, 2H), 3.66(2H, t, J=5.9Hz), 2.42-2.40(m, 2H), 2.08-2.00(m, 2H), 1.99-1.91(m, 2H). ESI-MS(m / z):497.1[M+H] + .

[0153] Example 17 Preparation of 2-(4,4-difluoroazepan-1-yl)-6,7-difluoro-N-(2-sulfamoylpyridin-4-yl)quinoline-3-carboxamide (KH17) [ka] The synthesis of 2-(4,4-difluoroazepan-1-yl)-6,7-difluoro-N-(2-sulfamoylpyridin-4-yl)quinoline-3-carboxamide was the same as steps a-d of Example 10 and Example 6, except that 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid in step f of Example 6 was changed to 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylic acid that can be synthesized by steps a-d of Example 10, and the stirring at room temperature for 2 hours in step e of Example 6 was changed to stirring at room temperature for 5 hours. Yellow solid 2-(4,4-difluoroazepan-1-yl)-6,7-difluoro-N-(2-sulfamoylpyridin-4-yl)quinoline-3-carboxamide (13.9 mg, yield 24%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.38(s, 1H), 8.64(d, J=5.3Hz, 1H), 8.41(s, 1H), 8.32(s, 1H), 7.92(t, J=10.0Hz, 1H), 7.86(d, J =5.4Hz, 1H), 7.60(dd, J=11.8, 7.9Hz, 1H), 7.47(s, 2H), 3.73(s, 2H), 3.54(s, 2H), 2.40(s, 2H), 1.99(s, 2H), 1.89(s, 2H). ESI-MS(m / z):498.2[M+H] + .

[0154] Example 18 Preparation of N-(2-carbamoylpyridin-4-yl)-7-(4,4-difluoroazepan-1-yl)quinoline-6-carboxamide (KH18) [ka] Step a): Preparation of 7-fluoroquinoline-6-carbonitrile [ka] Zn(CN)2 (2.07 g, 17.68 mmol) and Pd(PPh3)4 (2.04 g, 1.77 mmol) were added to a solution of 6-bromo-7-fluoroquinoline (2 g, 8.84 mmol) in NMP (20 mL), and the reaction was stirred at 120 °C for 16 h under nitrogen protection. After the reaction was completed, it was diluted with water and extracted with ethyl acetate (20 mL × 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give 7-fluoroquinoline-6-carbonitrile (1.2 g, 78.8% yield) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ9.06 (dd, J=4.3, 1.5Hz, 1H), 8.24 (dd, J=11.7, 3.8Hz, 2H), 7.88 (d, J=10.0Hz, 1H), 7.53 (dd, J=8.4, 4.3Hz, 1H). ESI-MS(m / z):173.0[M+H] + .

[0155] Step b): Preparation of 7-(4,4-difluoroazepan-1-yl)quinoline-6-carbonitrile [ka] 4,4-Difluoroazepane hydrochloride (4.7 g, 34.85 mmol), K2CO3 (4.8 g, 34.85 mmol) and DIEA (4.5 g, 34.85 mmol) were added to a solution of 7-fluoroquinoline-6-carbonitrile (1.2 g, 6.97 mmol) in DMSO (10 mL), respectively, and stirred at 100 °C for 16 h. After the reaction was completed, the reaction system was diluted with water and extracted with ethyl acetate (20 mL × 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to obtain a pale yellow solid of 7-(4,4-difluoroazepane-1-l)quinoline-6-carbonitrile (800 mg, 24.1% yield). 1H NMR (400MHz, DMSO-d6) delta8.998.84 (m, 1H), 8.54 (s, 1H), 8.30 (d, J=8.2Hz, 1H), 7.45 (s, 1H), 7.41 (dd, J=8.2, 4.2Hz, 1H), 3.65-3.48(m, 4h), 2.50-2.37(m, 2H), 2.32-2.14(m, 2H), 2.06-1.88(m, 2H). ESI-MS(m / z):288.0[M+H] + .

[0156] Step c): Preparation of 7-(4,4-difluoroazepan-1-yl)quinoline-6-carboxamide [ka] Cesium carbonate (3.16 g, 9.72 mmol) was added to a solution of 7-(4,4-difluoroazepan-1-yl)quinoline-6-carbonitrile (800 mg, 2.77 mmol) in dimethyl sulfoxide (10 mL), and 30% hydrogen peroxide (2.5 mL) was added slowly at 0° C. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction was quenched with ice water (10 mL), extracted with ethyl acetate (60 mL×2), and the combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 7-(4,4-difluoroazepan-1-yl)quinoline-6-carboxamide (80 mg, 95% yield) as a white solid. ESI-MS (m / z): 306.1 [M+H] + .

[0157] Step d): Preparation of N-(2-(bis(4-methoxybenzyl)carbamoyl)pyridin-4-yl)-7-(4,4-difluoroazepan-1-yl)quinoline-6-carboxamide [ka] For the synthesis of 4-bromo-N,N-bis(4-methoxybenzyl)pyridine-2-carboxamide, see Example 15, step j.

[0158] 4-Bromo-N,N-bis(4-methoxybenzyl)pyridine-2-carboxamide (530 mg, 1.19 mmol), Brettphos-Pd-G3 (98.7 mg, 0.109 mmol) and cesium carbonate (880 mg, 2.72 mmol) were added to a solution of 7-(4,4-difluoroazepan-1-yl)quinoline-6-carboxamide (350 mg, 1.06 mmol) in toluene (5 mL) and stirred under nitrogen protection at 110° C. for 16 h. After completion of the reaction, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (15 mL×3), the combined organic phase was washed with saturated brine (10 mL×3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 1) to give a yellow solid of N-(2-(bis(4-methoxybenzyl)carbamoyl)pyridin-4-yl)-7-(4,4-difluoroazepan-1-yl)quinoline-6-carboxamide (200 mg, yield 26.2%). 1 H NMR (400MHz, DMSO-d6) δ11.13(s, 1H), 8.86(dd, J=4.3, 1.7Hz, 1H), 8.54(d, J=5.6Hz, 1H), 8.41-8.26(m, 1 H), 8.14(s, 1H), 8.01(d, J=1.7Hz, 1H), 7.77(dd, J=5.6, 2.0Hz, 1H), 7.50(s, 1H), 7.39(dd, J=8.2, 4.3Hz, 1H), 7.20(dd, J=21.2, 8.6Hz, 4h), 6.92(dd, J=18.3, 8.6Hz, 4h), 4.47(s, 2H), 4.41(s, 2H), 3.75(d, J=10. 4Hz, 6h), 3.42(t, J=5.8Hz, 4h), 2.34-2.18(m, 2H), 2.08(dd, J=16.0, 10.4Hz, 2H), 1.83(d, J=5.3Hz, 2H). ESI-MS(m / z):665.9[M+H] + .

[0159] Step e): Preparation of N-(2-carbamoylpyridin-4-yl)-7-(4,4-difluoroazepan-1-yl)quinoline-6-carboxamide [ka] Trifluoroacetic acid (2 mL) was added to a solution of N-(2-(bis(4-methoxybenzyl)carbamoyl)pyridin-4-yl)-7-(4,4-difluoroazepan-1-yl)quinoline-6-carboxamide (200 mg, 0.30 mmol) in dichloroethane (2 mL). The reaction was stirred at 80° C. for 2 H. After the reaction was completed, the reaction mixture was concentrated and the crude product was purified by Prep-HPLC (1% formic acid in water, methanol) to give N-(2-carbamoylpyridin-4-yl)-7-(4,4-difluoroazepan-1-yl)quinoline-6-carboxamide (40 mg, 31.2% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ11.33(s, 1H), 9.02(d, J=4.0Hz, 1H), 8.79(d, J=7.8Hz, 1H), 8.58(d, J=5.5Hz, 1H), 8.45-8.30(m, 2H), 8.12(s, 1H), 7.92 (dd. ESI-MS(m / z):426.0[M+H] + .

[0160] Example 19 Preparation of N-(3-carbamoyl-4-fluorophenyl)-7-(4,4-difluoroazepan-1-yl)quinoline-6-carboxamide (KH19) [ka] Step a): Preparation of N-(3-cyano-4-fluorophenyl)-7-(4,4-difluoroazepan-1-yl)quinoline-6-carboxamide [ka] For the synthesis of 7-(4,4-difluoroazepan-1-yl)quinoline-6-carboxamide, see steps a-c of Example 18.

[0161] 5-Bromo-2-fluorobenzonitrile (238 mg, 1.19 mmol), Brettphos-Pd-G3 (98.7 mg, 0.109 mmol) and cesium carbonate (880 mg, 2.72 mmol) were added to a solution of 7-(4,4-difluoroazepan-1-yl)quinoline-6-carboxamide (350 mg, 1.06 mmol) in toluene (5 mL) and stirred under nitrogen protection at 110° C. for 16 h. After the reaction was completed, the reaction was quenched with ethyl acetate (50 mL) and extracted with ethyl acetate (15 mL×3), the combined organic phase was washed with saturated brine (10 mL×3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 1) to give a yellow solid, N-(3-cyano-4-fluorophenyl)-7-(4,4-difluoroazepan-1-yl)quinoline-6-carboxamide (200 mg, 44.3% yield). ESI-MS (m / z): 424.9 [M+H] + .

[0162] Step b): Preparation of N-(3-carbamoyl-4-fluorophenyl)-7-(4,4-difluoroazepan-1-yl)quinoline-6-carboxamide (KH19) [ka] Cesium carbonate (535 mg, 1.64 mmol) was added to a solution of N-(3-cyano-4-fluorophenyl)-7-(4,4-difluoroazepane-1-l)quinoline-6-carboxamide (200 mg, 0.47 mmol) in dimethyl sulfoxide (5 mL), 30% hydrogen peroxide (0.5 mL) was slowly added at 0° C., and the reaction was allowed to proceed for 4 h at room temperature. After the reaction was complete, the reaction was quenched with ice water (10 mL), extracted with ethyl acetate (20 mL×3), and the combined organic phase was washed with saturated brine (60 mL), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by Prep-HPLC (1% formic acid aqueous solution, methanol) to give N-(3-carbamoyl-4-fluorophenyl)-7-(4,4-difluoroazepan-1-yl)quinoline-6-carboxamide (22.12 mg, yield 30.56%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.91(s, 1H), 8.99(d, J=3.9Hz, 1H), 8.75(d, J=8.1Hz, 1H), 8.30(s, 1H), 8.05(dd, J=6.4, 2.7Hz, 1H), 7.92-7 .80(m, 1H), 7.72-7.54(m, 3H), 7.40(s, 1H), 7.31(d, J=9.2Hz, 1H), 3.67-3.43(m, 4h), 2.35-2.30(m, 2H), 2.13-2.09(m, 2H), 1.91(br s, 2H). ESI-MS(m / z):443.3[M+H] + .

[0163] Example 20 Preparation of N-(2-carbamoylpyridin-4-yl)-6-chloro-3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxamide (KH20) [ka] KH20 The synthesis of N-(2-carbamoylpyridin-4-yl)-6-chloro-3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxamide was similar to that of Example 15, except that 2-methyl-1H-indole in step a was replaced with 5-chloro-2-methyl-1H-indole. Yellow solid N-(2-carbamoylpyridin-4-yl)-6-chloro-3-(4,4-difluoroazepan-1-yl)quinoline-2-carboxamide (6.67 mg, 18% yield) was obtained. 1 H NMR (400MHz, DMSO-d6) δ11.38(s, 1H), 8.57(d, J=5.4Hz, 1H), 8.42(d, J=1.8Hz, 1H), 8.12(s, 1H), 8.02(d, J=2.3Hz, 1H), 7.98(d, J=8.9Hz, 1H), 7.9 2(dd, J=5.5, 2.1Hz, 1H), 7.88(s, 1H), 7.67(s, 1H), 7.57(dd, J=8.9, 2.3H z, 1H), 3.47-3.40(m, 4h), 2.29-2.24(m, 2H), 2.16-2.04(m, 2H), 1.87(br s, 2H). ESI-MS(m / z):460.1[M+H] + .

[0164] Example 21 Preparation of N-(3-carbamoyl-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxamide (KH21) [ka] 2-(4,4-Difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylic acid was prepared similarly to steps a-d of Example 10.

[0165] HATU (187.7 mg, 0.494 mmol), DIEA (196.1 mg, 1.520 mmol) and 5-amino-2-fluorobenzamide (58.5 mg, 0.380 mmol) were added to a solution of 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylic acid (130 mg, 0.380 mmol) in dichloromethane (4 mL) and DMF (1 mL) at room temperature and reacted for 48 h at 40° C. After the reaction was completed, water was added to quench the reaction, and the organic phase (15 mL) was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to give N-(3-carbamoyl-4-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxamide (64.17 mg, 35% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.83(s, 1H), 8.31(s, 1H), 8.11-8.00(m, 1H), 7.95-7.88(m, 1 H), 7.86-7.81(m, 1H), 7.70(s, 2H), 7.60-7.57(m, 1H), 7.30(t, J=9.5Hz, 1H), 3.74(br s, 2H), 3.59(t, J=5.7Hz, 2H), (2.492.39m, 2H), 2.02-1.90(m, 2H), 1.89(br s, 2H). ESI-MS(m / z):479.2[M+H] + .

[0166] Example 22 Preparation of N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-carboxamide (KH22) [ka] Step a): Preparation of 2-chloro-7-methoxyquinoline-3-carboxylic acid [ka] A solution of silver nitrate (2.45 g, 14.44 mmol) and sodium hydroxide (1.80 g, 45.12 mmol) in ethanol / water (v / v=4 / 1, 10 mL) was added to a solution of 2-chloro-7-methoxyquinoline-3-carbaldehyde (2.0 g, 9.02 mmol) in ethanol (20 mL) and stirred at room temperature for 16 h. After the reaction was completed, the reaction was diluted with 20 mL of water, then extracted with ethyl acetate (30 mL×3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude 2-chloro-7-methoxyquinoline-3-carboxylic acid (1.0 g, 50% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ13.58(br s, 1H), 8.86(s, 1H), 8.08(d, J=9.0Hz, 1H), 7.41(d, J=2.4Hz, 1H), 7.38-7.32(m, 1H), 3.95(s, 3H). ESI-MS(m / z):237.8[M+H] + .

[0167] Step b): Preparation of ethyl 2-chloro-7-methoxyquinoline-3-carboxylate [ka] 2-Chloro-7-methoxyquinoline-3-carboxylic acid (1.0 g, 4.21 mmol) was dissolved in DMF (15 mL) and K2CO3 (1.16 g, 8.42 mmol) was added. The reaction was placed in an ice-water bath at 0 °C, and then ethane iodide (1.31 g, 8.42 mmol) was added. The ice-water bath was then removed, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction was diluted with 20 mL of water, extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 8 / 1) to give ethyl 2-chloro-7-methoxyquinoline-3-carboxylate (600 mg, 60% yield) as a white solid. ESI-MS (m / z): 265.9 [M+H] + .

[0168] Step c): Preparation of ethyl 2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-carboxylate [ka] 4,4-Difluoroazepane hydrochloride (503.82 mg, 2.94 mmol) and N,N-diisopropylethylamine (875.61 g, 6.77 mmol) were added to a solution of ethyl 2-chloro-7-methoxyquinoline-3-carboxylate (600 mg, 2.26 mmol) in N-methylpyrrolidone (10 mL). After the reaction was completed, the reaction was diluted with water (30 mL) and then extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 8) to give ethyl 2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-carboxylate (400 mg, 66.7% yield) as a colorless oil. ESI-MS(m / z):365.5[M+H] + .

[0169] Step d): Preparation of 2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-carboxylic acid [ka] Lithium hydroxide (262.87 mg, 10.98 mmol) was slowly added to ethyl 2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-carboxylate (400 mg, 1.1 mmol) in a mixed solvent of water (1 mL) / methanol (5 mL) / tetrahydrofuran (1 mL) and reacted at 50° C. for 12 h. After the reaction was completed, water (20 mL) was added to dilute the reaction mixture, and the pH was adjusted to about 4 with 1M dilute hydrochloric acid. The organic phase was then extracted with ethyl acetate (30 mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-carboxylic acid (320 mg, 80% yield) as a white solid. ESI-MS (m / z): 336.9 [M+H] + .

[0170] Step e): Preparation of 2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-formyl chloride [ka] Thionyl chloride (222.36 mg, 1.9 mmol) was added to a solution of 2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-carboxylic acid (320 mg, 0.951 mmol) in dichloromethane (5 mL) at 0° C. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a colorless oil, 2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-formyl chloride (320 mg, 100% yield), which was used directly in the next step without purification. ESI-MS (m / z): 335.6 [M+H] + .

[0171] Step f): Preparation of methyl 4-(2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-carboxamide)pyridine-2-carboxylate [ka] Triethylamine (182.54 mg, 1.8 mmol) and methyl 4-amino-pyridine-2-carboxylate (205.85 mg, 1.35 mmol) were added to a solution of 2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-formyl chloride (320 mg, 0.9 mmol) in dichloromethane (5 mL) at 0° C. After the reaction was completed, the reaction mixture was diluted with water (20 mL) and then extracted with ethyl acetate (20 mL×2), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 1) to give a yellow solid, methyl 4-(2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-carboxamide)pyridine-2-carboxylate (140 mg, yield 43.75%). 1 H NMR (400MHz, CDCl3) δ8.71-8.67(m, 2H), 8.24(s, 1H), 8.05(s, 1H), 7.72(d, J=8.9Hz, 1H), 7.23-7.21(m, 1H), 7.12(d , J=9.0Hz, 1H), 4.12(d, J=7.2Hz, 2H), 4.03(s, 3H), 3.99-3.97(m, 3H), 3.77-3.73(m, 2H), 3.57-3.53(m, 2H), 2.22(br s, 2H), 1.97(br s, 2H). ESI-MS(m / z):470.8[M+H] + .

[0172] Step g): Preparation of N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-carboxamide [ka] Ammonium chloride (127.33 mg, 2.38 mmol) and aqueous ammonia (417.15 mg, 2.98 mmol) were added to a solution of methyl 4-(2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-carboxamide)pyridine-2-carboxylate (140 mg, 0.297 mmol) in dimethyl sulfoxide (4 mL) and stirred at 70° C. for 24 h in a sealed tank. After the reaction was completed, water (15 mL) was added to dilute the reaction mixture, which was then extracted with ethyl acetate (20 mL×2), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by C18 reverse phase column under formic acid condition to obtain yellow solid powder N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-carboxamide (52.93 mg, yield 37.8%). 1 H NMR (400MHz, DMSO-d6) δ11.14(s, 1H), 8.54(d, J=5.5Hz, 1H), 8.38(d, J=1.5Hz, 1H), 8.31(s, 1H), 8.10(s, 1H), 7.91(dd, J=5 .3, 1.8Hz, 1H), 7.75(d, J=8.8Hz, 1H), 7.65(s, 1H), 7.03(d, J=2.2Hz, 1H), 6.95(dd, J=8.8, 2.4Hz, 1H), 3.89(s, 3H), 3.77(br s, 2H), 3.54 (2H, t, J=5.8Hz), 2.44-2.38 (m, 2H), 1.99-1.89 (m, 2H), 1.88-1.82 (m, 2H). ESI-MS(m / z):456.2[M+H] + .

[0173] Example 23 Preparation of N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-7-methylquinoline-3-carboxamide (KH23) [ka] KH23 N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-7-methylquinoline-3-carboxamide was synthesized in the same manner as in Example 22, except that 2-chloro-7-methoxyquinoline-3-formaldehyde in step a was replaced with 2-chloro-7-methylquinoline-3-formaldehyde. The 70° C. sealed tank in step g was replaced with an 80° C. sealed tank to obtain yellow solid N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-7-methylquinoline-3-carboxamide (30.27 mg, 21% yield). 1 H NMR (400MHz, DMSO-d6) δ11.16(s, 1H), 8.55(d, J=5.5Hz, 1H), 8.38(d, J=2.0Hz, 1H), 8.33(s, 1H), 8.10(s, 1H), 7.90(d, J=5.4, 2.1Hz) , 1H), 7.74(d, J=8.2Hz, 1H), 7.64(s, 1H), 7.46(s, 1H), 7.16(d, J=8.3, 1.5Hz, 1H), 3.76-3.70(m, 2H), 3.55(2H, t, J=5.9Hz), 2.46(br s, 3H), 2.45-2.31(m, 2H), 2.04-1.99(m, 2H), (1.901.81m, 2H). ESI-MS(m / z):440.3[M+H] + .

[0174] Example 24 Preparation of N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxamide (KH24) [ka] KH24 N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxamide was synthesized in the same manner as in Example 22, except that 2-chloro-7-methoxyquinoline-3-formaldehyde in step a) was replaced with 2-chloro-6,7-dimethoxyquinoline-3-formaldehyde. The 70°C tank in step g was replaced with an 85°C tank to obtain yellow solid N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxamide (110.22 mg, 56% yield). 1 H NMR (400MHz, DMSO-d6) δ11.09(s, 1H), 8.54(d, J=5.5Hz, 1H), 8.39(s, 1H), 8.22(s, 1H), 8.10(s, 1H) ), 7.90(d, J=3.3Hz, 1H), 7.64(s, 1H), 7.28(s, 1H), 7.06(s, 1H), 3.91(s, 3H), 3.84(s, 3H), 3.68(br s, 2H), 3.51(t, J=5.8Hz, 2H), 2.40(br s, 2H), 1.99-1.95(m, 2H), 1.901.83(m, 2H). ESI-MS(m / z):486.2[M+H] + .

[0175] Example 25 Preparation of N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-carboxamide (KH25) [ka] KH25 N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-carboxamide was synthesized in the same manner as in Example 22, except that 2-chloro-7-methoxyquinoline-3-formaldehyde in step a was replaced with 2-chloro-6-methoxyquinoline-3-formaldehyde. The 70°C tank in step g was replaced with an 85°C tank to obtain yellow solid N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-carboxamide (35.20 mg, 28% yield). 1 H NMR (400MHz, DMSO-d6) δ11.16(s, 1H), 8.55(d, J=5.4Hz, 1H), 8.39(s, 1H), 8 .30(s, 1H), 8.12(d, J=13.3Hz, 1H), 7.89(d, J=1.9Hz, 1H), 7.64(d, J=13.8Hz , 1H), 7.60(d, J=9.3Hz, 1H), 7.34(d, J=2.9Hz, 1H), 7.31(s, 1H), 3.84(s, 3H) , 3.68(m, 2H), 3.53(2H, t, J=5.9Hz), 2.35(m, 2H), 1.99(m, 2H), 1.86(m, 2H). ESI-MS(m / z):456.1[M+H] + .

[0176] Here, the synthesis method of 2-chloro-6-methoxyquinoline-3-formaldehyde is as follows. [ka]

[0177] Phosphorus oxytrichloride (41.77g, 272.41mmol) was slowly added to DMF (7.96g, 108.96mmol) at 0°C and stirred continuously for 1 hour. p-Methoxyacetanilide (4.5g, 27.24mmol) was added to the reaction mixture, and the temperature was raised to 80°C and the reaction system was stirred continuously for 12 hours. After the reaction was completed, the reaction system was quenched with ice water, then stirred for 10 minutes, filtered, and the filter cake was washed with water and dried to obtain a brown solid 2-chloro-6-methoxyquinoline-3-formaldehyde (1.8g, 40% yield) crude product, which was used directly in the next step without purification. 1 H NMR (400MHz, DMSO-d6) δ8.76(s, 1H), 8.13(d, J=8.1Hz, 1H), 7.98(d, J=8.4Hz, 1H), 7.88(t, J=7.6Hz, 1H), 7.70(t, J=7.5Hz, 1H), 3.69(s, 3H). ESI-MS(m / z):221.9[M+H] + .

[0178] Example 26 Preparation of 2-(4,4-difluoroazepan-1-yl)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)quinoline-3-carboxamide (KH26) [ka] Step a): Preparation of 2-chloroquinoline-3-carboxylic acid [ka] To an aqueous solution of silver nitrate (29.61 g, 174.31 mmol), an aqueous solution of sodium hydroxide (14.61 g, 365.32 mmol) was added, followed by the addition of 2-chloroquinoline-3-formaldehyde (20 g, 104.38 mmol), and the mixture was stirred at 0° C. for 3 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was adjusted to pH=5 with 3N HCl, filtered, and a yellow filter cake, i.e., crude 2-chloroquinoline-3-carboxylic acid (15 g, 69.2% yield), was obtained and used directly in the next step. 1H NMR (400MHz, DMSO-d6) δ10.38(s, 1H), 8.85(s, 1H), 7.96(d, J=9.2Hz, 1H), 7.71(d, J=2.8Hz, 1H), 7.63(dd, J=9.2, 2.8Hz, 1H). ESI-MS(m / z):207.8[M+H] + .

[0179] Step b): Preparation of ethyl 2-chloroquinoline-3-carboxylate [ka] K2CO3 (30.62 g, 221.57 mmol) was added to a solution of 2-chloroquinoline-3-carboxylic acid (23 g, 110.78 mmol) in DMF (200 mL), iodine ethane (34.55 g, 221.57 mmol) was added dropwise at 0 °C, then the reaction system was warmed to room temperature and the reaction continued for 16 h. After the reaction was completed, 200 mL of water was added to dilute the reaction mixture, then it was extracted with ethyl acetate (200 mL × 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 9 / 1) to obtain ethyl 2-chloroquinoline-3-carboxylate (14 g, 53.6% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.96(s, 1H), 8.22-8.18(m, 1H), 8.05-8.01(m, 1H), 7.96(m, 1H), 7.76(m, 1H), (4.484.37m, 2H), 1.41-1.34(m, 3H). ESI-MS(m / z):235.9[M+H] + .

[0180] Step c): Preparation of ethyl 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylate [ka] 4,4-Difluoroazepane hydrochloride (28.05 g, 165.00 mmol) and DIEA (49.15 g, 381.00 mmol) were added to a solution of ethyl 2-chloroquinoline-3-carboxylate (30 g, 127.00 mmol) in NMP (400 ml) and reacted at 140 °C for 16 h. After the reaction was completed, 500 mL of water was added to dilute the reaction system, extracted with ethyl acetate (600 mL x 3), and the combined organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to obtain a yellow solid of ethyl 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylate (35 g, 82.23% yield). 1 H NMR (400MHz, DMSO-d6) δ18.42(d, J=7.0Hz, 1H), 7.84(d, J=8.0Hz, 1H), 7.69-7.54(m, 2H), 7.35-7.19(m, 1H), 4.35(q, J=7.1Hz, 2H), 3.78-3.63(m, 2H), 3.44(2H, t, J=5.8Hz), 2.48-2.34(m, 2H), 2.08-1.85(m, 4h), 1.34(t, J=7.1Hz, 3H). ESI-MS(m / z):335.1[M+H] + .

[0181] Step d): Preparation of 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid [ka] Lithium hydroxide (11.86 g, 495.00 mmol) was added to a solution of ethyl 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylate (35 g, 105.00 mmol) in methanol (400 mL) / water (80 mL) and stirred at room temperature overnight. After the reaction was completed, the methanol in the reaction mixture was removed by vacuum rotary evaporation, the pH of the resulting mixture was adjusted to 3-4 with dilute hydrochloric acid, the product was precipitated, filtered, and the filter cake was pulped with petroleum ether to obtain a white solid of 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid (25 g, 78% yield). 1 H NMR (400MHz, DMSO-d6) δ8.43(s, 1H), 7.84(d, J=7.8Hz, 1H), 7.65-7.51(m, 2H ), 7.27(m, 1H), 3.74-3.68(m, 2H), 3.50(t, J=5.9Hz, 2H), 1.99-1.90(m, 6H). ESI-MS(m / z):307.1[M+H] + .

[0182] Step e): Preparation of 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide [ka] Ammonium chloride (12.05 g, 225.26 mmol), DIEA (29.11 g, 225.26 mmol) and HATU (34.26 g, 90.10 mmol) were added in sequence to a solution of 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid (23 g, 75.09 mmol) in DMF (200 ml) and reacted at room temperature for 16 h. After the reaction was completed, the reaction was diluted with 200 mL of water, extracted with ethyl acetate (200 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to obtain 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide (9 g, 39.26% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ8.15(d, J=12.5Hz, 2H), 7.84(d, J=8.0Hz, 1H), 7.64(d, J=3.9Hz, 2H), 7.39-7.23(m, 1H) , 3.82-3.75(m, 2H), 3.68(2H, t, J=6.0Hz), 2.49-2.45(m, 2H), 2.08(td, J=14.3, 8.2Hz, 2H), 2.02-1.91(m, 2H). ESI-MS(m / z):305.9[M+H] + .

[0183] Step f): Preparation of 2-(4,4-difluoroazepan-1-yl)-N-(2-(methylsulfinyl)pyridin-4-yl)quinoline-3-carboxamide [ka] 2-(4,4-Difluoroazepan-1-yl)quinoline-3-carboxamide (305 mg, 1.00 mmol), 4-bromo-2-(methylsulfinyl)pyridine (220 mg, 1.00 mmol), Cs2CO3 (1.14 g, 3.50 mmol), and Ruphos-Pd-G2 (77 mg, 0.10 mmol) were dissolved in toluene (5 mL), the reaction system was purged with nitrogen, and stirred at 110 °C for 16 h. After the reaction was completed, 10 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate (10 mL x 2), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel plate (ethyl acetate / petroleum ether (v / v)=2 / 1) to give 2-(4,4-difluoroazepan-1-yl)-N-(2-(methylsulfinyl)pyridin-4-yl)quinoline-3-carboxamide (386 mg, 86.7% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ11.41(s, 1H), 8.65(d, J=5.4Hz, 1H), 8.47(s, 1H), 8.36(s, 1H), 7.94-7.85(m, 2H), 7.71(d, J=3.7Hz, 2H), 7.41-7.35(m, 1H), 3.86-3.75(m, 2H), 3.63(2H, t, J=5.8Hz), 2.87(s, 3H), (2.522.40m, 2H), 2.13-2.05(m, 2H), 1.98-1.90(m, 2H). ESI-MS(m / z):445.1[M+H] + .

[0184] Step g): Preparation of 2-(4,4-difluoroazepan-1-yl)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)quinoline-3-carboxamide [ka] 2-(4,4-Difluoroazepan-1-yl)-N-(2-(methylsulfinyl)pyridin-4-yl)quinoline-3-carboxamide (350 mg, 0.786 mmol) was dissolved in Eaton's reagent (5 mL), NaN3 (102 mg, 1.573 mmol) was added and stirred at 50° C. for 1 H. After the reaction was completed, the reaction was quenched with water (10 mL), extracted with dichloromethane (10 mL×2), the combined organic phase was washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by reverse phase preparation to give 2-(4,4-difluoroazepan-1-yl)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)quinoline-3-carboxamide (47.31 mg, 13.1% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ11.37(s, 1H), 8.63(d, J=5.4Hz, 1H), 8.44(d, J=1.5Hz, 1H), 8.40(s, 1H), 7.90(dd, J=5.4, 1.8Hz, 1H), 7.85(d, J=8.0Hz, 1H), 7.65(d, J =3.7Hz, 2H), 7.35-7.28(m, 1H), 4.36(s, 1H), 3.81-3.70(m, 2H), 3.56(2H, t, J= 5.7Hz), 3.16(s, 3H), 2.47-2.35(m, 2H), 2.08-1.95(m, 2H), 1.93-1.83(m, 2H). ESI-MS(m / z):460.2[M+H] + .

[0185] Example 27 Preparation of 2-(4,4-difluoroazepan-1-yl)-6,7-difluoro-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)quinoline-3-carboxamide (KH27) [ka] KH27 The synthesis of 2-(4,4-difluoroazepan-1-yl)-6,7-difluoro-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)quinoline-3-carboxamide is similar to steps e-g of Example 26, except that 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid in step e is replaced with 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylic acid. The synthesis of 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylic acid is described in steps a-d of Example 10. 1H NMR (400MHz, DMSO-d6) δ11.46(s, 1H), 8.67(d, J=5.5Hz, 1H), 8.46(s, 1H), 8.40(s, 1H), 7.95-7.90(m, 2H), 7.62-7.57(m, 1H), 3.73(br s, 2H), 3.54(2H, t, J=5.6Hz), 3.28(s, 3H), 2.452.39(m, 2H), 2.03-1.97(m, 2H), 1.93-1.88(m, 2H). ESI-MS(m / z):496.3[M+H] + .

[0186] Example 28 Preparation of 2-(4,4-difluoroazepan-1-yl)-N-(2-(N-methylsulfamoyl)pyridin-4-yl)quinoline-3-carboxamide (KH28) [ka] Step a): Preparation of 4-bromo-N-methylpyridine-2-sulfonamide [ka] DIEA (5.786 g, 44.85 mmol) and 4-bromopyridine-2-sulfonyl chloride (2.87 g, 11.21 mmol) were added to a solution of methylamine (2.78 g, 25% aqueous solution) in tetrahydrofuran (10 mL) and stirred at room temperature for 2 h. After the reaction was completed, 30 mL of water was added, then extracted with ethyl acetate (30 mL x 2), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 1). A yellow solid 4-bromo-N-methylpyridine-2-sulfonamide (1.36 g, 48.3% yield) was obtained. 1H NMR (400MHz, DMSO-d6) δ8.64 (d, J=5.2Hz, 1H), 8.10 (d, J=1.8Hz, 1H), 7.99 (dd, J=5.2, 1.8Hz, 1H), 7.87-7.81 (m, 1H), 2.57 (d, J=4.9Hz, 3H). ESI-MS(m / z):250.9[M+H] + .

[0187] Step b): Preparation of 4-bromo-N-(4-methoxybenzyl)-N-methylpyridine-2-sulfonamide [ka] 4-Bromo-N-methylpyridine-2-sulfonamide (400 mg, 1.59 mmol), PMBCl (500 mg, 3.19 mmol) and K2CO3 (440 mg, 3.19 mmol) were dissolved in DMF (4 mL) and stirred at room temperature for 6 h. After the reaction was completed, 10 mL of water was added, then extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified and purified by silica gel plate (ethyl acetate / petroleum ether (v / v) = 1 / 4) to obtain a yellow solid 4-bromo-N-(4-methoxybenzyl)-N-methylpyridine-2-sulfonamide (500 mg, 84.5% yield). 1 H NMR (400MHz, CDCl3) δ8.45(d, J=5.1Hz, 1H), 8.06(d, J=1.7Hz, 1H), 7.58(dd, J=5.1, 1.7H z, 1H), 7.23(d, J=8.5Hz, 1H), 6.85-6.76(m, 3H), 4.30(s, 2H), 3.74(s, 3H), 2.74(s, 3H). ESI-MS(m / z):371.0[M+H] + .

[0188] Step c): Preparation of 2-(4,4-difluoroazepan-1-yl)-N-(2-(N-(4-methoxybenzyl)-N-methylsulfamoyl)pyridin-4-yl)quinoline-3-carboxamide [ka] For the synthesis of 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide, see steps a-e of Example 26.

[0189] 4-Bromo-N-(4-methoxybenzyl)-N-methylpyridine-2-sulfonamide (250 mg, 0.67 mmol), 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide (205 mg, 0.67 mmol), Ruphos-Pd-G2 (52 mg, 0.067 mmol) and Cs2CO3 (768 mg, 2.36 mmol) were dissolved in toluene (5 mL) and stirred at 110° C. for 12 H under nitrogen protection. After the reaction was completed, 10 mL of water was added, followed by extraction with ethyl acetate (10 mL×2), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel plate (petroleum ether / ethyl acetate (v / v) = 2 / 3) to give a yellow solid 2-(4,4-difluoroazepan-1-yl)-N-(2-(N-(4-methoxybenzyl)-N-methylsulfamoyl)pyridin-4-yl)quinoline-3-carboxamide (370 mg, 92.1% yield). H NMR 1 (400MHz, DMSO-d6) δ11.46(s, 1H), 8.75(d, J=5.5Hz, 1H), 8.50(s, 1H), 8.40(s, 1H) ), 8.03(d, J=3.6Hz, 1H), 7.91(d, J=7.9Hz, 1H), 7.74-7.69(m, 2H), 7.42-7.36(m, 1 H), 7.34-7.29(m, 2H), 7.01-6.97(m, 2H), 4.36(s, 2H), 3.85-3.76(m, 6h), 3.66-3 .58(m, 2H), 2.78(s, 2H), 2.51-2.40(m, 2H), 2.12-2.01(m, 2H), 2.00-1.91(m, 2H). ESI-MS(m / z):596.2[M+H] + .

[0190] Step d): Preparation of 2-(4,4-difluoroazepan-1-yl)-N-(2-(N-methylsulfamoyl)pyridin-4-yl)quinoline-3-carboxamide [ka] 2-(4,4-Difluoroazepan-1-yl)-N-(2-(N-(4-methoxybenzyl)-N-methylsulfamoyl)pyridin-4-yl)quinoline-3-carboxamide (370 mg, 0.62 mmol) was dissolved in trifluoroacetic acid (5 mL), trifluoromethanesulfonic acid (0.5 mL) was added and stirred at 70° C. for 2 h. After the reaction was completed, the reaction was allowed to warm to room temperature, then poured into ice water (10 mL) and extracted with 2-methyltetrahydrofuran (10 mL×2). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified to obtain a pale yellow solid powder of 2-(4,4-difluoroazepan-1-yl)-N-(2-(N-methylsulfamoyl)pyridin-4-yl)quinoline-3-carboxamide (105.74 mg, yield 35.8%). 1 H NMR (400MHz, DMSO-d6) δ11.36(s, 1H), 8.65(d, J=5.5Hz, 1H), 8.44(s, 1H), 8.3 2(s, 1H), 7.95-7.90(m, 1H), 7.85(d, J=7.9Hz, 1H), 7.75-7.69(m, 1H), 7.67(d , J=3.8Hz, 2H), 7.37-7.30(m, 1H), 3.78-3.71(m, 2H), 3.56(t, J=5.8Hz, 2H), 2 .57(3H, d, J=4.8Hz), 2.46-2.35(m, 2H), 2.06-1.94(m, 2H), 1.93-1.85(m, 2H). ESI-MS(m / z):476.1[M+H] + .

[0191] Example 29 Preparation of 2-(4,4-difluoroazepan-1-yl)-6,7-difluoro-N-(2-(N-methylsulfamoyl)pyridin-4-yl)quinoline-3-carboxamide (KH29) [ka] KH29 The synthesis of 2-(4,4-difluoroazepan-1-yl)-6,7-difluoro-N-(2-(N-methylsulfamoyl)pyridin-4-yl)quinoline-3-carboxamide is similar to that of Example 28, except that 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide is replaced with 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxamide (see steps a-d of Example 10 and step e of Example 26 for synthesis), to give a pale yellow solid of 2-(4,4-difluoroazepan-1-yl)-6,7-difluoro-N-(2-(N-methylsulfamoyl)pyridin-4-yl)quinoline-3-carboxamide (61.82 mg, 23.13% yield). 1 H NMR (400MHz, DMSO-d6) δ11.40(s, 1H), 8.66(d, J=5.5Hz, 1H), 8.42(s, 1H), 8.30(d, J=1.9Hz, 1H), 7.95-7.88(m, 2H), 7.73(q, J=4.9Hz, 1H), 7 .63-7.58(m, 1H), 3.76-3.67(m, 2H), 3.54(2H, t, J=5.8Hz), 2.56(d, J=4.9Hz, 3H), 2.47-2.33(m, 2H), 2.07-1.93(m, 2H), 1.90-1.84(m, 2H). ESI-MS(m / z):512.1[M+H] + .

[0192] Example 30 Preparation of 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide (compound in Example 66 of Patent WO2014120815A1) [ka] Step a): Preparation of methyl 2-(2-chloro-4-fluorophenoxy)quinoline-3-carboxylate [ka] 2-Chloroquinoline-3-methyl carboxylate (0.117 g, 0.53 mmol), cesium carbonate (0.525 g, 1.6 mmol), 10 mL of DMF and 2-chloro-4-fluorophenol (0.159 g, 1.1 mmol) were added to a 100 mL one-neck flask, the reaction system was purged with nitrogen three times, and the temperature was raised to 100 °C to continue the reaction. After the reaction was confirmed by TLC point plate, the reaction system was cooled to room temperature. 50 mL of pure water was added, and the mixture was extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness by vacuum rotary evaporation. The crude product was purified by thin layer chromatography silica gel preparative plate (developer: petroleum ether / ethyl acetate (v / v) = 4 / 1, eluent: dichloromethane / methanol (v / v) = 10 / 1) to give a yellow solid, methyl 2-(2-chloro-4-fluorophenoxy)quinoline-3-carboxylate (0.132 g, 75.5% yield). ESI-MS (m / z): 332.4 [M+H] + .

[0193] Step b): Preparation of 2-(2-chloro-4-fluorophenoxy)quinoline-3-carboxylic acid [ka] Methyl 2-(2-chloro-4-fluorophenoxy)quinoline-3-carboxylate (0.122 g, 0.37 mmol) and 4 mL of methanol were added to a 100 mL one-neck flask and stirred for 10 min, then 20 mL of pure water and lithium hydroxide (36 mg, 1.5 mmol) were added, and the reaction system was allowed to react at 45 °C for 10 h. The reaction mixture was concentrated to dryness under reduced pressure, then 20 mL of pure water was added, and extracted with ethyl acetate (20 mL x 2). The aqueous phase was adjusted to pH 4-5 with 1 M hydrochloric acid, then extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-(2-chloro-4-fluorophenoxy)quinoline-3-carboxylic acid (0.102 g, 87.3% yield) as a white solid. ESI-MS (m / z): 316.0 [MH] - .

[0194] Step c): Preparation of 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide [ka] 2-(2-chloro-4-fluorophenoxy)quinoline-3-carboxylic acid (60 mg, 0.189 mmol), 3-aminobenzenesulfonamide (39 mg, 0.226 mmol) and 4 mL of DMF were added to a 250 mL three-neck flask, and the reaction system was purged with nitrogen three times to protect the reaction system. After cooling in an ice-water bath for 20 minutes, DIPEA (53 mg, 0.41 mmol) was added, then a solution of propylphosphonic anhydride (0.331 g, 0.52 mmol) was added dropwise, the reaction was continued for 1 h after the addition, and then the temperature was raised to room temperature and stirred overnight. After the reaction was completed, 30 mL of pure water was added, then extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by thin layer chromatography silica gel preparative plate (developer: dichloromethane / methanol (v / v) = 10 / 1, eluent: dichloromethane / methanol (v / v) = 10 / 1) to give a white solid of 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide (17 mg, 19.06% yield). 1 H NMR (400MHz, DMSO-d6) δ10.94(s, 1H), 8.79(s, 1H), 8.39(s, 1H), 8.09(d, J=8.0Hz , 1H), 7.95-7.82(m, 1H), 7.79-7.71(m, 1H), 7.68-7.54(m, 6h), 7.48-7.32(m, 3H). ESI-MS(m / z):472.2[M+H] + .

[0195] Example 31 Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-4-trifluoromethylbenzamide (Compound A6 in Patent CN112457294B) [ka] Step a): Preparation of 5-chloro-2-fluoro-4-trifluoromethylbenzamide [ka] Oxalyl chloride (25 mL) and DMF (400 mg, 5.47 mmol) were added to a solution of 5-chloro-2-fluoro-4-trifluoromethylbenzoic acid (22 g, 90 mol) in dichloromethane (100 mL) at 0° C. and stirred continuously for 0.5 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a yellow oil, dichloromethane (100 mL) was added, the reaction was placed in an ice-water bath, and then aqueous ammonia (50 mL) was slowly added and stirred for 1 H. After the reaction was completed, the reaction was diluted with water (100 mL), extracted with dichloromethane (100 mL×2), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sulfuric acid, and filtered. The filtrate was concentrated under reduced pressure to obtain a white solid 5-chloro-2-fluoro-4-trifluoromethylbenzamide (21 g, 95% yield). 1 H NMR (400MHz, DMSO-d6) δ8.06(s, 1H), 7.96(s, 1H), 7.93(s, 1H), 7.91(d, J=2.5Hz, 1H). ESI-MS(m / z):239.7[MH] - .

[0196] Step b): Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-trifluoromethylbenzamide [ka] 4,4-Difluoroazepane hydrochloride (30.6 g, 0.18 mol) and N,N-diisopropylethylamine (34.8 g, 0.27 mol) were added to a solution of 5-chloro-2-fluoro-4-trifluoromethylbenzamide (21.7 g, 0.09 mol) in N-methylpyrrolidone (200 mL) and stirred at 100 °C for 16 h. After the reaction was completed, the reaction was quenched with water (600 mL), then extracted with ethyl acetate (400 mL x 2), and the combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sulfuric acid, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 3) to obtain a yellow solid 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-trifluoromethylbenzamide (27 g, 84% yield). 1 H NMR (400MHz, DMSO-d6) δ8.06(s, 1H), 7.69(s, 1H), 7.49(s, 1H), 7.27(s, 1H), 3.44-3.3 8(m, 2H), (3.35-3.30m, 2H), 2.31-2.22(m, 2H), 2.17-2.05(m, 2H), 1.89-1.80(m, 2H). ESI-MS(m / z):357.0[M+H] + .

[0197] Step c): Preparation of N-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)pyridin-4-yl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-4-trifluoromethylbenzamide [ka] 4-Bromo-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide (16 g, 33.5 mmol), Pd2(dba)3 (2.3 g, 2.5 mmol), BINAP (3.14 g, 5.0 mmol) and cesium carbonate (27.3 g, 84.0 mmol) were added to a solution of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-trifluoromethylbenzamide (12 g, 33.5 mmol) in toluene (100 mL) and stirred at 85 °C for 16 h. After the reaction was complete, the reaction was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 2), and the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 5) to give a yellow solid N-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)pyridin-4-yl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-4-trifluoromethylbenzamide (20 g, 79% yield). ESI-MS (m / z): 753.2 [M+H] + .

[0198] Step d): Preparation of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-4-trifluoromethylbenzamide [ka] Trifluoromethanesulfonic acid (1 mL, 7.1 mmol) was slowly added to a solution of N-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)pyridin-4-yl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-4-trifluoromethylbenzamide (7 g, 9.29 mmol) in trifluoroacetic acid (13 mL) and reacted at 50° C. for 0.5 h. After the reaction was completed, the reaction solution was slowly added to ice water (100 mL), stirred for 0.5 h, and filtered to obtain the crude product. The crude product was purified by C18 reverse phase column (trifluoroacetic acid system) to obtain a white solid (2.3 g, 48% yield). 1H NMR (400MHz, DMSO-d6) δ11.21(s, 1H), 8.63(d, J=5.2Hz, 1H), 8.31(s, 1H), 7.88-7.80(m, 1H), 7.76(s, 1H), 7.47(s , 2H), 7.36(s, 1H), 3.41-3.39(m, 1H), 3.36-3.34(m, 1H), 2.29-2.14(m, 2H), 2.12-1.98(m, 2H), 1.83-1.74(m, 2H). ESI-MS(m / z):513.2[M+H] + .

[0199] Example 32 Preparation of 2-(4-fluoro-2-methylphenoxy)-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (parent drug of VX150) [ka] Step a): Preparation of 2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide [ka] Triethylamine (1.7 g, 16.8 mmol) was added to a solution of 2-fluoro-4-trifluoromethylbenzoic acid (1 g, 4.8 mmol), 2-methoxy-4-aminopyridine (0.626 g, 5 mmol) and HATU (2.741 g, 7.2 mmol) in dichloromethane (30 mL) under nitrogen protection and stirred at room temperature for 16 h. After the reaction was completed, 50 mL of pure water was added and stirred uniformly, the liquid was separated to keep the lower organic phase, and the upper aqueous phase was extracted with dichloromethane (30 mL x 3), all the organic phases were combined, then washed with saturated NaCl solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness by vacuum rotary evaporation. The crude product was purified by silica gel column chromatography (PE / EA (v / v)=8 / 1-3 / 1) to give a white solid of 2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide (1.179 g, yield 78.1%).

[0200] Step b): Preparation of 2-fluoro-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide [ka] Hydrobromic acid / acetic acid solution (10 mL, 33%) was added to 2-fluoro-N-(2-methoxy-pyridin-4-yl)-4-(trifluoromethyl)benzamide (0.5 g, 1.6 mmol) under nitrogen protection. The solution was reacted at 100° C. for 5 h, then at room temperature for 12 h. 40 mL of pure water was added and stirred for 30 min, then filtered, the filter cake was washed with pure water (10 mL×2) and dried under reduced pressure at 50° C. to give a grey solid 2-fluoro-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (0.215 g, 45% yield).

[0201] Step c): Preparation of 2-(4-fluoro-2-methylphenoxy)-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide [ka] DMF (6 mL) was added to a mixture of 2-fluoro-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (0.21 g, 0.7 mmol), 4-fluoro-2-methylphenol (0.261 g, 2 mmol) and cesium carbonate (0.684 g, 2 mmol) under nitrogen protection and reacted at 80 ° C for 2 H. After the reaction was completed, the reaction system was cooled to room temperature, 50 mL of pure water was added, stirred for 30 min, then filtered, the filter cake was washed in turn with pure water (20 mL × 2) and petroleum ether (20 mL × 2), and then dried under reduced pressure to obtain 0.278 g of crude product. The crude product was completely dissolved in ethyl acetate (about 5 mL) and stirred for 5 min, then petroleum ether (about 15 mL) was slowly added to precipitate a large amount of precipitate, stirred for 2 h and filtered. The filter cake was washed with petroleum ether (10 mL×2) and dried under reduced pressure to give a white solid, 2-(4-fluoro-2-methylphenoxy)-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (0.212 g, 75.6% yield). 1 H NMR (400MHz, DMSO-d6) δ11.29(s, 1H), 10.64(s, 1H), 7.84(d, J=7.9Hz, 1H), 7.60(d, J=8.5Hz, 1H), 7.31(d, J=7.2Hz, 1 H), 7.277.20(m, 1H), 7.10(dd, J=6.7, 3.1Hz, 1H), 6.97(s, 1H), 6.75(s, 1H), 6.38(dd, J=7.2, 2.0Hz, 1H), 2.16(s, 3H). ESI-MS(m / z):407.2[M+H] + .

[0202] Example 33 Electrophysiological Assays The patch clamp technique is known as the "gold standard" for studying ion channels, and uses glass microelectrodes to seal the cell membrane and measure the currents of various membrane channels. Nav is a type of transmembrane protein and contains three different states: resting, active, and inactive. The patch clamp technique can evaluate the inhibitory strength of different compounds against different states of Nav by measuring the changes in membrane channel currents after different compounds bind to different states of Nav.

[0203] Representative compounds of the present invention were assessed for their inhibitory potency by measuring their effect on Nav1.8 currents by manual patch clamp experiments using stable CHO or HEK293 cell lines transfected with specific ion channels.

[0204] Method 1: The manual patch clamp assay protocol is as follows. 1)Cell culture CHO cell lines stably expressing hNav1.8 were cultured in F12 medium containing 10% fetal bovine serum at a constant temperature of 37°C, and the carbon dioxide concentration was maintained at 5%. The old culture medium was removed and washed once with PBS, after which 1 mL of 0.25%-Trypsin-EDTA solution was added and incubated at 37°C for 1 min. When the cells detached from the bottom of the culture dish, 5 mL of complete medium pre-warmed at 37°C was added, and the aggregated cells were detached by blowing gently with a straw. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000 rpm for 5 min to collect the cells. The cells were then inoculated (2.5 × 10 5 Cells / Petri dish, 5 mL of medium) were expanded or maintained.

[0205] To maintain the electrophysiological activity of the cells, the cell density needs to be less than 80%.

[0206] Before the assay, cells were detached with 0.25% Trypsin-EDTA and diluted to 5 × 10 3Cells were seeded on cover slips and cultured in 24-well plates (final volume: 500 μL) for 18 h before the assay.

[0207] 2) Preparation of compound samples The compounds prepared in the examples of the present invention were dissolved in dimethyl sulfoxide (DMSO) to prepare DMSO stock solutions at a concentration of 10 mM for assay, which were then diluted to various concentrations with extracellular solution (140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2, 2 mM CaCl2, 10 mM Glucose, 10 mM HEPES, 1.25 mM NaH2PO4, pH=7.4 adjusted with NaOH) to make the final concentration of DMSO in each compound sample 0.1% or less.

[0208] 3) Patch clamp measurement of sodium channel blocking effect Capillary glass pipettes (BF150-86-10, Sutter Instruments) were pulled into recording electrodes with a micropipette puller (P97, Sutter Instruments). A micromanipulator (MP285, Sutter Instruments) was maneuvered under an inverted microscope (IX71, Olympus) to contact the recording electrode with the cell, and negative pressure suction was applied to form a GΩ seal. Rapid capacitance compensation was then performed, and the negative pressure was continued to disrupt the cell membrane by suction, forming the whole-cell recording mode. Subsequently, gentle capacitance compensation was performed without leakage compensation, and the membrane capacitance and series resistance were recorded. When the whole-cell recording current stabilized, dosing was started, and the next concentration was detected every 5 min for each drug concentration. Multiple cells were detected independently and repeatedly during recording. All electrophysiological assays were performed at room temperature. Specifically, six concentrations (IC 50 The IC50 at a particular concentration is calculated by calculating the relative percentage of peak current generated before and after treatment of cells with each compound concentration. 50 Values ​​or percentage inhibition were calculated with IGOR pro software.

[0209] The voltage stimulation protocol for recording hNav1.8 sodium channel currents using whole-cell patch clamp is as follows: the membrane potential is clamped at -120 mV, the command voltage starts at -130 mV and is held for 8 seconds in 10 mV steps, then depolarized to 0 mV (or current size is 0 pA) and held for 30 ms, and the half-inactivation voltage is measured. After the whole-cell seal is formed, the cell membrane voltage is clamped at -120 mV, the clamp voltage is depolarized to 0 mV and held for 50 ms, and then the voltage is restored to the measured half-inactivation voltage and held for 8 s. The cell membrane potential is then restored to -120 mV and held for 20 ms, then depolarized to 0 mV and held for 50 ms, and finally restored to a clamp voltage of -120 mV and held for 30 ms. Data was collected every 20 s to observe the effect of drugs on the peak current of the hNav1.8 sodium channel.

[0210] The inhibitory activity (resting state) of several examples against hNav1.8 was calculated as shown in Table 2 below. Inhibitory activity of the examples against hNav1.8 [Table 2] hNav1.8 Inhibition Rate of Compounds of the Examples [Table 3]

[0211] Method 2 Human Nav1.8 ion channels are stably expressed in HEK293 cells. After the Nav1.8 currents are stabilized, the effect of compounds on the Nav1.8 ion channels can be confirmed by comparing the NaV1.8 currents before and after compound application.

[0212] 1) Compounding method All reagents were purchased from Sigma (St. Louis, MO) except for NaOH and KOH used for acid-base titrations. Test compounds were accurately weighed and prepared in DMSO at a concentration of 9 mM. All final concentrations were prepared on the day of the assay and then dissolved in extracellular solution. The extracellular solution (mM) was: NaCl, 137; KCl, 4; CaCl2, 1.8; MgCl2, 1; HEPES, 10; glucose, 10; pH 7.4 (NaOH titration). All test and control compound solutions contained 1 μM TTX.

[0213] 2) Assay method All assays were performed at room temperature, and controls were set for each cell. All compounds were perfused by their own gravity perfusion system. At least two cells were tested for each concentration. After the current stabilized (or after 5 min), the change in current intensity before and after applying the compound was compared to calculate the blocking effect of the compound.

[0214] a) Assay Equipment Patch clamp amplifier: Patch clamp PC-505B (WARNER instruments) / MultiClamp 700A (Axon instrument) Digital to Analog Converter: Digidata 1440A(Axon CNS) / Digidata 1550A(Axon Instruments) Micromanipulator: MP-225 (SUTTER Instruments) Inverted microscope: TL4 (Olympus) Glass micropipette puller: PC-10 (NARISHIGE) Microelectrode glass capillary: B12024F (Wuhan Microtanyi Scientific Instrument Co.,LTD.) b) Electrophysiology Cells were transferred to a perfusion tank for perfusion with extracellular solution. Intracellular solution (mM): Aspartate, 140; MgCl2, 2; EGTA, 11; HEPES, 10; pH 7.2 (CsOH titration). Intracellular solution was stored in small batches in a refrigerator at -80°C and thawed on the day of the study. Electrodes were fabricated by pulling with a PC-10 (Narishige, Japan). During whole-cell patch-clamp recordings, noise was filtered at one-fifth of the sampling frequency.

[0215] c) Assay Protocol (Static Conditions) The cells were clamped at -80mV and then depolarized to 10mV with a square wave of 10ms duration to obtain Nav1.8 current (see attached Figure 1). This procedure was repeated every 5 seconds. The maximum current triggered by the square wave was detected and when it stabilized, the test compound was perfused and when the response was stable, the strength of the block was calculated.

[0216] The inhibitory activity of several examples against hNav1.8 was calculated as shown in Table 4 below. Inhibitory activity of the examples against hNav1.8 [Table 4]

[0217] Example 34 Kinetic Solubility Assay 1) Preparation of stock solutions Stock solutions of test compounds and the standard progesterone were prepared at a concentration of 10 mM in DMSO.

[0218] 2) Solubility Assay Procedure 30 μL of 10 mM stock solutions of test compounds and standards were placed in sequence in the appropriate 96-well plate. 970 μL of phosphate buffer at the given pH was added to the appropriate vial in the sample plate. The assay was a duplicate assay. Each vial was provided with a stir bar and capped with a Teflon / silicone plug. The sample tray was then placed in an Eppendorf Thermomixer Comfort and shaken at 1100 RPM for 2 hours at 25°C. After 2 hours, the plug was removed, the stir bar was removed with a large magnet, and the samples were transferred from the sample plate to a filter plate. The samples were filtered by generating negative pressure using a vacuum pump. 5 μL of the filtrate was transferred to a new sample plate, after which the solvent was diluted by adding 5 μL of DMSO and 490 μL of water / acetonitrile (V / V=1 / 1). The dilution factor may be adjusted depending on the solubility value of the substance being tested or the intensity of its LC-MS signal response.

[0219] 3) Preparation of standard solutions From the 10 mM DMSO stock solution, 15 μL was transferred to a blank plate and 485 μL DMSO was added to prepare 300 μM standards. From the 300 μM standard plate, 5 μL was transferred to another blank plate and 5 μL of phosphate buffer at the given pH and 490 μL of water / acetonitrile (V / V=1 / 1) dilution solvent were added to the standard to a final concentration of 3 μM. The concentration of the standard may be adjusted depending on the intensity of the LC-MS signal response.

[0220] 4) Sample analysis step The sample plate was placed in the sample tray of an autosampler and the samples were evaluated by LC-MS / MS analysis.

[0221] 5) Data Analysis All calculations were performed using Microsoft Excel.

[0222] The sample filtrates were analyzed and quantified using LC-MS spectrum peaks identified and quantified against standards of known concentration. The solubility values ​​of the reference drug and the tested compound were calculated as follows: [Sample]: Concentration of the sample AREA Sample : Peak area of ​​sample INJ VOL Std : Standard sample injection volume Defender Sample : sample dilution factor [STD]: Standard substance concentration AREA Std : Peak area of ​​standard substance INJ VOL Sample :Sample injection volume Kinetic solubility of the compounds of the examples (unit: μM) (compounds of equivalent activity) [Table 5]

[0223] Example 35 In Vitro Stability Assay Method for Human Liver Microsomes 1.Material Human liver microsomes were purchased from Corning or Xenotech and stored in a -80°C refrigerator. Nicotinamide adenine dinucleotide phosphate (NADPH), Chem-impex international, 00616 Control compounds: testosterone, diclofenac, propafenone

[0224] 2. Equipment Water bath (HH-60, Guohua, Changzhou, China) Pipette workstation (PP-550DS, Apricot, Covina, USA) Centrifuge (5810R, Eppendorf, Hamburg, Germany) Mass spectrometer (Sciex API 4000, Singapore) High performance liquid chromatography (LC 20-AD, Shimadzu, Kyoto, Japan) Sampler (ADDA, Apricot Designs, California, USA)

[0225] 3. Assay Procedure 3.1 Preparation of working solution Stock solution: 10 mM DMSO Working solution concentration: 10 mM stock solution was diluted to 100 μM with 100% acetonitrile (organic phase content: 99% ACN, 1% DMSO).

[0226] 3.2 Assay procedure The two 96-well incubation plates were named T60 incubation plate and NCF60 incubation plate. 445 μL of microsome working solution (liver microsomal protein concentration: 0.56 mg / mL) was added to each of the T60 and NCF60 incubation plates, and then the incubation plates were placed in a 37° C. water bath and pre-incubated for about 10 minutes.

[0227] After the pre-incubation was completed, 5 μL of the test compound working solution was added to the T60 and NCF60 incubation plates, respectively, and mixed evenly. The reaction was started by adding 50 μL of potassium phosphate buffer per well in the NCF60 incubation plate. 180 μL of stop solution (acetonitrile solution containing 200 ng / mL tolbutamide and 200 ng / mL labetalol) and 6 uL of NADPH regenerating system working solution were added to the T0 stop plate, and 54 μL of sample was removed from the T60 incubation plate to the T0 stop plate (T0 sample generation). The reaction was started by adding 44 μL of NADPH regenerating system working solution per well in the T60 incubation plate. Only 54 μL of microsome working solution, 6 uL of NADPH regenerating system working solution, and 180 μL of stop solution were added to the blank plate. Thus, in the test or control compound samples, the final reaction concentrations of the compounds, testosterone, diclofenac and propafenone were 1 μM, the concentration of liver microsomes was 0.5 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v).

[0228] After incubation for an appropriate time (e.g., 5, 10, 20, 30, and 60 min), 180 μL of stop solution (a solution in acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol) was added to each sample well of the stop plate, respectively, and then 60 μL of sample was removed from the T60 incubation plate to stop the reaction.

[0229] All sample plates were shaken evenly and centrifuged at 3220×g for 20 min. Then, 80 μL of supernatant was taken from each well and diluted in 240 μL of pure water for LC-MS / MS analysis.

[0230] 4. Liquid Chromatography Tandem Mass Spectrometry All samples were injected and analyzed. The liver microsomal stability results are shown in Table 6. Human liver microsome stability (T 1 / 2 ) Test results [Table 6]

[0231] Example 36 Efficacy test in rat postoperative pain model Experimental animals Male Sprague-Dawley rats purchased from Zhejiang Vital River Laboratory Animal Technology Co., LTD. Sample solution preparation The compounds of Examples 10, 14, 16 and 31 of the present invention were weighed and prepared into a 3mg / mL solution with 5% DMSO (Anhui Senrise Technologies Co., Ltd.) + 30% Solutol HS15 (Beijing Ouhe Technology Co., Ltd.) + 65% water for injection, and administered orally at a volume of 10mL / kg. The dose was 30mg / kg.

[0232] Experimental procedure The animals were anesthetized with Zoletil 50 + xylazine (20 mg / kg + 8 mg / kg, intraperitoneal injection). The surgical site of the plantar skin of the left hind paw was disinfected three times with iodophor and 70% ethanol, and surgery was started after the skin was dried.

[0233] A longitudinal incision of approximately 1 cm was made on the left hind paw 0.5 cm away from the heel toward the toes. After incision of the skin, the flexor digitorum brevis was elevated and a longitudinal blunt injury was applied. After compression hemostasis, the wound was sutured. After surgery, the animals were placed on an electric heating pad and 5 mL of saline was injected subcutaneously to prevent dehydration. After 24 h modeling, all animals (including the normal control group) were tested for mechanical allodynia baseline (PWT). Modeling animals without mechanical hypersensitivity (PWT >5 g) were excluded, and 50 animals were selected and randomly divided into 5 groups, with 9 animals assigned to each group except for 5 normal groups (negative control group).

[0234] Animals were weighed and orally administered at a volume of 10 mL / kg. Besides normal control animals, other animals received a single dose of the compound, and mechanical allodynia testing was performed on animals in all groups with the test fiber 1 h, 2 h, and 4 h after administration. Rats were individually placed in a plexiglass box with a grid on the bottom so that their paws could be tested. Rats were allowed to acclimate for 15 min before testing. After acclimatization was complete, rats were tested at the mid-plantar left hind paw with the test fiber. The test fiber was pressed perpendicularly against the skin, and a force was applied to bend the fiber for 6-8 s, with a 5-s interval between each test. If the animal suddenly retracted its paw during the test, it was recorded as a pain response. If the animal retracted its paw when the fiber was removed from the skin, it was also recorded as a pain response. If the animal moved or walked, it was not recorded as a pain response and the test should be repeated.

[0235] Calculation methods and data processing Mechanical allodynia was expressed as paw withdrawal threshold (PWT) in behavioral tests in rats and was calculated according to the following formula: 50% response threshold (g) = (10 (Xf+k□) ) / 10,000 Xf = Final test fiber value used in the test k = table value (Chaplan et al. 1994, page 62) □=average deviation Data were collected using excel software and analyzed by two-way ANOVA followed by Dunnett's multiple comparison test using Prism 7.0 (Graph pad software, Inc.) software.

[0236] result The results are shown in Figure 2. In this experiment, Example Compound 31 suppressed mechanical allodynia induced by rat postoperative pain model after 2h and 4h of single oral administration at 30mg / kg. Example Compounds 10, 14, and 16 suppressed mechanical allodynia induced by rat postoperative pain model after 1h, 2h, and 4h of single oral administration at 30mg / kg. Compound 14 was significantly more effective than Example Compound 31 after 1h and 4h of administration, and Example Compound 16 was significantly more effective than Example Compound 31 after 1h of administration.

[0237] Note: *p<0.05, **p<0.01, ***p<0.001 compared to normal group, #p<0.05, ###p<0.001 compared to example compound 31.

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 Formula I During the ceremony, X １ , X ２ , Z １ , Z ２ is independently selected from substituted or unsubstituted C or N; R １ are independently hydrogen, halogen, or -NH ２ , -CN, -OH, -C １ -C ６ Alkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkoxy, -C １ -C ６ Alkylamino, -SO ２ R ２ , -S(O)(NH)R ２ , -COR ２ , -CONR ２ R ３ is selected from the group consisting of ２ and R ３ are independently hydrogen, -NH ２ , and -C １ -C ３ alkyl, Ring A is a substituted or unsubstituted benzene ring or a 6-membered heteroaryl; A compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein ring B is a substituted or unsubstituted 3- to 10-membered aliphatic ring or aliphatic heterocyclic ring.

2. X １ and X ２ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein at least one of:

3. Ring A is selected from 6-membered aryl or heteroaryl containing 0-3 nitrogen atoms, where said aryl or heteroaryl is optionally selected from hydrogen, halogen, -NH ２ , -CN, -OH, -C １ -C ６ Alkyl, carbonyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkoxy, -C １ -C ６ Alkylamino, -SO ２ R ２ , -S(O)(NH)R ２ , -COR ２ , -CONR ２ R ３ or -POR ２ R ３ where R １ and R ２ are independently hydrogen, -NH ２ , -NHCH ３ , and -C １ -C ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of aryl, ... and aryl;

4. Ring B is selected from a 3-10 membered aliphatic or aliphatic heterocyclic ring having 0-3 heteroatoms selected from N, O, and S, and optionally the aliphatic or aliphatic heterocyclic ring is selected from a halogen, a carbonyl group, -NH ２ , -CN, -OH, -C １ -C ６ Haloalkyl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkoxy, -C １ -C ６ Alkylamino, -C ３ -C ６ Cycloalkyl or -C ３ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which is substituted by cycloheteroalkyl.

5. The compound is represented by formula II: 【Chemistry 2】 Formula II In the formula, X １ , X ２ are independently selected from C or N, and at least X １ is N, R １ are independently hydrogen, halogen, or -NH ２ , -CN, -OH, -C １ -C ６ Alkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkoxy, -C １ -C ６ Alkylamino, -SO ２ R ２ , -S(O)(NH)R ２ , -COR ２ , -CONR ２ R ３ is selected from the group consisting of ２ and R ３ are independently hydrogen, -NH ２ , and -C １ -C ３ alkyl, Y is selected from CH or N; R ５ is hydrogen, halogen, -NH ２ , -CN, -OH, -C １ -C ６ Alkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkoxy, -C １ -C ６ alkylamino; n is an integer from 0 to 6, Ring A is selected from 6-membered aryl or heteroaryl containing 0-3 nitrogen atoms, where said aryl or heteroaryl is optionally selected from hydrogen, halogen, -NH ２ , -CN, -OH, -C １ -C ６ Alkyl, carbonyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkoxy, -C １ -C ６ Alkylamino, -SO ２ R ２ , -S(O)(NH)R ２ , -COR ２ , -CONR ２ R ３ or -POR ２ R ３ where R ２ and R ３ are independently hydrogen, -NH ２ , -NHCH ３ , and -C １ -C ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of aryl, ... and aryl;

6. The ring A is a group represented by the following formula: However, R ４ is hydrogen, halogen, -NH ２ , -CN, -OH, -C １ -C ６ Alkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkoxy, -C １ -C ６ Alkylamino, -SO ２ R ２ , -S(O)(NH)R ２ , -COR ２ , -CONR ２ R ３ , or -POR ２ R ３ and R ２ and R ３ are independently hydrogen, -NH ２ , -NHCH ３ , -C １ -C ３ alkyl, or R ２ and R ３ The compound according to claim 5, wherein, together with phosphorus, forms a 3- to 8-membered ring, or a pharma- ceutically acceptable salt thereof. 【Chemistry 3】

7. The compound is represented by formula III: 【Chemistry 4】 Formula III In the formula, X １ and X ２ are independently selected from C or N, and at least X １ is N, R １ are independently hydrogen, halogen, or -NH ２ , -CN, -OH, -C １ -C ６ Alkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkoxy, -C １ -C ６ Alkylamino, -SO ２ R ２ , -S(O)(NH)R ２ , -COR ２ , -CONR ２ R ３ is selected from the group consisting of ２ and R ３ are independently hydrogen, -NH ２ , and -C １ -C ３ alkyl, T is CR ６ or N, R ６ is hydrogen, halogen or -C １ -C ６ is alkyl, R ９ is hydrogen, halogen, -NH ２ , -CN, -OH, -C １ -C ６ Alkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkoxy, -C １ -C ６ Alkylamino, -SO ２ R ２ , -S(O)(NH)R ２ , -COR ２ , -CONR ２ R ３ , or -POR ２ R ３ and R ２ and R ３ are independently hydrogen, -NH ２ , -NHCH ３ , -C １ -C ３ alkyl, or R ２ and R ３ forms a 3- to 8-membered ring with phosphorus, R ５ is hydrogen, halogen, -NH ２ , -CN, -OH, -C １ -C ６ Alkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Alkoxy, -C １ -C ６ Haloalkoxy, -C １ -C ６ alkylamino; 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein n is an integer from 0 to 6.

8. 8. The compound according to claim 7, wherein Y is nitrogen and n is an integer from 1 to 4, or a pharma- ceutically acceptable salt thereof.

9. 9. The compound of claim 8, or a pharma- ceutically acceptable salt thereof, wherein n is 3.

10. The compound is represented by formula IV: 【Chemistry 5】 Formula IV In the formula, R １０ and R １１ is independently selected from hydrogen or halogen; 8. The compound of claim 7, or a pharma- ceutically acceptable salt thereof, wherein the other substituents are as defined above.

11. R １ are independently hydrogen, halogen, -C １ -C ６ Alkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Alkoxy or -C １ -C ６ 11. The compound of any one of claims 7 to 10, or a pharma- ceutically acceptable salt thereof, selected from haloalkoxy.

12. R １ are independently hydrogen, halogen, -CH ３ , -OCH ３ or a pharma- ceutically acceptable salt thereof.

13. R １ is independently selected from hydrogen or halogen, or a pharma- ceutically acceptable salt thereof.

14. X １ is N, and X ２ or a pharma- ceutically acceptable salt thereof.

15. X １ is N, and X ２ is N, or a pharma- ceutically acceptable salt thereof.

16. R ６ The compound according to claim 7, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen or halogen.

17. R ９ is -SO ２ R ２ , -S(O)(NH)R ２ , -COR ２ Or -CONR ２ R ３ where R ２ and R ３ are independently hydrogen, -NH ２ , -NHCH ３ , and -C １ -C ３ 8. The compound of claim 7, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of alkyl, aryl, aryl, arylsulfates, arylalkyl, arylsulfates ...

18. The compound is represented by formula V: 【Chemistry 6】 Formula V In the formula, R ７ , R ８ are independently hydrogen, halogen, -CH ３ , -OCH ３ is selected from R ９ is -SO ２ R ２ , -S(O)(NH)R ２ , -COR ２ , -CONR ２ R ３ is selected from R ２ and R ３ are independently hydrogen, -NH ２ , -NHCH ３ , -C １ -C ３ alkyl, T is CR ６ or N, R ６ is hydrogen, halogen or -C １ - ６ is alkyl, R １０ and R １１ or a pharma- ceutically acceptable salt thereof, according to claim 7, wherein:

19. R ９ is -SO ２ N.H. ２ , -CONH ２ 19. The compound of claim 18, selected from:

20. R ９ Ha-SO ２ N.H. ２ 20. The compound of claim 19, wherein:

21. R ７ and R ８ 19. The compound of claim 18, or a pharma- ceutically acceptable salt thereof, wherein is independently selected from hydrogen or halogen.

22. R ６ or a pharma- ceutically acceptable salt thereof.

23. R １０ and R １１ 20. The compound of claim 18, or a pharma- ceutically acceptable salt thereof, wherein is halogen.

24. 【Chemical 7】 【Chemistry 8】 24. The compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof, selected from:

25. 【Chemical 9】 25. The compound of claim 24, selected from:

26. 26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

27. 30. Use of a compound according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament for treating pain.

28. 26. A method for preventing or treating pain comprising administering to a patient a compound according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof.

29. 29. The use according to claim 28 or the method according to claim 27, wherein the pain is chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, post-operative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or arrhythmia.

Images