Bicyclic compounds as nav1.8 inhibitors and uses thereof

Abstract

The present application provides a kind of as sodium channel blocker and cyclophane compound and its use, it has inhibitory activity to sodium ion channel Nav1.8, can be used as the drug for treating a wide range of pain.

Description

Technical Field

[0001] This invention relates to cyclic compounds that have inhibitory activity against sodium ion channel Nav1.8 and their uses. Background Technology

[0002] Pain is a complex physiological and psychological activity and one of the most common symptoms in clinical practice. Originally intended as a protective mechanism to alert people to potential dangers, abnormal pain can cause physiological dysfunction, especially chronic pain, which severely impacts 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 is 12%–30%. In the United States, the number of people suffering from pain has surpassed the number suffering from diabetes, heart disease, and cancer, with annual economic losses due to pain reaching $560 billion–635 billion (https: / / www.physio-pedia.com / Epidemiology_of_Pain); while statistics from China in 2015 show that the pain market reached 20.8 billion RMB (https: / / paindoctor.com / resources / chronic-pain-statistics / ). Currently used analgesics such as opioid receptor agonists, cyclooxygenase inhibitors, and GABA receptor agonists may have addictive properties, respiratory depression, gastrointestinal side effects, or cause adverse cardiovascular reactions and central nervous system depression, and clinical needs are far from being met. This shows that the pain market has huge 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 encompasses various types. Based on the nature of the stimulus, it can be classified as mechanical pain, thermal pain, and chemical pain; based on the inflammatory cause, it can be classified as inflammatory pain and non-inflammatory pain; based on the nerve location, it can be classified as central nervous system pain, peripheral nervous system pain, and autonomic nervous system pain; and based on the duration of the illness, it can be classified as acute pain and chronic pain. Regardless of the form of pain, sodium ion channels (Navs) are involved.

[0004] The generation of pain in the human body originates from pain receptors located in the peripheral nerve endings throughout the body. These receptors convert mechanical, thermal, cold, and chemical stimuli into nerve impulses, which are then transmitted via afferent nerves to the dorsal root ganglion (DRG), and then via efferent nerves to the central nervous system, thus allowing 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.). The role of the nerve impulse receptors (NAVs) is to trigger and transmit signals during this process, acting as the primary mediator of the rising phase of the action potential (i.e., nerve impulse) (Mark D. Baker, John N. Wood. Involvement of NAVs). + 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 NaVs can help relieve and treat pain. However, existing NaVs inhibitors such as lidocaine, carbamazepine, and lamotrigine have the drawbacks of narrow therapeutic window and large side effects due to their lack of selectivity for NaVs. Therefore, research has turned to selective NaV inhibitors.

[0005] Navs are a class of transmembrane ion channel proteins composed of an α subunit with a molecular weight of 260 kDa and a β subunit with a molecular weight of 30–40 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.). Based on the strength of their inhibitory activity against tetrodotoxin (TTX), Navs subtypes can be divided into two categories: TTX-sensitive (TTX-S), including Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6, and Nav1.7; and TTX-resistant (TTX-R), including Nav1.5, Nav1.8, and Nav1.9. Based on 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 Solé, 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 As shown in Table 1, Nav1.1, Nav1.2, and Nav1.3 are mainly distributed in the CNS area and are associated with CNS diseases such as epilepsy and local anesthesia; Nav1.4 is mainly distributed in skeletal muscle, and its inhibitors are used as local anesthetics for myotonia; Nav1.5 is mainly distributed in cardiomyocytes, and its inhibitors are used to treat arrhythmias; Nav1.6 is involved in movement disorders; currently, the main targets related to pain are Nav1.7, Nav1.8, and Nav1.9.Among them, Nav1.7 inhibitors have been most widely studied in the field of pain, but no related clinical trials have been successful to date; Nav1.9 has been studied less, and its mechanism of action in pain is not yet fully understood, nor has any evidence of pain efficacy models for related inhibitors been reported; 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, believing that Nav1.8 is the main contributor to the rising branch of the action potential. Its rapid initiation supports high-frequency discharge, has a high activation threshold, and a slow kinetic process. Blocking Nav1.8 can block the generation of action potential and the transmission of electrical signals; Blair and Bean's research (Blair NT, Bean BP. Roles of tetrodotoxin (TTX)-sensitive Na) + current, TTX-resistant Na + current, and Ca 2+(J Neurosci 2002, 22:10277-10290.) suggests that although both Nav1.8 and Nav1.9 are expressed in DRG, Nav1.8 contributes the most to TTX-R current. In the acute phase of nerve injury, Nav1.8 is downregulated in damaged neurons but upregulated in neighboring undamaged neurons, thereby increasing spontaneous firing. In the chronic phase, crosstalk occurs between damaged and undamaged neurons, leading to upregulation of Nav1.8 in damaged neurons, which further increases and maintains idiopathic firing.In addition to mechanistic studies, the efficacy of Nav1.8 inhibitors in animal models of pain has also been validated: for example, Abbott's A-803467 showed an analgesic effect of more than 50% compared to the model groups in carrageenan, complete Freund's adjuvant (CFA), chronic sciatic nerve compression pain (CCI), spinal nerve ligation pain (SNL), and acute mechanical pain models (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.); and A-803467 showed better efficacy than lidocaine when administered systemically in a streptozotocin (STZ)-induced diabetic neuropathic thermal pain model, while the two were comparable when administered via local plantar injection, but A-803467 maintained its efficacy for a longer period (Mert). T, Gunes Y. Antinociceptive activities of lidocaine and the nav1.8 blocker a803467indiabetic rats. J Am Assoc Lab Anim Sci. 2012; 51(5):579-585.); Pfizer's PF-01247324 also showed significant pain relief 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, Vertex's highly selective Nav1.8 inhibitor VX150 has been successful in three pain-related phase II clinical trials. In conclusion, Nav1.8 is a very promising target for treating pain or pain-related diseases.

[0006] Table 1. Overview of Navs subtypes

[0007]

[0008]

[0009] Currently, there are not many companies reporting on Nav1.8 inhibitors in development. Internationally, these include Abbott, Pfizer (WO2013114250A1), Gilead (AU2015224425A1), Sumitomo (WO2015008861A1), AbbVie (WO2016149169A1), Raqualia (WO2020138271A1), Merck (WO2020092187A1), Lieber (WO2020014243A1), and Vertex (WO2019014352A1). Domestically, these include Hengrui (WO2020151728A1) and Shanghai Jiyu Pharmaceutical (CN111808019A). Most of the companies' patents did not disclose the specific inhibitory activity of Nav1.8, or the activity was not good. Only Pfizer's PF-04531083 and Vertex's VX-150 entered Phase II clinical trials. However, PF-04531083 was discontinued because it did not show superior activity to placebo in postoperative toothache. VX-150 was successful in three Phase II clinical trials for inflammatory pain, postoperative acute pain, and neuropathic pain, which initially validated the role of Nav1.8 in pain. However, according to Vertex's official report, it was discontinued due to its unsatisfactory pharmacokinetic (PK) properties. Nevertheless, they are continuing to search for compounds with better PK properties and activity to bring to clinical trials. Therefore, the development of new Nav1.8 inhibitors still has broad prospects and is very necessary. Summary of the Invention

[0010] The purpose of this invention is to provide cyclic compounds that have inhibitory activity against sodium ion channels, particularly Nav1.8 sodium ion channels, and their uses.

[0011] To achieve the above objectives, the present invention provides a solvate, tautomer, or pharmaceutically acceptable salt of formula I:

[0012]

[0013] in,

[0014] X is selected from carbon or nitrogen;

[0015] Ring A is a 3-8 substituted or unsubstituted aliphatic ring or aliphatic heterocycle;

[0016] Ring B is a substituted or unsubstituted benzene ring or a 6-membered aromatic heterocycle;

[0017] The C ring is a substituted or unsubstituted 3-10 member alicyclic or alicyclic heterocyclic ring.

[0018] In some embodiments, ring A is selected from 3-8 membered aliphatic rings or aliphatic heterocycles containing 0-3 heteroatoms selected from N, O and S. Optionally, the aliphatic ring or aliphatic heterocycle is substituted with halogen, carbonyl, NH2, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, or forms a fused ring with C3-C6 cycloalkyl.

[0019] In some embodiments, ring A is selected from 5-7 membered alicyclic or alicyclic heterocycles containing 0-3 heteroatoms selected from N, O and S, wherein the alicyclic or alicyclic heterocycle is substituted with C1-C4 alkyl groups.

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

[0021]

[0022] In some embodiments, ring B is a six-membered aromatic ring or heterocyclic ring containing 0-3 N atoms, wherein the aromatic ring or heterocyclic ring is optionally substituted with 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; wherein R2 and R3 are independently selected from hydrogen, NH2, C 1-3 alkyl.

[0023] In some implementations, ring B is Wherein R1 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; wherein R2 and R3 are independently selected from hydrogen, NH2, C 1-3 Alkyl groups, or R2, R3, together with P to form 3-8 membered rings.

[0024] In some implementations, ring B is selected from:

[0025]

[0026] In some embodiments, the ring C is selected from 3-10 membered alicyclic or aliphatic heterocyclic rings containing 0-3 heteroatoms selected from N, O and S. Optionally, the aliphatic or aliphatic heterocyclic ring is substituted with halogen, carbonyl, NH2, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, or C3-C6 cyclohexaalkyl.

[0027] In some implementations, ring C is: Wherein, Y is selected from carbon and nitrogen; the ring C is substituted by m R4s, where R4 is hydrogen, halogen, NH2, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkylamino; m is an integer from 0 to 2(n+3), and n is an integer from 0 to 6.

[0028] In some implementations, n is an integer from 1 to 4.

[0029] In some implementations, n is 3; R4 is hydrogen or halogen.

[0030] In some implementations, ring C is:

[0031]

[0032] In some embodiments, the compound is selected from:

[0033]

[0034]

[0035] A second object of the present invention is to provide a pharmaceutical composition comprising the compound described in the first object of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0036] A third object of the present invention is to provide the use of the compound described in the first object of the invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pain.

[0037] In another implementation, the pain is selected from: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain, visceral pain, multiple sclerosis, Sharma-Tutankhamun syndrome, incontinence, and arrhythmia.

[0038] definition

[0039] As used herein, the term "alkyl" itself, or in part as another substituent, means (unless otherwise stated) a straight-chain or branched hydrocarbon group having a specified number of carbon atoms (i.e., C646-C ... 1-8(This refers to one to eight carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0040] As used herein, the term "aromatic heterocycle" refers to a group having 5 to 10 heterocyclic atoms, preferably a 5- or 6-membered monocyclic aromatic heterocycle or an 8- to 10-membered bicyclic aromatic heterocycle; and having 1 to 3 heteroatoms in addition to carbon atoms. "Heteroatoms" refers to nitrogen, oxygen, or sulfur.

[0041] The term "alicylic ring" refers to monocyclic or polycyclic alkanes with saturated or unsaturated bonds, preferably saturated monocyclic alkanes such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane. Polycyclic alkanes can be classified into spirocyclic and bridged rings according to their bonding mechanisms.

[0042] The term "aliphatic heterocycle" refers to a monocyclic or polycyclic alkane with saturated or unsaturated bonds containing one or more heteroatoms in addition to a carbon atom. Heteroatoms include, for example, nitrogen, oxygen, or sulfur.

[0043] The term "replaced" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on the basis of chemical feasibility.

[0044] As used herein, the term "halogen," either on its own or as part of another substituent, refers (unless otherwise stated) to a fluorine, chlorine, bromine, or iodine atom. Additionally, the term "haloalkyl" is intended to include both monohaloalkyl and polyhaloalkyl. For example, the term "C" 1-4 "Halogenated alkyl" is intended to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, etc.

[0045] As used herein, “alkoxy” refers to the aforementioned alkyl group having a specific number of carbon atoms connected by an oxygen bridge, unless otherwise specified. 1-6 Alkoxy groups include 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-pentoxy, and S-pentoxy.

[0046] Unless otherwise specified, the structures described herein also mean all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers) of that structure; for example, R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers of these compounds, as well as mixtures of enantiomers, diastereomers, and geometric isomers (or conformational isomers), are within the scope of this invention. Unless otherwise specified, all tautomers of the compounds of this invention are within the scope of this invention. Furthermore, unless otherwise specified, the structures described herein also mean compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except that hydrogen is replaced by deuterium or tritium, or carbon is replaced by... 13 C- or 14 Compounds having the structure of this invention, other than those with C-enriched carbon substitution, are within the scope of this invention.

[0047] Unless otherwise specified, the structures described herein also mean solvates that include such structures. A solvate refers to the physical association of the compound of this application with one or more solvent molecules; such physical association involves ionic and covalent bonds of various degrees, including hydrogen bonds; in some cases, such as when one or more solvent molecules are introduced into the lattice of a crystalline solid, the solvate can be separated; "solvate" encompasses both solution phases and separable solvates; suitable solvents include, but are not limited to, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine; "hydrate" is a solvate in which the solvent molecule is H2O.

[0048] As used herein, the term "composition" is intended to cover products containing a specified amount of a specified ingredient, and any product derived directly or indirectly from a combination of the specified amount of the specified ingredient. The phrase "pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other components in the formulation and harmless to the recipient of the drug.

[0049] As used herein, the term "pharmaceutically acceptable salt" is intended to include salts from which active compounds are prepared using relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines (including substituted amines, cyclic amines, naturally occurring amines, etc.), such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either pure or in a suitable inert solvent. Pharmaceutically acceptable examples of acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrocarbonic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, succinic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Salts of amino acids such as arginine and organic acids such as glucuronic acid or galacturonic acid are also included.

[0050] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of this invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals.

[0051] Compositions containing Formula I compounds are typically formulated according to standard pharmaceutical practices as pharmaceutical compositions. Typical formulations are prepared by mixing the compounds of the invention with diluents, carriers, or excipients. Formulations may also include one or more of buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, diluents, and other known additives.

[0052] The compounds of this invention can be administered in any convenient form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional to pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0053] The compounds of this invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural, and intranasal administration, and, if necessary, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, intracerebral, intraocular, intralesional, or subcutaneous administration.

[0054] The term "pain" in this invention refers to pain associated with an abnormality of a voltage-gated sodium channel, specifically, a voltage-gated sodium channel, Nav1.8. The pain described in this 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, Sharma-Tutankhamun syndrome, incontinence, and arrhythmias.

[0055] These include intestinal pain such as inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain. Musculoskeletal pain such as osteoarthritis pain, back pain, cold pain, burning pain, or toothache. Inflammatory pain such as rheumatoid arthritis pain or vulvar pain; idiopathic pain including fibromyalgia. Neuropathic pain such as postherpetic neuralgia, diabetic neuropathy, painful HIV-associated sensory neuropathy, trigeminal neuralgia, oral burn syndrome, post-operative pain after amputation, phantom pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radiculopathy, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug-induced neuralgia, chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; post-spinal cord injury pain, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal neuralgia.

[0056] The efficacy of the analgesic can be validated using conventional pain models in the field, such as Michael F. Jarvis et al., A-803467, a potent and selective Nav1.8 sodium channelblocker, attenuates neuropathic and inflammatory pain in the rat. PNAS., 2007, 140(20):8520–8525. In some specific embodiments, the efficacy model of the present invention is, for example, a carrageenan or CFA (complete Freund's adjuvant) induced thermal pain model, an SNL (spinal nerve ligation) pain model, an incision pain model, etc. When using a carrageenan or CFA-induced thermal pain model, in some embodiments, the ED50 of the compound of the present invention is less than 200 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 150 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 100 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 80 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 70 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 60 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 50 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 40 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 30 mg / kg; and in some specific embodiments, the ED50 of the compound of the present invention is less than 20 mg / kg. When using the SNL (spinal nerve ligation) pain model, in some specific embodiments, the ED50 of the compound of the present invention is less than 150 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 100 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 80 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 70 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 60 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 50 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 40 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 30 mg / kg; and in some specific embodiments, the ED50 of the compound of the present invention is less than 20 mg / kg.When using an incision pain model, in some specific embodiments, the ED50 of the compound of the present invention is less than 150 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 100 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 80 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 70 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 60 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 50 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 40 mg / kg; in some specific embodiments, the ED50 of the compound of the present invention is less than 30 mg / kg; and in some specific embodiments, the ED50 of the compound of the present invention is less than 20 mg / kg.

[0057] The compounds of this invention are named manually or using Chemdraw software, while commercially available compounds are named according to the supplier's catalog.

[0058] Compared with the prior art, the main advantages of the present invention are:

[0059] A series of novel cyclic compounds with inhibitory activity against Nav1.8 were provided, which could be used as drugs for the treatment of a wide range of pain. Detailed Implementation

[0060] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. The chemical reactions described in the examples (preparation) can be readily 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 invention. Unless otherwise defined, the terminology used herein has the same meaning as is familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the present invention.

[0061] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6Units (ppm) are given. NMR measurements were performed using a Bruker AVANCE III HD (400MHz) or Bruker NEO (400MHz) NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard. MS measurements were performed using liquid chromatography-mass spectrometry (LC-MS): Shimadzu LC-20AD / LCMS-2020 or Agilent 1260 / 6125. High performance liquid chromatography (HPLC) analysis was performed using Shimadzu LC-20AD or LC-2030C, or Agilent 1100 / 1200. Preparative purification was performed using a Waters 2767 or Gilson GX281.

[0062] Example 1

[0063] 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (KH01)

[0064]

[0065] Step a): Preparation of 2-(dimethylamino)methylenecyclopentanone

[0066]

[0067] A mixture of cyclopentanone (10 g, 119 mmol) and DMF-DMA (21.24 g, 178.5 mmol) was reacted at 100 °C for 24 h under nitrogen protection. After the reaction was completed as monitored by TLC, the reaction solution was concentrated to obtain a crude, brownish-brown oily product, 2-(dimethylamino)methylenecyclopentanone (15 g, yield 91%), which was used directly as a starting material for the next reaction without further purification.

[0068] Step b): Preparation of methyl 2-hydroxy-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylate

[0069]

[0070] Methyl cyanoacetate (16 g, 162 mmol) was added to a methanol (75 mL) solution of 15 g (108 mmol) of 2-(dimethylamino)methylenecyclopentanone and the mixture was stirred at 70 °C for 6 h. The methanol was removed by concentration under reduced pressure, and then toluene (75 mL) and acetic acid (6.48 g, 108 mmol) were added. The mixture was refluxed at 100 °C for 12 h. After the reaction was complete, the solvent was removed by reduced pressure, and the solution was poured into ice water and the pH was adjusted to approximately 8 with saturated sodium bicarbonate solution. The solution was extracted three times with dichloromethane, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to give a yellow solid methyl 2-hydroxy-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylate (6 g, yield 28%). 1 H NMR (400MHz, CDCl3) δ8.07 (s, 1H), 3.94 (s, 3H), 3.02 (t, J = 7.7Hz, 2H), 2.86 (t, J = 7.4Hz, 2H), 2.20-2.11 (m, 2H). ESI-MS(m / z):194.0[M+H] + .

[0071] Step c): Preparation of methyl 2-chloro-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylate

[0072]

[0073] Phosphorus oxychloride (3.94 g, 25.75 mmol) was added to a solution of methyl 2-hydroxy-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylate (1 g, 5.15 mmol) in 20 mL of 1,4-dioxane, and the mixture was stirred overnight at 100 °C. After the reaction was complete, the phosphorus oxychloride in the reaction solution was removed under reduced pressure. The crude product was poured into ice water, and the pH was adjusted to approximately 7 to 8 with a saturated sodium bicarbonate aqueous solution. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 50 / 1) to give a yellow solid methyl 2-chloro-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylate (800 mg, yield 73%). 1 H NMR (400MHz, DMSO-d6) δ8.05(s,1H),3.86(s,3H),3.01-2.89(m,4H),2.19-2.05(m,2H). ESI-MS(m / z):212.0[M+H] + .

[0074] Step d): 2-(4,4-difluoroaza) Preparation of methyl 1-(b)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylate

[0075]

[0076] Anhydrous potassium carbonate (326 mg, 2.368 mmol) and 4,4-difluoroazacycloheptan-3-carboxylate (323 mg, 1.894 mmol) were added to a DMF solution of methyl 2-chloro-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylate (200 mg, 0.947 mmol), and the mixture was stirred overnight at 100 °C under nitrogen protection. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 1) to give a pale yellow solid 2-(4,4-difluoroazacycloheptan-3-carboxylate). Methyl 1-(b)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylate (120 mg, 41% yield). 1 H NMR (400MHz, CDCl3) δ7.71 (s, 1H), 3.85 (s, 3H), 3.74-3.62 (m, 2H), 3.29 (t, J = 5.9H z,2H),2.86-2.82(m,4H),2.48-2.30(m,2H),2.14-2.05(m,2H),2.04-1.88(m,4H). ESI-MS(m / z):311.2[M+H] + .

[0077] Step e): 2-(4,4-difluoroaza) Preparation of 1-yl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylic acid

[0078]

[0079] To 2-(4,4-difluoroaza) A solution of methyl 6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylate (120 mg, 0.387 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) was added to a solution of potassium hydroxide (433 mg, 1.935 mmol) in 1 mL, and the mixture was stirred at 60 °C for 2 h. After the reaction was complete, the mixture was extracted with ethyl acetate. The aqueous phase was adjusted to pH 6 with 1.0 M hydrochloric acid solution and then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a white solid 2-(4,4-difluoroazapyridine) (-1-yl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylic acid, (80 mg, 70% yield). ESI-MS (m / z): 297.2 [M+H] + .

[0080] Step f): 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide

[0081]

[0082] Nitrogen protection for 2-(4,4-difluoroaza) HATU (64.2 mg, 0.169 mmol) and DIEA (87.2 mg, 0.676 mmol) were added to a DMF solution of 2-(4,4-difluoroazines)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylic acid (50 mg, 0.169 mmol). The mixture was stirred at room temperature for 1 h, followed by the addition of m-aminobenzenesulfonamide (87 mg, 0.507 mmol). The reaction was then heated to 60 °C and reacted for 4 h. After the reaction was complete, the mixture was purified by reversed-phase preparative chromatography to obtain a white solid, 2-(4,4-difluoroazines). -1-yl)-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide, (28.4 mg, yield 31%). 1 H NMR (400MHz, DMSO-d6) δ10.58(s,1H),8.31(s,1H),7.79(d,J=3.8Hz,1H),7.57-7.53(m,3H),7.38(s ,2H),3.57-3.53(m,4H),2.83-2.79(m,4H),2.37-2.25(m,2H),2.07-1.92(m,4H),1.87-1.76(m,2H). ESI-MS(m / z):451.1[M+H] + .

[0083] Example 2

[0084] 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-dimethylphosphorylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (KHO2)

[0085]

[0086] Step a): Preparation of 3-nitrophenyl dimethylphosphine oxide

[0087]

[0088] To a solution of 1-iodo-3-nitrobenzene (200 mg, 0.806 mmol) in 1,4-dioxane, dimethylphosphine oxide (125 mg, 1.6 mmol), cesium carbonate (365 mg, 1.12 mmol), Pd₂(dba)₃ (37 mg, 0.08 mmol), and Xant-phos (47 mg, 0.08 mmol) were added sequentially. The mixture was heated to 90 °C for 3 h under nitrogen protection. After the reaction was complete, ethyl acetate was added to the reaction solution, and the mixture was filtered. A suitable amount of water was added to the filtrate, and the organic phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 10 / 1) to obtain a yellow solid 3-nitrophenyl dimethylphosphine oxide (130 mg, yield 81%). 1 H NMR (400MHz, CDCl3) δ8.52 (d, J=11.8Hz, 1H), 8.40 (dd, J=8.2, 1.0Hz, 1H), 8.16 (dd,J=10.8,7.6Hz,1H),7.75(dd,J=7.8,2.4Hz,1H),1.83(s,3H),1.80(s,3H). ESI-MS(m / z):199.9[M+H] + .

[0089] Step b): Preparation of 3-aminophenyldimethylphosphine oxide

[0090]

[0091] Ammonium chloride (68.5 mg, 1.28 mmol) and iron powder (191 mg, 3.4 mmol) were added to a mixed solution of 3-nitrophenyl dimethylphosphine oxide (170 mg, 0.85 mmol) in methanol (7 mL) and water (1.3 mL), and the mixture was reacted at 75 °C for 1 h. After the reaction was complete, the mixture was filtered through diatomaceous earth, washed with methanol, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 10 / 1) to obtain a yellow solid 3-aminophenyl dimethylphosphine oxide (91.8 mg, yield 63%). 1 H NMR (400MHz, DMSO-d6) δ7.15-7.10(m,1H),6.97-6.91(m,1H),6.81(dd,J=1 1.4,7.4Hz,1H),6.71-6.66(m,1H),5.30(s,2H),1.57(s,3H),1.54(s,3H).

[0092] Step c): 2-(4,4-difluoroaza) Preparation of 1-yl)-N-(3-dimethylphosphorylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide

[0093]

[0094] The procedure is the same as in Example 1, except that the m-aminobenzenesulfonamide in step f is replaced with 3-aminophenyl dimethylphosphine oxide, yielding a white solid 2-(4,4-difluoroaza) -1-yl)-N-(3-dimethylphosphorylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (30.5 mg, yield 31%). 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),8.08(d,J=12.6Hz,1H),7.89(d,J=7.5Hz,1H),7.58(s,1H),7.51-7.46(m,1H),7.46-7.40(m,1H),3 .64-.54(m,2H),3.44-3.37(m,2H),2.86-2.77(m,4H),2.40-2.25(m, 2H),2.09-1.91(m,4H),1.86-1.78(m,2H),1.65(s,3H),1.62(s,3H). ESI-MS(m / z):448.3[M+H] + .

[0095] Example 3

[0096] 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-methanesulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (KHO3)

[0097]

[0098] The procedure is the same as in Example 1, except that the m-aminobenzenesulfonamide in step f is replaced with 3-methanesulfonylaniline, yielding a white solid 2-(4,4-difluoroazapyridine). -1-yl)-N-(3-methanesulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (48.3 mg, yield 26.5%). 1H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.36(s,1H),8.00-7.92(m,1H),7.63(d,J=0.8Hz,1H),7.62(d,J=2.4Hz,1H),7.60(s,1H),3.65-3.54( m,2H),3.42-3.36(m,2H),3.23-3.19(m,3H),2.85-2.78(m,4H),2.40- 2.25(m,2H),2.08-2.03(m,2H),2.02-1.91(m,2H),1.88-1.76(m,2H). ESI-MS(m / z):450.3[M+H] + .

[0099] Example 4

[0100] 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-carbamoylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (KH04)

[0101]

[0102] The procedure is the same as in Example 1, except that 3-aminobenzenesulfonamide is used instead of m-aminobenzamide in step f. No heating is required during the reaction; simply maintain room temperature for 24 hours to obtain a white solid, 2-(4,4-difluoroazapyridine). -1-yl)-N-(3-carbamoylphenyl)-6,7-dihydro-5H-cyclopentadieno[b]pyridine-3-carboxamide (68.1 mg, yield 60%). 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.17(s,1H),7.93(s,1H),7.82(d,J=8.1Hz,1H),7.56(d,J=5.7Hz,2H),7.39(t,J=7.9Hz,1H ),7.34(s,1H),3.65-3.53(m,2H),3.46-3.38(m,2H),2.88-2.76(m,4H),2.38-2.23(m,2H),2.11-1.92(m,4H),1.87-1.76(m,2H). ESI-MS(m / z):415.3[M+H] + .

[0103] Example 5

[0104] 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-aminoiminosulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (KH05)

[0105]

[0106] Step a): Preparation of N-(tert-butyldiphenylsilyl)-3-nitrobenzenesulfonamide

[0107]

[0108] Triethylamine (7.56 mL, 54.41 mmol) and TBDPSCl (8.04 mL, 30.91 mmol) were added to a tetrahydrofuran solution (300 mL) of 3-nitrobenzenesulfonamide (5.00 g, 24.73 mmol). The mixture was stirred overnight at 50 °C under nitrogen protection. After the reaction was complete, the reaction solution was evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA(v / v) = 1 / 0-20 / 1, PE / DCM(v / v) = 5 / 1-2 / 1-1 / 1) to give a white solid N-(tert-butyldiphenylsilyl)-3-nitrobenzenesulfonamide (8.20 g, yield 75%). 1 H NMR (400MHz, CDCl3) δ8.25-8.19(m,1H),8.07(t,J=1.9Hz,1H),7.65-7.62(m,1H),7.6 1-7.60(m,2H),7.60-7.58(m,2H),7.46-7.39(m,3H),7.35-7.29(m,4H),1.07(s,9H). ESI-MS(m / z):439.1[MH] - .

[0109] Step b): Preparation of N'-(tert-butyldiphenylsilyl)-3-nitrobenzenesulfonylimide

[0110]

[0111] Under nitrogen protection, a CHCl3 solution (14 mL) of PPh3 (1.43 g, 5.45 mmol) and C2Cl6 (1.29 g, 5.45 mmol) was stirred for 6 h. After cooling to room temperature, a CHCl3 solution of Ph3PCl2 (14 mL, 5.45 mmol, 0.39 M, yield ~100%) was obtained. Triethylamine (1.0 mL, 7.26 mmol) was then added, and the mixture was stirred at room temperature for 0.5 h. Subsequently, N-(tert-butyldiphenylsilyl)-3-nitrobenzenesulfonamide and CHCl3 (4 mL) were added to the reaction solution at 0 °C. After 0.5 h, ammonia gas was introduced into the reaction solution, and the mixture was stirred at room temperature for another 1 h. After the reaction was complete, the reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography (PE / EA(v / v)=1 / 0-15 / 1-10 / 1-5 / 1) to give a yellow oily compound N'-(tert-butyldiphenylsilyl)-3-nitrobenzenesulfonamide (465 mg, yield 47%). ESI-MS (m / z): 440.1 [M+H] + .

[0112] Step c): Preparation of N'-(tert-butyldiphenylsilyl)-3-aminobenzenesulfonylimide

[0113]

[0114] Pd / C (112 mg, 0.11 mmol) was added to 10 mL of an ethanol solution of N'-(tert-butyldiphenylsilyl)-3-nitrobenzenesulfonylimide (465 mg, 1.06 mmol), and the mixture was stirred at room temperature for 6 h under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered and evaporated to dryness to give a yellow oily compound N'-(tert-butyldiphenylsilyl)-3-aminobenzenesulfonylimide (305 mg, yield 70%). ESI-MS (m / z): 410.2 [M+H] + .

[0115] Step d): N-(3-(N'-(tert-butyldiphenylsilyl))aminoiminosulfonylphenyl)-2-(4,4-difluoroazines) Preparation of 1-yl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide

[0116]

[0117] 2-(4,4-difluoroaza) The synthesis of (-1-yl)-6,7-dihydro-5H-cyclopentanoid[b]pyridine-3-carboxylic acid is the same as step ae in Example 1.

[0118] Under nitrogen protection, 2-(4,4-difluoroaza) DIEA (0.09 mL, 0.51 mmol) was added to a DMF (2 mL) solution of N'-(tert-butyldiphenylsilyl)-3-aminobenzenesulfonylimide (104 mg, 0.25 mmol) and HATU (96 mg, 0.25 mmol). The mixture was stirred overnight at room temperature and then reacted at 70 °C for 6 h. After the reaction was complete, the reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with saturated NaCl (20 mL × 3), dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. The crude product was purified using a preparative plate (PE / EA (v / v) = 2 / 1) to give a yellow oily compound N-(3-(N'-(tert-butyldiphenylsilyl))aminoiminosulfonylphenyl)-2-(4,4-difluoroazines). -1-yl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (75 mg, yield 64.61%). ESI-MS (m / z): 688.4 [M+H] + .

[0119] Step e): 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-aminoiminosulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide

[0120]

[0121] To N-(3-(N'-(tert-butyldiphenylsilyl))aminoiminosulfonylphenyl)-2-(4,4-difluoroazines) HCl / dioxane (1 mL) was added to a solution of 1,4-dioxane (1 mL) of 1-(4,4-difluoroazines)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (75 mg, 0.109 mmol) and stirred overnight at room temperature. After the reaction was complete, the reaction solution was evaporated to dryness. The crude product was purified by reverse-phase preparation (NH3·H2O). The resulting solution was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and dried over anhydrous Na2SO4. After filtration and evaporation, the crude product was purified again by reverse-phase preparation (NH3·H2O). The resulting solution was extracted again with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous Na2SO4. After filtration and evaporation, the crude product was lyophilized to give a white solid 2-(4,4-difluoroazines). -1-yl)-N-(3-aminoiminosulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (18.05 mg, yield 36.83%). 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.34(s,1H),7.77(d,J=8.0Hz,1H),7.62(d,J=8.3Hz,1H),7.56(s,1H),7.46(t,J=7.9Hz,1H),3. 62-3.53(m,2H),3.43-3.38(m,2H),2.81(t,J=7.5Hz,4H),2.38-2.24(m,2H),2.08-2.02(m,2H),2.00-1.88(m,2H),1.88-1.76(m,2H). ESI-MS(m / z):450.1[M+H] + .

[0122] Example 6

[0123] 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (KH06)

[0124]

[0125] Step a): 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(2-methoxypyridin-4-yl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide

[0126]

[0127] 2-(4,4-difluoroaza) The synthesis of (-1-yl)-6,7-dihydro-5H-cyclopentanoid[b]pyridine-3-carboxylic acid is the same as step ae in Example 1.

[0128] Nitrogen protection for 2-(4,4-difluoroaza) 2-Methoxypyridine-4-amine (251 mg, 2.028 mmol) and NMI (207 mg, 2.535 mmol) were added to a solution of 150 mg (150 mg, 0.507 mmol) in acetonitrile (3 mL). The mixture was stirred at room temperature for 0.5 h, then TCFH (284 mg, 1.014 mmol) was added, and the mixture was heated to 60 °C and stirred for another 4 h. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a white solid 2-(4,4-difluoroazines). -1-yl)-N-(2-methoxypyridin-4-yl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (90 mg, yield 44%). ESI-MS (m / z): 403.3 [M+H] + .

[0129] Step b): 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide

[0130]

[0131] To 2-(4,4-difluoroaza) TMSI (766 mg, 3.85 mmol) was added to a solution of 155 mg (0.385 mmol) of 1-(2-methoxypyridin-4-yl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide in acetonitrile (5 mL), and the mixture was stirred at 70 °C for 16 h. After the reaction was complete, the reaction solution was concentrated under vacuum, dissolved in DMF (3 mL), and then purified by reverse preparative chromatography to obtain a white solid 2-(4,4-difluoroazines). -1-yl)-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (45 mg, 30% yield). 1H NMR (400MHz, DMSO-d6) δ11.19(s,1H),10.36(s,1H),7.55(s,1H),7.29(d,J=7.2Hz,1H),6.79(s,1H),6.41(d,J=5.5Hz,1H),3.60 -3.51(m,2H),3.37-3.33(m,2H),2.86-2.76(m,4H),2.38-2.24(m,2H),2.09-2.00(m,2H),2.00-1.89(m,2H),1.87-1.78(m,2H). ESI-MS(m / z):389.3[M+H] + .

[0132] Example 7

[0133] 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cyclohexano[b]pyridine-3-carboxamide (KH07)

[0134]

[0135] The procedure is the same as in Example 1, except that cyclopentanone in step a is replaced with cyclohexanone, yielding a white solid 2-(4,4-difluoroazapyridine). -1-yl)-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cyclohexano[b]pyridine-3-carboxamide (22.7 mg, yield 22.63%). 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),8.30(s,1H),7.80(d,J=5.5Hz,1H),7.56-7.50(m,2H),7.44(s,1H),7.38(s,2H) ,3.58-3.56(m,2H),3.37-3.31(m,2H),2.73-2.61(m,4H),2.31(d,J=9.8Hz,2H),1.98-1.91(m,2H),1.86-1.69(m,6H). ESI-MS(m / z):465.0[M+H] + .

[0136] Example 8

[0137] 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cycloheptane[b]pyridine-3-carboxamide (KH08)

[0138]

[0139] The operation procedure is the same as in Example 1, except that cyclopentanone in step a is replaced with cyclohexanone, the reaction time in step e is changed from 2 hours to 15 hours, and the reaction time at 60°C for 4 hours in step f is changed to 15 hours at room temperature, yielding a white solid 2-(4,4-difluoroaza) -1-yl)-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cycloheptane[b]pyridine-3-carboxamide (60.1 mg, yield 20%). 1 HNMR (400MHz, CD3OD) δ8.33(d,J=1.7Hz,1H),7.80(d,J=9.2Hz,1H),7.66(d,J=8.4Hz,1H),7.59(s,1H),7.52(t,J=8.0Hz,1H),3.72-3.65(m, 2H),3.49(t,J=5.8Hz,2H),3.00-2.93(m,2H),2.79-2.73(m,2H),2.40 -2.28(m,2H),2.08-1.95(m,2H),1.94-1.85(m,4H),1.72-1.61(m,4H). ESI-MS(m / z):479.0[M+H] + .

[0140] Example 9

[0141] 6-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-aminosulfonylphenyl)-2,3-dihydro-1H-indene-5-carboxamide (KH09)

[0142]

[0143] Step a): Preparation of 6-iodo-2,3-dihydro-1H-inden-5-ammonia

[0144]

[0145] Silver sulfate (1169 mg, 3.76 mmol) and iodine (951.3 mg, 3.76 mmol) were added to a methanol (20 mL) solution of 2,3-dihydro-1H-indene-5-amine (500 mg, 3.76 mmol), and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was filtered, the filter cake was washed with a small amount of methanol, and the filtrate was poured into a saturated sodium thiosulfate solution. The solution was extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 50 / 1) to give a brown solid 6-iodo-2,3-dihydro-1H-indene-5-amine (620 mg, yield 64%). ESI-MS (m / z): 260.1 [M+H] + .

[0146] Step b): Preparation of 6-amino-2,3-dihydro-1H-inden-5-nitrile

[0147]

[0148] Cuprous cyanide (691 mg, 7.72 mmol) was added to a DMF (15 mL) solution of 6-iodo-2,3-dihydro-1H-indene-5-amino(1 g, 3.86 mmol) and reacted at 160 °C for 1.5 h. After the reaction solution cooled to room temperature, it was poured into water, filtered, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 25 / 1) to give a brown solid 6-amino-2,3-dihydro-1H-indene-5-onitrile (457 mg, yield 75%). 1 H NMR (400MHz, DMSO-d6) δ7.18 (s, 1H), 6.66 (s, 1H), 5.72 (s, 2H), 2.75 (t, J = 7.5Hz, 2H), 2.68 (t, J = 7.3Hz, 2H), 1.98-1.89 (m, 2H). ESI-MS(m / z):159.4[M+H] + .

[0149] Step c): Preparation of 6-iodo-2,3-dihydro-1H-inden-5-nitrile

[0150]

[0151] Iodine (874 mg, 3.45 mmol) was added to a chloroform (25 mL) solution of 6-amino-2,3-dihydro-1H-indene-5-onitrile (500 mg, 3.14 mmol), and the mixture was stirred for 5 min. Then, tert-butyl nitrite (646 mg, 6.28 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 h. After the reaction was complete, the reaction solution was poured into a saturated sodium thiosulfate solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 50 / 1) to give a yellow solid 6-iodo-2,3-dihydro-1H-indene-5-onitrile (600 mg, yield 65%). 1 H NMR (400MHz, CDCl3) δ7.76 (s, 1H), 7.46 (s, 1H), 2.95 (t, J = 7.6Hz, 2H), 2.89 (t, J = 7.6Hz, 2H), 2.15-2.07 (m, 2H).

[0152] Step d): 6-(4,4-difluoroaza) Preparation of (-1-yl)-2,3-dihydro-1H-inden-5-nitriles

[0153]

[0154] To a 12 mL NMP solution of 6-iodo-2,3-dihydro-1H-indene-5-onitrile (600 mg, 2.23 mmol), 4,4-difluoroazacycloheptan hydrochloride (760 mg, 4.46 mmol), cesium carbonate (1430 mg, 6.69 mmol), and Xantphos (130 mg, 0.22 mmol) were added. Then, under nitrogen protection, Pd₂(dba)₃ (100 mg, 0.11 mmol) was added, and the mixture was stirred overnight at 130 °C. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 1) to give a pale yellow solid 6-(4,4-difluoroazacycloheptan) (-1-yl)-2,3-dihydro-1H-indene-5-onitrile (90 mg, yield 15%). ESI-MS (m / z): 277.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.35 (s, 1H), 6.84 (s, 1H), 3.50-3.41 (m, 4H), 2.88 (t, J = 7.5Hz, 2H), 2.83 (t,J=7.4Hz,2H),2.48-2.35(m,2H),2.26-2.15(m,2H),2.12-2.03(m,2H),2.02-1.94(m,2H).

[0155] Step e): 6-(4,4-difluoroaza) Preparation of 1-yl)-2,3-dihydro-1H-indene-5-carboxylic acid

[0156]

[0157] Add 6-(4,4-difluoroaza) to 3 mL of 50% sulfuric acid. 6-(4,4-dihydro-1H-indene-5-onitrile) (90 mg, 0.326 mmol) was reacted at 100 °C for 5 h. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give a white solid 6-(4,4-difluoroazines). -1-yl)-2,3-dihydro-1H-indene-5-carboxylic acid (48 mg, yield 50%).

[0158] Step f): 6-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-aminosulfonylphenyl)-2,3-dihydro-1H-indene-5-carboxamide

[0159]

[0160] Nitrogen protection for 6-(4,4-difluoroaza) HATU (92.6 mg, 0.244 mmol) and DIEA (139.8 mg, 1.084 mmol) were added to a DMF (1.5 mL) solution of (80 mg, 0.271 mmol) of (-1-yl)-2,3-dihydro-1H-indene-5-carboxylic acid (DIA), and the mixture was stirred at room temperature for 1 h. Then, m-aminobenzenesulfonamide (93.2 mg, 0.542 mmol) was added, and stirring was continued for 16 h. After the reaction was complete, the reaction solution was quenched with water (15 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated NaCl (60 mL × 3), dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. The crude product was purified by reversed-phase preparative chromatography to give a white solid 6-(4,4-difluoroazines). 1-(3-aminosulfonylphenyl)-2,3-dihydro-1H-indene-5-carboxamide (80 mg, yield 66%). ESI-MS (m / z): 450.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),8.45(s,1H),7.73-7.67(m,1H),7.54(d,J=5.1Hz,2H),7.47(s,1H),7.39(s ,2H),7.18(s,1H),3.26-3.15(m,4H),2.92-2.81(m,4H),2.34-2.19(m,2H),2.18-1.98(m,4H),1.81-1.71(m,2H).

[0161] Example 10

[0162] Preparation of 2-cycloheptyl-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cyclopentyl[b]pyridine-3-carboxamide (KH10)

[0163] Step a): Preparation of cycloheptene-1-yltrifluoromethanesulfonate

[0164]

[0165] Under ice-water bath and nitrogen protection, Na₂CO₃ (1.89 g, 17.83 mmol) and Tf₂O (2.40 mL, 14.26 mmol) were added to a DCM solution (50 mL) of cycloheptanone (1.00 g, 1.05 mL, 8.91 mmol), and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was poured into ice water (80 mL) and extracted with DCM (80 mL × 3). The organic phase was washed with saturated NaCl (50 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether) to give a colorless oily compound cyclohepten-1-yltrifluoromethanesulfonate (1.72 g, yield 79%). 1 H NMR (400MHz, CDCl3) δ5.88 (t, J = 6.4Hz, 1H), 2.64-.40 (m, 2H), 2.28-2.02 (m, 2H), 1.75-1.67 (m, 4H), 1.66-1.59 (m, 2H).

[0166] 19 F NMR (376MHz, CDCl3) δ-73.96 (s).

[0167] Step b): Preparation of 2-(cyclohepten-1-yl)boronic acid pinacol ester

[0168]

[0169] Under nitrogen protection, Pd(dppf)Cl2 (183 mg, 0.25 mmol), KBr (892 mg, 7.49 mmol), and KOPh (991 mg, 7.49 mmol) were added to a toluene solution (25 mL) of cyclohepten-1-yltrifluoromethanesulfonate (1.22 g, 5.00 mmol) and pinacol diboronate (1.65 g, 6.49 mmol). The mixture was stirred at 50 °C for 2 h. After the reaction was complete, the reaction solution was quenched with water (30 mL), the organic phase was extracted with ethyl acetate (50 mL × 3), washed with saturated NaCl (30 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane (v / v) = 1 / 0-5 / 1) to give a colorless oily product, 2-(cyclohepten-1-yl)boronic acid pinacol ester (565 mg, yield 50.92%). 1 H NMR (400MHz, CDCl3) δ6.77 (t, J = 6.2Hz, 1H), 2.29-2.20 (m, 4H), 1.76-1.71 (m, 2H), 1.49-1.44 (m, 4H), 1.25 (s, 12H).

[0170] Step c): Preparation of methyl 2-(cyclohepten-1-yl)-6,7-dihydro-5H-cyclopentyl[b]pyridine-3-carboxylate

[0171]

[0172] Under nitrogen protection, Pd(dppf)Cl2 (121 mg, 0.16 mmol) and Na2CO3 (526 mg, 4.96 mmol) were added to a mixed solution of 2-chloro-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylmethyl ester (350 mg, 1.65 mmol) and 2-(cyclohepten-1-yl)boronic acid pinacol ester (565 mg, 2.54 mmol) in toluene (9 mL) and water (3 mL). The mixture was stirred overnight at 100 °C. After the reaction was complete, the reaction solution was quenched with water (30 mL), the organic phase was extracted with ethyl acetate (40 mL × 3), washed with saturated NaCl (30 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0-40 / 1-20 / 1-10 / 1) to give a colorless oily methyl 2-(cyclohepten-1-yl)-6,7-dihydro-5H-cyclopentyl[b]pyridine-3-carboxylate (385 mg, yield 85.79%). ESI-MS (m / z): 272.2 [M+H] + .

[0173] Step d): Preparation of methyl 2-cycloheptyl-6,7-dihydro-5H-cyclopentyl[b]pyridine-3-carboxylate

[0174]

[0175] Pd / C (151 mg, 0.14 mmol) was added to a methanol solution (10 mL) of methyl 2-(cyclohepten-1-yl)-6,7-dihydro-5H-cyclopentyl[b]pyridine-3-carboxylate (385 mg, 1.42 mmol) at room temperature, and the mixture was stirred overnight under hydrogen gas. After the reaction was complete, the reaction solution was filtered and evaporated to dryness. The crude product was purified by preparative agar (PE / EA(v / v) = 10 / 1) to give a white solid methyl 2-cycloheptenyl-6,7-dihydro-5H-cyclopentyl[b]pyridine-3-carboxylate (120 mg, yield 30.94%). ESI-MS (m / z): 274.1 [M+H] + .

[0176] Step e): Preparation of 2-cycloheptyl-6,7-dihydro-5H-cyclopentyl[b]pyridine-3-carboxylic acid

[0177]

[0178] Under nitrogen protection, KOH (49 mg, 0.88 mmol) was added to a mixed solution of methyl 2-cycloheptyl-6,7-dihydro-5H-cyclopentyl[b]pyridine-3-carboxylic acid (120 mg, 0.44 mmol) in tetrahydrofuran (2 mL), methanol (2 mL), and water (0.5 mL), and the mixture was stirred at 60 °C for 4 h. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and the solution was dissolved in water (10 mL). The solution was acidified with concentrated HCl to pH 5 and extracted with ethyl acetate (20 mL × 4). The organic phase was dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness to give a white solid 2-cycloheptyl-6,7-dihydro-5H-cyclopentyl[b]pyridine-3-carboxylic acid (crude product, 120 mg, 0.44 mmol). ESI-MS (m / z): 260.1 [M+H] + .

[0179] Step f): Preparation of 2-cycloheptyl-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cyclopentyl[b]pyridine-3-carboxamide

[0180]

[0181] Under nitrogen protection, HATU (147 mg, 0.39 mmol) and DIPEA (0.19 mL, 1.16 mmol) were added to a DMF (2 mL) solution of 2-cycloheptanyl-6,7-dihydro-5H-cyclopentyl[b]pyridine-3-carboxylic acid (100 mg, 0.39 mmol). The mixture was stirred at room temperature for 0.5 h, and then m-aminobenzenesulfonamide (100 mg, 0.58 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated NaCl (20 mL × 3), dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. The crude product was purified by reverse-phase preparation (NH₃·H₂O) to give a white solid compound (24.48 mg, yield 15.35%). 1 H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.36(s,1H),7.83-7.74(m,1H),7.63(s,1H),7.58-7.50(m,2H),7.37(s,2H) ,3.18-3.05(m,1H),2.98-2.83(m,4H),2.12-2.02(m,2H),1.89-1.65(m,6H),1.63-1.47(m,4H),1.47-1.34(m,2H). ESI-MS(m / z): 414.1[M+H] + .

[0182] Example 11

[0183] 2-(4,4-difluoroaza) Preparation of -1-yl)-7-methyl-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (KH11)

[0184]

[0185] The procedure is the same as in Example 1, except that cyclopentanone in step a is replaced with 2-methylcyclopentanone, yielding a white solid 2-(4,4-difluoroazapyridine). -1-yl)-7-methyl-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (53.40 mg, yield 35.68%). 1 H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.31(s,1H),7.85-7.73(m,1H),7. 56(s,1H),7.55-7.48(m,2H),7.38(s,2H),3.72-3.52(m,2H),3.51-3.40 (m,2H),3.10-2.95(m,1H),2.87-2.64(m,2H),2.45-2.22(m,3H),2.06-1 .88(m,2H),1.88-1.75(m,2H),1.67-1.50(m,1H),1.24(d,J=6.9Hz,3H). ESI-MS(m / z):465.2[M+H] + .

[0186] Example 12

[0187] 2-(4,4-difluoroaza) Preparation of -1-yl)-7,7-dimethyl-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (KH12)

[0188]

[0189] The procedure is the same as in Example 1, except that cyclopentanone in step a is replaced with 2,2-dimethylcyclopentanone, yielding a pale pink solid 2-(4,4-difluoroazapyridine). -1-yl)-7,7-dimethyl-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cyclopentadieno[b]pyridine-3-carboxamide (17.8 mg, yield 57.45%). 1H NMR (400MHz, DMSO-d6) δ10.59(s,1H),8.32(s,1H),7.79(s,1H),7.55-7.52(m,3H),7.38(s,2H),3.62(br s,2H),3.41(br s,2H),2.76(t,J=6.6Hz,2H),2.33(br s,2H),2.03-1.88(m,4H),1.83(br s,2H),1.20(s,6H). ESI-MS(m / z):479.3[M+H] + .

[0190] Example 13

[0191] 2-(4,4-difluoroaza) Preparation of 1-yl)-7-methyl-N-(3-aminosulfonylphenyl)-5,7-dihydrofurano[3,4-b]pyridine-3-carboxamide (KH13)

[0192]

[0193] The procedure is the same as in Example 1, except that the cyclopentanone in step a is replaced with 4-methyldihydrofuran-3(2H)-one, yielding a white solid 5-(4,4-difluoroazapyridine). -1-yl)-3-methyl-N-(3-aminosulfonylphenyl)-2,3-dihydrofurano[3,2-b]pyridine-6-carboxamide (78.05 mg, yield 35%). 1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),8.31(s,1H),7.84-7.76(m,1H),7.71(s,1H),7.54(d,J=6.0Hz,2H),7.39(s,2H),5.05-4.96(m,2H),4 .91(d,J=11.2Hz,1H),3.71-3.55(m,2H),3.52-3.37(m,2H),2.40-2.2 5(m,2H),2.06-1.90(m,2H),1.89-1.78(m,2H),1.39(d,J=6.3Hz,3H). ESI-MS(m / z):467.3[M+H] + .

[0194] Example 14

[0195] Preparation of 2-(2,2-difluoro-6-azabicyclo[3.2.1]octane-6-yl)-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (KH14)

[0196]

[0197] The procedure was the same as in Example 1, except that the 4,4-difluoroazacycloheptane hydrochloride in step d was replaced with 2,2-difluoro-6-azabicyclo[3.2.1]octane hydrochloride, the time for adding m-aminobenzenesulfonamide in step f was changed from 1 h to 30 min, and the reaction was carried out at 60 °C for 24 h to obtain a white solid 2-(2,2-difluoro-6-azabicyclo[3.2.1]octane-6-yl)-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (28.3 mg, yield 31%). 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),8.32(s,1H),7.78(t,J=6.3,2.3Hz,1H),7.56-7.51(m,3H),7.3 9(s,2H),4.50(d,J=4.3Hz,1H),3.60-3.50(m,2H),3.24(d,J=11.0Hz,1H),2.86-2.70(m,5H),2.30(br s,1H),2.09-1.99(m,2H),1.97-1.82(m,3H),1.49(d,J=8.5Hz,1H). ESI-MS(m / z):463.1[M+H] + .

[0198] Example 15

[0199] Preparation of 2-(2,2-difluoro-6-azabicyclo[3.2.1]octane-6-yl)-N-(3-aminosulfonylphenyl)-5,6,7,8-tetrahydro-5,8-methyl-bridged quinoline-3-carboxamide (KH15)

[0200]

[0201] The operation process is the same as in Example 1, except that cyclopentanone in step a is replaced with 2-norborneone; 4,4-difluoroazacycloheptane hydrochloride in step d is replaced with 2,2-difluoro-6-azabicyclo[3.2.1]octane hydrochloride, and the reaction temperature is adjusted from 100℃ to 115℃; the time for adding m-aminobenzenesulfonamide in step f is changed from 1h to 30min, and the reaction is carried out at 60℃ for 24h to obtain a white solid 2-(2,2-difluoro-6-azabicyclo[3.2.1]octane-6-yl)-N-(3-aminosulfonylphenyl)-5,6,7,8-tetrahydro-5,8-methylbridged quinoline-3-carboxamide (22.8mg, yield 20%). 1H NMR (400MHz, DMSO-d6) δ10.70 (s, 1H), 8.34 (s, 1H), 7.76 (d, J = 4.7Hz, 1H), 7.55-7.49 (m,2H),7.43(s,1H),7.38(s,2H),4.53(d,J=36.5Hz,1H),3.62-3.41(m,1H),3.36(br s,1H),3.29(br s,1H),3.21(br s,1H),3.09(d,J=10.4Hz,1H),2.73(br s,1H),2.00-1.81(m,5H),1.68(d,J=7.5Hz,1H),1.57-1.43(m,3H),1.14(d,J=6.6Hz,2H). ESI-MS(m / z):489.2[M+H] + .

[0202] Examples 16 and 17

[0203] 2-(4,4-difluoroaza) 1-(3-aminosulfonylphenyl)-5,7-dihydrospiro[cyclopentano[b]pyridine-6,1'-cyclopropane]-3-carboxamide (KH16) and 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-aminosulfonylphenyl)-6,7-dihydrospiro[cyclopentano[b]pyridine-5,1'-cyclopropane]-3-carboxamide (KH17)

[0204]

[0205] The procedure is the same as in Example 1, except that the cyclopentanone in step a is replaced with spiro[2,4]heptane-5-one, yielding a white solid 2-(4,4-difluoroaza) -1-yl)-N-(3-aminosulfonylphenyl)-5,7-dihydrospiro[b]pyridine-6,1'-cyclopropane-3-carboxamide (26.2 mg) and 2-(4,4-difluoroaza) -1-yl)-N-(3-aminosulfonylphenyl)-6,7-dihydrospiro[cyclopentano[b]pyridine-5,1'-cyclopropane]-3-carboxamide (40.1 mg), total yield 28%.

[0206] KH16: 1H NMR (400MHz, DMSO-d6) δ10.59(s,1H),8.31(s,1H),7.80(d,J=3.7Hz,1H),7.56(s,1H),7.53(d,J=5.7Hz,2H),7.38(s,2H),3.58(s,2H),3.4 0(t,J=5.7Hz,2H),2.83(s,2H),2.80(s,2H),2.32(s,2H),1.94(d,J=13.9Hz,2H),1.83(d,J=4.8Hz,2H),0.65(s,2H),0.60(d,J=7.0Hz,2H). ESI-MS(m / z):477.1[M+H] + .

[0207] KH17: 1 H NMR(400MHz,DMSO-d6)δ10.52(s,1H),8.27(s,1H),7.81(d,J=3.4Hz,1H),7 .52(d,J=5.9Hz,2H),7.37(s,2H),7.13(s,1H),3.57(d,J=3.3Hz,2H),3.39( t,J=5.9Hz,2H),2.94(t,J=7.7Hz,2H),2.30(d,J=16.7Hz,2H),2.12-2.07( m, 2H), 1.93 (d, J = 14.2Hz, 2H), 1.82 (d, J = 5.2Hz, 2H), 0.88 (d, J = 6.2Hz, 4H). ESI-MS (m / z): 477.0 [M+H] + .

[0208] Example 18

[0209] 2-(4,4-difluoroaza) Preparation of -1-yl)-5-carbonyl-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (KH18)

[0210]

[0211] The synthesis steps of ethyl 2-hydroxy-5-carbonyl-6,7-cyclopentanopyridine-3-carboxylate are the same as steps ab in Example 1, except that cyclopentanone in step a is replaced with 1,3-cyclopentanedione, and the reaction is carried out overnight at room temperature; methanol in step b is replaced with ethanol, methyl cyanoacetate is replaced with ethyl cyanoacetate, and the reaction is carried out at 85°C for 64 h.

[0212] Step c): 2-(4,4-difluoroaza) Preparation of ethyl 1-(b)-5-carbonyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylate

[0213]

[0214] Under nitrogen protection, 1,8-diazabicycloundec-7-ene (1.20 mL, 8.00 mmol) was added to a solution of ethyl 2-hydroxy-5-carbonyl-6,7-cyclopentano[b]pyridine-3-carboxylate (1.18 g, 5.33 mmol) and benzotriazol-1-oxytris(dimethylamino)phosphine hexafluorophosphate (3.54 g, 8.00 mmol) in dichloromethane (25 mL). After reacting at room temperature for 0.5 h, 1,8-diazabicycloundec-7-ene (1.20 mL, 8.00 mmol) and 4,4-difluoroazacycloheptane hydrochloride (1.37 g, 8.00 mmol) were added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction solution was quenched with water (40 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0-10 / 1-5 / 1-2 / 1) to give a black oily compound 2-(4,4-difluoroaza) -1-yl)-5-carbonyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylic acid ethyl ester (1.18 g, yield 65.38%, containing HOBt). 1 H NMR (400MHz, CDCl3) δ8.23 (s, 1H), 4.33 (q, J = 7.1Hz, 2H), 3.86-3.79 (m, 2H), 3.37 (t, J = 5.1Hz, 2H), 3.07-2.99(m,2H),2.77-2.65(m,2H),2.49-2.31(m,2H),2.03-1.97(m,4H),1.36(t,J=7.1Hz,3H). ESI-MS(m / z):339.1[M+H] + .

[0215] Step de is the same as step ef in Example 1, yielding a white solid 2-(4,4-difluoroaza) -1-yl)-5-carbonyl-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (20.22 mg, yield 30.37%). 1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.28(s,1H),7.91(s,1H),7.87-7.81(m,1H),7.59-7.51(m,2H),7.39(s,2H),3 .82-3.73(m,2H),3.53(t,J=5.4Hz,2H),3.04-2.98(m,2H),2.66-2.59(m,2H),2.44-2.30(m,2H),2.04-1.87(m,4H). ESI-MS(m / z):465.3[M+H] + .

[0216] Example 19

[0217] 6-(4,4-difluoroaza) Preparation of -1-yl)-3-carbonyl-N-(3-aminosulfonylphenyl)-2,3-dihydro-1H-indene-5-carboxamide (KH19)

[0218]

[0219] Step a): Preparation of 5-bromo-6-nitro-2,3-dihydro-1H-inden-1-one

[0220]

[0221] At -20°C, 5-bromo-2,3-dihydro-1H-indene-1-one (8 g, 37.90 mmol) was added in portions to 80 mL of fuming nitric acid, and the reaction was carried out at -15°C for 1 h. After the reaction was complete, the reaction solution was poured into ice water, and the organic phase was extracted with dichloromethane (100 mL × 3). The solution was then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a yellow solid 5-bromo-6-nitro-2,3-dihydro-1H-indene-1-one (6 g, yield 61%). 1 H NMR (400MHz, CDCl3) δ8.14(s,1H),7.90(s,1H),3.26-3.20(m,2H),2.83-2.77(m,2H).

[0222] Step b): Preparation of 6-amino-5-bromo-2,3-dihydro-1H-inden-1-one

[0223]

[0224] Stannous chloride dihydrate (16.7 g, 74.5 mmol) was added to an anhydrous ethanol (40 mL) solution of 5-bromo-6-nitro-2,3-dihydro-1H-inden-1-one (3.8 g, 14.9 mmol), and the reaction was carried out at 75 °C for 5 h. After the reaction was completed, the reaction solution was poured into ice water, the pH was adjusted to about 8 with saturated sodium bicarbonate solution, filtered, and the filter cake was washed three times with an appropriate amount of dichloromethane. The filtrate was concentrated under reduced pressure to remove ethanol and dichloromethane, and then extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a yellow solid 6-amino-5-bromo-2,3-dihydro-1H-inden-1-one (1.6 g, yield 46%). 1 H NMR (400MHz, CDCl3) δ7.58(s,1H),7.08(s,1H),4.21(s,2H),3.07-2.97(m,2H),2.70-2.61(m,2H). ESI-MS(m / z):226.1[M+H] + .

[0225] Step c): Preparation of 6-bromo-3-carbonyl-2,3-dihydro-1H-inden-5-carboxynitrile

[0226]

[0227] Add 0.5 g (2.2 mmol) of 6-amino-5-bromo-2,3-dihydro-1H-inden-1-one and 1 mL of hydrochloric acid (6 M) to 2.5 mL of water, cool to 0 °C, and add 182 mg (2.64 mmol) of sodium nitrite aqueous solution dropwise. After the addition is complete, continue stirring for 0.5 h, then add sodium bicarbonate (850 mg, 10.12 mmol) in portions to adjust the pH to approximately 8, yielding a diazonium salt for later use. Add 881 mg (9.9 mmol) and 1.65 mL of toluene to a 12 mL solution of KCN (793.5 mg, 12.1 mmol) in water; then add the prepared diazonium salt, react at 50 °C for 1 h, and then continue the reaction at room temperature for 16 h. After the reaction was completed, the reaction solution was poured into water, filtered, and the filter cake was washed twice with dichloromethane. The filtrates were combined, separated, and the aqueous phase was extracted once with dichloromethane. The organic layers were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give a yellow solid 6-bromo-3-carbonyl-2,3-dihydro-1H-indene-5-carboxynitrile (350 mg, yield 67%). 1H NMR (400MHz, CDCl3) δ8.02(s,1H),7.87(s,1H),3.25-3.19(m,2H),2.79-2.74(m,2H).

[0228] Step d): Preparation of 5-bromo-2,3-dihydrospiro[indene-1,2'-[1,3]dithiamonane]-6-carboxynitrile

[0229]

[0230] To a solution of 6-bromo-3-carbonyl-2,3-dihydro-1H-indene-5-carboxynitrile (2.2 g, 9.32 mmol) in dichloromethane, 1,2-ethanedithiol (1.32 g, 14 mmol) and boron trifluoride diethyl ether solution (1.99 g, 14 mmol) were added, and the mixture was stirred at room temperature for 16 h. After the reaction was complete, the reaction solution was poured into water, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 50 / 1) to give a yellow solid 5-bromo-2,3-dihydrospiro[indene-1,2'-[1,3]dithiopentane]-6-carboxynitrile (2.33 g, yield 80%). 1 H NMR (400MHz, CDCl3) δ7.80 (s, 1H), 7.50 (s, 1H), 3.58-3.51 (m, 2H), 3.50-3.42 (m, 2H), 3.01 (t, J = 6.7Hz, 2H), 2.70 (t, J = 6.8Hz, 2H).

[0231] Step e): Preparation of 2,6-dibromo-3,3-difluoro-2,3-dihydro-1H-inden-5-carboxynitrile

[0232]

[0233] Under nitrogen protection, a solution of dibromohydantoin (9.93 g, 34.7 mmol) in dichloromethane (65 mL) was cooled to -78 °C, and hydrogen fluoride-pyridine (9.72 mL) was added dropwise, reacting for 0.5 h. Then, a solution of 5-bromo-2,3-dihydrospiro[indene-1,2'-[1,3]dithiopentane]-6-carboxynitrile (2.7 g, 8.65 mmol) in dichloromethane was added dropwise, and the reaction was continued at this temperature for 1 h. After the reaction was complete, the reaction solution was poured into ice water, the organic phase was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 20 / 1) to give a yellow solid 2,6-dibromo-3,3-difluoro-2,3-dihydro-1H-indene-5-carboxynitrile (2 g, yield 69%). 1H NMR (400MHz, CDCl3) δ7.91(s,1H),7.71(s,1H),4.72-4.50(m,1H),3.82-3.60(m,1H),3.44-3.22(m,1H).

[0234] Step f): Preparation of 5-bromo-1,1-difluoro-1H-inden-6-carboxynitrile

[0235]

[0236] To a solution of 1,8-diazabicycloundec-7-ene (1.36 g, 8.96 mmol) in dichloromethane (15 mL) containing 2,6-dibromo-3,3-difluoro-2,3-dihydro-1H-inden-5-carboxynitrile (1.5 g, 4.48 mmol), 1.5 g of 1H-diazabicycloundec-7-ene (1.36 g, 8.96 mmol) was added, and the mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was poured into water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give a yellow solid 5-bromo-1,1-difluoro-1H-inden-6-carboxynitrile (1 g, yield 87%). 1 H NMR (400MHz, CDCl3) δ7.68 (s, 1H), 7.51 (s, 1H), 6.81 (dd, J = 6.0, 0.6Hz, 1H), 6.42 (d, J = 6.0Hz, 1H).

[0237] Step g): Preparation of 6-bromo-3,3-difluoro-2,3-dihydro-1H-inden-5-carboxynitrile

[0238]

[0239] Under ice bath conditions, o-nitrobenzenesulfonyl chloride (3.288 g, 14.88 mmol) was added to a solution of 5-bromo-1,1-difluoro-1H-inden-6-carboxynitrile (950 mg, 3.72 mmol) in acetonitrile (35 mL), followed by the slow addition of hydrazine hydrate (1.488 g, 29.76 mmol). The mixture was stirred at room temperature for 48 h. After the reaction was complete, the reaction solution was poured into water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give a yellow solid 6-bromo-3,3-difluoro-2,3-dihydro-1H-inden-5-carboxynitrile (725 mg, yield 76%). 1 H NMR (400MHz, CDCl3) δ7.83(s,1H),7.67(s,1H),3.15-3.07(m,2H),2.70-2.58(m,2H).

[0240] Step h): 6-(4,4-difluoroaza) Preparation of -1-yl)-3,3-difluoro-2,3-dihydro-1H-inden-5-carboxynitrile

[0241]

[0242] To a solution of 6-bromo-3,3-difluoro-2,3-dihydro-1H-indene-5-carboxynitrile (288 mg, 1.116 mmol) in 1,4-dioxane (20 mL), 4,4-difluoroazacycloheptane hydrochloride (381.7 mg, 2.232 mmol), cesium carbonate (1088.1 mg, 3.348 mmol), BINAP (69.664 mg, 0.112 mmol), and Pd2(dba)3 (51 mg, 0.056 mmol) were added. The reaction was carried out under nitrogen protection at 100 °C for 16 h. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE / EA(v / v) = 10 / 1) to give a white solid 6-(4,4-difluoroazacycloheptane). -1-yl)-3,3-difluoro-2,3-dihydro-1H-indene-5-carboxynitrile (35 mg, yield 10%). ESI-MS (m / z): 313.0 [M+H] + .

[0243] Step i): 6-(4,4-difluoroaza) Preparation of -1-yl)-3-carbonyl-2,3-dihydro-1H-inden-5-carboxynitrile

[0244]

[0245] Add compound 6-(4,4-difluoroaza) to a 50% sulfuric acid aqueous solution (2 mL). 1-(4,4-difluoro-2,3-dihydro-1H-indene-5-carboxynitrile) (100 mg, 0.32 mmol) was stirred at 100 °C for 0.5 h. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give a white solid 6-(4,4-difluoroazanitrile) -1-yl)-3-carbonyl-2,3-dihydro-1H-indene-5-carboxynitrile (74.3 mg, yield 80%). 1H NMR(400MHz,DMSO-d6)δ7.83(s,1H),7.10(s,1H),3.77-3.64(m,4H),3.12-3.00(m ,2H),2.64-2.56(m,2H),2.44-2.32(m,2H),2.22-2.09(m,2H),2.00-1.91(m,2H). ESI-MS(m / z):291.0[M+H] + .

[0246] Step j): 6-(4,4-difluoroaza) Preparation of 1-yl)-3-carbonyl-2,3-dihydro-1H-indene-5-carboxylic acid

[0247]

[0248] Add 6-(4,4-difluoroaza) to a 50% aqueous sulfuric acid solution. 1-(4,4-dihydro-1H-indene-5-carboxynitrile) (100 mg, 0.34 mmol) was stirred at 100 °C for 6 h. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give a white solid 6-(4,4-difluoroazapyridine) (-1-yl)-3-carbonyl-2,3-dihydro-1H-indene-5-carboxylic acid (30 mg, yield 28%). ESI-MS (m / z): 310.1 [M+H] + .

[0249] Step k): 6-(4,4-difluoroaza) Preparation of -1-yl)-3-carbonyl-N-(3-aminosulfonylphenyl)-2,3-dihydro-1H-indene-5-carboxamide

[0250]

[0251] Nitrogen protection for 6-(4,4-difluoroaza) HATU (33 mg, 0.087 mmol) and DIEA (62.5 mg, 0.485 mmol) were added to a DMF (1 mL) solution of (-1-yl)-3-carbonyl-2,3-dihydro-1H-indene-5-carboxylic acid (30 mg, 0.097 mmol). The mixture was stirred at room temperature for 1 h, followed by the addition of m-aminobenzenesulfonamide (50 mg, 0.291 mmol). The reaction mixture was then heated to 60 °C and reacted for 4 h. After the reaction was complete, the solution was purified by reversed-phase preparative chromatography to obtain a white solid, 6-(4,4-difluoroazines). -1-yl)-3-carbonyl-N-(3-aminosulfonylphenyl)-2,3-dihydro-1H-indene-5-carboxamide (9.6 mg, yield 21%). 1 H NMR (400MHz, DMSO-d6) δ10.74(s,1H),8.32(s,1H),7.83(s,1H),7.59(s,1H),7.55(s,2H),7.38(s,2H),7.06(s,1H),3.51(br s,2H),3.47(br s,2H),3.06(br s,2H),2.58(br s,2H),2.30(br s,2H),2.05(d,J=15.9Hz,2H),1.85(br s,2H). ESI-MS(m / z):464.3[M+H] + .

[0252] Example 20

[0253] 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-5,7-dihydrospiro[cyclopentano[b]pyridin-6,1'-cyclopropane]-3-carboxamide (KH2O)

[0254]

[0255] The procedure is the same as in Example 16, except that the m-aminobenzenesulfonamide in the last step is replaced with 2-methoxypyridine-4-amine, and then the methyl group is removed according to step b of Example 6, yielding a yellow solid 2-(4,4-difluoroazapyridine). -1-yl)-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-5,7-dihydrospiro[cyclopentano[b]pyridin-6,1'-cyclopropane]-3-carboxamide (14.4 mg, yield 9%). 1 H NMR (400MHz, DMSO-d6) δ11.19(s,1H),10.36(s,1H),7.54(s,1H),7.29(d,J=7.2Hz,1H),6.79(s,1H),6.40(dd,J=7.2,1.8Hz,1H),3.55(d,J=3.0Hz ,2H),3.34(t,J=5.8Hz,2H),2.82(s,2H),2.79(s,2H),2.30(s,2H),2.07 (s, 1H), 1.94 (d, J = 14.3Hz, 2H), 1.83 (d, J = 5.0Hz, 2H), 0.64-0.60 (m, 4H). ESI-MS(m / z):415.1[M+H] + .

[0256] Example 21

[0257] 6-(4,4-difluoroaza) Preparation of -1-yl)-2,2-difluoro-N-(3-aminosulfonylaniline)-2,3-dihydro-1H-indene-5-carboxamide (KH21)

[0258]

[0259] Step a): Preparation of 5-nitro-1,3-dihydro-2H-inden-2-one

[0260]

[0261] 1,3-Dihydro-2H-indene-2-one (11.5 g, 87.01 mmol) was slowly added to a single-necked flask containing fuming nitric acid (100 mL) at -30 °C. After the addition was complete, the reaction was continued at -30 °C for 20 min. After the reaction was complete, the reaction solution was added dropwise to ice water, and a solid precipitated out. The solid was filtered, washed with methanol, and dried to obtain 5-nitro-1,3-dihydro-2H-indene-2-one (15 g, 100% yield). 1 H NMR (400MHz, CDCl3) δ 8.18 (d, J = 8.9 Hz, 2H), 7.48 (d, J = 8.1 Hz, 1H), 3.67 (d, J = 5.9 Hz, 4H).

[0262] Step b): Preparation of 2,2-difluoro-5-nitro-2,3-dihydro-1H-indene

[0263]

[0264] Diethylaminosulfur trifluoride (29.8 mL, 225.79 mmol) was added to a solution of 5-nitro-1,3-dihydro-2H-indenhydride (10 g, 56.45 mmol) in 100 mL of dichloromethane at 0 °C under nitrogen protection and reacted overnight at room temperature. After the reaction was complete, the mixture was placed in an ice-water bath, and the pH was adjusted to 7-8 with saturated NaHCO3 aqueous solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 30 / 1) to give a pale green solid 2,2-difluoro-5-nitro-2,3-dihydro-1H-indenhydride (3.1 g, yield 27.6%). 1 H NMR (400MHz, CDCl3) δ8.20-8.06 (m, 2H), 7.39 (d, J = 8.3Hz, 1H), 3.60-3.47 (m, 4H).

[0265] Step c): Preparation of 2,2-difluoro-2,3-dihydro-1H-inden-5-amine

[0266]

[0267] Pd(OH)₂ (2.12 g, 2.26 mmol) was added to a methanol (45 mL) solution of 2,2-difluoro-5-nitro-2,3-dihydro-1H-indene (4.5 g, 22.60 mmol), and the reaction was carried out at -40 °C under a hydrogen atmosphere for 16 h. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0-20 / 1-10 / 1) to give an orange solid 2,2-difluoro-2,3-dihydro-1H-indene-5-amine (3.1 g, yield 70%). 1 H NMR (400MHz, CDCl3) δ6.98 (d, J = 7.8Hz, 1H), 6.59-6.53 (m, 2H), 3.61 (s, 2H), 3.36-3.27 (m, 4H). ESI-MS(m / z):170.2[M+H] + .

[0268] Step d): Preparation of 6-bromo-2,2-difluoro-2,3-dihydro-1H-inden-5-amine

[0269]

[0270] N-bromosuccinimide (3.26 g, 18.32 mmol) was slowly added to a solution of 2,2-difluoro-2,3-dihydro-1H-indene-5-amine (3.1 g, 18.32 mmol) in acetonitrile (30 mL) under nitrogen protection at -16 °C, and the reaction was carried out at -15 °C for 20 min. After the reaction was complete, 30 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was dried over anhydrous Na₂SO₄, filtered, and the filtrate was evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 20 / 1-10 / 1) to give a white solid 6-bromo-2,2-difluoro-2,3-dihydro-1H-indene-5-amine (4.3 g, yield 94%). ESI-MS (m / z): 247.8 [M+H] + .

[0271] Step e): Preparation of 6-bromo-2,2-difluoro-2,3-dihydro-1H-inden-5-onitrile

[0272]

[0273] Under nitrogen protection, tert-butyl nitrite (1.53 g, 14.87 mmol) and boron trifluoride diethyl ether solution (884 mg, 6.13 mmol) were added to a dichloromethane (30 mL) solution of 6-bromo-2,2-difluoro-2,3-dihydro-1H-inden-5-amine (3 g, 12.09 mmol). After reacting for 30 min, diethyl ether (30 mL) was added and the mixture was filtered. The filter cake was dried and dissolved in toluene (30 mL). Under nitrogen protection, a water (10 mL) solution of NaCN (2 g, 40.51 mmol) and CuCN (1.45 g, 16.21 mmol) was slowly added dropwise. The mixture was then allowed to rise to room temperature and reacted for 30 min. After the reaction was complete, the mixture was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), dried over anhydrous Na2SO4, filtered and evaporated to dryness, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 20 / 1) to give an orange-red solid 6-bromo-2,2-difluoro-2,3-dihydro-1H-inden-5-onitrile (1.4 g, yield 44.8%). 1 HNMR (400MHz, CDCl3) δ7.57(s,1H),7.52(s,1H),3.52-3.39(m,4H).

[0274] Step f): 6-(4,4-difluoroaza) Preparation of -1-yl)-2,2-difluoro-2,3-dihydro-1H-inden-5-onitrile

[0275]

[0276] To a toluene (10 mL) solution of 6-bromo-2,2-difluoro-2,3-dihydro-1H-indene-5-onitrile (500 mg, 1.94 mmol), 4,4-difluoroazacycloheptane hydrochloride (837 mg, 4.84 mmol), Pd₂(dba)₃ (177 mg, 0.194 mmol), Cs₂CO₃ (2.21 g, 6.78 mmol), and binaphthalenediphenylphosphine (241 mg, 0.387 mmol) were added. The system was protected with nitrogen and reacted at 110 °C for 16 h. After the reaction was complete, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (15 mL × 3). The resulting organic phase was dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 20 / 1) to give a yellow solid 6-(4,4-difluoroazacycloheptane) -1-yl)-2,2-difluoro-2,3-dihydro-1H-indene-5-onitrile (170 mg, yield 28%). 1H NMR (400MHz, CDCl3) δ7.37 (s, 1H), 6.80 (s, 1H), 3.51 (d, J = 5.8Hz, 2H), 3.48-3.30 (m, 6H), 2.46-2.36 (m, 2H), 2.24-2.14 (m, 2H), 2.03-1.97 (m, 2H). ESI-MS(m / z):312.9[M+H] + .

[0277] Step g): 6-(4,4-difluoroaza) Preparation of 1-yl)-2,2-difluoro-2,3-dihydro-1H-indene-5-carboxylic acid

[0278]

[0279] To 6-(4,4-difluoroaza) 6-(4,4-difluoro-2,3-dihydro-1H-indene-5-onitrile) (75 mg, 0.24 mmol) was added to an aqueous solution of 40% H₂SO₄ (1 mL), and the reaction was carried out at 100 °C under nitrogen protection for 16 h. After the reaction was complete, the pH was adjusted to weakly acidic with ammonia at 0 °C, and then extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give a white solid 6-(4,4-difluoroazines). -1-yl)-2,2-difluoro-2,3-dihydro-1H-indene-5-carboxylic acid (40 mg, yield 50%). 1 H NMR (400MHz, CDCl3) δ8.16 (s, 1H), 7.25 (s, 1H), 3.52-3.41 (m, 6H), 3.18 (d, J = 5.2Hz, 2H), 2.51-2.27 (m, 6H). ESI-MS(m / z):332.0[M+H] + .

[0280] Step h): 6-(4,4-difluoroaza) Preparation of 1-yl)-2,2-difluoro-N-(3-aminosulfonylphenyl)-2,3-dihydro-1H-indene-5-carboxamide

[0281]

[0282] Nitrogen protection for 6-(4,4-difluoroaza) HATU (43.9 mg, 0.115 mmol) and DIEA (43.9 mg, 0.339 mmol) were added to a DMF solution of 1-(4,4-dihydro-1H-indene-5-carboxylic acid (45 mg, 0.136 mmol). The mixture was reacted at room temperature for 1 h, followed by the addition of m-aminobenzenesulfonamide (35 mg, 0.204 mmol), and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the mixture was purified by reversed-phase preparative chromatography to obtain a white solid, 6-(4,4-difluoroazines). -1-yl)-2,2-difluoro-N-(3-aminosulfonylphenyl)-2,3-dihydro-1H-indene-5-carboxamide (42.0 mg, yield 47.8%). 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.41(s,1H),7.76-7.70(m,1H),7.56-7.52(m,2H),7.42(s,1H),7.39(s,2 H),7.15(s,1H),3.51-3.38(m,4H),3.28-3.20(m,4H),2.24-2.21(m,2H),2.14-2.03(m,2H),1.76-1.74(m,2H). ESI-MS(m / z):486.0[M+H] + .

[0283] Examples 22-24

[0284] (R)-6-(4,4-difluoroaza) -1-yl)-N-(3-aminosulfonylphenyl)-1-trifluoromethyl-1,3-dihydroisobenzofuran-5-carboxamide (KH22), (S)-6-(4,4-difluoroaza) -1-yl)-N-(3-aminosulfonylphenyl)-1-trifluoromethyl-1,3-dihydroisobenzofuran-5-carboxamide (KH23), 6-(4,4-difluoroaza) Preparation of 1-(3-aminosulfonylphenyl)-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-carboxamide (KH24)

[0285]

[0286] Step a): Preparation of 5-bromo-3-hydroxy-3-trifluoromethylisobenzofuran-1(3H)-one & 6-bromo-3-hydroxy-3-trifluoromethylisobenzofuran-1(3H)-one

[0287]

[0288] CuI (83.6 mg, 0.44 mmol), KF (510 mg, 8.8 mmol), and 1,10-o-phenanthroline (79.2 mg, 0.44 mmol) were added to a tetrahydrofuran (22 mL) solution of 5-bromoisobenzofuran-1,3-dione (1 g, 4.4 mmol). Under nitrogen protection, TMS-CF3 (750 mg, 5.28 mmol) was added dropwise, and the reaction was carried out at 50 °C for 8 h. After the reaction was complete, the reaction solution was poured into water and extracted three times with ethyl acetate. The organic phases were combined, 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) = 20 / 1) to give a mixture of light yellow liquid 5-bromo-3-hydroxy-3-trifluoromethylisobenzofuran-1(3H)-one and 6-bromo-3-hydroxy-3-trifluoromethylisobenzofuran-1(3H)-one (490 mg, yield 38%). 1 H NMR(400MHz, DMSO-d6)δ9.95(s,2H),8.25(d,J=1.5Hz,1H),8.14(dd,J=8.1,1.8Hz,1H) ,8.10(s,1H),8.06(dd,J=8.1,1.6Hz,1H),7.95(d,J=8.1Hz,1H),7.79(d,J=8.1Hz,1H).

[0289] Step b): Preparation of 1-(5-bromo-2-hydroxymethylphenyl)-2-trifluoromethylethanol & 1-(4-bromo-2-hydroxymethylphenyl)-2-trifluoromethylethanol

[0290]

[0291] Lithium aluminum hydride (566 mg, 14.9 mmol) was added in portions to a 20 mL solution of tetrahydrofuran containing the mixture obtained in step a, under ice bath conditions, and the mixture was stirred at room temperature for 2 h. After the reaction was complete, ethyl acetate was slowly added to quench the reaction, and the mixture was then poured into ice water. The phases were separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 20 / 1) to give a yellow oily mixture of 1-(5-bromo-2-hydroxymethylphenyl)-2-trifluoromethylethanol and 1-(4-bromo-2-hydroxymethylphenyl)-2-trifluoromethylethanol (300 mg, yield 30%). ESI-MS (m / z): 283.0 [MH] - .

[0292] Step c): Preparation of 6-bromo-1-trifluoromethyl-1,3-dihydroisobenzofuran & 5-bromo-1-trifluoromethyl-1,3-dihydroisobenzofuran

[0293]

[0294] Add Bu3P (992 mg, 4.912 mmol) and N,N,N',N'-tetramethylazodicarbonamide (971 mg, 5.649 mmol) to a toluene (30 mL) solution of the mixture obtained in step b, and stir overnight at room temperature. After the reaction is complete, pour the reaction solution into water, extract three times with ethyl acetate, combine the organic phases, wash with saturated NaCl solution, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 50 / 1) to a mixture of 6-bromo-1-trifluoromethyl-1,3-dihydroisobenzofuran and 5-bromo-1-trifluoromethyl-1,3-dihydroisobenzofuran (320 mg, yield 48%). 1 H NMR (400MHz, CDCl3) δ7.56-7.52(m,2H),7.49(d,J=8.2Hz,1H),7.45(s,1H),7.28(s, 1H), 7.17 (d, J = 8.5Hz, 1H), 5.47-5.38 (m, 2H), 5.29-5.20 (m, 2H), 5.19-5.11 (m, 2H).

[0295] Step d): Preparation of 6-bromo-5-nitro-1-trifluoromethyl-1,3-dihydroisobenzofuran & 5-bromo-6-nitro-1-trifluoromethyl-1,3-dihydroisobenzofuran

[0296]

[0297] A solution of potassium nitrate (1.44 g, 14.28 mmol) in sulfuric acid (60 mL) was added dropwise to a 20 mL solution of sulfuric acid containing potassium nitrate (1.44 g, 14.28 mmol) under ice bath conditions. After the reaction was complete, the reaction mixture was poured into crushed ice, and the organic phase was extracted with ethyl acetate. The mixture was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a mixture (3.6 g, 90% yield) of 6-bromo-5-nitro-1-trifluoromethyl-1,3-dihydroisobenzofuran and 5-bromo-6-nitro-1-trifluoromethyl-1,3-dihydroisobenzofuran. 1 H NMR (400MHz, CDCl3) δ7.87 (s, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.70 (s, 1H), 5.54-5.46 (m, 2H), 5.31 (t, J = 12.7Hz, 2H), 5.26-5.20 (m, 2H).

[0298] Step e): Preparation of 6-bromo-1-trifluoromethyl-1,3-dihydroisobenzofuran-5-amine & 6-bromo-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-amine

[0299]

[0300] To an ethanol (80 mL) solution of the mixture obtained in step d (4 g, 12, 8 mmol), ammonium chloride (1.35 g, 25.6 mmol), water (20 mL), and iron powder (3.6 g, 64 mmol) were added, and the mixture was reacted at 75 °C for 4 h. After the reaction was complete, the reaction solution was filtered, the organic phase was extracted three times with dichloromethane, the organic phases were combined, 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 to give a mixture of 6-bromo-1-trifluoromethyl-1,3-dihydroisobenzofuran-5-amine and 6-bromo-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-amine (2.7 g, yield 80%). ESI-MS (m / z): 282.0 [M+H] + .

[0301] Step f): Preparation of 6-bromo-1-trifluoromethyl-1,3-dihydroisobenzofuran-5-onitrile & 6-bromo-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-onitrile

[0302]

[0303] At 0°C, 4 mL of hydrochloric acid (6 M) and 6 mL of water were added to the mixture obtained in step e (1124 mg, 4 mmol), followed by dropwise addition of 6 mL of sodium nitrite (331.2 mg, 4.8 mmol) aqueous solution. After 0.5 h, the pH of the reaction solution was adjusted to neutral with sodium bicarbonate (4.2 g), and then added dropwise to a mixture of CuCN (1.6 g, 18 mmol), KCN (1.43 g, 22 mmol), toluene (4 mL), and water (20 mL). The mixture was reacted at 50°C for 1 h, then cooled to room temperature and stirred overnight. After the reaction was complete, the reaction solution was filtered, the filter cake was washed with dichloromethane, the phases were separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered under vacuum, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 20 / 1) to give a mixture of 6-bromo-1-trifluoromethyl-1,3-dihydroisobenzofuran-5-onitrile and 6-bromo-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-onitrile (600 mg, yield 50%). 1HNMR (400MHz, CDCl3) δ7.74(s,1H),7.69(s,1H),7.67(s,1H),7.61(s,1H),5.55-5.42(m,2H),5.34-5.16(m,4H).

[0304] Step g): 6-(4,4-difluoroaza) -1-yl)-1-trifluoromethyl-1,3-dihydroisobenzofuran-5-nitrile &6-(4,4-difluoroaza) Preparation of 1-yl)-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-nitrile

[0305]

[0306] Cesium carbonate (4.48 g, 13.79 mmol), BINAP (490 mg, 0.788 mmol), Pd2(dba)3 (361 mg, 0.394 mmol), and 4,4-difluoroazacycloheptan hydrochloride (1.48 g, 8.66 mmol) were added to a 50 mL solution of the mixture obtained in step f. The mixture was reacted at 110 °C for 16 h. After the reaction was complete, the reaction solution was poured into water, and the organic phase was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 20 / 1) to give a brown oily substance 6-(4,4-difluoroazacycloheptan) -1-yl)-1-trifluoromethyl-1,3-dihydroisobenzofuran-5-onitrile (150 mg, yield 12.5%) 1 ¹H NMR (400MHz, CDCl₃) δ 7.45 (s, ¹H), 6.92 (s, ¹H), 5.43–5.36 (m, ¹H), 5.20 (dd, J = 11.9, 1.8 Hz, ¹H), 5.11 (d, J = 11.9 Hz, ¹H), 3.62–3.46 (m, 4H), 2.51–2.38 (m, 2H), 2.23–2.20 (m, 2H), 2.03 (dt, J = 9.0, 6.2 Hz, 2H); and a white solid compound 6-(4,4-difluoroaza) -1-yl)-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-onitrile (150 mg, yield 12.5%) 1H NMR (400MHz, CDCl3) δ7.54(s,1H),6.79(s,1H),5.42-5.33(m,1H),5.22(dd,J=13.4,1.7Hz,1H),5.13( d,J=13.3Hz,1H),3.63-3.59(m,4H),2.50-2.36(m,2H),2.21-2.18(m,2H),2.03(dt,J=6.2,4.6Hz,2H).

[0307] Step h): 6-(4,4-difluoroaza) Preparation of 1-(1-yl)-1-trifluoromethyl-1,3-dihydroisobenzofuran-5-carboxylic acid

[0308]

[0309] To 6-(4,4-difluoroaza) 12 mL of 40% sulfuric acid was added to 120 mg of 1,3-dihydroisobenzofuran-5-onitrile, and the mixture was stirred at 100 °C for 12 h. After the reaction was complete, the mixture was poured into crushed ice, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by Flash column chromatography to give a white solid 6-(4,4-difluoroazines). -1-yl)-1-trifluoromethyl-1,3-dihydroisobenzofuran-5-carboxylic acid (57 mg, yield 45%).

[0310] Step i): 6-(4,4-difluoroaza) Preparation of 1-(3-aminosulfonylphenyl)-1-trifluoromethyl-1,3-dihydroisobenzofuran-5-carboxamide

[0311]

[0312] To 6-(4,4-difluoroaza) HATU (46 mg, 0.11 mmol) and DIEA (100 mg, 0.774 mmol) were added to a DMF (1.0 mL) solution of 1-(4,4-dihydroisobenzofuran-5-carboxylic acid) (47 mg, 0.129 mmol). The mixture was stirred at room temperature for 1 h, followed by the addition of m-aminobenzenesulfonamide (141 mg, 0.387 mmol), and stirring was continued for another 16 h. After the reaction was complete, the reaction solution was purified by reversed-phase preparative chromatography to obtain a white solid 6-(4,4-difluoroazines). -1-yl)-N-(3-aminosulfonylphenyl)-1-trifluoromethyl-1,3-dihydroisobenzofuran-5-carboxamide (28.74 mg, yield 42.8%). 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),8.41(s,1H),7.82-7.71(m,1H),7.55(d,J=6.1Hz,2H),7.51(s,1H),7.40(s,2H),7.15 (s,1H),5.82(d,J=6.2Hz,1H),5.15(s,2H),3.33-3.24(m,4H),2.23(t,J=10.5Hz,2H),2.14-2.00(m,2H),1.82-1.72(m,2H). ESI-MS(m / z):520.2[M+H] + .

[0313] Step j): (R)-6-(4,4-difluoroaza) -1-yl)-N-(3-aminosulfonylphenyl)-1-trifluoromethyl-1,3-dihydroisobenzofuran-5-carboxamide &(S)-6-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-aminosulfonylphenyl)-1-trifluoromethyl-1,3-dihydroisobenzofuran-5-carboxamide

[0314]

[0315] The racemic mixture (60 mg) obtained in step i was resolved by SFC to give (R)-6-(4,4-difluoroaza) -1-yl)-N-(3-aminosulfonylphenyl)-1-trifluoromethyl-1,3-dihydroisobenzofuran-5-carboxamide (13.15 mg, yield 43%) 1 ¹H NMR (400MHz, DMSO-d⁶) δ 10.81 (s, ¹H), 8.40 (s, ¹H), 7.79–7.73 (m, ¹H), 7.54 (d, J = 5.9 Hz, 2H), 7.51 (s, ¹H), 7.40 (s, 2H), 7.15 (s, ¹H), 5.82 (d, J = 6.4 Hz, ¹H), 5.15 (s, 2H), 3.31–3.24 (m, 4H), 2.21 (d, J = 14.7 Hz, 2H), 2.07 (d, J = 8.0 Hz, 2H), 1.77 (d, J = 5.6 Hz, 2H); and (S)-6-(4,4-difluoroaza) -1-yl)-N-(3-aminosulfonylphenyl)-1-trifluoromethyl-1,3-dihydroisobenzofuran-5-carboxamide (11.95 mg, yield 40%)1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),8.40(s,1H),7.82-7.72(m,1H),7.57-7.53(m,2H),7.51(s,1H),7.40(s,2H),7.15(s,1H),5. 82(d,J=6.5Hz,1H),5.20-5.09(m,2H),3.28(dd,J=12.0,5.8Hz,4H),2.22(t,J=10.8Hz,2H),2.14-1.98(m,2H),1.81-1.70(m,2H).

[0316] The preparation of Example 24 was the same as that of Examples 22 and 23, except that the racemic mixture was not separated after obtaining it, and the white solid 6-(4,4-difluoroaza) was directly prepared. -1-yl)-N-(3-aminosulfonylphenyl)-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-carboxamide (KH24) (36.03 mg, yield 31.8%). 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),8.39(s,1H),7.80-7.73(m,1H),7.54(d,J=5.5Hz,2H),7.44(s,1H),7.39(s,2H),7.20(s, 1H), 5.76 (d, J = 6.1Hz, 1H), 5.16 (d, J = 13.6Hz, 2H), 3.33 (s, 2H), 3.31-3.28 (m, 2H), 2.26 (s, 2H), 2.06 (s, 2H), 1.78-1.76 (m, 2H). ESI-MS(m / z):520.1[M+H] + .

[0317] Examples 25 and 26

[0318] (S)-2-(4,4-difluoroaza) -1-yl)-N-(3-aminosulfonylphenyl)-5-trifluoromethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (KH25), (R)-2-(4,4-difluoroazapyridine) Preparation of -1-yl)-N-(3-aminosulfonylphenyl)-5-trifluoromethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (KH26)

[0319]

[0320]

[0321] Starting material 2-(4,4-difluoroaza) The preparation process of ethyl pyridine-3-carboxylate (-1-yl)-5-carbonyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylate is the same as step c in Example 18.

[0322] Step a): 2-(4,4-difluoroaza) Preparation of ethyl 1-(b)-5-hydroxy-5-trifluoromethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylate

[0323]

[0324] Nitrogen protection for 2-(4,4-difluoroaza) TMS-CF3 (504 mg, 3.6 mmol) was added to a tetrahydrofuran (10 mL) solution of ethyl pyridine-3-carboxylate (1 g, 2.96 mmol), followed by the dropwise addition of tetrabutylammonium fluoride (3.7 mL, 14.8 mmol). The reaction was carried out at room temperature for 16 h. After the reaction was complete, the reaction solution was poured into water, 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 Flash column chromatography to obtain 2-(4,4-difluoroazapyridine) -1-yl)-5-hydroxy-5-trifluoromethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylic acid ethyl ester (700 mg, yield 58%). 1 H NMR (400MHz, CDCl3) δ7.94 (s, 1H), 4.32 (q, J = 7.1Hz, 2H), 3.73 (dt, J = 8.1, 5.1Hz, 2H), 3.29 (d, J = 6.2Hz, 2H), 3 .10-2.89(m,2H),2.68-2.65(m,1H),2.54(s,1H),2.39-2.36(m,2H),2.03-1.90(m,4H),1.37(t,J=7.1Hz,3H). ESI-MS(m / z):409.3[M+H] + .

[0325] Step b): 2-(4,4-difluoroaza) Preparation of ethyl 1-(b)-5-trifluoromethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylate

[0326]

[0327] To 2-(4,4-difluoroaza) Triethylsilane (1.16 g, 10 mmol) was added to a solution of ethyl pyridine-3-carboxylate (408 mg, 1 mmol) in 10 mL of trifluoroacetic acid, and the mixture was reacted at 75 °C for 16 h. After the reaction was complete, the mixture was poured into ice water, the pH was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The 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) = 10 / 1) to give a white solid 2-(4,4-difluoroazines). -1-yl)-5-trifluoromethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylic acid ethyl ester (294 mg, yield 75%). 1 HNMR (400MHz, CDCl3) δ7.84 (s, 1H), 4.33 (q, J = 7.1Hz, 2H), 3.81-3.61 (m, 3H), 3.33-3.28 (m, 2H), 3 .06-3.00(m,1H),2.91-2.79(m,1H),2.45-2.19(m,4H),2.01-1.95(m,4H),1.37(t,J=7.1Hz,3H). ESI-MS(m / z):393.2[M+H] + .

[0328] Step c): 2-(4,4-difluoroaza) Preparation of -1-yl)-5-trifluoromethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylic acid

[0329]

[0330] To 2-(4,4-difluoroaza) 3 mL of methanol and 3 mL of an aqueous solution of lithium hydroxide (54 mg, 1.275 mmol) in tetrahydrofuran (3 mL) were added to a solution of ethyl 2-(4,4-difluoroazines)-5-trifluoromethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylate (100 mg, 0.255 mmol). The mixture was reacted at 60 °C for 2 h. After the reaction was complete, the mixture was extracted with ethyl acetate. The aqueous phase was adjusted to pH 5 with 1.0 M hydrochloric acid and then extracted with ethyl acetate. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid 2-(4,4-difluoroazines). -1-yl)-5-trifluoromethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylic acid (83 mg, 90% yield). ESI-MS (m / z): 365.1 [M+H] + .

[0331] Step d): 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-aminosulfonylphenyl)-5-trifluoromethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide

[0332]

[0333] To 2-(4,4-difluoroaza) A solution of 1-(4,4-difluoromethyl)-5-trifluoromethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylic acid (60 mg, 0.164 mmol) in dichloromethane (5 mL) was added with thionyl chloride (29.4 mg, 0.247 mmol) and one drop of DMF, and the reaction was allowed to proceed at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure, and 2 mL of tetrahydrofuran was added. This was then added dropwise to a solution of triethylamine (66.2 mg, 0.656 mmol) and m-aminobenzenesulfonamide (56.4 mg, 0.328 mmol) in tetrahydrofuran (2 mL). After reacting for 4 h, the solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography to obtain a white solid 2-(4,4-difluoroazines). -1-yl)-N-(3-aminosulfonylphenyl)-5-trifluoromethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (10 mg, yield 12%). 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.28(s,1H),7.82(d,J=6.1Hz,1H),7.62(s,1H),7.56-7.50(m,2H),7.38(s,2H),4.17-4.01(m,1H),3.63(br s,2H),3.43(t,J=5.8Hz,2H),2.97-2.86(m,2H),2.43-2.26(m,3H),2.16-2.11(m,1H),1.96-1.94(m,2H),1.84-1.82(m,2H). ESI-MS(m / z):519.4[M+H] + .

[0334] Step e): (S)-2-(4,4-difluoroaza) -1-yl)-N-(3-aminosulfonylphenyl)-5-trifluoromethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide &(R)-2-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-aminosulfonylphenyl)-5-trifluoromethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide

[0335]

[0336] 2-(4,4-difluoroaza) -1-yl)-N-(3-aminosulfonylphenyl)-5-trifluoromethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (120 mg) was resolved by SFC to give a white solid (S)-2-(4,4-difluoroazapyridine) -1-yl)-N-(3-aminosulfonylphenyl)-5-trifluoromethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (48.24 mg), 1 H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.28(s,1H),7.86-7.77(m,1H),7.62( s,1H),7.57-7.51(m,2H),7.38(s,2H),4.16-4.03(m,1H),3.63(d,J=5.3Hz, 2H),3.43(t,J=5.8Hz,2H),2.94-2.88(m,2H),2.44-2.26(m,3H),2.19-2.13 (m,1H),2.03-1.90(m,2H),1.84(d,J=5.0Hz,2H); ESI-MS(m / z):519.1[M+H] + ; and white solid (R)-2-(4,4-difluoroazines) -1-yl)-N-(3-aminosulfonylphenyl)-5-trifluoromethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (29.73 mg), 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.28(s,1H),7.84-7.79(m,1H),7.62(s,1H),7.56-7.52(m,2H),7.38(s,2H),4.15-4.03(m,1H),3.63( d,J=3.9Hz,2H),3.43(t,J=5.8Hz,2H),2.94-2.87(m,2H),2.42-2.36(m,3H),2.18-2.12(m,1H),2.04-1.78(m,4H), ESI-MS(m / z):519.1[M+H] + The combined yield was 65%.

[0337] Example 27

[0338] 5-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-aminosulfonylphenyl)-2,3-dihydrobenzofuran-6-carboxamide (KH27)

[0339]

[0340] Step a): Preparation of 5-nitro-2,3-dihydrobenzofuran

[0341]

[0342] Fuming nitric acid (9.45 g, 0.15 mol) was added dropwise to a solution of 2,3-dihydrobenzofuran (12 g, 0.1 mol) in 300 mL of trifluoroacetic acid at 0 °C, and the reaction was carried out at room temperature for 3 h. After the reaction was complete, the mixture was poured into ice water, extracted with ethyl acetate, and the resulting 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) = 20 / 1) to give a yellow solid 5-nitro-2,3-dihydrobenzofuran (7.5 g, yield 45%). 1 H NMR (400MHz, CDCl3) δ 8.13-8.06 (m, 2H), 6.84-6.78 (m, 1H), 4.74 (t, J = 8.8Hz, 2H), 3.30 (t, J = 8.8Hz, 2H).

[0343] Step b): Preparation of 2,3-dihydrobenzofuran-5-amine

[0344]

[0345] Ethanol (30 mL) and Pd / C (0.6 g, 10% wt) were added to a tetrahydrofuran (30 mL) solution of 6.0 g (36.3 mmol) of 5-nitro-2,3-dihydrobenzofuran, and the mixture was purged with hydrogen and stirred at room temperature for 16 h. After the reaction was complete, the reaction solution was filtered and concentrated under reduced pressure to give a yellow solid of 2,3-dihydrobenzofuran-5-amine (4.1 g, yield 85%). ESI-MS (m / z): 136.3 [M+H] + .

[0346] Step c): Preparation of N-(2,3-dihydrobenzofuran-5-yl)acetamide

[0347]

[0348] Pyridine (584.6 mg, 7.4 mmol) was added to a solution of 2,3-dihydrobenzofuran-5-amine (1 g, 7.4 mmol) in 1,4-dioxane (10 mL) under ice bath conditions, followed by the addition of acetic anhydride (1.51 g, 14.8 mg). The mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the resulting organic phase was washed with saturated sodium bicarbonate solution, then 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) = 1 / 1) to give a pale yellow solid N-(2,3-dihydrobenzofuran-5-yl)acetamide (1.15 g, yield 86%). 1 H NMR (400MHz, DMSO-d6) δ9.69 (s, 1H), 7.48 (s, 1H), 7.18 (d, J = 8.5Hz, 1H), 6.6 6(d,J=8.5Hz,1H), 4.47(t,J=8.7Hz,2H), 3.14(t,J=8.6Hz,2H), 1.98(s,3H). ESI-MS(m / z):178.3[M+H] + .

[0349] Step d): Preparation of N-(6-nitro-2,3-dihydrobenzofuran-5-yl)acetamide

[0350]

[0351] Fuming nitric acid (0.5 g, 7.9 mmol) was added to a solution of N-(2,3-dihydrobenzofuran-5-yl)acetamide (1 g, 5.65 mmol) in acetic acid (10 mL), and the mixture was stirred at 30 °C for 1 h. After the reaction was complete, the mixture was poured into ice water, the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid N-(6-nitro-2,3-dihydrobenzofuran-5-yl)acetamide (1.1 g, 90% yield). ESI-MS (m / z): 223.1 [M+H] + .

[0352] Step e): Preparation of 6-nitro-2,3-dihydrobenzofuran-5-amine

[0353]

[0354] Hydrochloric acid (5 mL) was added to a 10 mL ethanol solution of N-(6-nitro-2,3-dihydrobenzofuran-5-yl)acetamide (1 g, 4.48 mmol), and the mixture was refluxed for 2 h. After the reaction was complete, the solution was poured into ice water, the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, the organic phase was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow solid, 6-nitro-2,3-dihydrobenzofuran-5-amine (720 mg, 90% yield). ESI-MS (m / z): 181.2 [M+H] + .

[0355] Step f): Preparation of 6-nitro-2,3-dihydrobenzofuran

[0356]

[0357] At 0°C, an aqueous solution of sodium nitrite (1.38 g, 20 mmol) was added dropwise to a sulfuric acid (27 mL) solution of 6-nitro-2,3-dihydrobenzofuran-5-amine (3 g, 16.7 mmol). After stirring for 1 h, the solution was added dropwise to a copper sulfate ethanol solution at 60°C, and stirring was continued for another 1 h. After the reaction was complete, the reaction solution was concentrated, poured into ice water, and the organic phase was extracted with ethyl acetate. The solution was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 20 / 1) to give a yellow solid 6-nitro-2,3-dihydrobenzofuran (1.7 g, yield 62%). 1 H NMR (400MHz, CDCl3) δ7.76 (dd, J=8.1, 2.0Hz, 1H), 7.58 (d, J=2.0Hz, 1H), 7.29 (d, J=8.1Hz, 1H), 4.70 (t, J=8.8Hz, 2H), 3.30 (t, J=8.8Hz, 2H).

[0358] Step g): Preparation of 2,3-dihydrobenzofuran-6-amine

[0359]

[0360] To a solution of 3.0 g (18.1 mmol) of 6-nitro-2,3-dihydrobenzofuran (15 mL) in tetrahydrofuran (15 mL), ethanol (15 mL) and Pd / C (0.3 g, 10% wt) were added, followed by hydrogen purging. The mixture was stirred at room temperature for 16 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to give a yellow solid, 2,3-dihydrobenzofuran-6-amine (2.1 g, yield 86%). ESI-MS (m / z): 136.2 [M+H] + .

[0361] Step h): Preparation of 5-iodo-2,3-dihydrobenzofuran-6-amine

[0362]

[0363] N-iodosuccinimide (2.53 g, 11.26 mmol) was added in portions to a solution of 2,3-dihydrobenzofuran-6-amine (1.6 g, 11.85 mmol) in acetonitrile (48 mL) under ice bath conditions, and the mixture was stirred for 0.33 h. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give a yellow solid 5-iodo-2,3-dihydrobenzofuran-6-amine (2.6 g, yield 89%). 1 H NMR (400MHz, CDCl3) δ7.38 (s, 1H), 6.27 (s, 1H), 4.53 (t, J = 8.5Hz, 2H), 4.01 (s, 2H), 3.10 (t, J = 8.5Hz, 2H).

[0364] Step i): Preparation of 5-iodo-2,3-dihydrobenzofuran-6-nitrile

[0365]

[0366] Cuprous cyanide (931 mg, 10.46 mmol) was added to DMSO (50 mL), and the mixture was heated to 60 °C to dissolve it. Then, tert-butyl nitrite (2.48 g, 24.12 mmol) was added, followed by dropwise addition of a DMSO (14 mL) solution of 5-iodo-2,3-dihydrobenzofuran-6-amine (2.1 g, 8.04 mmol). The mixture was stirred at 60 °C for 1 h, then cooled to 45 °C, and 4.0 M hydrochloric acid (4.1 mL) was added. The mixture was stirred for another 10 min. The reaction mixture was poured into ice water, and the organic phase was extracted with ethyl acetate. The solution was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 20 / 1) to give a yellow solid 5-iodo-2,3-dihydrobenzofuran-6-onitrile (0.45 g, yield 21%). 1 H NMR (400MHz, CDCl3) δ7.48 (s, 1H), 7.23 (s, 1H), 4.70 (t, J = 8.8 Hz, 2H), 3.29 (t, J = 8.8 Hz, 2H).

[0367] Step j): 5-(4,4-difluoroaza) Preparation of 1-yl)-2,3-dihydrobenzofuran-6-nitrile

[0368]

[0369] To a solution of 5-iodo-2,3-dihydrobenzofuran-6-onitrile (220 mg, 0.812 mmol) in 1,4-dioxane (8 mL), 4,4-difluoroazacycloheptan hydrochloride (278 mg, 1.624 mmol), cesium carbonate (1.055 g, 3.248 mmol), BINAP (101 mg, 0.162 mmol), and Pd(OAc)₂ (18 mg, 0.0812 mmol) were added under nitrogen protection and stirred at 120 °C for 48 h. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 20 / 1) to give a pale yellow solid 5-(4,4-difluoroazacycloheptan) -1-yl)-2,3-dihydrobenzofuran-6-onitrile (120 mg, yield 53%). 1 HNMR (400MHz, CDCl3) δ6.94 (s, 1H), 6.90 (s, 1H), 4.58 (t, J = 8.7Hz, 2H), 3.35-3.28 (m ,4H),3.21(t,J=8.6Hz,2H),2.46-2.32(m,2H),2.29-2.23(m,2H),1.96-1.94(m,2H). ESI-MS(m / z):279.1[M+H] + .

[0370] Step k): 5-(4,4-difluoroaza) Preparation of 1-yl)-2,3-dihydrobenzofuran-6-carboxylic acid

[0371]

[0372] To 5-(4,4-difluoroaza) 130 mg of 1,1-dihydrobenzofuran-6-onitrile was added to 10 mL of 40% sulfuric acid, and the mixture was reacted at 100 °C for 16 h. After the reaction was complete, the reaction solution was poured into crushed ice, the organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Flash column chromatography to give a white solid 5-(4,4-difluoroazines). (-1-yl)-2,3-dihydrobenzofuran-6-carboxylic acid (85 mg, yield 61%). ESI-MS (m / z): 298.0 [M+H] + .

[0373] Step l): 5-(4,4-difluoroaza) Preparation of 1-yl)-N-(3-aminosulfonylphenyl)-2,3-dihydrobenzofuran-6-carboxamide

[0374]

[0375] To 5-(4,4-difluoroaza) A solution of 1-(4,4-difluoroazino-6-carboxylic acid) in dichloromethane (5 mL) was mixed with one drop of DMF and SOCl2 (30 mg, 0.252 mmol). The mixture was stirred at room temperature for 0.5 h and then concentrated. Tetrahydrofuran (2 mL) was added to dissolve the soluble compound, which was then added dropwise to a mixture of tetrahydrofuran (1 mL), triethylamine (34 mg, 0.336 mmol), and m-aminobenzenesulfonamide (36 mg, 0.21 mmol). After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by reverse preparative chromatography to give a white solid 5-(4,4-difluoroazino-6-carboxylic acid). -1-yl)-N-(3-aminosulfonylphenyl)-2,3-dihydrobenzofuran-6-carboxamide (8.06 mg, yield 21%). 1 H NMR (400MHz, DMSO-d6) δ11.72(s,1H),8.44(s,1H),7.67(dd,J=7.8,3.3Hz,1H),7.54(d,J=5.0Hz,2H),7.38(s,2H),7.34(s,1H),7.08(s,1H) ,4.55(t,J=8.6Hz,2H),3.22(t,J=8.6Hz,2H),3.19-3.14(m,2H),3.14 -3.08(m,2H),2.35-2.22(m,2H),2.16-2.13(m,2H),1.81-1.71(m,2H). ESI-MS(m / z):452.3[M+H] + .

[0376] Example 28

[0377] 5-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-aminosulfonylphenyl)-2,3-dihydrofurano[3,2-b]pyridine-6-carboxamide (KH28)

[0378]

[0379] Step a): Preparation of 1-(3-hydroxypyridin-2-yl)-N,N,N-trimethylmethyleneamine iodide

[0380]

[0381] Iodomethane (38 g, 261 mmol) was added dropwise to a solution of 2-(dimethylaminomethylene)pyridine-3-hydroxy (10 g, 65.8 mmol) in acetone (100 mL) at 0 °C, and the mixture was stirred for 3 h. After the reaction was complete, the reaction solution was filtered, and the filter cake was dried under vacuum to give a white solid 1-(3-hydroxypyridine-2-yl)-N,N,N-trimethylmethyleneamine iodide (1 g, yield 91%). ESI-MS (m / z): 167.2 [MI] + .

[0382] Step b): Preparation of 2,3-dihydrofurano[3,2-b]pyridine

[0383]

[0384] To a solution of trimethyl sulfoxide (1.776 g, 8.08 mmol) in DMSO (30 mL), NaH (0.673 g, 16.8 mmol) was added, purged with nitrogen, and stirred at room temperature for 3 h. Then, 1-(3-hydroxypyridin-2-yl)-N,N,N-trimethylmethyleneamine iodide (2.0 g, 6.73 mmol) was added, and the mixture was stirred at room temperature for 16 h. After the reaction was complete, the reaction system was poured into ice water, extracted three times with ethyl acetate, and the organic layers were combined. The organic phase was washed three times with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a pale yellow solid 2,3-dihydrofurano[3,2-b]pyridine (470 mg, yield 11%). 1 H NMR (400MHz, CDCl3) δ8.02 (d, J = 2.6 Hz, 1H), 7.00 (d, J = 2.8 Hz, 2H), 4.65 (t, J = 8.9 Hz, 2H), 3.32 (t, J = 8.9 Hz, 2H). ESI-MS(m / z):122.1[M+H] + .

[0385] Step c): Preparation of 5-nitro-2,3-dihydrofurano[3,2-b]pyridine

[0386]

[0387] A mixture of fuming nitric acid (5 mL) and concentrated sulfuric acid (1 mL) was added dropwise to a sulfuric acid (4 mL) solution of 600 mg (4.96 mmol) of 2,3-dihydrofurano[3,2-b]pyridine in an ice bath and the reaction was allowed to proceed for 1 h. After the reaction was complete, the reaction mixture was poured into ice water and extracted three times with ethyl acetate. The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid of 5-nitro-2,3-dihydrofurano[3,2-b]pyridine (500 mg, yield 61%). ESI-MS (m / z): 166.9 [M+H] + .

[0388] Step d): Preparation of 2,3-dihydrofurano[3,2-b]pyridine-5-amine

[0389]

[0390] 5-Nitro-2,3-dihydrofurano[3,2-b]pyridine (3.1 g, 18.7 mmol) was dissolved in methanol (10 mL), Pd / C (310 mg, 1.5 mmol) was added, and the mixture was stirred at room temperature for 16 h after hydrogen purging. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a black solid 2,3-dihydrofurano[3,2-b]pyridine-5-amine (2.4 g, 98% yield). 1 H NMR (400MHz, CDCl3) δ6.90 (d, J = 8.5Hz, 1H), 6.26 (d, J = 8.5Hz, 1H), 4.57 (t, J = 8.9Hz, 2H), 4.11 (br s, 2H), 3.19 (t, J = 8.8Hz, 2H). ESI-MS(m / z):137.1[M+H] + .

[0391] Step e): Preparation of 6-bromo-2,3-dihydrofurano[3,2-b]pyridine-5-amine

[0392]

[0393] A mixture of liquid bromine (1.85 g, 11.6 mmol) and acetic acid (10 mL) was added dropwise to a solution of 2,3-dihydrofurano[3,2-b]pyridine-5-amine (1.5 g, 11.03 mmol) in acetic acid (10 mL), and the mixture was stirred at room temperature for 16 h. After the reaction was complete, sodium bicarbonate was added to the reaction system to adjust the pH to weakly alkaline, and the mixture was extracted three times with ethyl acetate. The resulting organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a pale yellow oily substance, 6-bromo-2,3-dihydrofurano[3,2-b]pyridine-5-amine (1.54 g, yield 65%). 1 HNMR (400MHz, CDCl3) δ7.14 (s, 1H), 4.59 (d, J = 8.9Hz, 2H), 3.16 (t, J = 8.8Hz, 2H). ESI-MS(m / z):217.0[M+H] + .

[0394] Step f): Preparation of 5-amino-2,3-dihydrofurano[3,2-b]pyridine-6-nitrile

[0395]

[0396] 6-Bromo-2,3-dihydrofurano[3,2-b]pyridine-5-amine (200 mg, 0.93 mmol) was added to a microwave tube, followed by NMP (5 mL), Zn(CN)₂ (164 mg, 1.39 mmol), and Pd(PPh₃)₄ (107.8 mg, 0.09 mmol). The reaction was carried out in a microwave-assisted 120 °C environment for 1.5 h. After the reaction was complete, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and washed three times with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by a reverse-phase system to obtain a yellow solid, 5-amino-2,3-dihydrofurano[3,2-b]pyridine-6-onitrile (119 mg, yield 79%). ESI-MS (m / z): 162.2 [M+H] + .

[0397] Step g): Preparation of 5-chloro-2,3-dihydrofurano[3,2-b]pyridine-6-nitrile

[0398]

[0399] 5-Amino-2,3-dihydrofurano[3,2-b]pyridine-6-onitrile (600 mg, 3.7 mmol) was dissolved in hydrochloric acid (6 M, 10 mL). When the reaction system cooled to -5 °C, NaNO2 (511 mg, 7.4 mmol) solution was added. The reaction was continued at -5 °C for 10 min, then heated to room temperature for 3 h. After the reaction was complete, water was added to quench the reaction, and the pH of the reaction solution was adjusted to weakly alkaline with NaHCO3. The mixture was extracted three times with ethyl acetate, and the organic layer was washed three times with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel plate preparation (petroleum ether / ethyl acetate (v / v) = 1 / 1) to obtain a white solid 5-chloro-2,3-dihydrofurano[3,2-b]pyridine-6-onitrile (409 mg, yield 61%). ESI-MS (m / z): 181.2 [M+H] + .

[0400] Step h): 5-(4,4-difluoroaza) Preparation of -1-yl)-2,3-dihydrofurano[3,2-b]pyridine-6-nitrile

[0401]

[0402] 5-Chloro-2,3-dihydrofurano[3,2-b]pyridine-6-onitrile (150 mg, 0.83 mmol) was dissolved in 5 mL of 1,4-dioxane, followed by the addition of 4,4-difluoroazacycloheptane hydrochloride (285 mg, 1.67 mmol), Cs₂CO₃ (948 mg, 2.92 mmol), BINAP (104 mg, 0.17 mmol), and Pd(OAc)₂ (18.7 mg, 0.08 mmol). The reaction was carried out at 130 °C for 48 h. After the reaction was completed, the mixture was quenched with water, extracted three times with ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel plate (petroleum ether / ethyl acetate (v / v) = 10 / 1) to obtain a white solid 5-(4,4-difluoroazacycloheptane) -1-yl)-2,3-dihydrofurano[3,2-b]pyridine-6-onitrile (63 mg, yield 27%). ESI-MS (m / z): 280.3 [M+H] + .

[0403] Step i): 5-(4,4-difluoroaza) Preparation of 1-yl)-2,3-dihydrofurano[3,2-b]pyridine-6-carboxylic acid

[0404]

[0405] To 5-(4,4-difluoroaza) 30 mL of 10% KOH aqueous solution was added to 5-(4,2-b)-2,3-dihydrofurano[3,2-b]pyridine-6-nitrile (70 mg, 0.25 mmol), and the mixture was reacted at 110 °C for 16 h. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was discarded. The aqueous phase was adjusted to pH 5-6 with dilute hydrochloric acid and then extracted three more times with ethyl acetate. The organic layers were combined and washed three times with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid 5-(4,4-difluoroazines). -1-yl)-2,3-dihydrofurano[3,2-b]pyridine-6-carboxylic acid (45 mg, yield 60%). ESI-MS (m / z): 299.1 [M+H] + .

[0406] Step j): 5-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-aminosulfonylphenyl)-2,3-dihydrofurano[3,2-b]pyridine-6-carboxamide

[0407]

[0408] To 5-(4,4-difluoroaza) 5-(4,2-b)pyridine-6-carboxylic acid (60 mg, 0.2 mmol) was reacted with SOCl2 (1.2 mL) for 1 h, concentrated under reduced pressure, and then reacted with tetrahydrofuran (1.5 mL) and triethylamine (1.5 mL) for 1 h. After the reaction was complete, the solvent was evaporated, the pH was adjusted to neutral with acetic acid, and then extracted three times with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid 5-(4,4-difluoroazines). -1-yl)-N-(3-aminosulfonylphenyl)-2,3-dihydrofurano[3,2-b]pyridine-6-carboxamide (15 mg, yield 16%). 1 H NMR (400MHz, DMSO) δ10.69(s,1H),8.33(s,1H),7.82-7.74(m,1H),7.57-7.51(m,2H),7.38(s,2H),7.22(s,1H),4.60(t,J=8.8Hz, 2H), 3.50-3.44 (m, 2H), 3.35 (s, 2H), 3.21 (t, J = 8.8Hz, 2H), 2.31 (d, J = 11.2Hz, 2H), 1.98 (t, J = 13.1Hz, 2H), 1.80 (d, J = 5.6Hz, 2H). ESI-MS(m / z):453.1[M+H] + .

[0409] Example 29

[0410] 5-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-aminosulfonylphenyl)-[1,3]dioxolane-[4,5-b]pyridine-6-carboxamide (KH29)

[0411]

[0412] Step a): Preparation of [1,3]dioxolane[4,5-b]pyridine

[0413]

[0414] To a solution of 2,3-dihydroxypyridine (25 g, 225.2 mmol) in 150 mL of NMP, dibromomethane (58 g, 337.8 mmol) and potassium carbonate (46.6 g, 337.8 mmol) were added, purged with nitrogen, and stirred at 80 °C for 24 h. After the reaction solution cooled to room temperature, it was diluted with ethyl acetate, filtered, and water was added to the filtrate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give a pale yellow liquid [1,3]dioxolane[4,5-b]pyridine (2.5 g, yield 9%). 1 H NMR (400MHz, CDCl3) δ7.65 (br s, 1H), 6.98 (dd, J = 7.6, 1.3Hz, 1H), 6.79-6.71 (m, 1H), 6.04 (s, 2H). ESI-MS(m / z):124.0[M+H] + .

[0415] Step b): Preparation of 5-nitro-[1,3]dioxolane[4,5-b]pyridine

[0416]

[0417] [1,3]dioxolane[4,5-b]pyridine (1 g, 8.13 mmol) was added to 10 mL of sulfuric acid at 0 °C, followed by slow dropwise addition of a 5 mL solution of potassium nitrate (1.23 g, 12.2 mmol). The reaction was allowed to proceed at room temperature for 2 h. After the reaction was complete, the reaction mixture was poured into crushed ice, and the organic phase was extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a yellow solid, 5-nitro-[1,3]dioxolane[4,5-b]pyridine (1.05 g, yield 77%). ESI-MS (m / z): 169.1 [M+H] + .

[0418] Step c): Preparation of [1,3]dioxolane[4,5-b]pyridine-5-amine

[0419]

[0420] Raney nickel (0.2 mL) was added to a methanol (10 mL) solution of 5-nitro-[1,3]dioxolane[4,5-b]pyridine (500 mg, 2.97 mmol) under ice bath conditions, followed by dropwise addition of hydrazine hydrate (744 mg, 14.88 mmol). The reaction was carried out at room temperature for 2 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to give a pale yellow solid, [1,3]dioxolane[4,5-b]pyridine-5-amine (370 mg, 90% yield). ESI-MS (m / z): 139.1 [M+H] + .

[0421] Step d): Preparation of 6-bromo-[1,3]dioxolane[4,5-b]pyridine-5-amine

[0422]

[0423] A solution of bromine (640 mg, 4 mmol) in acetic acid (5 mL) was added dropwise to a solution of [1,3]dioxolane-[4,5-b]pyridine-5-amine (500 mg, 3.62 mmol) in acetic acid (20 mL). The reaction was carried out at room temperature for 2 h. After the reaction was complete, the solution was poured into ice water, and sodium bicarbonate was added to adjust the pH to 8. The organic phase 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 silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a white solid 6-bromo-[1,3]dioxolane-[4,5-b]pyridine-5-amine (600 mg, yield 76%). 1 H NMR (400MHz, CDCl3) δ7.08 (d, J = 1.0 Hz, 1H), 5.98 (d, J = 0.9 Hz, 2H), 4.50 (br s, 2H). ESI-MS(m / z):217.0[M+H] + .

[0424] Step e): Preparation of 5-amino-[1,3]dioxolane[4,5-b]pyridine-6-nitrile

[0425]

[0426] Zn(CN)₂ (1.57 g, 17.55 mmol) was added to a 20 mL NMP solution of 1.9 g (8.75 mmol) of 6-bromo-[1,3]dioxolane[4,5-b]pyridine-5-amine (NMP). The reaction was carried out at 120 °C for 16 h. After the reaction was complete, the solution was poured into water, the organic phase was extracted with ethyl acetate, washed with saturated brine, dried over 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) = 5 / 1) to give a white solid 5-amino-[1,3]dioxolane[4,5-b]pyridine-6-nitrile (750 mg, yield 52%). ESI-MS (m / z): 164.1 [M+H] + .

[0427] Step f): Preparation of 5-iodo-[1,3]dioxolane[4,5-b]pyridine-6-nitrile

[0428]

[0429] Iodine (1402 mg, 5.5 mmol) was added to a chloroform (20 mL) solution of 5-amino-[1,3]dioxolane[4,5-b]pyridine-6-onitrile (750 mg, 4.6 mmol), followed by the slow addition of tert-butyl nitrite (948 mg, 9.2 mmol). The reaction was carried out at room temperature for 16 h. After the reaction was complete, the solution was poured into ice water, and the organic phase was extracted with ethyl acetate. The organic phase was washed with sodium thiosulfate aqueous solution, then 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) = 10 / 1) to give a pale yellow solid 5-iodo-[1,3]dioxolane[4,5-b]pyridine-6-onitrile (550 mg, yield 44%). 1 H NMR (400MHz, DMSO-d6) δ7.67 (s, 1H), 6.29 (s, 2H). ESI-MS(m / z):274.9[M+H] + .

[0430] Step g): 5-(4,4-difluoroaza) Preparation of -1-yl)-[1,3]dioxolane[4,5-b]pyridine-6-nitrile

[0431]

[0432] To a solution of 5-iodo-[1,3]dioxolane[4,5-b]pyridin-6-onitrile (500 mg, 0.1824 mmol) in 1,4-dioxane (20 mL), 4,4-difluoroazacycloheptan hydrochloride (780 mg, 0.4562 mmol), BINAP (340 mg, 0.05824 mmol), cesium carbonate (2080 mg, 0.6385 mmol), and palladium acetate (81 mg, 0.364 mmol) were added. The mixture was purged with nitrogen three times and reacted at 110 °C for 16 h. After the reaction was complete, the mixture was quenched with water, the organic phase 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 silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 1) to give a pale yellow solid 5-(4,4-difluoroazacycloheptan... -1-yl)-[1,3]dioxolane[4,5-b]pyridine-6-nitrile (220 mg, yield 43%). 1 H NMR (400MHz, DMSO-d6) δ7.43(s,1H),6.13(s,2H),3.74-3.64(m,4H),2.29-2.25(m,2H),2.15-2.08(m,2H),1.95-1.85(m,2H). ESI-MS(m / z):282.1[M+H] + .

[0433] Step h): 5-(4,4-difluoroaza) Preparation of -1-yl)-[1,3]dioxolane[4,5-b]pyridine-6-carboxamide

[0434]

[0435] To 5-(4,4-difluoroaza) Potassium carbonate (750 mg, 5.4 mmol) was added to a solution of 1,3-dioxolane-[4,5-b]pyridine-6-onitrile (140 mg, 0.49 mmol) in dimethyl sulfoxide (3 mL). 30% hydrogen peroxide solution (1 mL) was slowly added under ice bath conditions, and the mixture was allowed to rise naturally to room temperature for 4 h. After the reaction was complete, the mixture was quenched with ice water, and the organic phase was extracted with dichloromethane. The solution 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 (dichloromethane / methanol (v / v) = 20 / 1) to obtain a white solid 5-(4,4-difluoroazapyridine) -1-yl)-[1,3]dioxolane[4,5-b]pyridine-6-carboxamide (42 mg, yield 28%). 1H NMR (400MHz, DMSO-d6) δ7.77(s,1H),7.29(d,J=6.1Hz,1H),7.23(s,1H),6.07(d,J=7.6Hz,2H),3.40(dd,J=6.7, 3.9Hz, 2H), 3.29 (t, J = 6.0Hz, 2H), 2.35-2.24 (m, 2H), 2.00 (dd, J = 14.8, 7.3Hz, 2H), 1.83 (dd, J = 11.2, 5.6Hz, 2H). ESI-MS(m / z):300.1[M+H] + .

[0436] Step i): Preparation of 3-bromo-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide

[0437]

[0438] To a solution of 3-bromobenzenesulfonyl chloride (600 mg, 2.34 mmol) in dichloromethane (6 mL), di(2,4-dimethoxybenzyl)amine (820 mg, 2.58 mmol) and triethylamine (470 mg, 4.69 mmol) were added, and the reaction was carried out at room temperature for 2 h. After the reaction was complete, the mixture was quenched with water, the organic phase was extracted with dichloromethane, 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) = 4 / 1) to give a transparent oily substance, 3-bromo-N,N-di(2,4-dimethoxybenzyl)benzenesulfonamide (1.2 g, yield 95%). 1 H NMR (400MHz, DMSO-d6) δ7.78(d,J=8.0Hz,1H),7.68(d,J=7.9Hz,1H),7.54(s,1H),7.46(t,J=7.9Hz,1H),7.0 5(d,J=8.3Hz,2H),6.44(dd,J=8.3,2.2Hz,2H),6.39(d,J=2.1Hz,2H),4.29(s,4H),3.73(s,6H),3.61(s,6H). ESI-MS(m / z):558.0[M+Na] + .

[0439] Step j: N-(3-(N,N-bis(2,4-dimethoxybenzyl)aminesulfonyl)phenyl)-5-(4,4-difluoroaza) Preparation of -1-yl)-[1,3]dioxolane[4,5-b]pyridine-6-carboxamide

[0440]

[0441] To 5-(4,4-difluoroaza) To a solution of 1,4-dioxane (2 mL) of 1,4-dioxane-6-carboxamide (44 mg, 0.49 mmol) containing 3-bromo-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide (98.2 mg, 0.1759 mmol), Brettphos-Pd-G3 (26.5 mg, 0.029 mmol), and cesium carbonate (96 mg, 0.2933 mmol), the mixture was purged with nitrogen three times and reacted at 100 °C for 2.5 h. After the reaction was complete, the mixture was quenched with water, extracted with dichloromethane, 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 plate (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a pale yellow solid N-(3-(N,N-bis(2,4-dimethoxybenzyl)aminesulfonyl)phenyl)-5-(4,4-difluoroaza) -1-yl)-[1,3]dioxolane[4,5-b]pyridine-6-carboxamide (82 mg, yield 74%). ESI-MS (m / z): 755.2 [M+H] + .

[0442] Step k): 5-(4,4-difluoroaza) Preparation of -1-yl)-N-(3-aminosulfonylphenyl)-[1,3]dioxolane-[4,5-b]pyridine-6-carboxamide

[0443]

[0444] At 0℃, N-(3-(N,N-bis(2,4-dimethoxybenzyl)aminesulfonyl)phenyl)-5-(4,4-difluoroazines) 12 mL of ethyl hydrochloride solution was slowly added to a solution of ethyl acetate (6 mL) of 1-(4,4-difluoroazines)-[1,3]dioxolane-[4,5-b]pyridine-6-carboxamide (77 mg, 0.102 mmol) and the reaction was carried out at room temperature for 2 h. After the reaction was complete, the mixture was quenched with ice water, the pH was adjusted to about 7 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The 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 reverse-phase preparation under formic acid conditions to obtain a white solid 5-(4,4-difluoroazines). -1-yl)-N-(3-aminosulfonylphenyl)-[1,3]dioxolane[4,5-b]pyridine-6-carboxamide (15.3 mg, yield 33%). 1HNMR(400MHz,DMSO-d6)δ10.53(s,1H),8.30(s,1H),7.78(s,1H),7.55-7.50(m,2H),7.36(d,J=9.4Hz,3H ), 6.10 (s, 2H), 3.46 (s, 3H), 2.67 (d, J = 1.7Hz, 1H), 2.38-2.23 (m, 3H), 1.97 (s, 2H), 1.81 (d, J = 5.9Hz, 2H). ESI-MS(m / z):455.2[M+H] + .

[0445] Example 30

[0446] 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide (KH30)

[0447]

[0448] Step a): Preparation of 1-aldehyde-2-cyclohexanone-1-yl sodium salt

[0449]

[0450] Cyclohexanone (30 g, 305.6 mmol) and ethyl formate (23.78 g, 320.9 mmol) were dissolved in ether (150 mL), placed in an ice-water bath, and sodium ethoxide (20.8 g, 305.6 mmol) was added. The mixture was stirred at room temperature for 10 h, filtered, and the filter cake was washed with ether to give a white solid 1-aldehyde-2-cyclohexanone-1-yl sodium salt (42 g, yield 92.1%). 1 H NMR (400MHz, DMSO-d6) δ9.19 (s, 1H), 2.12-2.04 (m, 2H), 1.90-1.83 (m, 2H), 1.54 (dd, J = 11.9, 5.8Hz, 2H), 1.45-1.40 (m, 2H).

[0451] Step b): Preparation of 2-carbonyl-1,2,5,6,7,8-hexahydroquinoline-3-carboxynitrile

[0452]

[0453] A solution of 1-aldehyde-2-cyclohexanone-1-yl sodium salt in toluene (300 mL) was added to cyanoacetamide (28.1 g, 335.2 mmol). The mixture was stirred at room temperature for 1 h, followed by the addition of 30 mL of 2 M piperidine dichloromethane solution. The reaction was then heated to 110 °C and reacted for 16 h. After the reaction was complete, the mixture was acidified with acetic acid, filtered, and the filtrate was evaporated to dryness and washed with diethyl ether to give a white solid, 2-carbonyl-1,2,5,6,7,8-hexahydroquinoline-3-carboxynitrile (6.7 g, yield 28.6%). ESI-MS (m / z): 175.1 [M+H] + .

[0454] Step c): Preparation of 2-chloro-5,6,7,8-tetrahydroquinoline-3-carboxynitrile

[0455]

[0456] To a toluene (100 mL) solution of 2-carbonyl-1,2,5,6,7,8-hexahydroquinoline-3-carboxynitrile (6.7 g, 38.4 mmol), DIEA (34.8 g, 269.2 mmol) and phosphorus oxychloride (23.5 g, 153.8 mmol) were added, and the mixture was stirred at 110 °C for 4 h. After the reaction solution cooled to room temperature, it was concentrated, and the reaction was quenched with 100 mL of saturated NH4Cl aqueous solution. The mixture was extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, 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) = 5 / 1) to give a yellow solid 2-chloro-5,6,7,8-tetrahydroquinoline-3-carboxynitrile (6.6 g, yield 89.0%). ESI-MS (m / z): 193.1 [M+H] + .

[0457] Step d): 2-(4,4-difluoroaza) Preparation of (-1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxynitrile

[0458]

[0459] 2-Chloro-5,6,7,8-tetrahydroquinoline-3-carboxynitrile (2.5 g, 12.9 mmol) was dissolved in NMP (50 mL), and DIEA (5.03 g, 38.9 mmol) and 4,4-difluoroazacycloheptan hydrochloride (2.4 g, 14.2 mmol) were added. The reaction was carried out at 140 °C for 16 h. After the reaction solution cooled to room temperature, 50 mL of saturated NH4Cl aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate (60 mL × 3), the organic phase was separated, 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 normal-phase preparative chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a white solid 2-(4,4-difluoroazacycloheptan) -1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxynitrile (2.2 g, yield 58.2%). 1 H NMR(400MHz, DMSO-d6)δ7.65(s,1H),3.75(dd,J=12.1,6.1Hz,4H),2.67(t,J=6.4Hz,2H),2.58 (t,J=6.2Hz,2H),2.37-2.25(m,2H),2.15-2.00(m,2H),1.95-1.85(m,2H),1.80-1.64(m,4H). ESI-MS(m / z):292.1[M+H] + .

[0460] Step e): 2-(4,4-difluoroaza) Preparation of 1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide

[0461]

[0462] 2-(4,4-difluoroaza) 2-(4,4-difluoroazinonitrile)-5,6,7,8-tetrahydroquinoline-3-carboxynitrile (2 g, 6.8 mmol) was dissolved in DMSO (20 mL), potassium carbonate (2.8 g, 20.5 mmol) was added, and the mixture was placed in an ice-water bath. Hydrogen peroxide (1.17 g, 34.3 mmol, 30% wt) was slowly added dropwise, and the mixture was then allowed to return to room temperature for 3 h. After the reaction was complete, 20 mL of saturated NH4Cl aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL × 3), the organic phase was separated, 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 normal-phase preparative chromatography to give a white solid 2-(4,4-difluoroazinonitrile). (-1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide (1.4 g, yield 66.0%). ESI-MS (m / z): 310.1 [M+H] + .

[0463] Step f): 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(2-methoxypyridin-4-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide

[0464]

[0465] To 2-(4,4-difluoroaza) 4-bromo-2-methoxypyridine (72.7 mg, 0.387 mmol), Ruphos-Pd-G2 (25 mg, 0.033 mmol), and cesium carbonate (210 mg, 0.645 mmol) were added to a solution of 1-(4,4-difluoroazine)-5,6,7,8-tetrahydroquinoline-3-carboxamide (100 mg, 0.332 mmol) in toluene (8 mL), and the mixture was reacted at 110 °C for 16 h. After the reaction was complete, the mixture was quenched with water, and the organic phase was extracted with ethyl acetate (100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel plate (ethyl acetate / petroleum ether (v / v) = 1 / 3) to give a white solid 2-(4,4-difluoroazine). -1-yl)-N-(2-methoxypyridin-4-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide (120 mg, yield 89%). 1 H NMR (400MHz, DMSO-d6) δ10.61 (s, 1H), 8.04 (d, J = 5.6Hz, 1H), 7.43 (s, 1H), 7.20 (br s,1H),7.18(s,1H),3.82(s,3H),3.55(d,J=5.0Hz,2H),3.35(d,J=6.0Hz,2H) ,2.68(t,J=6.1Hz,2H),2.63(t,J=6.0Hz,2H),2.30(d,J=11.7Hz,2H),1.99(br s, 2H), 1.80 (br s, 4H), 1.72 (d, J = 5.2Hz, 2H). ESI-MS(m / z):417.1[M+H] + .

[0466] Step g): 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide

[0467]

[0468] To 2-(4,4-difluoroaza) A solution of 150 mg (0.362 mmol) of tetrahydroquinoline-3-carboxamide (150 mg, 0.362 mmol) in tetrahydrofuran (10 mL) was added to sodium iodide (135 mg, 0.905 mmol) and trimethylchlorosilane (98 mg, 0.905 mmol), and the mixture was reacted at 50 °C for 5 h. After the reaction was complete, the mixture was quenched with water, 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 crude product was subjected to a C18 reverse-phase column chromatography to prepare a white solid 2-(4,4-difluoroazine). -1-yl)-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide (66.87 mg, yield %). 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),10.37(s,1H),7.40(s,1H),7.29(d,J=7.2Hz,1H),6.79(s,1H),6.51-6.35(m,1H),3.55(br s,2H),3.34(br s,2H),2.68(t,J=6.1Hz,2H),2.63(t,J=6.0Hz,2H),2.31(d,J=12.5Hz,2H ), 2.01-1.91 (m, 2H), 1.81 (dd, J = 10.2, 5.3Hz, 4H), 1.72 (d, J = 5.0Hz, 2H). ESI-MS(m / z):403.1[M+H] + .

[0469] Example 31

[0470] 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(2-aminosulfonylpyridin-4-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide (KH31)

[0471]

[0472] Step a): N-(2-(N,N-bis(2,4-dimethoxybenzyl)aminosulfonyl)pyridin-4-yl)-2-(4,4-difluoroaza) Preparation of 1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide

[0473]

[0474] The preparation of 3-bromo-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide is the same as step i in Example 29, and 2-(4,4-difluoroaza) The preparation process of (-1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide is the same as step ae in Example 30.

[0475] 3-Bromo-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide (127 mg, 0.2 mmol) and 2-(4,4-difluoroazine) -1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide (87.7 mg, 0.2 mmol) was dissolved in toluene (2 mL), and cesium carbonate (230.9 mg, 0.7 mmol) and Ruphos Pd G2 (18.3 mg, 0.02 mmol) were added. The mixture was reacted at 110 °C for 16 h under nitrogen protection. After the reaction was complete, the reaction solution was concentrated, quenched with 10 mL of saturated NH4Cl aqueous solution, and extracted with dichloromethane (10 mL × 3). The organic phase was separated, 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 reverse preparative chromatography to obtain a white solid N-(2-(N,N-bis(2,4-dimethoxybenzyl)aminosulfonyl)pyridin-4-yl)-2-(4,4-difluoroazines). -1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide (52 mg, yield 28.7%). ESI-MS (m / z): 766.2 [M+H] + .

[0476] Step b): 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(2-aminosulfonylpyridin-4-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide

[0477]

[0478] N-(2-(N,N-bis(2,4-dimethoxybenzyl)aminosulfonyl)pyridin-4-yl)-2-(4,4-difluoroaza) 1-(4,4-difluoroazine)-5,6,7,8-tetrahydroquinoline-3-carboxamide (50 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (74.4 mg, 0.6 mmol) was added. The reaction was carried out at room temperature for 2 h. After the reaction was complete, the reaction system was concentrated. The reaction was quenched by adding 10 mL of saturated NaHCO3 aqueous solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The crude product obtained by concentration under reduced pressure was purified by reverse preparative chromatography to give a white solid 2-(4,4-difluoroazine) -1-yl)-N-(2-aminosulfonylpyridin-4-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide (13.49 mg, yield 43.6%).1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.58(d,J=5.4Hz,1H),8.31(d,J=1.7Hz,1H),7.82(dd,J=5.5,2.0Hz,1H),7.49(s,1H),7.43(s,2H),3.57(br s,2H),3.34(br s,1H),3.30(br s,1H),2.70(t,J=6.2Hz,2H),2.64(t,J=5.8Hz,2H),2.32(d,J=8.9Hz,2H),1.93(br s, 2H), 1.85-1.77 (m, 4H), 1.73 (d, J = 4.5Hz, 2H). ESI-MS (m / z): 466.0 [M+H] + .

[0479] Example 32

[0480] N-(2-Carbamoylpyridin-4-yl)-2-(4,4-Difluoroaza) Preparation of -1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide (KH32)

[0481]

[0482] Step a): N-(2-cyanopyridin-4-yl)-2-(4,4-difluoroaza) Preparation of 1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide

[0483]

[0484] 2-(4,4-difluoroaza) The preparation process of (-1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide is the same as step ae in Example 30.

[0485] To 2-(4,4-difluoroaza) A solution of N-(2-cyanopyridin-4-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide (200 mg, 0.645 mmol) in toluene (15 mL) was added to 4-bromopyridin-2-carboxynitrile (140 mg, 0.774 mmol), Ruphos-Pd-G2 (50 mg, 0.0645 mmol), and cesium carbonate (420 mg, 1.29 mmol). The reaction was carried out at 110 °C for 16 h. After the reaction was complete, the mixture was quenched with water, and the organic phase was extracted with ethyl acetate (30 mL), 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 preparative plate (ethyl acetate / petroleum ether (v / v) = 1 / 3) to give a white solid N-(2-cyanopyridin-4-yl)-2-(4,4-difluoroazine) -1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide (170 mg, yield 64%). 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),8.62(d,J=5.6Hz,1H),8.20(d,J=1.8 Hz,1H),7.90(dd,J=5.6,2.1Hz,1H),7.49(s,1H),3.59-3.53(m,2H),2.70( t,J=6.2Hz,2H),2.64(t,J=6.0Hz,2H),2.32(d,J=5.7Hz,2H),1.97(d,J=13 .4Hz, 2H), 1.91 (d, J = 14.1Hz, 2H), 1.84-1.76 (m, 4H), 1.73 (d, J = 4.3Hz, 2H). ESI-MS(m / z):412.1[M+H] + .

[0486] Step b): N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroaza) Preparation of 1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide

[0487]

[0488] To N-(2-cyanopyridin-4-yl)-2-(4,4-difluoroaza) Cesium carbonate (356 g, 1.09 mmol) was added to a DMSO (5 mL) solution of N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazine)-5,6,7,8-tetrahydroquinoline-3-carboxamide (150 mg, 0.364 mmol), and 30% hydrogen peroxide (2.5 mL) was slowly added dropwise at 0 °C. After the reaction was complete, the reaction was quenched with ice water, and then extracted with ethyl acetate. The resulting 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 formic acid preparation using a C18 reverse-phase column to obtain a white solid N-(2-carbamoylpyridin-4-yl)-2-(4,4-difluoroazine)-3 ... -1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide (82.2 mg, yield 52.7%). 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.50(d,J=5.4Hz,1H),8.34(s,1H),8.07(s,1H),7.86(d,J=5.3Hz,1H),7.61(s,1H),7.48(s,1H),3.58(br s,2H),3.37-3.33(m,2H),2.69(t,J=6.2Hz,2H),2.65(d,J=6.1Hz,2H),2.30(brs,2H),1.93(br s,2H),1.81(br s,4H),1.73(d,J=5.4Hz,2H). ESI-MS(m / z):430.1[M+H] + .

[0489] Example 33

[0490] 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(6-carbonyl-1,6-dihydropyridazine-4-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide (KH33)

[0491]

[0492] Step a): 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(6-methoxypyridazine-4-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide

[0493]

[0494] 2-(4,4-difluoroaza) The preparation process of (-1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide is the same as step ae in Example 30.

[0495] 5-bromo-3-methoxypyridazine (70 mg, 0.3 mmol) and 2-(4,4-difluoroazine) (-1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide (137.4 mg, 0.4 mmol) was dissolved in toluene (3 mL), and cesium carbonate (362 mg, 1.1 mmol) and Ruphos Pd G2 (28.7 mg, 0.03 mmol) were added. The mixture was reacted at 110 °C for 16 h under nitrogen protection. After the reaction was complete, the reaction solution was concentrated, and the reaction was quenched with 10 mL of saturated NH4Cl aqueous solution. The mixture was extracted with dichloromethane (15 mL × 3), and the organic phase was separated and washed with saturated brine. The solution was dried over anhydrous sodium sulfate and filtered. The crude product obtained after concentration under reduced pressure was purified by reverse preparative chromatography to give a white solid 2-(4,4-difluoroazines). -1-yl)-N-(6-methoxypyridazine-4-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide (45 mg, yield 28.5%). ESI-MS (m / z): 418.1 [M+H] + .

[0496] Step b): 2-(4,4-difluoroaza) Preparation of -1-yl)-N-(6-carbonyl-1,6-dihydropyridazine-4-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide

[0497]

[0498] 2-(4,4-difluoroaza) -1-yl)-N-(6-methoxypyridazine-4-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide (45 mg, 0.1 mmol) was dissolved in tetrahydrofuran (1 mL), and sodium iodide (40.3 mg, 0.2 mmol) and trimethylchlorosilane (29.2 mg, 0.2 mmol) were added. The mixture was reacted at 50 °C for 4 h. The reaction solution was concentrated and quenched with 10 mL of water. The solution was extracted with dichloromethane (15 mL × 3), and the organic phase was separated and washed with saturated brine. The solution was dried over anhydrous sodium sulfate and filtered. The crude product obtained by concentration under reduced pressure was purified by reverse preparative chromatography to give a white solid 2-(4,4-difluoroazine) -1-yl)-N-(6-carbonyl-1,6-dihydropyridazine-4-yl)-5,6,7,8-tetrahydroquinoline-3-carboxamide (24.68 mg, yield 56.7%). 1H NMR (400MHz, DMSO-d6) δ12.75(s,1H),10.71(s,1H),7.95(d,J=2.2Hz,1H),7.48(s,1H),7.24(s,1H),3.55(br s,2H),3.33(br s,1H),3.30-3.28(m,1H),2.69(t,J=6.3Hz,2H),2.64(t,J=6.0Hz,2H),2.31(d,J=10.8Hz,2H),1.94(br s, 2H), 1.80 (d, J = 6.0Hz, 4H), 1.73 (d, J = 5.0Hz, 2H). ESI-MS(m / z):404.1[M+H] + .

[0499] Example 34 (VX150 technical grade)

[0500] Preparation of 2-(4-fluoro-2-methylphenol)-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide

[0501]

[0502] Step a): Preparation of 2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide

[0503]

[0504] Under nitrogen protection, 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). The mixture was stirred at room temperature for 16 h. After the reaction was complete, 50 mL of pure water was added and stirred until homogeneous. The mixture was separated, and the lower organic phase was retained. The upper aqueous phase was extracted with dichloromethane (30 mL × 3), and all organic phases were combined and washed with saturated NaCl solution (30 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA(v / v) = 8 / 1-3 / 1) to give a white solid 2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide (1.179 g, yield 78.1%).

[0505] Step b): Preparation of 2-fluoro-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide

[0506]

[0507] Under nitrogen protection, 10 mL of hydrobromic acid / glacial acetic acid solution (33%) was added to 0.5 g (1.6 mmol) of 2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide and reacted at 100 °C for 5 h, followed by 12 h at room temperature. 40 mL of pure water was added and the mixture was stirred for 30 min. The mixture was filtered, and the filter cake was washed with pure water (10 mL × 2). The cake was then dried under reduced pressure at 50 °C to obtain a gray solid 2-fluoro-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (0.215 g, yield 45%).

[0508] Step c): Preparation of 2-(4-fluoro-2-methylphenol)-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide

[0509]

[0510] Under nitrogen protection, DMF (6 mL) was added to 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). The mixture was reacted at 80 °C for 2 h. After the reaction was complete, the system was cooled to room temperature, 50 mL of pure water was added, and the mixture was stirred for 30 min. The mixture was then filtered, and the filter cake was washed successively with pure water (20 mL × 2) and petroleum ether (20 mL × 2) and 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. Petroleum ether (about 15 mL) was slowly added dropwise, and a large amount of precipitate was precipitated. Stirring was continued for 2 h. The mixture was filtered, and the filter cake was washed with petroleum ether (10 mL × 2) and dried under reduced pressure to obtain a white solid 2-(4-fluoro-2-methylphenol)-N-(2-carbonyl-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (0.212 g, yield 75.6%). 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,1H ),7.27-7.20(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] + .

[0511] Example 35 (Compound 120 in WO2020014246)

[0512] Preparation of 2-(4-fluoro-2-methoxyphenol)-N-(3-methanesulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide

[0513]

[0514] Step a): Preparation of (4-fluoro-2-methoxyphenol)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylmethyl ester

[0515]

[0516] To a DMF (8 mL) solution of 2-chloro-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxyl methyl ester (300 mg, 1.42 mmol), K₂CO₃ (392 mg, 2.84 mmol) and 4-fluoro-2-methoxyphenol (403 mg, 2.84 mmol) were added, and the mixture was reacted at 100 °C for 16 h. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude product. The crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 50 / 1) to give a white solid (4-fluoro-2-methoxyphenolyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxyl methyl ester (65 mg, yield 14%). ESI-MS (m / z): 318.2 [M+H] + .

[0517] Step b): Preparation of (4-fluoro-2-methoxyphenol)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylic acid

[0518]

[0519] A solution of (4-fluoro-2-methoxyphenol)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxymethyl ester (65 mg, 0.205 mmol) in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) was added to a solution of potassium hydroxide (57.4 mg, 1.025 mmol) and water (0.5 mL), and the mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was back-extracted with ethyl acetate. The resulting aqueous phase was adjusted to pH 6 with 1.0 M hydrochloric acid, and the organic phase was then extracted with ethyl acetate. The mixture was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a white solid (4-fluoro-2-methoxyphenol)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylic acid (55 mg, yield 88%). 1H NMR(400MHz,DMSO-d6)δ12.81(s,1H),8.03(s,1H),7.11-7.01(m,2H),6.82-6.74(m ,1H),3.69(s,3H),2.85(t,J=7.4Hz,2H),2.70(t,J=7.7Hz,2H),2.08-2.00(m,2H). ESI-MS(m / z):304.0[M+H] + .

[0520] Step c): Preparation of 2-(4-fluoro-2-methoxyphenol)-N-(3-methanesulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide

[0521]

[0522] Under nitrogen protection, HATU (127.68 mg, 0.336 mmol) and DIEA (144.48 mg, 1.120 mmol) were added to a DMF (1.5 mL) solution of (4-fluoro-2-methoxyphenol)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxylic acid (85 mg, 0.280 mmol). After stirring at room temperature for 1 h, 3-(methanesulfonyl)aniline (95.76 mg, 0.560 mmol) was added, and the reaction mixture was then heated to 60 °C and reacted for 4 h. After the reaction was complete, the reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated NaCl (60 mL × 3), dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. The crude product was purified by reversed-phase preparative chromatography to give a white solid 2-(4-fluoro-2-methoxyphenol)-N-(3-methanesulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide (51 mg, yield 40%). 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.41(s,1H),7.95(d,J=7.5Hz,2H),7.69-7.59(m,2H),7.29(d,J=8.6,6.0Hz,1H),7.07(d,J=10 .7,2.9Hz,1H),6.82(t,J=8.5,2.9Hz,1H),3.71(s,3H),3.21(s,3H),2.89(t,J=7.3Hz,2H),2.75(t,J=7.7Hz,2H),2.10–2.01(m,2H). ESI-MS(m / z):457.1[M+H] + .

[0523] Example 36 Electrophysiological Measurement

[0524] Patch-clamp technique is considered the "gold standard" for studying ion channels. It uses glass microelectrodes sealed to the cell membrane to measure the currents of various membrane channels. Navs are a class of transmembrane proteins that exist in three different states: resting, activated, and inactive. Patch-clamp technique assesses the inhibitory effect of different compounds on different Navs states by measuring the changes in membrane channel currents after different compounds bind to them in these states.

[0525] The representative compounds of this invention were transfected into stable CHO cell lines with specific ion channels, and their effects on Nav1.8 current were determined by manual patch-clamp assays to assess their inhibitory strength.

[0526] The manual patch-clamp experimental protocol is as follows:

[0527] 1) Cell Culture

[0528] CHO cell lines stably expressing hNav1.8 were cultured in F12 medium containing 10% fetal bovine serum at a constant temperature of 37°C, with the carbon dioxide concentration maintained at 5%. The old medium was removed, and the cells were washed once with PBS. Then, 1 mL of 0.25% Trypsin-EDTA solution was added, and the cells were incubated at 37°C for 1 min. After the cells detached from the bottom of the dish, 5 mL of preheated (37°C) complete medium was added, and the aggregated cells were gently separated by pipetting. The cell suspension was transferred to sterile centrifuge tubes, centrifuged at 1000 rpm for 5 min to collect the cells, and then seeded into 6 cm diameter cell culture dishes (2.5 × 10⁶ cells / mL). 5 Cells / culture dish, 5mL culture medium), for amplification or maintenance culture.

[0529] To maintain the electrophysiological activity of cells, the cell density must be below 80%.

[0530] Before the experiment, cells were separated using 0.25% Trypsin-EDTA, and 5 × 10⁶ cells were used. 3 Cells were seeded onto coverslips and cultured in 24-well plates (final volume: 500 μL). After 18 hours, experimental results were obtained.

[0531] 2) Preparation of compound samples

[0532] The compounds prepared in the embodiments of the present invention were dissolved in dimethyl sulfoxide (DMSO) to prepare 10 mM DMSO stock solutions for experiments. The 10 mM DMSO stock solutions were diluted with extracellular fluid (140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2, 2 mM CaCl2, 10 mM Glucose, 10 mM HEPES, 1.25 mM NaH2PO4, pH adjusted to 7.4 with NaOH) to various concentrations, ensuring that the final concentration of DMSO in each compound was 0.1% or less.

[0533] 3) Patch-clamp measurement of sodium ion channel blocking effect

[0534] The capillary glass tube (BF150-86-10, Sutter Instruments) was drawn into a recording electrode using a microelectrode drawing instrument (P97, Sutter Instruments). Under an inverted microscope (IX71, Olympus), the microelectrode manipulator (MP285, Sutter Instruments) was manipulated to bring the recording electrode into contact with the cell, and negative pressure was applied to aspirate and form a GΩ seal. Rapid capacitance compensation was then performed, and negative pressure was continued to rupture the cell membrane, establishing a whole-cell recording mode. Slow capacitance compensation was then performed, and membrane capacitance and series resistance were recorded without leakage compensation. Once the current recorded in the whole cell stabilized, drug administration began. Each drug concentration was treated for 5 minutes before moving to the next concentration, and multiple cells were independently tested during recording. All electrophysiological experiments were performed at room temperature. Specifically, six concentrations were set for each compound (IC50-86-10 concentrations were measured). 50 Two concentrations (either for initial screening) were used. The percentage of sodium channel inhibition by the compound was determined by calculating the relative percentage of peak current generated before and after cell treatment at each concentration. The IC50 value was then calculated using IGOR Pro software. 50 Value or percentage of inhibition at a specific concentration.

[0535] The voltage stimulation protocol for whole-cell patch-clamp recording of hNav1.8 sodium channel currents was as follows: The membrane potential was clamped at -120 mV, the command voltage was started at -130 mV, maintained in 10 mV increments for 8 seconds, depolarized to 0 mV (or 0 pA current), maintained for 30 ms, and the half-inactivation voltage was measured. After whole-cell sealing, the cell membrane voltage was clamped at -120 mV, the clamping voltage was depolarized to 0 mV and maintained for 50 ms, then the voltage was restored to the measured half-inactivation voltage and maintained for 8 seconds. Next, the cell membrane potential was restored to -120 mV and maintained for 20 ms, then depolarized to 0 mV and maintained for 50 ms, and finally restored to the clamping voltage of -120 mV and maintained for 30 ms. Data were collected repeatedly every 20 seconds to observe the effect of the drug on the peak current of the hNav1.8 sodium channel.

[0536] The calculated inhibitory activity of some of the compounds in the examples against hNav1.8 is shown in Tables 2-3 below.

[0537] Table 2

[0538]

[0539]

[0540] Table 3

[0541] serial number 10nM inhibition percentage KH3 62.11％ KH4 49.13％ KH11 98.87％ KH12 89.56％ KH13 76.77％ KH15 10.77％ KH16 95.94％ KH22 85.74％ KH23 48.87％ KH24 70.58％ KH25 70.71％ KH26 96.76％ KH27 7.38％ KH28 33.61％ KH29 41.48％ Example 34 38.12％

[0542] Example 36 Determination of kinetic solubility

[0543] 1. Preparation of buffer solution

[0544] Preparation of 50 mM phosphate buffer (PB) at pH 7.4 and pH 3.5:

[0545] a. Preparation of 50mM NaH2PO4 solution: Dissolve 3.000g NaH2PO4 in 500mL of water, and the pH of the resulting solution is measured to be 4.5;

[0546] b. Preparation of 50mM Na2HPO4 solution: 3.549g Na2HPO4 was dissolved in 500mL of water, and the pH of the resulting solution was measured to be 9.4;

[0547] c. Preparation of 50mM H3PO4 solution: 14.7M H3PO4 was diluted with water to 50mM, and the pH of the resulting solution was measured to be 1.8;

[0548] d. Preparation of 50mM PB (pH 7.4): Take 15mL of 50mM Na2HPO4 solution into a 50mL test tube, and adjust the pH to 7.4 with 50mM NaH2PO4 solution;

[0549] e. Preparation of 50mM PB (pH 3.5): Take 15mL of 50mM NaH2PO4 solution into a 50mL test tube, and adjust the pH to 3.5 with 50mM H3PO4 solution.

[0550] 2. Experimental Procedure

[0551] a. Prepare 10 mM DMSO stock solutions of the test sample and positive control (compound of Example 34) separately, and take 10 μL of each into the lower compartment of a Whatman Mini-UniPrep (GE Halthcare Whatman) bottle;

[0552] b. Add 490 μL of 50 mM PB (pH 7.4 or 3.5) to both the test sample and the positive control;

[0553] c. Vortex the above solution sample for at least 2 minutes;

[0554] d. Then place it on a shaker and shake it at room temperature for 24 hours at a speed of 800 rpm;

[0555] e. Centrifuge for 20 minutes (4000 rpm);

[0556] f. Compress the Mini-UniPrep bottle, filter it through a filter membrane, inject the filtrate into the HPLC system for detection, and calculate the solution concentration using a standard curve.

[0557] 3. Results

[0558] Table 4. Results of water solubility test

[0559] compound pH 3.5 (μM) pH 7.4 (μM) KH5 94.7 59.9 KH7 151 <1.56 KH30 160 <1.56 KH31 132 7.86 KH32 10.5 <1.56 KH33 152 104 Example 34 <1.56 <1.56

[0560] Example 37 Pharmacokinetic Evaluation

[0561] 1. Experimental Objective

[0562] This experiment used male SD rats as test animals and employed high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS) to determine the concentration of the compound in plasma, and studied the pharmacokinetic characteristics of the compound described in this invention in rats.

[0563] 2. Test Plan

[0564] 2.1 Experimental Animals

[0565] Six healthy male SD rats, aged 7-10 weeks and weighing 260-310g, were randomly divided into two groups of three rats each and purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0566] 2.2 Drug Preparation

[0567]

[0568] Note: The prodrug in Example 34 was prepared according to the method described in document CN108395452A.

[0569] 2.3 Administration

[0570] All rats were fasted for at least 12 hours before administration, and were given food 4 hours after administration. They had free access to water throughout the experiment. The intravenous injection dose of compound KH33 was 1 mg / kg, and the gavage dose was 10 mg / kg. The prodrug (VX150) in Example 34 was administered at an intravenous injection dose of 2 mg / kg and a gavage dose of 10 mg / kg.

[0571] 3. Operation process

[0572] Rats were administered the drug by gavage. Whole blood samples (approximately 0.2 mL) were collected via jugular vein puncture at specified times (or other suitable sampling sites) before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24.0 hours after administration. The actual blood collection time was recorded in the experimental log. The acceptable error for collection time points was ±1 minute for time points within 1 hour of administration and ±5% for theoretical time points at other time points. All blood samples were immediately transferred to labeled commercially available centrifuge tubes containing K2-EDTA. After blood sample collection, the sample was centrifuged at 3200g for 10 min at 4°C, and the supernatant plasma was quickly placed on dry ice and kept at -70±10°C for LC-MS / MS analysis. In Example 34, the prodrug (VX150) was used for administration, and the original drug (Example 34) was tested during analysis. For tail vein administration, whole blood samples (approximately 0.2 mL) were collected at specified times (or other suitable blood collection sites) via jugular vein puncture before administration and 5 min after administration, and at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24.0 hours after administration. The remaining procedures were the same as for gavage administration.

[0573] 4. Pharmacokinetic parameters of gavage administration

[0574] Table 5. Results of pharmacokinetic parameters after gavage administration.

[0575]

[0576] Note: F% represents absolute bioavailability.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: In the formula, X is selected from carbon and nitrogen; wherein Ring A is selected from: Ring B is a phenyl ring or a six-membered aromatic heterocycle containing 0-3 N atoms, wherein said phenyl ring or aromatic heterocycle is optionally substituted with hydrogen, -CN, OH, C1-C6alkoxy, -SO2R2, -S(O)(NH)R2, -COR2; wherein R2is independently selected from NH2, C1-C6alkyl; and 1-3 alkyl; The ring C is a 3-10 member saturated aliphatic ring or saturated aliphatic heterocycle containing 0-3 N atoms, either unsubstituted or halogenated.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is wherein R1is hydrogen, -CN, OH, C1-C6alkoxy, -SO2R2, -S(O)(NH)R2, -COR2; wherein R2, is independently selected from NH2, C 1-3 alkyl.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from:

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring C is: wherein Y is selected from carbon, nitrogen; The ring C is replaced by m R4 atoms, where R4 is a halogen; m is an integer from 0 to 2(n+3), and n is an integer from 0 to 6.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein Ring C is:

6. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein n is an integer between 1 and 4.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein n is 3; R4 is a halogen.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein The compound is selected from:

9. A pharmaceutical composition, characterized by It comprises the compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. Use of the compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pain.

11. Use according to claim 10, characterized in that, The pain referred to includes chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain, visceral pain, multiple sclerosis, Sharma-Tutankhamun syndrome, incontinence, and arrhythmia.

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