N-substituted phenylsulfonamide compounds and their applications

Abstract

The present invention relates to an N-substituted phenylsulfonamide compound and its use. Specifically, the present invention provides a compound of formula I, or its optical isomer, or its racemate, or its pharma- ceutically acceptable salt. The compound described in the present invention has excellent inhibitory effect on transient receptor potential channel protein, and has excellent therapeutic effect on diseases related to transient receptor potential channel protein, such as inflammatory bowel disease, irritable bowel syndrome, pain and inflammation.

Description

[Technical Field]

[0001] This invention relates to the fields of medical chemistry and pharmacotherapy, and more specifically to N-substituted phenylsulfonamide compounds and their uses. [Background technology]

[0002] Transient receptor potential channel protein A1 (transient receptor potential ankyrin 1, TRPA1), also known as ANKTM1, is a member of the transient receptor potential (TRP) channel family. TRPA1 is mainly distributed in primary sensory neurons of the dorsal root nerve (DRG), trigeminal nerve (TG), and vagus nerve (VG), and is abundant in peptidolytic neurons (rich in neuropeptides CGRP and SP, as well as neurotrophic factor receptor TrkA) and non-peptidolytic neurons (purine receptors P2X3, Neuroturin, Artemin, G protein-coupled receptors of the Mrg family, and GFR of the GDNF receptor family). α1 and GFR α2 TRPA1 is expressed in both (and co-expresses). In distributed human systems, TRPA1 is highly expressed in the gastrointestinal, peripheral nervous, respiratory, and urinary systems, and when functional abnormalities appear in these organs and tissues, the expression and function of the TRPA1 channel are usually also abnormal at the same time.

[0003] Inflammatory bowel disease (IBD) is a chronic inflammatory disease that causes erosion or ulceration of the intestinal mucosa. The main types are classified into two categories: ulcerative colitis (UC) and Crohn's disease (CD). The former is primarily limited to the colon, while the latter can affect any part of the digestive tract, with the most common symptoms being diarrhea and abdominal pain. Currently, the pathogenesis of IBD is not fully understood, and commonly used treatments include four types: 5-aminosalicylic acid, glucocorticoids, antibiotics, and immunosuppressants. These drugs have drawbacks such as resistance, limited scope of application, and low therapeutic efficacy. Research has shown that TRPA1 plays a crucial role in regulating the gastrointestinal tract. TRPA1 immune responses are detected in inhibitory motor neurons, descending interneurons, cholinergic neurons, and proprioceptive neurons in the mouse cecum and colon. There is growing evidence that TRPA1 is expressed in endogenous sensory neurons of the enteric and submucosal plexuses, as well as in surface epithelial cells of the colonic mucosa. Studies of biopsy material from active and inactive CD and UC patients have found TRPA1 mRNA to be significantly upregulated. Furthermore, other studies, including surgery and endoscopy, have reported increased TRPA1 expression in colonic stricture areas in CD patients. In in vivo models of colitis induced by DNBS, TNBS, or DSS, administering the selective TRPA1 inhibitor HC-030031 or knocking out the TRPA1 gene significantly reduces the symptoms of colitis in animals. Therefore, TRPA1 inhibitors can be used to treat IBD.

[0004] Animal model studies of diseases such as irritable bowel syndrome (IBS), pancreatitis, and gastric mucosal injury have shown that TRPA1 expression is significantly upregulated. In rodent models, both TRPA1 and TRPV1 promote stress-induced visceral hyperalgesia, also known as irritable bowel syndrome. In acute pancreatitis models, TRPA1 and TRPV1 have a synergistic effect, jointly regulating the transition from acute inflammation and hyperalgesia phenotype to chronic inflammation and hyperalgesia phenotype. In rat models of acute gastric mucosal injury, the TRPA1 antagonist HC-030031 also showed positive results.

[0005] Visceral pain, the primary visceral sensation, is often caused by visceral stimulation due to mechanical stretching, spasms, ischemia, or inflammation. Through various animal models of visceral hypersensitivity, such as colitis, rectal and colonic dilation, or stress, TRPA1 has been confirmed to be involved in controlling visceral hypersensitivity. Neuropathic pain is a pain syndrome caused by damage or disease of the central or peripheral nervous system, and manifests primarily as hyperalgesia, abnormal pain sensitivity, and spontaneous pain. Unlike inflammatory pain, neuropathic pain has no relation to vascular responses in the central nervous system, but relies on damage and dysfunction of the nervous system, often caused by peripheral nerve damage. In recent years, an increasing number of studies have shown that TRPA1 channels play an important role in various neuropathic pains, including diabetic neuropathy and neuropathy caused by chemotherapy drugs. Recent studies have shown that TRPA1 also plays a mediating role in pain such as toothaches and migraines, and that administering TRPA1 antagonists can significantly alleviate pain symptoms.

[0006] Inflammation is a defense mechanism of vascular tissues against damaging factors, where stimulation of inflammatory mediators such as prostaglandins, 5-hydroxytryptamine, and bradykinin is the primary cause of localized pain induced by inflammation. Inflammatory pain is a common problem in certain chronic diseases, yet effective clinical treatments remain lacking. Animal studies have shown that TRPA1 is involved in inflammatory responses and plays a crucial role in inflammatory pain, and that the use of TRPA1-specific inhibitors can significantly reduce inflammatory pain responses in laboratory rats. The pathogenesis of asthma and cough is becoming increasingly clearer with further research. Current research suggests that TRPA1 plays a significant role in the development of asthma and cough. Compounds that induce asthma and cough, whether endogenous or exogenous, may activate TRPA1. TRPA1 antagonists can alleviate asthma symptoms and block airway hyperresponsiveness.

[0007] TRPA1 is widely distributed and expressed in the human body, so the importance of its function is self-evident. In addition to the physiological functions in which TRPA1 is involved as described above, the indications for which TRPA1 inhibitors have been reported to date include chronic obstructive pulmonary disease, cough suppression, antipruritic effects, allergic rhinitis, ear disorders, antidiabetic effects, and urinary incontinence. TRPA1 has been proven to be a novel target point in the treatment of inflammatory bowel disease, irritable bowel syndrome, pain, and inflammation, but currently there are no commercially available drugs that target this point.

[0008] Inflammatory bowel disease, irritable bowel syndrome, and pain are all considered intractable diseases. Therefore, in this field, there is an urgent need to develop therapeutic drugs that target the TRPA1 target point to improve therapeutic efficacy. [Overview of the project] [Problems that the invention aims to solve]

[0009] The object of the present invention is to provide a novel compound structure targeting TRPA1 and its applications. [Means for solving the problem]

[0010] A first aspect of the present invention provides a compound of formula I, or an optical isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. [ka] In the formula, Ar is a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 3-12 membered heteroaryl group, a 3-12 membered heterocycloalkane ring fused C6-C12 aryl group, a substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C8 alkyl-, or a substituted or unsubstituted 3-12 membered heteroaryl-substituted or unsubstituted C1-C8 alkyl-. X 1 , X 2 , X 3 and X 4 These are, independently, C, O, S, or N. Labeled a, b, c, d, and e [ka] It is either a single bond or a double bond. R 1 is hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C7 cycloalkyl group, or a halogen. R 2 is hydrogen, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C3-C10 cycloalkyl group. A is [ka] A substituted or unsubstituted C2-C6 ester group, a substituted or unsubstituted C2-C6 carboxyl group, a substituted or unsubstituted C2-C6 amide group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 2HN-HN-C(O)- m is 0, 1, 2 or 3, Y 1 is N, Y 2 is O or S, Y 3 is NH, O or S, Y 4 is O or S, Y 5 is N, R 3 and R 4 are each independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C3 alkyl-, a substituted or unsubstituted C2-C6 acyl group, or R 3 and R 4 are joined together with the adjacent Y 1 to form a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, R 5 is hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a hydroxy group, a mercapto group or a substituted or unsubstituted C1-C6 alkoxy group, n is 0, 1, 2, 3, 4 or 5, wherein any said "substituted" means that one or more (preferably 1, 2, 3, 4, 5 or 6) hydrogen atoms on the ring or group are substituted by a substituent selected from the group consisting of a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C1-C8 haloalkyl group, a C3-C8 halocycloalkyl group, halogen, a nitro group, -CN, a hydroxy group, a mercapto group, an amino group, a C1-C4 carboxy group, a C2-C4 ester group, a C2-C4 amide group, a C1-C8 alkoxy group, a C1-C8 alkylthio group, a C1-C8 haloalkoxy group, a C1-C8 haloalkylthio group, a C6-C12 aryl group, a 5- to 10-membered heteroaryl group, a 5- to 10-membered heterocycloalkyl group, The heterocyclic group, heterocycloalkane ring, and heterocycloalkyl group each independently have 1 to 4 heteroatoms (preferably 1, 2, 3, or 4) selected from N, O, and S.

[0011] In another preferred example, Ar is a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 3- to 10-membered heteroaryl group, a 3- to 10-membered heterocycloalkane ring-fused C6-C10 aryl group, a substituted or unsubstituted C6-C10 aryl-substituted or unsubstituted C1-C6 alkyl-, or a substituted or unsubstituted 3- to 10-membered heteroaryl-substituted or unsubstituted C1-C6 alkyl-.

[0012] In another preferred example, Ar is a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 3- to 8-membered heteroaryl group, a 3- to 8-membered heterocycloalkane C6-C10 aryl group, a substituted or unsubstituted C6-C10 aryl-substituted or unsubstituted C1-C4 alkyl-, or a substituted or unsubstituted 3- to 8-membered heteroaryl-substituted or unsubstituted C1-C4 alkyl-.

[0013] In another preferred example, Ar is a substituted or unsubstituted C6-C8 aryl group, a substituted or unsubstituted 5- to 8-membered heteroaryl group, a 5- to 8-membered heterocycloalkane C6-C8 aryl group, a substituted or unsubstituted C6-C8 aryl-substituted or unsubstituted C1-C3 alkyl-, or a substituted or unsubstituted 5- to 8-membered heteroaryl-substituted or unsubstituted C1-C3 alkyl-.

[0014] In another preferred example, Ar is a substituted or unsubstituted C6-C10 aryl group, or a substituted or unsubstituted 3- to 8-membered (preferably 5- to 8-membered) heteroaryl group.

[0015] In another preferred example, Ar is a phenyl group, a halophenyl group, a methoxyphenyl group, a trifluoromethoxyphenyl group, a trifluoromethylphenyl group, a methylphenyl group, a naphthyl group, a dihydrofracene, a benzothiazolyl group, a pyridyl group, a halopyridyl group, an imidazolyl group, a methylimidazolyl group, a thienyl group, a halothienyl group, or a benzyl group.

[0016] In another preferred example, Ar is a phenyl group or a thienyl group. In another preferred example, the halophenyl group is a monohalophenyl group or a dihalophenyl group.

[0017] In another preferred example, dihydroflacene is [ka] That is the case. In another preferred example, the substituent on Ar is selected from the group consisting of halogens (preferably fluorine), C1-C4 alkyl groups, C1-C4 haloalkyl groups, C1-C4 alkoxy groups, and C1-C4 haloalkoxy groups.

[0018] In another preferred example, R 1 This is hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C7 cycloalkyl group, or a halogen. In another preferred example, R 1 This is hydrogen, a substituted or unsubstituted C1-C2 alkyl group, a substituted or unsubstituted C3-C7 cycloalkyl group, or a halogen.

[0019] In another preferred example, R 1 This is hydrogen, a substituted or unsubstituted C1-C4 alkyl group, preferably hydrogen. In another preferred example, R 1 These are hydrogen and a methyl group.

[0020] In another preferred example, R 2This is hydrogen, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C3-C7 cycloalkyl group. In another preferred example, R 2 This is hydrogen, a substituted or unsubstituted C1-C4 alkyl group, preferably hydrogen.

[0021] In another preferred example, R 2 It is either hydrogen or a methyl group. In another preferred example, A is [ka] It is a substituted or unsubstituted C2-C4 ester group, a substituted or unsubstituted C1-C4 carboxyl group, a substituted or unsubstituted C1-C4 amide group, or a substituted or unsubstituted 2HN-HN-C(O)- group.

[0022] In another preferred example, A is [ka] It is a methyl ester group, an ethyl ester group, a formic acid group, an acetamide group, a formamide group, or a 2HN-HN-C(O)- group.

[0023] In another preferred example, A is [ka] That is the case. In another preferred example, A is [ka] That is the case.

[0024] In another preferred example, Y 3 It is N. In another preferred example, m is 0, 1, or 2.

[0025] In another preferred example, R 3 and R 4Each of these is independently a hydrogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C2-C4 acyl group, or R 3 , R 4 is adjacent to Y 1 It combines with other molecules to form substituted or unsubstituted 3- to 6-membered heterocycloalkyl groups.

[0026] In another preferred example, R 3 and R 4 Each of these independently consists of hydrogen, a substituted or unsubstituted C1-C2 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C2-C4 acyl group, or R 3 , R 4 is adjacent to Y 1 It combines with other molecules to form substituted or unsubstituted 3- to 6-membered heterocycloalkyl groups.

[0027] In another preferred example, R 3 and R 4 Each of these is independently a hydrogen atom, a methyl group, a trifluoromethyl-methyl- group, an ethyl group, a cyclopropyl group, a cyclobutyl group, or an acetyl group. 3 , R 4 is adjacent to Y 1 It combines with other elements to form substituted or unsubstituted azetidinyl groups.

[0028] In another preferred example, A [ka] If R 3 R is a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, or a substituted or unsubstituted C2-C4 acyl group. 4 is hydrogen, preferably R 3 , R 4 Both are hydrogen.

[0029] In another preferred example, A [ka] If R 3 R is hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C1-C3 alkyl group, and 5 is hydrogen, a substituted or unsubstituted C1-C6 alkyl group.

[0030] In another preferred example, A [ka] If R 3 R is hydrogen, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C3-C6 cycloalkyl group. 5 is hydrogen, a substituted or unsubstituted C1-C6 alkyl group.

[0031] In another preferred example, R 5 This is a hydrogen atom, a hydroxyl group, a mercapto group, or a substituted or unsubstituted C1-C4 alkoxy group. In another preferred example, R 5 These are hydrogen, a hydroxyl group, a mercapto group, or a methoxy group. In another preferred example, R 3 , R 4 is adjacent to Y 1 It combines with it to form a haloazetidinyl group.

[0032] In another preferred example, X 1 , X 2 , X 3 and X 4 These are, independently, C, O, S, or N. In another preferred example, X 1 It is C, O, S, or N. In another preferred example, X 2 It is C, O, S, or N.

[0033] In another preferred example, X 3 It is C, O, S, or N. In another preferred example, X 4 It is C, O, S, or N. In another preferred example, X 1 , X 2 , X 3 and X 4 One or more (two or three) of these are O, S, or N, and the rest are C.

[0034] In another preferred example, labeled a, b, c, d, and e [ka] Each of these is independently either a single bond or a double bond. In another preferred example, labeled a [ka] It is either a single bond or a double bond. In another preferred example, labeled b [ka] It is either a single bond or a double bond.

[0035] In another preferred example, labeled c [ka] It is either a single bond or a double bond. In another preferred example, labeled d [ka] It is either a single bond or a double bond. In another preferred example, labeled e [ka] It is either a single bond or a double bond.

[0036] In another preferred example, X 1 , X 2 , X 3 , X 4 These are labeled a, b, c, d and e [ka] It forms an aromatic ring or a heteroaromatic ring. In another preferred example, each heterocycle of the heteroaromatic ring independently has 1 to 4 heteroatoms (preferably 1, 2, 3, or 4) selected from N, O, and S.

[0037] In another preferred example, X 1 , X 2 , X 3 , X 4 These are labeled a, b, c, d and e [ka] It forms a furan ring, thiophene ring, pyrrole ring, thiazole ring, pyrazole ring, isoxazole ring, oxazole ring, imidazole ring, and triazole ring. In another preferred example, n is 0, 1, 2, 3, or 4.

[0038] In another preferred example, the arbitrary "substitution" means that one or more (preferably 1, 2, 3, 4, 5, or 6) hydrogen atoms on the ring or group are substituted by substituents selected from the group consisting of C1-C6 alkyl groups, C3-C8 cycloalkyl groups, C1-C6 haloalkyl groups, C3-C8 halocycloalkyl groups, halogens, nitro groups, -CN groups, hydroxyl groups, mercapto groups, amino groups, C1-C4 carboxyl groups, C2-C4 ester groups, C2-C4 amide groups, C1-C6 alkoxy groups, C1-C6 alkylthio groups, C1-C6 haloalkoxy groups, C1-C6 haloalkylthio groups, C6-C12 aryl groups, 5-10 membered heteroaryl groups, and 5-10 membered heterocycloalkyl groups.

[0039] In another preferred example, the aforementioned "substitution" means that one or more (preferably 1, 2, 3, 4, 5, or 6) hydrogen atoms on the ring or group are substituted by substituents selected from the group consisting of C1-C4 alkyl groups, C3-C8 cycloalkyl groups, C1-C4 haloalkyl groups, C3-C8 halocycloalkyl groups, halogens, nitro groups, -CN groups, hydroxyl groups, mercapto groups, amino groups, C1-C4 carboxyl groups, C2-C4 ester groups, C2-C4 amide groups, C1-C4 alkoxy groups, C1-C4 alkylthio groups, C1-C4 haloalkoxy groups, C1-C4 haloalkylthio groups, C6-C12 aryl groups, 5-10 membered heteroaryl groups, and 5-10 membered heterocycloalkyl groups.

[0040] In another preferred example, the heteroaryl group, heterocycloalkane ring, and heterocycloalkyl group each independently have 1 to 4 (preferably 1, 2, 3, or 4) heteroatoms selected from N, O, and S.

[0041] In another preferred example, the compound has the structure of formula I-1. [ka]

[0042] In another preferred example, the compound has the structure of formula I-2. [ka]

[0043] In another preferred example, the compound has the structure of formula I-3. [ka]

[0044] In another preferred example, the compound has the structure of formula I-4. [ka]

[0045] In another preferred example, the compound has the structure of formula I-5. [ka]

[0046] In another preferred example, the compound has the structure of formula I-6. [ka]

[0047] In another preferred example, the compound has the structure of formula I-7. [ka]

[0048] In another preferred example, the compound has the structure of formula I-8. [ka]

[0049] In another preferred example, the compound has the structure of formula Z, [ka] Here, R 1 , R 2 , X 1 , X 2 , X 3 , X 4 Ar, a, b, c, d, e, and n are as described above. RA, RB, and RC are each independently hydrogen, substituted, or unsubstituted C1-C6 alkyl groups. In another preferred example, R 1 , R 2 , X 1 , X2 , X 3 , X 4 , Ar, A, a, b, c, d, e, and n are, independently of each other, the corresponding groups in the compounds prepared in the examples.

[0050] In another preferred example, the compound is selected from the group consisting of the following.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0051] The second aspect of the present invention provides a pharmaceutical composition, which comprises the compound of formula I described in the first aspect of the present invention, or its optical isomer, or its racemate, or its pharmaceutically acceptable salt, or its prodrug, and a pharmaceutically acceptable carrier.

[0052] In another preferred example, the dosage form of the pharmaceutical composition is an oral preparation, an injection preparation or a topical preparation. In another preferred example, the dosage form of the pharmaceutical composition is a solid preparation, a liquid preparation or a semi-solid preparation. In another preferred example, the dosage form of the pharmaceutical composition is a tablet, an injection, an infusion, an ointment, a gel, a solution, a microsphere, a film.

[0053] The third aspect of the present invention provides a method for preparing the compound of formula I described in the first aspect of the present invention, or its optical isomer, or its racemate, or its pharmaceutically acceptable salt, or its prodrug, the method comprising

Chemical formula

[0054] In another preferred example, the method

Chemical formula

[0055] In another preferred example, the method

Chemical formula

[0056] In another preferred example, the method

Chemical formula

[0057] In another preferred example, the method

Chemical formula

[0058] In another preferred example, the method

Chemical formula

[0059] In another preferred example, the method

Chemical formula

[0060] A fourth aspect of the present invention provides uses for a compound of formula I as described in the first aspect of the present invention, or an optical isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the second aspect of the present invention, for use in (a) preparing an inhibitor of transient receptor potential channel protein TRPA1, and / or (b) preparing a drug for preventing and / or treating a disease associated with transient receptor potential channel protein TRPA1.

[0061] In another preferred example, the disease associated with the transient receptor potential channel protein TRPA1 is selected from the group consisting of inflammatory bowel disease, irritable bowel syndrome, pain, inflammation, or a combination thereof.

[0062] In another preferred example, the inflammatory bowel disease includes Crohn's disease and / or ulcerative colitis. In another preferred example, the pain includes visceral pain, acute inflammatory pain, chronic inflammatory pain, neuropathic pain, myofibrogia, headache, neuralgia, or pain due to cancer.

[0063] In another preferred example, the prevention and / or treatment of the inflammatory bowel disease includes: (i) Improvement of ulcers, (ii) Improvement of intestinal infarction, (iii) Improvement of intestinal adhesion, (iv) Increased thickening of the intestinal wall, and / or (v) One or more methods selected from the group consisting of reducing the levels of intestinal inflammatory factors.

[0064] In another preferred example, the prevention and / or treatment of Crohn's disease and / or ulcerative colitis is (i) Improvement of ulcers, (ii) Improvement of intestinal infarction, (iii) Improvement of intestinal adhesion, (iv) Increased thickening of the intestinal wall, and / or (v) One or more methods selected from the group consisting of reducing the levels of intestinal inflammatory factors.

[0065] In another preferred example, the inflammatory factor is selected from the group consisting of TNF-α, IL-10, or a combination thereof.

[0066] A fifth aspect of the present invention provides an in vitro non-therapeutic and non-diagnostic method for inhibiting the activity of a transient receptor potential channel protein, comprising the step of contacting a transient receptor potential channel protein or a protein-expressing cell with a compound of formula I described in the first aspect of the present invention, or an optical isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, thereby inhibiting the activity of the transient receptor potential channel protein.

[0067] A sixth aspect of the present invention provides a method for inhibiting a transient receptor potential channel protein or preventing and / or treating a disease associated with the transient receptor potential channel protein TRPA1, comprising the step of administering to a target subject of interest a compound of formula I described in the first aspect of the present invention, or an optical isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a pharmaceutical composition described in the second aspect of the present invention.

[0068] A seventh aspect of the present invention provides a compound, the compound being as shown in any of the following formulas II-1 to II-6: [ka] In the formula, Ar is a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 3-12 membered heteroaryl group, a 3-12 membered heterocycloalkane ring fused C6-C12 aryl group, a substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C8 alkyl-, or a substituted or unsubstituted 3-12 membered heteroaryl-substituted or unsubstituted C1-C8 alkyl-. X 1 , X 2 , X 3 and X 4These are, independently, C, O, S, or N. Labeled a, b, c, d, and e [ka] It is either a single bond or a double bond. R 1 is hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C7 cycloalkyl group, or a halogen. R 2 is hydrogen, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C3-C10 cycloalkyl group. n is 0, 1, 2, 3, 4, or 5. Here, the aforementioned "any substitution" means that one or more (preferably 1, 2, 3, 4, 5, or 6) hydrogen atoms on a ring or group are substituted by substituents selected from the group consisting of C1-C8 alkyl groups, C3-C8 cycloalkyl groups, C1-C8 haloalkyl groups, C3-C8 halocycloalkyl groups, halogens, nitro groups, -CN groups, hydroxyl groups, mercapto groups, amino groups, C1-C4 carboxyl groups, C2-C4 ester groups, C2-C4 amide groups, C1-C8 alkoxy groups, C1-C8 alkylthio groups, C1-C8 haloalkoxy groups, C1-C8 haloalkylthio groups, C6-C12 aryl groups, 5-10 membered heteroaryl groups, and 5-10 membered heterocycloalkyl groups. The heterocyclic group, heterocycloalkane ring, and heterocycloalkyl group each independently have 1 to 4 heteroatoms (preferably 1, 2, 3, or 4) selected from N, O, and S.

[0069] In another preferred example, the intermediate is [ka] It is selected from the group consisting of the following. [Effects of the Invention]

[0070] Within the scope of the present invention, it should be understood that new or preferred technical solutions can be constructed by combining the above-described technical features of the present invention with the technical features specifically described below (e.g., in the Examples). Due to space limitations, the phrases "and" will not be repeated here. [Brief explanation of the drawing]

[0071] [Figure 1] The results for colon length (A), colon weight (B), ulcer area (C), and gross colon injury score (D) for compounds IA-51, IA-30, ID-5, and IA-55 of the present invention in a DNBS-induced rat colitis model are shown. [Figure 2] The images show representative colorectal photographs of animals in each group of compounds IA-51, IA-30, ID-5, and IA-55 of the present invention in a DNBS-induced rat colitis model (A is the blank control group, B is the model vehicle group, C is the orsalazine sodium group, D is the compound IA-51 group, E is the compound IA-30 group, F is the compound ID-5 group, and G is the compound IA-55 group). [Figure 3] The DAI scores for compounds IA-51, IA-30, ID-5, and IA-55 of the present invention in a DSS-induced inflammatory bowel disease model using C57BL / 6 mice are shown. [Figure 4] The effects of the compounds IA-51, IA-30, ID-5, and IA-55 of the present invention on colorectal weight and length in a DSS-induced inflammatory bowel disease model using C57BL / 6 mice are shown. [Figure 5] The results of ELISA analysis of the colorectal inflammatory factors TNF-α and IL-10 for compounds IA-51, IA-30, ID-5, and IA-55 of the present invention in a DSS-induced inflammatory bowel disease model using C57BL / 6 mice are shown. [Figure 6] The results for the number of writhing episodes for compounds IA-51, IA-30, ID-5, and IA-55 of the present invention in an acetic acid-induced writhing pain model of ICR mice are shown. [Modes for carrying out the invention]

[0072] Through extensive and meticulous research, the inventors unexpectedly developed, for the first time, a compound of formula I, its optical isomer, its racemic mixture, or its pharmaceutically acceptable salt. Experiments demonstrate that the compound of formula I of the present invention has a remarkable inhibitory effect on TRPA1. The compound of formula I of the present invention can effectively treat inflammatory bowel disease, irritable bowel syndrome, pain, and inflammation related to the TRPA1 target point. Based on this, the present invention was completed.

[0073] term As used herein, the terms “contains,” “includes,” and “contains” may be used interchangeably and further include not only the closed definition but also the semi-closed and open definitions. In other words, the terms include “consisting of” and “essentially consisting of.”

[0074] As used herein, the terms “transient receptor potential channel protein TRPA1,” “TRPA1,” and “transient receptor potential channel protein A1” are used interchangeably, and the English name is transient receptor potential ankyrin 1.

[0075] Those skilled in the art can select substituents and substitution patterns on the compounds of the present invention to produce chemically stable compounds, which can be synthesized by techniques known in the art and by methods described below. It should be understood that when substitution is made by more than one substituent, these substituents may be on the same carbon or on different carbons, as long as a stable structure is produced.

[0076] As used herein, the terms “substitution” or “substituted” refer to the substitution of a hydrogen atom on a group with a non-hydrogen group, provided that the substitution satisfies valence requirements and produces a chemically stable compound, i.e., a compound that does not undergo spontaneous transformations such as cyclization or removal.

[0077] As used herein, "R 1 "R 1 " and "R 1 These terms have the same meaning and can be substituted for each other; other similar definitions also have the same meaning.

[0078] As used herein, the term “alkyl group” refers to a linear (i.e., non-branched) or branched saturated hydrocarbon group containing only carbon atoms, or a group combining linear and branched elements. When the number of carbon atoms preceding the alkyl group is limited (e.g., C1-C10 alkyl group), the alkyl group contains 1 to 10 carbon atoms, for example, a C1-C4 alkyl group refers to an alkyl group containing 1 to 4 carbon atoms, and typical examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, or similar groups.

[0079] In this invention, the term "halogen" refers to F, Cl, Br, or I. In this invention, the term "halo" refers to substitution by a halogen.

[0080] As used herein, the term “haloalkyl group” means that one or more (preferably 1, 2, 3, or 4) hydrogen atoms of an alkyl group are substituted with a halogen, and the alkyl group and halogen are as defined above, and if the number of carbon atoms preceding the alkyl group is limited (e.g., C1-C6 haloalkyl group), then the alkyl group contains 1 to 6 carbon atoms, for example, C1-C6 haloalkyl group refers to a haloalkyl group containing 1 to 6 carbon atoms, and typical examples include, but are not limited to, -CF3, -CHF2, monofluoroisopropyl group, bisfluorobutyl group, or similar groups.

[0081] As used herein, the term “cycloalkyl group” refers to a group having a saturated or partially saturated unit ring, dicyclic or polycyclic (fused, bridging, or spirocyclic) ring system. When the number of carbon atoms preceding a particular cycloalkyl group is limited (e.g., C3–C12), the cycloalkyl group refers to having 3–12 ring carbon atoms. In some preferred examples, the term “C3–C8 cycloalkyl group” refers to a saturated or partially saturated monocyclic or dicycloalkyl group having 3–8 ring carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or analogous groups. “Spirocycloalkyl group” refers to a dicyclic or polycyclic group having one carbon atom (called a spiro atom) between the monocyclic rings, which may contain one or more double bonds, but do not have rings with a fully conjugated π-electron system. A "condensed cycloalkyl group" refers to a bicyclic or polycyclic group of all carbon atoms in which each ring in the system shares a pair of adjacent carbon atoms with another ring in the system, where one or more rings may contain one or more double bonds, but no rings have a fully conjugated π-electron system. A "bridged cycloalkyl group" refers to a polycyclic group of all carbon atoms in which any two rings share two carbon atoms that are not directly bonded, where these may contain one or more double bonds, but no rings have a fully conjugated π-electron system. The following are typical examples of cycloalkyl groups: [ka] This includes, but is not limited to, these items.

[0082] As used herein, the term “halocycloalkyl group” means that one or more (preferably 1, 2, 3, or 4) hydrogen atoms of a cycloalkyl group are substituted with a halogen, the cycloalkyl group and halogen being as defined above, and where the number of carbon atoms preceding the cycloalkyl group is limited (e.g., C3-C8 haloalkyl group), the cycloalkyl group comprises 3 to 8 ring carbon atoms, for example, C3-C8 haloalkyl group refers to a halocycloalkyl group comprising 3 to 6 carbon atoms, typical examples including, but not limited to, monofluorocyclopropyl, monochlorocyclobutyl, monofluorocyclopentyl, bisfluorocycloheptyl, or similar groups.

[0083] The term "alkoxy group" refers to an RO- group, where R is an alkyl group, and an alkyl group is as defined herein above, and the number of carbon atoms preceding the alkoxy group is checked, for example, a C1-C8 alkoxy group means that the alkyl group in the alkoxy group has 1 to 8 carbon atoms. Typical examples of alkoxy groups include, but are not limited to, methoxy groups, ethoxy groups, n-propoxy groups, isopropoxy groups, t-butoxy groups, or similar groups.

[0084] As used herein, the term “alkylthio group” refers to an RO- group, where R is an alkyl group, and an alkyl group is as defined herein above, and the number of carbon atoms preceding the alkylthio group is checked, for example, a C1-C8 alkylthio group means that the alkyl group in the alkylthio group has 1 to 8 carbon atoms. Typical examples of alkylthio groups include, but are not limited to, methylthio groups, ethylthio groups, n-propylthio groups, isopropylthio groups, t-butylthio groups, or similar groups.

[0085] As used herein, the term “haloalkoxy group” refers to a haloalkyl-O- group, where the haloalkyl group is as described above, for example, a C1-C6 haloalkoxy group refers to a haloalkoxy group containing 1 to 6 carbon atoms, and typical examples include, but are not limited to, a monofluoromethoxy group, a monofluoroethoxy group, a bisfluorobutoxy group, or similar groups.

[0086] As used herein, the term “haloalkylthio group” refers to a haloalkyl-S- group, where the haloalkyl group is as described above, for example, a C1-C6 haloalkylthio group refers to a haloalkylthio group containing 1 to 4 carbon atoms, and typical examples include, but are not limited to, a monofluoromethylthio group, a monofluoroethylthio group, a bisfluorobutylthio group, or similar groups.

[0087] The term "heterocycloalkane ring" refers to a fully saturated or partially unsaturated ring (e.g., a 3- to 7-membered monoring, a 7- to 11-membered diring, or an 8- to 16-membered triring), where at least one heteroatom is present in a ring having at least one carbon atom. If there is a restriction on the number of members before the heteroring, it refers to the number of ring atoms in the heteroring; for example, a 3- to 16-membered heteroring refers to a heteroring having 3 to 16 ring atoms. Each heteroring containing heteroatoms can have one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from a nitrogen atom, an oxygen atom, or a sulfur atom, where the nitrogen atom or sulfur atom can be oxidized, and the nitrogen atom can also be quaternized. Heterorings can be bonded to any heteroatom or carbon atom residue of a ring or ring system molecule. Typical monocyclic heterocycloalkane rings include, but are not limited to, azetidine rings, oxetane, imidazoline rings, imidazolidine rings, tetrahydrofuran rings, piperidine rings, piperazine rings, 2-oxopiperazine rings, 2-oxopiperidine rings, 4-piperidone rings, tetrahydropyran rings, morpholine rings, thiomorpholine rings, thiomorpholine sulfoxide rings, thiomorpholine sulfone rings, 1,3-dioxane rings, and tetrahydro-1,1-dioxythiophene rings. Polycyclic heterocycloalkane rings include heterocycles of spiro rings, fused rings, and bridging rings, which, as mentioned herein, are optionally bonded to other rings via single bonds or further bonded to other cycloalkanes, heterocycles, via any two or more atoms on the ring.

[0088] The term "heterocycloalkyl group" refers to a fully saturated or partially unsaturated cyclic group (including, but not limited to, 3- to 7-membered monocyclics, 7- to 11-membered dicyclics, or 8- to 16-membered tricyclics) where at least one heteroatom is present in a ring having at least one carbon atom. If there is a restriction on the number of members in the heterocycloalkyl group, it refers to the number of ring atoms in the heterocycloalkyl group; for example, a 3- to 16-membered heterocycloalkyl group refers to a heterocycloalkyl group having 3 to 16 ring atoms. Each heterocyclic ring containing a heteroatom may have one or more (e.g., 1, 2, 3, or 4) heteroatoms, each of which is independently selected from a nitrogen atom, an oxygen atom, or a sulfur atom, where the nitrogen atom or sulfur atom may be oxidized, and the nitrogen atom may also be quaternized. Heterocycloalkyl groups can be bonded to any heteroatom or carbon atom residue of a ring or ring system molecule. Typical monocyclic heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 4-piperidinone, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholine sulfone, 1,3-dioxanyl, and tetrahydro-1,1-dioxythiophene. Polycyclic heterocycloalkyl groups include heterocyclic groups of spirocycles, fused rings, and crosslinking rings, which, as mentioned herein, are optionally bonded to other groups via single bonds or further bonded to other cycloalkane rings, heterocyclic rings, or any two or more atoms on the ring.

[0089] The term "aromatic ring" refers to a monocyclic or polycyclic ring of all carbon atoms having a conjugated π-electron system (i.e., a ring that shares adjacent pairs of carbon atoms), and is an aromatic cyclic hydrocarbon compound. If there is a restriction on the number of carbon atoms preceding the aromatic ring, for example, in the case of a C6-C12 aromatic ring, the aromatic ring has 6 to 12 ring carbon atoms, such as a benzene ring and a naphthalene ring. The aromatic ring can condense with other carbocyclic rings (including saturated or unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and at the same time, the linkage point to the parent must be a carbon atom on the ring having a conjugated π-electron system. Typical aromatic rings are the benzene ring and the naphthalene ring, or analogous rings.

[0090] The term "aryl group" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, and is an aromatic cyclic hydrocarbon compound group. There is a restriction on the number of carbon atoms preceding the aryl group; for example, in the case of a C6-C12 aryl group, the aryl group has 6 to 12 ring carbon atoms, such as the phenyl group and the naphthyl group. The aryl ring can condense with other cyclic groups (including saturated or unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and simultaneously, the parent linkage must be on a carbon atom on the ring having a conjugated π-electron system. Typical examples of aryl groups are as follows: [ka] This includes, but is not limited to, these items.

[0091] The term "heteroaromatic ring" refers to an aromatic heteroring having one to more (preferably 1, 2, 3, or 4) heteroatoms, which can be monocyclic (monocyclic) or polycyclic (dicyclic, tricyclic, or polycyclic) fused together or covalently bonded, and each heteroring containing heteroatoms may have one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen. If there is a restriction on the number of members in the heteroaromatic ring, it refers to the number of ring atoms in the heteroaromatic ring, for example, a 5-12 membered heteroaromatic ring refers to a heteroaromatic ring having 5 to 12 ring atoms, and typical examples include, but are not limited to, pyrrole rings, pyrazole rings, imidazole rings, oxazole rings, isoxazole rings, thiazole rings, thiadiazole rings, isothiazole rings, furan rings, pyridine rings, pyrazine rings, pyrimidine rings, pyridazine rings, triazine rings, triazole rings, and tetrazole rings.

[0092] The term "heteroaryl group" refers to an aromatic heterocyclic group having one or more (preferably 1, 2, 3, or 4) heteroatoms, which can be monocyclic (monocyclic formula) or polycyclic (bicyclic, tricyclic, or polycyclic) fused or covalently bonded together, and each heterocyclic ring containing heteroatoms may have one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen. When there is a restriction on the number of members in front of a heteroaryl group, it refers to the number of ring atoms in the heteroaryl group. For example, a 5-12 membered heteroaryl group refers to a heteroaryl group having 5 to 12 ring atoms. Typical examples include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, triazazinyl, triazolyl, and tetrazolyl groups.

[0093] As used herein, the term “carboxyl group” refers to a -COOH group or an -alkyl-COOH group, where alkyl groups are as defined herein above, for example, “C2-C4 carboxyl group” refers to a group of the -C1-C3 alkyl-COOH structure, and typical examples of carboxyl groups include (but are not limited to) -COOH, -CH2COOH, -C2H4COOH, or analogous groups.

[0094] As used herein, the term “ester group” refers to an R-CO-O- group or an -CO-OR group, where R is an alkyl group, and alkyl groups are as defined herein above. For example, “C2-C4 ester group” refers to a group with a C1-C3 alkyl-CO-O- structure or a group with a -CO-O-C1-C3 alkyl structure. Typical examples of ester groups include, but are not limited to, CH3COO-, C2H5COO-, C3H8COO-, (CH3)2CHCOO-, -COOCH3, -COOC2H5, -COOC3H8, or similar groups.

[0095] As used herein, the term “amide group” refers to an R-CO-N- group or an -CO-NR group, where R is an alkyl group, and alkyl groups are as defined herein above. For example, “C2-C4 amide group” refers to a group with a C1-C3 alkyl-CO-N- structure or a -CO-N-C1-C3 alkyl structure. Typical examples of amide groups include, but are not limited to, CH3CO-N-, C2H5CO-N-, C3H8CO-N-, (CH3)2CHCO-N-, -CO-N-CH3, -CO-N-C2H5, -CO-N-C3H8, or similar groups.

[0096] As used herein, the term "amino group," when used alone or as part of another substituent, refers to -NH2. As used herein, the term "nitro group," when used alone or as part of another substituent, refers to -NO2.

[0097] As used herein, the term "hydroxyl group," when used alone or as part of another substituent, refers to -OH. As used herein, the term "mercapto group," when used alone or as part of another substituent, refers to -SH.

[0098] In this specification, unless explicitly stated as “substituted,” all substituents should be interpreted as unsubstituted. The term “substituted” refers to the substitution of one or more hydrogen atoms on a particular group by a particular substituent. The specific substituents are substituents as appropriate in the preceding specification or substituents appearing in each example, and preferably, the substitution means that one or more (preferably 1, 2, 3, 4, 5, or 6) hydrogen atoms on a ring or group are substituted by substituents selected from the group consisting of C1-C8 alkyl groups, C3-C8 cycloalkyl groups, C1-C8 haloalkyl groups, C3-C8 halocycloalkyl groups, halogens, nitro groups, -CN groups, hydroxyl groups, mercapto groups, amino groups, C1-C4 carboxyl groups, C2-C4 ester groups, C2-C4 amide groups, C1-C8 alkoxy groups, C1-C8 alkylthio groups, C1-C8 haloalkoxy groups, C1-C8 haloalkylthio groups, C6-C12 aryl groups, 5-10 membered heteroaryl groups, and 5-10 membered heterocycloalkyl groups.

[0099] In the present invention, the term “prevention” refers to a method of preventing the onset of a disease and / or associated symptoms, or protecting a subject from contracting the disease. As used herein, “prevention” includes delaying the onset of a disease and / or associated symptoms, and reducing the risk of developing the disease in the subject.

[0100] The “treatment” described in the present invention includes delaying, halting, or eliminating the progression of a disease, and does not require 100% inhibition, elimination, and reversal. In some embodiments, the compositions, pharmaceutical kits, food kits, or healthcare product kits described in the present invention reduce, inhibit, and / or reverse, for example, at least about 10%, at least about 30%, at least about 50%, or at least about 80% of the disease associated with transient receptor potential channel protein TRPA1, compared to the levels observed in the absence of the active ingredient combination.

[0101] Active ingredients As used herein, “compound of the present invention,” “N-substituted phenylsulfonamide compound of the present invention,” or “compound of formula I” are interchangeable and refer to the compound of formula I, its optical isomers, its racemates, its pharmaceutically acceptable salts, or its prodrugs. It should be understood that these terms further include mixtures of the above components.

[0102] The present invention provides a compound of formula I, its optical isomer, its racemic mixture, its pharmaceutically acceptable salt, or its prodrug. [ka] In the formula, Ar is a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 3-12 membered heteroaryl group, a 3-12 membered heterocycloalkane ring fused C6-C12 aryl group, a substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C8 alkyl-, or a substituted or unsubstituted 3-12 membered heteroaryl-substituted or unsubstituted C1-C8 alkyl-. X 1 , X 2 , X 3 and X 4 These are, independently, C, O, S, or N. Labeled a, b, c, d, and e [ka] It is either a single bond or a double bond. R 1 is hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C7 cycloalkyl group, or a halogen. R 2 is hydrogen, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C3-C10 cycloalkyl group. A is [ka] It is a substituted or unsubstituted C2-C6 ester group, a substituted or unsubstituted C2-C6 carboxyl group, a substituted or unsubstituted C2-C6 amide group, or a substituted or unsubstituted 2HN-HN-C(O)-, where m is 0, 1, 2, or 3. Y 1 N is, Y 2 is either O or S, Y 3 is NH, O, or S, Y 4 is either O or S, Y 5 N is, R 3 and R 4 Each of these is independently a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C2-C6 acyl group, or R 3 , R 4 is adjacent to Y 1 It combines with to form a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, R 5 These are hydrogen, a hydroxyl group, a mercapto group, or a substituted or unsubstituted C1-C6 alkoxy group. n is 0, 1, 2, 3, 4, or 5. Here, the aforementioned "any substitution" means that one or more (preferably 1, 2, 3, 4, 5, or 6) hydrogen atoms on a ring or group are substituted by substituents selected from the group consisting of C1-C8 alkyl groups, C3-C8 cycloalkyl groups, C1-C8 haloalkyl groups, C3-C8 halocycloalkyl groups, halogens, nitro groups, -CN groups, hydroxyl groups, mercapto groups, amino groups, C1-C4 carboxyl groups, C2-C4 ester groups, C2-C4 amide groups, C1-C8 alkoxy groups, C1-C8 alkylthio groups, C1-C8 haloalkoxy groups, C1-C8 haloalkylthio groups, C6-C12 aryl groups, 5-10 membered heteroaryl groups, and 5-10 membered heterocycloalkyl groups. The heterocyclic group, heterocycloalkane ring, and heterocycloalkyl group each independently have 1 to 4 heteroatoms (preferably 1, 2, 3, or 4) selected from N, O, and S.

[0103] Preferably, the compound of formula I is as described in the first aspect of the present invention.

[0104] The term "pharmaceutically acceptable salt" refers to a salt formed with the compound of the present invention and an acid or base as a pharmaceutical product. Pharmaceutically acceptable salts include inorganic salts and organic salts. Preferred salts are salts formed with the compound of the present invention and an acid, and suitable acids for salt formation include (but are not limited to) inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenemethanesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid. Preferred salts are metal salts formed with the compound of the present invention and a base, and suitable bases for salt formation include (but are not limited to) inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphate; and organic bases such as aqueous ammonia, triethylamine, and diethylamine.

[0105] Compounds such as those represented by Formula I in the present invention can be converted to their pharmaceutically acceptable salts by conventional methods. For example, a solution of the corresponding acid can be added to a solution of the compound, and after the formation of the salt is measured, the solvent can be removed to obtain the corresponding salt of the compound described in the present invention.

[0106] Preferred compounds of the present invention are the specific compounds prepared in the examples of this application. Typically, the compounds described in the present invention are selected from Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3]

[0107] Preparation method The present invention relates to compound I represented by formula I of the present invention. A ~I W Further methods for preparing it are provided. The present invention relates to intermediate I used to prepare the above compound. V Further preparation methods for ~XXVII are provided.

[0108] The specific synthesis strategy is as follows: I A ~I F Synthesis of: [ka] Here, X 1 , X 2 , X 3 , X 4 , R 1 , n, Ar, R 2 and R 3 The definition is as described in the first aspect of the present invention above.

[0109] Substituted iodobenzene II, substituted or unsubstituted five-membered heteroarylboronic acid III, tetrakistriphenylphosphine palladium, and sodium carbonate are dissolved in a mixture of toluene, methanol, and water, and heated overnight under nitrogen gas protection. After the reaction is complete, the solvent is evaporated, water is added to the system, and the mixture is extracted three times with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by column chromatography to obtain intermediate I. V To obtain.

[0110] Intermediate I V Substituted or unsubstituted sulfonyl chloride is dissolved in a mixed solution of pyridine and tetrahydrofuran, sealed, and reacted overnight at 50-100°C. After the reaction is complete, the solvent is evaporated and the residue is separated by column chromatography to obtain intermediate V.

[0111] Intermediate V is dissolved in tetrahydrofuran solution, appropriate amounts of acetic acid and Raney nickel are added, and the mixture is reacted at 50-100°C for 1-2 hours. After the reaction is complete, the Raney nickel is removed by suction filtration, the filtrate is evaporated and dried, and the residue is separated by column chromatography to obtain intermediate VI.

[0112] Intermediate VI is dissolved in ethanol solution, the substituted amine is added, and the reaction is carried out overnight at room temperature. After the reaction is complete, the solvent is evaporated and the residue is separated by column chromatography to obtain compound I. C To obtain.

[0113] Intermediate VI is dissolved in ethanol solution, the substituted amine is added, and the mixture is reacted overnight at room temperature. The next day, sodium borohydride is added to the system in batches and the mixture is reacted for 1 hour. After the reaction is complete, the solvent is evaporated and the residue is separated by column chromatography to obtain compound I. A To obtain.

[0114] Intermediate V is dissolved in an ammonia-methanol solution, Raney nickel is added, hydrogen gas is passed through, and the reaction is allowed to proceed overnight at room temperature. After the reaction is complete, Raney nickel is removed by suction filtration, the filtrate is evaporated and dried, and the residue is separated by column chromatography to obtain compound I. D To obtain.

[0115] Compound I D Dissolve in dichloromethane solution, add triethylamine and acetic anhydride, and react overnight at room temperature. After the reaction is complete, evaporate the solvent and separate the residue by column chromatography to obtain compound I. E To obtain.

[0116] Intermediate V is dissolved in acetonitrile solution, potassium carbonate and substituted alkyl iodide are added, and the mixture is reacted at 60-80°C for 3 hours. After the reaction is complete, the solvent is evaporated and the residue is separated by column chromatography to obtain intermediate VII.

[0117] Intermediate VII is dissolved in tetrahydrofuran solution, appropriate amounts of acetic acid and Raney nickel are added, and the mixture is reacted at 50-100°C for 1-2 hours. After the reaction is complete, the Raney nickel is removed by suction filtration, the filtrate is evaporated and dried, and the residue is separated by column chromatography to obtain intermediate VIII.

[0118] Intermediate VIII is dissolved in ethanol solution, the substituted amine is added, and the mixture is reacted overnight at room temperature. The next day, sodium borohydride is added to the system in batches and the mixture is reacted for 1 hour. After the reaction is complete, the solvent is evaporated and the residue is separated by column chromatography to obtain compound I. B To obtain.

[0119] Intermediate VII is dissolved in an ammonia-methanol solution, Raney nickel is added, hydrogen gas is passed through, and the reaction is allowed to proceed overnight at room temperature. After the reaction is complete, Raney nickel is removed by suction filtration, the filtrate is evaporated and dried, and the residue is separated by column chromatography to obtain compound I. F To obtain.

[0120] I G , I H , I J , I K and I P Synthesis of: [ka] Here, X 1 , X 2 , X 3 , X 4 , R 1 , n, Ar, R 3 and R 4 The definition is as described in the first aspect of the present invention above.

[0121] Substituted iodobenzene IX, substituted or unsubstituted five-membered heteroarylboronic acid III, tetrakistriphenylphosphine palladium, and sodium carbonate are dissolved in a mixed solution of toluene, methanol, and water, and heated overnight under nitrogen gas protection. After the reaction is complete, the solvent is evaporated, water is added to the system, and the mixture is extracted three times with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by column chromatography to obtain intermediate X.

[0122] Intermediate X, a substituted or unsubstituted sulfonyl chloride, is dissolved in a mixed solution of pyridine and tetrahydrofuran, sealed, and reacted overnight at 50-100°C. After the reaction is complete, the solvent is evaporated and the residue is separated by column chromatography to obtain compound I. G To obtain.

[0123] Compound I G Dissolve in tetrahydrofuran solution, and under nitrogen gas protection, add lithium aluminum tetrahydrogen in batches under ice bath conditions and react at room temperature for 1-4 hours. After post-treatment, sequentially add water, aqueous sodium hydroxide solution and water to the system, filter by suction, evaporate and dry the filtrate, and separate the residue by column chromatography to obtain compound I H To obtain.

[0124] Compound IH Dissolve in dichloromethane solution, add triphenylphosphine and carbon tetrabromide under ice bath conditions, and react at room temperature for 1-4 hours. After the reaction is complete, evaporate the solvent, dissolve the residue in N,N-dimethylformamide solution, add the substituted amine and potassium carbonate, and react overnight at 60-90°C. After the reaction is complete, add water to the system, extract three times with ethyl acetate, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and separate the residue by column chromatography to obtain compound I J To obtain.

[0125] Compound I G Dissolve in ethanol solution, add the substituted amine, and react overnight at 60-100°C. After the reaction is complete, evaporate the solvent and separate the residue by column chromatography to obtain compound I. P To obtain.

[0126] Compound I G Dissolve in tetrahydrofuran solution, add aqueous lithium hydroxide solution, and react overnight at 40-60°C. After the reaction is complete, evaporate the solvent, adjust the pH to 3-4 by adding an appropriate amount of dilute hydrochloric acid to the system, extract three times with ethyl acetate, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and separate the residue by column chromatography to obtain compound I K To obtain.

[0127] I Q Synthesis of: [ka] Here, X 1 , X 2 , X 3 , X 4 , R 1 , n, Ar, R 3 and R 4 The definition is as described in the first aspect of the present invention above.

[0128] Substituted fluorobenzene XI and a substituted or unsubstituted five-membered nitrogen-containing heteroaromatic ring compound XII are dissolved in a dimethyl sulfoxide solution, sodium hydroxide is added, and the mixture is reacted overnight at 40-80°C under nitrogen gas protection. After the reaction is complete, water is added to the system, extracted three times with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by column chromatography to obtain intermediate XIII.

[0129] Intermediate XIII is dissolved in a mixture of ethanol and water, iron powder and ammonium chloride are added, and the mixture is reacted at 60-80°C for 1 hour. After the reaction is complete, the mixture is filtered by suction, the filtrate is concentrated, extracted three times with dichloromethane, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by column chromatography to obtain intermediate XI. V To obtain.

[0130] Intermediate XI V Substituted or unsubstituted sulfonyl chloride is dissolved in a mixed solution of pyridine and tetrahydrofuran, sealed, and reacted overnight at 50-100°C. After the reaction is complete, the solvent is evaporated and the residue is separated by column chromatography to obtain intermediate XV.

[0131] Intermediate XV is dissolved in a tetrahydrofuran solution, and under nitrogen gas protection, lithium aluminum tetrahydride is added under ice bath conditions, and the reaction is carried out at room temperature for 1 to 4 hours. After workup, water, aqueous sodium hydroxide solution and water are sequentially added to the system, filtered by suction, the filtrate is evaporated and dried, and the residue is separated by column chromatography to obtain intermediate XVI.

[0132] Intermediate XVI is dissolved in dichloromethane solution, pyridinium chlorochromate is added, and the mixture is reacted at room temperature for 1 hour. After workup, the mixture is filtered by suction, the filtrate is evaporated and dried, and the residue is separated by column chromatography to obtain intermediate XVII.

[0133] Intermediate XVII is dissolved in ethanol solution, the substituted amine is added, and the mixture is reacted overnight at room temperature. The next day, sodium borohydride is added to the system in batches and the mixture is reacted for 1 hour. After the reaction is complete, the solvent is evaporated and the residue is separated by column chromatography to obtain compound I. Q To obtain.

[0134] I R and I S Synthesis of: [ka] Here, X 1 , X 2 , X 3 , X 4 , R 1 The definition of n sum Ar is as described in the first aspect of the present invention above.

[0135] The amino group-substituted phenylacetonitrile is dissolved in acetonitrile solution, N-bromosuccinimide is added, and the reaction is carried out at room temperature for 0.5 to 2 hours. After the reaction is complete, the solvent is evaporated and the residue is separated by column chromatography to obtain intermediate XVIII.

[0136] Intermediate XVIII, substituted or unsubstituted five-membered heteroarylboronic acid III, tetrakistriphenylphosphine palladium, and sodium carbonate are dissolved in a mixed solution of toluene, methanol, and water, and heated overnight under nitrogen gas protection. After the reaction is complete, the solvent is evaporated, water is added to the system, and the mixture is extracted three times with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by column chromatography to obtain intermediate XIX.

[0137] Intermediate XIX, a substituted or unsubstituted sulfonyl chloride, is dissolved in a mixed solution of pyridine and tetrahydrofuran, sealed, and reacted overnight at 50-100°C. After the reaction is complete, the solvent is evaporated and the residue is separated by column chromatography to obtain intermediate XX.

[0138] Intermediate XX is dissolved in an ammonia-methanol solution, Raney nickel is added, hydrogen gas is passed through, and the reaction is allowed to proceed overnight at room temperature. After the reaction is complete, Raney nickel is removed by suction filtration, the filtrate is evaporated and dried, and the residue is separated by column chromatography to obtain compound I. R To obtain.

[0139] Compound I R Dissolve in a mixed solution of dichloromethane and methanol, add di-t-butyl dicarbonate, and react overnight at room temperature. After the reaction is complete, evaporate the solvent and separate the residue by column chromatography to obtain intermediate XXI.

[0140] Intermediate XXI is dissolved in tetrahydrofuran solution, and under nitrogen gas protection, lithium aluminum tetrahydride is added in an ice bath and reacted overnight at 60-80°C. After workup, water, aqueous sodium hydroxide solution and water are sequentially added to the system, filtered by suction, the filtrate is evaporated and dried, and the residue is separated by column chromatography to obtain compound I. S To obtain.

[0141] I U Synthesis of: [ka] Here, X 1 , X 2 , X 3 , X 4 , R 1 The definition of n sum Ar is as described in the first aspect of the present invention above.

[0142] Intermediate VIII, t-butylsulfenamide, and copper sulfate are dissolved in 30 mL of anhydrous 1,2-dichloroethane solution, heated, and allowed to react overnight. After the reaction is complete, the system is cooled to room temperature, filtered by suction, the filtrate is concentrated, and the residue is separated by column chromatography to obtain intermediate XXII.

[0143] Intermediate XXII is dissolved in anhydrous tetrahydrofuran solution, and methylmagnesium bromide in tetrahydrofuran solution is slowly added dropwise at -78°C. After the addition is complete, the temperature is slowly raised to -20°C to allow the reaction to proceed. After the reaction is complete, an aqueous solution of amine chloride is added to the system under ice bath conditions to quench it, water is added, the mixture is extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by column chromatography to obtain intermediate XXIII.

[0144] Intermediate XXIII is dissolved in ethanol solution, hydrochloric acid in ethanol solution is added, and the reaction is carried out at 60°C. After the reaction is complete, the solvent is evaporated and dried, water is added to the residue, an appropriate amount of sodium bicarbonate aqueous solution is added to adjust the pH to 8-9, extraction is carried out with ethyl acetate, washed with water, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by column chromatography to obtain compound I U To obtain.

[0145] I V Synthesis of: [ka] Here, X 1 , X 2 , X 3 , X 4 , R 1 The definition of n sum Ar is as described in the first aspect of the present invention above.

[0146] Intermediate XXV is obtained using the same method as in the synthesis of intermediate V. Intermediate XXV is dissolved in dichloromethane solution, methylamine in ethanol solution and tetraethoxytitanium are added, and the mixture is reacted overnight at room temperature. Sodium borohydride is slowly added under ice water conditions, and the mixture is reacted at room temperature. After the reaction is complete, water is added to the system, extracted with dichloromethane, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by column chromatography to obtain compound I. V To obtain.

[0147] I W Synthesis of: [ka] Here, X 1 , X 2 , X 3 , X 4 , R 1 The definition of n sum Ar is as described in the first aspect of the present invention above.

[0148] Intermediate XXVII is obtained using the same method as in the synthesis of intermediate V. Intermediate XXVII is dissolved in ethyl acetate solution, hydrochloric acid in ethanol solution is added, and the reaction is carried out at room temperature. After the reaction is complete, the solvent is evaporated and dried, water is added to the residue, an appropriate amount of sodium bicarbonate aqueous solution is added to adjust the pH to 8-9, the residue is extracted with ethyl acetate, washed with water, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by column chromatography to obtain compound I. W To obtain.

[0149] Transient receptor potential (TRP) Channel protein (TRP) Transient receptor potential channel proteins (TPPs) are a protein superfamily comprised of important cation channels located on the cell membrane. These PTPs include several subfamilies, such as the TRPA1, TRPC, TRPM, TRPV, TRPML, and TRPP subfamilies.

[0150] Research has revealed that the TRPA1 channel protein is associated with diseases such as inflammatory bowel disease, pain, irritable bowel syndrome, and inflammation, making TRPA1 a target for treating these conditions.

[0151] Purpose The present invention further provides a method for inhibiting the transient receptor potential channel protein TRPA1, and a method for treating TRPA1-related diseases. The compounds of the present invention can be used to inhibit the transient receptor potential channel protein TRPA1, thereby preventing or treating diseases associated with the transient receptor potential channel protein TRPA1.

[0152] In the present invention, examples of diseases associated with transient receptor potential channel protein TRPA1 include (but are not limited to) inflammatory bowel disease, pain, irritable bowel syndrome, and inflammation. Typically, inflammatory bowel disease includes ulcerative colitis and Crohn's disease, and pain includes (but is not limited to) visceral pain, acute inflammatory pain, chronic inflammatory pain, neuropathic pain, myofibrogia, headache, neuralgia, or cancer pain.

[0153] In a preferred embodiment, the present invention provides an in vitro non-therapeutic and non-diagnostic method for inhibiting the activity of transient receptor potential channel protein TRPA1, comprising contacting a cell expressing the transient receptor potential channel protein TRPA1 or the compound described in the present invention with the transient receptor potential channel protein TRPA1 in an in vitro culture system.

[0154] The present invention further provides a method for inhibiting the transient receptor potential channel protein TRPA1, which may be therapeutic or non-therapeutic. Typically, the method includes the step of administering a compound described in the present invention to a subject of interest. Preferably, the subjects include humans and non-human mammals (rodents, rabbits, monkeys, livestock, dogs, cats, etc.).

[0155] Crohn's disease Crohn's disease is an inflammatory bowel disease that causes inflammation of the gastrointestinal tract. People of any age can develop Crohn's disease, but it usually develops between the ages of 13 and 30. The most common sites of lesions are the lower part of the small intestine (called the ileum) and the upper part of the colon, but Crohn's disease lesions can occur anywhere in the gastrointestinal tract from the mouth to the anus.

[0156] ulcerative colitis Ulcerative colitis is a chronic, nonspecific inflammatory disease of the rectum and colon of unknown cause. The lesions are mainly limited to the mucosa and submucosa of the large intestine. The main clinical symptoms are diarrhea, mucous, purulent, and bloody stools, and abdominal pain, which often recur and persist.

[0157] Composition and administration method The present invention provides compositions for inhibiting the activity of the transient receptor potential channel protein TRPA1. The compositions include (but are not limited to) pharmaceutical compositions, food compositions, nutritional supplements, beverage compositions, and the like. Typically, the composition is a pharmaceutical composition comprising the compound described in the present invention and a pharmaceutically acceptable carrier.

[0158] In the present invention, the dosage form of the pharmaceutical composition includes (but is not limited to) oral preparations, injectable preparations, and topical preparations. Typical examples include (but are not limited to) tablets, injections, infusions, ointments, gels, solutions, microspheres, and membranes.

[0159] The term "pharmaceutically acceptable carrier" refers to one or more compatible solid, semi-solid, liquid, or gel fillers that are suitable for human or animal use, and are always sufficiently pure and sufficiently low in toxicity. "Compatibility" means that the individual components in a pharmaceutical composition and the active ingredients of a drug, as well as their mutual mixing, do not significantly impair the efficacy of the drug.

[0160] In the present invention, the carrier is not particularly limited and can be made from materials commonly used in the art, prepared by conventional methods, or purchased from the market. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween), wetting agents (e.g., sodium lauryl sulfate), buffers, chelating agents, thickeners, pH adjusters, skin penetration enhancers, colorants, fragrances, stabilizers, antioxidants, preservatives, bacteriostatic agents, pyrogen-free water, etc.

[0161] Typically, in addition to the active pharmaceutical ingredient, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, sesame oil, and sesame oil, or mixtures thereof. In addition to these inert diluents, the composition may also contain auxiliary agents such as wetting agents, emulsifiers, and suspending agents.

[0162] The formulation of the drug must be suitable for the method of administration. The drug of the present invention can also be used in combination with other synergistic therapeutic agents (including before, during, or after use). When using the pharmaceutical composition or formulation, it should be administered to a subject (e.g., human or non-human mammal) that requires a safe and effective amount of the drug, which is usually at least about 10 μg / kg body weight and in most cases does not exceed about 8 mg / kg body weight, preferably about 10 μg / kg body weight to about 1 mg / kg body weight. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, all of which are within the scope of the skill of a skilled physician.

[0163] The main advantages of this invention are as follows: (a) The present invention provides a compound of formula I which has a novel structure and excellent TRPA1 inhibitory activity. (b) The compounds of the present invention have excellent therapeutic effects against inflammatory bowel disease. (c) The compound of the present invention has excellent analgesic effects. (d) The compounds of the present invention have low toxicity and strong pharmacological effects, thus providing a large safety window. (e) The compound of the present invention exhibits excellent drug discovery properties. (f) The compounds of the present invention have excellent pharmacokinetic properties. (g) The compounds of the present invention are suitable for oral administration.

[0164] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are used solely for illustrative purposes and do not limit the scope of the invention. In the following embodiments, experimental methods that do not specify conditions generally follow conventional conditions or conditions proposed by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0165] Example 1 Compound I A Synthesis of: Stage 1: 3-amino-4-(furan-2-yl)benzonitrile (IV-1) [ka] 3-amino-4-iodobenzonitrile (244.0 mg, 1 mmol), furan-2-boronic acid (123.1 mg, 1.1 mmol), tetrakistriphenylphosphine palladium (57.8 mg, 0.05 mmol), and sodium carbonate (318.0 mg, 3 mmol) were dissolved in 26 mL of a toluene / methanol / water mixture (volt / volt / volt = 9:3:1) and the mixture was refluxed overnight. After the reaction was complete, the solvent was evaporated, water was added to the residue, and the mixture was extracted three times with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to obtain an off-white solid intermediate IV-1 (172.0 mg, 93.4%). 1 H NMR(400MHz,CDCl3)δ 7.69(d,J=1.9Hz,1H),7.50(dd,J=1.8,0.7Hz,1H),7.30(dd,J=8.4,2.0Hz,1H), 6.70(d,J=8.4Hz,1H),6.59(dd,J=3.4,0.7Hz,1H),6.51(dd,J=3.4,1.9Hz,1H).

[0166] Stage 2: N-(5-cyano-2-(furan-2-yl)phenyl)-4-fluorobenzenesulfonamide (V-1) [ka] Intermediate IV-1 (92.1 mg, 0.5 mmol) and 4-fluorobenzenesulfonyl chloride (97.3 mg, 0.5 mmol) were dissolved in 10 mL of a tetrahydrofuran / pyridine mixture (volume / volume = 1:1), sealed, and reacted overnight at 80°C. After the reaction was complete, the solvent was evaporated, and the residue was separated by column chromatography to obtain the yellow solid intermediate V-1 (94.8 mg, 55.4%). 1H NMR(500MHz,DMSO)δ 10.13(s,1H),8.04(d,J=1.9Hz,1H),7.81-7.77(m,2H),7.76(d,J=1.3Hz,1H),7.67(dd,J=8.4,2.0Hz,1H ),7.38(dd,J=12.2,5.5Hz,2H),7.20(d,J=8.4Hz,1H),7.01(d,J=3.4Hz,1H),6.60(dd,J=3.4,1.8Hz,1H).

[0167] Stage 3: 4-Fluoro-N-(5-Formyl-2-(Fran-2-yl)phenyl)benzenesulfonamide (Intermediate VI-1) [ka] Intermediate V-1 (68.5 mg, 0.2 mmol) is dissolved in 12 mL of a tetrahydrofuran / acetic acid (vol / vol = 5:1) mixed solution, an appropriate amount of Raney nickel aqueous solution is added to the system, hydrogen gas is passed through, and the reaction is carried out at 60°C for 1 hour. After the reaction is complete, Raney nickel is removed by suction filtration, the filtrate is evaporated and dried, and the residue is separated by column chromatography to obtain intermediate VI-1 (32.9 mg, 47.6%) as a yellow solid. 1 H NMR(400MHz,DMSO)δ 10.11(s,1H),9.94(s,1H),8.13(d,J=1.9Hz,1H),7.82-7.75(m,3H),7.71(dd,J=8.3,2.0Hz,1H), 7.40-7.33(m,2H),7.20(d,J=8.3Hz,1H),6.98(dd,J=3.4,0.5Hz,1H),6.60(dd,J=3.4,1.8Hz,1H).

[0168] Stages 4-5: 4-Fluoro-N-(2-(Fran-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (Compound I A -1) [ka] Intermediate VI-1 (27.6 mg, 0.08 mmol) is dissolved in ethanol solution, 1 mL of ethanol solution of methylamine (30-33 wt%) is added, and the mixture is reacted overnight. Sodium borohydride (3.0 mg, 0.08 mmol) is then added. After the reaction is complete, the solvent is evaporated and the residue is separated by column chromatography to obtain compound I, a white solid. A -1 was obtained (14.0 mg, 48.7%). HPLC:99.1%, LC-MS(m / z):361.10(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.82-7.66(m,2H),7.66-7.54(m,2H),7.38(d,J=3.1Hz,1H),7.25(d,J=1.5Hz,1H),7.22- 7.10(m,2H),6.81(d,J=7.7Hz,1H),6.51(dd,J=3.3,1.8Hz,1H),3.83(s,2H),2.40(s,3H).

[0169] I A The following compounds are obtained using the same method as in the synthesis of -1. 2-Fluoro-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I A -2) [ka] HPLC:99.0%, LC-MS(m / z):361.09(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.74(td,J=7.6,1.5Hz,1H),7.64-7.55(m,2H),7.51(s,1H),7.43-7.30(m,2H),7.13(dd,J=1 5.1,7.9Hz,2H),6.72(d,J=7.8Hz,1H),6.49(dd,J=3.2,1.8Hz,1H),3.85(s,2H),2.43(s,3H).

[0170] 3-Fluoro-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -3) [ka] HPLC:98.9%, LC-MS(m / z):361.11(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.64-7.55(m,2H),7.53(d,J=7.8Hz,1H),7.48-7.35(m,3H),7.32(d,J=1.3Hz,1H),7.19(td,J =8.5,2.3Hz,1H),6.76(d,J=8.1Hz,1H),6.51(dd,J=3.2,1.8Hz,1H),3.87(s,2H),2.43(s,3H).

[0171] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -4) [ka] HPLC:99.4%, LC-MS(m / z):343.10(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.75-7.66(m,2H),7.60(d,J=8.0Hz,2H),7.43-7.31(m,4H),7.21(s,1H),6 .82(d,J=8.0Hz,1H),6.51(dd,J=3.3,1.8Hz,1H),3.76(s,2H),2.35(s,3H).

[0172] 2-Methoxy-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -5) [ka] HPLC:98.8%, LC-MS(m / z):373.11(M+H)+, 1H NMR(400MHz,DMSO)δ 7.75(d,J=1.2Hz,1H),7.67(dd,J=7.8,1.6Hz,1H),7.58(d,J=8.0Hz,1H),7.54-7.45(m,1H),7.15-7.08(m,3H), 7.03(t,J=11.0Hz,1H),6.96(dd,J=17.7,10.3Hz,1H),6.63-6.53(m,1H),3.70(s,3H),3.59(s,2H),2.16(s,3H).

[0173] 4-Methoxy-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -6) [ka] HPLC:97.9%, LC-MS(m / z):373.16(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.67-7.56(m,4H),7.24(d,J=3.1Hz,1H),7.11(s,1H),6.94(d,J=8.8Hz, 3H), 6.53 (dd, J=3.3, 1.8Hz, 1H), 3.77 (s, 3H), 3.70 (s, 2H), 2.30 (s, 3H).

[0174] 4-Chloro-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -7) [ka] HPLC:99.4%, LC-MS(m / z):377.11(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.72-7.66(m,2H),7.61(d,J=8.1Hz,2H),7.42(d,J=8.5Hz,3H),7.28(s,1H), 6.80(d,J=7.5Hz,1H),6.51(dd,J=3.3,1.8Hz,1H),3.87(s,2H),2.44(s,3H).

[0175] 2-Trifluoromethoxy-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -8) [ka] HPLC:96.9%, LC-MS(m / z):427.10(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.93-7.87(m,1H),7.64-7.56(m,2H),7.53(s,1H),7.46(t,J=7.1Hz,1H),7.35-7.24 (m,3H),6.73(d,J=7.3Hz,1H),6.47(dd,J=3.2,1.8Hz,1H),3.85(s,2H),2.43(s,3H).

[0176] 4-Trifluoromethoxy-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -9) [ka] HPLC:98.8%, LC-MS(m / z):427.19(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.82-7.75(m,2H),7.61(dd,J=11.1,4.5Hz,2H),7.34(t,J=10.5Hz,3H),7.30(d,J=1. 5Hz,1H), 6.89(d,J=7.5Hz,1H),6.50(dd,J=3.3,1.8Hz,1H),3.90(s,2H),2.42(s,3H).

[0177] 4-Methyl-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -10) [ka] HPLC:98.7%, LC-MS(m / z):357.13(M+H)+, 1H NMR(400MHz,DMSO)δ 7.62(d,J=1.0Hz,1H),7.59(dd,J=8.1,4.0Hz,3H),7.29(d,J=3.2Hz,1H),7.20(d,J=8.0Hz,2H),7.16(d, J=1.2Hz,1H),6.88(d,J=7.9Hz,1H),6.52(dd,J=3.3,1.8Hz,1H),3.74(s,2H),2.33(s,3H),2.30(s,3H).

[0178] 2,4-Difluoro-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -11) [ka] HPLC:99.6%, LC-MS(m / z):379.10(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.72(dd,J=15.3,8.4Hz,1H),7.63(dd,J=13.7,4.5Hz,2H),7.36-7.22(m,3H) ,7.06(t,J=8.4Hz,2H),6.50(dd,J=3.3,1.8Hz,1H),3.95(s,2H),2.47(s,3H).

[0179] 2,6-Difluoro-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -12) [ka] HPLC:99.1%, LC-MS(m / z):379.11(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.51(dd,J=10.2,5.4Hz,3H),7.32-7.24(m,2H),6.91(t,J=8.3Hz,2H),6.72(d,J=8.1Hz,1H),6.48-6.39(m,1H),3.73(s,2H),2.33(s,3H).

[0180] 4-Trifluoromethyl-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -13) [ka] HPLC:98.5%, LC-MS(m / z):411.10(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.88(d,J=8.1Hz,2H),7.74(d,J=8.3Hz,2H),7.61(dd,J=14.2,4.5Hz,2H),7.33(t ,J=4.8Hz,2H),6.90(s,1H),6.49(dd,J=3.3,1.8Hz,1H),3.92(s,2H),2.44(s,3H).

[0181] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)naphthalene-2-sulfonamide(I A -14) [ka] HPLC:97.9%, LC-MS(m / z):393.13(M+H)+, 1 H NMR(500MHz,DMSO)δ 8.33(s,1H),8.00(d,J=7.2Hz,1H),7.92(dd,J=7.6,4.7Hz,2H),7.77(dd,J=8.6,1.5Hz,1H),7.64-7.53(m, 4H),7.38(s,1H),7.27(s,1H),6.84(d,J=7.6Hz,1H),6.50(dd,J=3.1,1.8Hz,1H),3.78(s,2H),2.28(s,3H).

[0182] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)-2,3-dihydrobenzofuran-5-sulfonamide(I A -15) [ka] HPLC:97.7%, LC-MS(m / z):385.14(M+H)+,1 H NMR(400MHz,DMSO)δ 7.67(d,J=1.2Hz,1H),7.60(d,J=8.0Hz,1H),7.51(s,1H),7.42(dd,J=8.4,1.9Hz,1H),7.19-7.11(m,2H),7.05(t,J=7.8Hz,1 H),6.75(d,J=8.4Hz,1H),6.54(dd,J=3.3,1.8Hz,1H),4.58(t,J=8.8Hz,2H),3.74(s,2H),3.15(t,J=8.7Hz,2H),2.32(s,3H).

[0183] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzothiazole-6-sulfonamide(I A -16) [ka] HPLC:99.3%, LC-MS(m / z):400.07(M+H)+, 1 H NMR(400MHz,DMSO)δ 9.46(d,J=8.4Hz,1H),8.54(d,J=1.4Hz,1H),8.04(d,J=8.5Hz,1H),7.84(dd,J=8.5,1.6Hz,1H),7.60(d,J=8.1H z,2H),7.40(d,J=18.2Hz,1H),7.29(s,1H),6.81(s,1H),6.50(dd,J=3.2,1.8Hz,1H),3.84(s,2H),2.35(s,3H).

[0184] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)pyridine-3-sulfonamide(I A -17) [ka] HPLC:99.6%, LC-MS(m / z):344.11(M+H)+, 1H NMR(400MHz,DMSO)δ 8.83(s,1H),8.53(d,J=3.9Hz,1H),8.10-7.93(m,1H),7.66-7.54(m,2H),7.39(dd,J= 15.7,10.9Hz,3H),6.79(s,1H),6.51(dd,J=3.2,1.8Hz,1H),3.91(s,2H),2.46(s,3H).

[0185] 6-Chloro-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)pyridine-3-sulfonamide(I A -18) [ka] HPLC:98.1%, LC-MS(m / z):378.06(M+H)+, 1 H NMR(500MHz,DMSO)δ 8.55(d,J=2.5Hz,1H),8.01(dd,J=8.4,2.6Hz,1H),7.71(d,J=8.1Hz,1H),7.67(d,J=1.3Hz,1H),7.64(d,J=8.4Hz,1H),7 .50(d,J=7.6Hz,1H),7.32(d,J=1.6Hz,1H),6.98(d,J=3.1Hz,1H),6.53(dd,J=3.4,1.8Hz,1H),4.09(s,2H),2.50(s,3H).

[0186] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)-1-methyl-1H-imidazole-4-sulfonamide(I A -19) [ka] HPLC:98.5%, LC-MS(m / z):347.12(M+H)+, 1H NMR(400MHz,DMSO)δ 7.79-7.71(m,4H),7.48(dd,J=8.2,1.7Hz,1H),7.34(d,J=1.5Hz,1H),7.13(t,J=5. 4Hz, 1H), 6.62 (dd, J=3.4, 1.8Hz, 1H), 4.04 (s, 2H), 3.70-3.64 (m, 3H), 2.50 (s, 3H).

[0187] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)thiophen-2-sulfonamide(I A -20) [ka] HPLC:98.9%, LC-MS(m / z):349.06(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.66-7.58(m,2H),7.52(d,J=4.7Hz,1H),7.45(s,1H),7.40(d,J=1.4Hz,1H),7.31-7.24(m,1H), 6.95-6.87(m,1H),6.82(d,J=6.9Hz,1H),6.52(dd,J=3.3,1.8Hz,1H),3.91(s,2H),2.46(s,3H).

[0188] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)thiophen-3-sulfonamide(I A -twenty one) [ka] HPLC:99.0%, LC-MS(m / z):349.08(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.96(d,J=1.9Hz,1H),7.68(d,J=7.9Hz,2H),7.58(dd,J=5.1,3.0Hz,1H),7.26(s,1H) ),7.18(dd,J=5.1,1.2Hz,3H),6.55(dd,J=3.4,1.8Hz,1H),3.94(s,2H),2.45(s,3H).

[0189] 5-Chloro-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)thiophen-2-sulfonamide(I A -twenty two) [ka] HPLC:96.9%, LC-MS(m / z):383.03(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.74-7.65(m,2H),7.40(s,1H),7.32(d,J=1.6Hz,1H),7.23(d,J=4.0Hz,1H),7.08( d,J=4.0Hz,1H),6.98(s,1H),6.53(dd,J=3.4,1.8Hz,1H),4.06(s,2H),2.50(s,3H).

[0190] 5-Bromo-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)thiophen-2-sulfonamide(I A -twenty three) [ka] HPLC:97.4%, LC-MS(m / z):426.99(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.73-7.58(m,2H),7.30(d,J=22.8Hz,2H),7.14(d,J=5.6Hz,3H),6.52(d,J=1.7Hz,1H),4.02(s,2H),2.50(s,3H).

[0191] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)-1-phenylmethanesulfonamide(I A -twenty four) [ka] HPLC:97.8%, LC-MS(m / z):357.16(M+H)+, 1H NMR(400MHz,DMSO)δ 7.68-7.61(m,2H),7.33-7.24(m,6H),7.13(d,J=3.4Hz,1H),7.03(d,J=7.9 Hz, 1H), 6.51 (dd, J=3.2, 1.8Hz, 1H), 4.31 (s, 2H), 3.81 (s, 2H), 2.42 (s, 3H).

[0192] N-(2-(furan-2-yl)-5-((2,2,2-trifluoroethyl)amino)methyl)phenyl)benzenesulfonamide(I A -twenty five) [ka] HPLC:99.3%, LC-MS(m / z):411.10(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.72(dd,J=4.4,2.6Hz,3H),7.69-7.61(m,2H),7.55(t,J=7.6Hz,2H),7.29(d,J=8.0Hz,1H),6.97(d,J=3 .3Hz,1H),6.90(s,1H),6.58(dd,J=3.3,1.8Hz,1H),3.68(d,J=3.5Hz,2H),3.10(dt,J=15.5,7.8Hz,2H).

[0193] N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)benzenesulfonamide (I A -26) [ka] HPLC:98.8%, LC-MS(m / z):343.16(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.77-7.62(m,4H),7.44(d,J=7.3Hz,3H),7.33(s,1H),7.06(d,J=7.8Hz,2H),6.56(dd,J=3.3,1.8Hz,1H),3.96(s,2H),2.50(s,3H).

[0194] 4-Fluoro-N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)benzenesulfonamide (I A -27) [ka] HPLC:99.2%, LC-MS(m / z):361.14(M+H)+, 1 H NMR(500MHz,MeOD)δ 7.67(ddd,J=8.1,4.9,2.5Hz,3H),7.56(d,J=1.7Hz,1H),7.39(d,J=8.3Hz,1H),7.27(dd,J=8.3,2.1Hz ,1H),7.14-7.09(m,2H),6.83(d,J=3.4Hz,1H),6.49(dd,J=3.4,1.8Hz,1H),3.98(s,2H),2.59(s,3H).

[0195] 2-Fluoro-N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)benzenesulfonamide (I A -28) [ka] HPLC:97.0%, LC-MS(m / z):361.09(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.70-7.64(m,2H),7.56(s,1H),7.53(s,1H),7.39-7.31(m,1H),7.16(d,J=8.6Hz,1H),7 .10(t,J=8.0Hz,2H),6.87(d,J=8.4Hz,1H),6.49-6.46(m,1H),3.89(s,2H),2.45(s,3H).

[0196] N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophen-2-sulfonamide(I A -29) [ka] HPLC:98.1%, LC-MS(m / z):349.07(M+H)+, 1H NMR(400MHz,DMSO)δ 7.74(d,J=1.9Hz,1H),7.65-7.57(m,2H),7.34-7.25(m,2H),7.16(d,J=8.3Hz,1H),7.08( d,J=7.8Hz,1H),6.99-6.93(m,1H),6.52(dd,J=3.2,1.8Hz,1H),3.97(s,2H),2.5(s,3H).

[0197] N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide(I A -30) [ka] HPLC:98.4%, LC-MS(m / z):349.09(M+H)+, 1 H NMR(500MHz,CDCl3)δ 7.70-7.65(m,1H),7.62(d,J=8.3Hz,1H),7.48(dt,J=5.1,2.6Hz,1H),7.37(d,J=1.9Hz,1H),7.25(dd,J=8.3, 2.0Hz,1H),7.18-7.12(m,1H),6.98-6.92(m,1H),6.43(ddd,J=4.1,3.4,1.3Hz,2H),3.72(s,2H),2.45(s,3H).

[0198] N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)pyridine-3-sulfonamide(I A -31) [ka] HPLC:98.6%, LC-MS(m / z): 344.11(M+H)+, 1H NMR(400MHz,DMSO)δ 8.80(s,1H),8.51(d,J=4.3Hz,1H),7.99(d,J=7.9Hz,1H),7.70(s,1H),7.61(s,1H),7.53(d,J=2.8Hz,1H),7.38( dd,J=7.8,4.9Hz,1H),7.22(d,J=8.4Hz,1H),6.93(d,J=8.5Hz,1H),6.53(s,1H),3.93(s,2H),2.49-2.48(m,3H).

[0199] N-(4-((ethylamino)methyl)-2-(furan-2-yl)phenyl)thiophen-3-sulfonamide(I A -32) [ka] HPLC:99.3%, LC-MS(m / z):363.09(M+H)+, 1 H NMR(500MHz,DMSO)δ 7.77(s,1H),7.70(d,J=2.1Hz,1H),7.63(s,1H),7.45(d,J=16.5Hz,2H),7.19(d,J=8.2Hz,1H),7.14(d,J=5.0Hz, 1H),6.98(d,J=7.4Hz,1H),6.54(dd,J=3.1,1.8Hz,1H),3.92(s,2H),2.87(q,J=7.1Hz,2H),1.15(t,J=7.2Hz,3H).

[0200] N-(4-((cyclopropylamino)methyl)-2-(furan-2-yl)phenyl)thiophene-3-sulfonamide(I A -33) [ka] HPLC:99.4%, LC-MS(m / z):375.09(M+H)+, 1H NMR(500MHz,DMSO)δ 7.98(d,J=1.8Hz,1H),7.72(d,J=1.4Hz,1H),7.67(dd,J=4.9,2.8Hz,2H),7.21(dd,J=5.1,1.2Hz,1H),7.11(dd,J=8.2,1.9Hz,1H), 7.06(d,J=2.8Hz,1H),6.88(d,J=8.1Hz,1H),6.57(dd,J=3.4,1.8Hz,1H),3.75(s,2H),2.10(s,1H),0.35(dd,J=32.6,11.5Hz,4H).

[0201] N-(4-((cyclobutylamino)methyl)-2-(furan-2-yl)phenyl)thiophene-3-sulfonamide(I A -34) [ka] HPLC:96.9%, LC-MS(m / z):389.09(M+H)+, 1 H NMR(500MHz,CDCl3)δ 7.69-7.64(m,1H),7.61(d,J=8.3Hz,1H),7.47(d,J=5.5Hz,1H),7.38(s,1H),7.24(d,J=1.9Hz,1H),7.16(dd,J=5.1,3.1Hz, 1H),6.97-6.94(m,1H),6.46-6.39(m,2H),3.68(s,2H),3.32-3.24(m,1H),2.25-2.14(m,2H),1.69(dd,J=16.8,12.4Hz,4H).

[0202] N-(5-((methylamino)methyl)-2-(5-methylfuran-2-yl)phenyl)benzenesulfonamide (I A -35) [ka] HPLC:96.8%, LC-MS(m / z):357.12(M+H)+, 1H NMR(400MHz,DMSO)δ 7.70-7.64(m,2H),7.57(d,J=8.0Hz,1H),7.48-7.38(m,3H),7.18(s,1H),7.11(s,1H),6.9 6(d,J=8.0Hz,1H),6.11(d,J=2.2Hz,1H),3.80(s,2H),2.37(s,3H),2.27(d,J=15.0Hz,3H).

[0203] N-(3-(furan-2-yl)-4-((methylamino)methyl)phenyl)benzenesulfonamide (I A -36) [ka] HPLC:97.5%, LC-MS(m / z):343.13(M+H)+, 1 H NMR(400MHz,CD3OD)δ 7.83-7.78(m,2H),7.69(dd,J=1.8,0.7Hz,1H),7.57-7.52(m,1H),7.49-7.44(m,2H),7.41(d,J=2.3Hz,1H),7.33(d,J=8. 3Hz,1H), 7.13(dd,J=8.3,2.3Hz,1H),6.71(dd,J=3.4,0.7Hz,1H),6.59(dd,J=3.5,1.9Hz,1H),4.19(s,2H),2.66(s,3H).

[0204] N-(4-(furan-2-yl)-3-((methylamino)methyl)phenyl)benzenesulfonamide(I A -37) [ka] HPLC:99.2%, LC-MS(m / z):343.03(M+H)+, 1H NMR(400MHz,DMSO)δ 7.78-7.71(m,2H),7.69(dd,J=1.8,0.7Hz,1H),7.59-7.47(m,3H),7.44(d,J=8.5Hz,1H),7.26(d,J=2.3Hz,1H), 7.02(dd,J=8.5,2.4Hz,1H),6.62(dd,J=3.4,0.6Hz,1H),6.53(dd,J=3.4,1.8Hz,1H),3.68(s,2H),2.21(s,3H).

[0205] N-(4-(furan-2-yl)-2-((methylamino)methyl)phenyl)benzenesulfonamide(I A -38) [ka] HPLC:97.6%, LC-MS(m / z):343.06(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.82-7.73(m,2H),7.61(d,J=1.1Hz,1H),7.42(dd,J=10.6,5.2Hz,4H),7.34(dd,J=8.5,2.1Hz,1H), 7.11(d,J=8.6Hz,1H),6.60(d,J=3.2Hz,1H),6.50(dd,J=3.3,1.8Hz,1H),3.96(s,2H),2.47(s,3H).

[0206] N-(3-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -39) [ka] HPLC:98.4%, LC-MS(m / z):343.17(M+H)+, 1H NMR(500MHz,DMSO)δ 7.83-7.78(m,2H),7.76(d,J=1.7Hz,1H),7.60(dt,J=5.0,4.4Hz,1H),7.55(t,J=7.4Hz,2H),7.46(s,1H),7.3 6(t,J=1.6Hz,1H),7.12(s,1H),6.80(d,J=3.4Hz,1H),6.59(dd,J=3.4,1.8Hz,1H),3.91(s,2H),2.40(s,3H).

[0207] N-(5-(furan-2-yl)-2-((methylamino)methyl)phenyl)benzenesulfonamide(I A -40) [ka] HPLC:99.0%, LC-MS(m / z):343.14(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.80(dd,J=6.6,3.0Hz,2H),7.68(d,J=1.2Hz,1H),7.48-7.39(m,4H),7.09(d,J=7.8Hz,1H),6.9 8(d,J=7.5Hz,1H),6.65(d,J=3.1Hz,1H),6.53(dd,J=3.3,1.8Hz,1H),3.90(s,2H),2.44(s,3H).

[0208] 4-Fluoro-N-(2-(Fran-3-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -41) [ka] HPLC:96.7%, LC-MS(m / z):361.20(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.95(s,1H),7.66(dd,J=7.0,3.5Hz,3H),7.57(d,J=7.3Hz,1H),7.51(d,J=8.0Hz ,1H),7.31(t,J=8.8Hz,2H),7.17(s,1H),6.73(s,1H),4.02(s,2H),2.44(s,3H).

[0209] N-(2-(furan-3-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -42) [ka] HPLC:97.7%, LC-MS(m / z):343.10(M+H)+, 1 H NMR(400MHz,DMSO)δ 8.32(s,1H),7.72-7.64(m,2H),7.62(t,J=1.7Hz,1H),7.50-7.35(m,4H), 7.11(s,1H),6.91(d,J=7.4Hz,1H),6.84(s,1H),3.73(s,2H),2.32(s,3H).

[0210] N-(2-(furan-3-yl)-5-((methylamino)methyl)phenyl)thiophen-3-sulfonamide(I A -43) [ka] HPLC:97.9%, LC-MS(m / z):349.08(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.97(d,J=1.7Hz,1H),7.93(s,1H),7.65(d,J=1.6Hz,1H),7.62(dd,J=5.2,2.9Hz,1H),7.50(d,J=8.1 Hz,1H),7.34(s,1H),7.18(s,1H),7.12(dd,J=5.1,1.4Hz,1H),6.72(s,1H),4.00(s,1H),2.50(s,3H).

[0211] N-(2-(furan-3-yl)-5-((methylamino)methyl)phenyl)thiophen-2-sulfonamide(I A -44) [ka] HPLC:96.6%, LC-MS(m / z):349.07(M+H)+,1 H NMR(400MHz,CD3OD)δ 7.70(s,1H),7.63(dd,J=5.0,1.3Hz,1H),7.46(t,J=1.7Hz,1H),7.41(dt,J=7.8,4.1Hz,2H),7.35(dd,J=3.7,1.3Hz, 1H),7.22(dd,J=8.0,1.8Hz,1H),7.00(dd,J=5.0,3.7Hz,1H),6.50(dd,J=1.9,0.8Hz,1H),3.99(s,2H),2.58(s,3H).

[0212] 4-Fluoro-N-(5-((methylamino)methyl)-2-(thiophen-2-yl)phenyl)benzenesulfonamide (I A -45) [ka] HPLC:98.5%, LC-MS(m / z):377.11(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.66(dd,J=8.6,5.3Hz,2H),7.60(t,J=6.9Hz,2H),7.49(d,J=8.2Hz,1H),7.38(d,J=3.3 Hz, 1H), 7.32 (t, J=8.8Hz, 2H), 7.15 (s, 1H), 7.10-7.03 (m, 1H), 4.04 (s, 2H), 2.48 (s, 3H).

[0213] N-(2-(thiophen-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -46) [ka] HPLC:99.2%, LC-MS(m / z):359.08(M+H)+, 1H NMR(400MHz,DMSO)δ 7.72(dd,J=7.8,1.5Hz,2H),7.61(d,J=8.0Hz,1H),7.50(d,J=3.2Hz,1H),7.45-7.34(m ,4H),7.26(s,1H),7.02(dd,J=5.1,3.8Hz,1H),6.86(s,1H),3.85(s,2H),2.40(s,3H).

[0214] N-(2-(thiophen-2-yl)-5-((methylamino)methyl)phenyl)thiophen-2-sulfonamide(I A -47) [ka] HPLC:98.9%, LC-MS(m / z):365.05(M+H)+, 1 H NMR(400MHz,CD3OD)δ 7.67(dd,J=5.0,1.3Hz,1H),7.60(d,J=1.7Hz,1H),7.50(d,J=8.0Hz,1H),7.42(dd,J=5.1,1.2Hz,1H),7.36(dd,J= 3.8,1.4Hz,1H),7.33-7.29(m,1H),7.02(ddd,J=5.3,3.7,1.8Hz,2H),6.99-6.93(m,1H),4.14(s,2H),2.68(s,3H).

[0215] N-(2-(thiophen-2-yl)-5-((methylamino)methyl)phenyl)thiophen-3-sulfonamide(I A -48) [ka] HPLC:97.4%, LC-MS(m / z):365.07(M+H)+, 1H NMR(400MHz,CD3OD)δ 7.87(dd,J=3.1,1.3Hz,1H),7.56(d,J=1.7Hz,1H),7.51-7.40(m,3H),7.31(dd,J=8.0,1.9Hz, 1H),7.08(dd,J=5.2,1.3Hz,1H),7.02(ddd,J=4.9,4.3,2.4Hz,2H),4.12(s,2H),2.66(s,3H).

[0216] N-(2-(thiophen-3-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -49) [ka] HPLC:96.7%, LC-MS(m / z):359.08(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.68(d,J=1.9Hz,1H),7.64-7.59(m,2H),7.54-7.47(m,2H),7.43(t,J=7.5Hz,2H),7.34(d,J=7 .8Hz,1H),7.29(d,J=5.0Hz,1H),7.10(s,1H),7.05(d,J=7.9Hz,1H),3.70(s,2H),2.29(s,3H).

[0217] N-(5-((methylamino)methyl)-2-(1H-pyrrole-2-yl)phenyl)benzenesulfonamide(I A -50) [ka] HPLC:98.8%, LC-MS(m / z):342.12(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.79-7.69(m,2H),7.50(d,J=8.0Hz,1H),7.44-7.31(m,3H),7.24(s,1H), 6.81(s,2H),6.46(d,J=2.6Hz,1H),6.06(s,1H),3.84(s,2H),2.39(s,3H).

[0218] N-(5-((methylamino)methyl)-2-(thiazole-2-yl)phenyl)benzenesulfonamide (I A -51) [ka] HPLC:98.1%, LC-MS(m / z):360.10(M+H)+, 1 H NMR(400MHz,DMSO)δ 8.20(d,J=8.1Hz,1H),7.85(t,J=4.4Hz,1H),7.79(dt,J=7.5,3.9Hz,2H),7.56(dd,J= 7.8,3.7Hz,2H),7.41-7.32(m,3H),6.72(t,J=23.0Hz,1H),3.94(s,2H),2.47(s,3H).

[0219] N-(5-((methylamino)methyl)-2-(1H-pyrazolyl-4-yl)phenyl)benzenesulfonamide(I A -52) [ka] HPLC:99.4%, LC-MS(m / z):343.12(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.97(s,2H),7.68(d,J=7.4Hz,2H),7.56(t,J=7.3Hz,1H),7.48(t,J=7.1Hz,3H),7.12(d,J=7.7Hz,1H),7.01(s,1H),3.73(s,2H),2.31(s,3H).

[0220] N-(2-(3,5-dimethylisoxazol-4-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -53) [ka] HPLC:97.3%, LC-MS(m / z):372.34(M+H)+, 1H NMR(400MHz,DMSO)δ 7.73(d,J=6.8Hz,2H),7.58-7.45(m,3H),7.09(d,J=7.7Hz,2H),6.98(d,J=7.7Hz,1H),3.70(s,2H),2.30(s,3H),2.20(s,3H),2.06(s,3H).

[0221] N-(5-((methylamino)methyl)-2-(1H-pyrazolyl-5-yl)phenyl)benzenesulfonamide (I A -54) [ka] HPLC:96.0%, LC-MS(m / z):343.16(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.81(d,J=2.2Hz,1H),7.73(d,J=7.4Hz,2H),7.67(d,J=8.0Hz,1H),7.56-7.49(m,2H),7.4 4(t,J=7.5Hz,2H),6.97(d,J=7.9Hz,1H),6.78(d,J=2.2Hz,1H),3.72(s,2H),2.29(s,3H).

[0222] N-(5-((methylamino)methyl)-2-(1H-pyrazolyl-3-yl)phenyl)benzenesulfonamide (I A -55) [ka] HPLC:97.4%, LC-MS(m / z):343.19(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.81(d,J=2.0Hz,1H),7.72(d,J=7.4Hz,2H),7.67(d,J=8.0Hz,1H),7.55-7.48(m,2H),7.4 4(t,J=7.5Hz,2H),6.98(d,J=7.6Hz,1H),6.77(d,J=2.1Hz,1H),3.73(s,2H),2.29(s,3H).

[0223] N-(2-(1-methyl-1H-pyrazole-4-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -56) [ka] HPLC:97.8%, LC-MS(m / z):357.13(M+H)+, 1 H NMR(400MHz,DMSO)δ 8.05(s,1H),7.77(s,1H),7.69(d,J=7.2Hz,2H),7.56(t,J=7.2Hz,1H),7.49(t,J=7.4Hz, 2H), 7.43(d,J=8.3Hz,1H),7.06(d,J=5.2Hz,2H),3.86(s,3H),3.72(s,2H),2.32(s,3H).

[0224] N-(5-((methylamino)methyl)-2-(1,3,5-trimethyl-1H-pyrazole-4-yl)phenyl)benzenesulfonamide (I A -57) [ka] HPLC:98.1%, LC-MS(m / z):385.16(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.77(d,J=7.3Hz,2H),7.64(t,J=7.4Hz,1H),7.55(t,J=7.5Hz,2H),7.20(d,J=5.7Hz,2H) ,7.07(d,J=8.2Hz,1H),3.84(s,2H),3.67(s,3H),2.38(s,3H),1.94(s,3H),1.90(s,3H).

[0225] N-(2-(3,5-dimethyl-1H-pyrazole-4-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -58) [ka] HPLC:98.5%, LC-MS(m / z):371.15(M+H)+,1 H NMR(400MHz,DMSO)δ 7.82(t,J=8.6Hz,2H),7.66(t,J=7.4Hz,1H),7.56(dd,J=18.5,11.1Hz,2H),7.28(t,J= 9.2Hz, 1H), 7.21 (s, 1H), 7.15 (t, J=9.5Hz, 1H), 3.99 (s, 2H), 2.48 (s, 3H), 1.95 (s, 6H).

[0226] N-(5-((methylamino)methyl)-2-(5-methylthiazole-2-yl)phenyl)benzenesulfonamide (I A -59) [ka] HPLC:99.3%, LC-MS(m / z):374.19(M+H)+, 1 H NMR(400MHz,DMSO)δ 8.09(t,J=7.6Hz,1H),7.77(dd,J=6.5,3.0Hz,2H),7.58-7.45(m,2H),7.43 -7.32(m,3H),6.75(d,J=7.7Hz,1H),3.90(s,2H),2.47(s,3H),2.44(s,3H).

[0227] N-(2-(1-methyl-1H-imidazole-5-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -60) [ka] HPLC:99.4%, LC-MS(m / z):357.13(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.64(dd,J=9.5,8.2Hz,3H),7.50(t,J=7.2Hz,1H),7.44(t,J=7.3Hz,2H),7.28(d,J=1.1Hz,1H),7.11(d, J=7.7Hz,1H),6.94(d,J=7.4Hz,1H),6.67(d,J=0.7Hz,1H),3.78(s,2H),3.40-3.34(s,3H),2.36(s,3H).

[0228] N-(2-(1H-imidazole-5-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide(I A -61) [ka] HPLC:98.3%, LC-MS(m / z):343.13(M+H)+, 1 H NMR(400MHz,DMSO)δ 8.00(s,1H),7.69(d,J=9.0Hz,3H),7.62(d,J=8.0Hz,1H),7.56-7.51(m,2H ),7.43(t,J=7.7Hz,2H),6.99(t,J=10.5Hz,1H),3.71(s,2H),2.28(s,3H).

[0229] N-(2-(furan-2-yl)-5-((2,2,2-trifluoroethyl)amino)methyl)phenyl)benzenesulfonamide(I A -62) [ka] HPLC:99.3%, LC-MS(m / z):411.35(M+H)+, 1 H NMR(400MHz,DMSO)δ 9.66(s,1H),7.72(dd,J=4.4,2.6Hz,3H),7.69-7.61(m,2H),7.55(t,J=7.6Hz,2H),7.29(d,J=8.0Hz,1H),6.97(d,J=3 .3Hz,1H),6.90(s,1H),6.58(dd,J=3.3,1.8Hz,1H),3.68(d,J=3.5Hz,2H),3.10(dt,J=15.5,7.8Hz,2H),2.85(s,1H).

[0230] Example 2 Compound I C Synthesis of: N-(2-(furan-2-yl)-5-((hydroxyimino)methyl)phenyl)benzenesulfonamide (I C -1) [ka] Intermediate VI-4 (65.5 mg, 0.2 mmol) is dissolved in 10 mL of ethanol solution, and 1 mL of hydroxyamine aqueous solution (50 wt%) is added. The reaction is carried out overnight at room temperature. After the reaction is complete, the solvent is evaporated and the residue is separated by column chromatography to obtain compound I, which is a yellow solid. C -1 (32.9 mg, 47.6%) was obtained. HPLC:99.2%, LC-MS(m / z):343.13(M+H)+, 1 H NMR(500MHz,DMSO)δ 11.33(s,1H),9.74(s,1H),8.01(s,1H),7.74-7.66(m,4H),7.62(t,J=7.4Hz,1H),7.53(t,J=7.6Hz,2H) ,7.48(dd,J=8.2,1.5Hz,1H),7.20(d,J=1.5Hz,1H),7.01(d,J=3.4Hz,1H),6.58(dd,J=3.4,1.8Hz,1H).

[0231] I C The following compounds are obtained using the same method as in the synthesis of -1. N-(2-(furan-2-yl)-5-((methoxyimino)methyl)phenyl)benzenesulfonamide (I C -2) [ka] HPLC:97.5%, LC-MS(m / z):357.01(M+H)+, 1 H NMR(400MHz,DMSO)δ 9.76(s,1H),8.02(d,J=5.7Hz,2H),7.73(dd,J=19.4,9.4Hz,5H),7.61(t,J=7.2 Hz,1H),7.52(t,J=7.6Hz,2H),7.06(d,J=3.3Hz,1H),6.59(s,1H),3.74(s,3H).

[0232] Example 3 Compound I D Synthesis of: N-(5-(aminomethyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I D -1) [ka] Intermediate V-4 (64.9 mg, 0.2 mmol) is dissolved in 5 mL of ammonia-methanol solution, an appropriate amount of Raney nickel aqueous solution is added, hydrogen gas is passed through, and the mixture is left at room temperature overnight. Workup: Raney nickel is removed by suction filtration, the filtrate is evaporated and dried, and the residue is separated by column chromatography to obtain compound I, a white solid. D -1 (44.3 mg, 63.8%) was obtained. HPLC:99%, LC-MS(m / z):329.10(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.71(dd,J=7.7,1.4Hz,2H),7.61(d,J=8.1Hz,2H),7.39(q,J=6.2Hz,3H),7 .29(s,2H),6.90(d,J=7.2Hz,1H),6.50(dd,J=3.1,1.8Hz,1H),3.81(s,2H).

[0233] I D The following compounds are obtained using the same method as in the synthesis of -1. N-(5-(aminomethyl)-2-(furan-2-yl)phenyl)-4-fluorobenzenesulfonamide(I D -2) [ka] HPLC:98.7%, LC-MS(m / z):347.09(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.74(dd,J=8.7,5.6Hz,2H),7.60(d,J=8.7Hz,2H),7.36(s,1H),7.30(s,1H),7.18 (t,J=8.9Hz,2H),6.83(d,J=7.6Hz,1H),6.50(dd,J=3.2,1.8Hz,1H),3.81(s,2H).

[0234] N-(5-(aminomethyl)-2-(furan-2-yl)phenyl)thiophen-3-sulfonamide(I D -3) [ka] HPLC:99.3%, LC-MS(m / z)335.04(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.81-7.75(m,1H),7.59(d,J=8.0Hz,2H),7.47-7.41(m,2H),7.36(s,1H),7.15(dd, J=5.0,1.1Hz,1H),6.74(d,J=8.1Hz,1H),6.50(dd,J=3.2,1.8Hz,1H),3.79(s,2H).

[0235] N-(4-(aminomethyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I D -4) [ka] HPLC:98.2%, LC-MS(m / z):329.15(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.70-7.64(m,3H),7.60(d,J=0.9Hz,1H),7.54(d,J=3.1Hz,1H),7.37-7.31(m,3H),7.14 (d,J=8.4Hz,1H),6.87(dd,J=8.5,2.2Hz,1H),6.52(dd,J=3.2,1.8Hz,1H),3.82(s,2H).

[0236] N-(4-(aminomethyl)-2-(furan-2-yl)phenyl)thiophen-3-sulfonamide(I D -5) [ka] HPLC:97.5%, LC-MS(m / z):335.06(M+H)+, 1H NMR(400MHz,DMSO)δ 8.09(d,J=1.8Hz,1H),7.87(d,J=1.5Hz,1H),7.80(s,1H),7.75(dd,J=5.0,3.0Hz,1H),7.33(dd,J=8.2,1.5Hz,1H),7 .29(d,J=4.3Hz,1H),7.05(d,J=3.3Hz,1H),6.95(d,J=8.2Hz,1H),6.64(dd,J=3.2,1.7Hz,1H),4.02(d,J=3.7Hz,2H).

[0237] N-(4-(aminomethyl)-2-(furan-2-yl)phenyl)-4-fluorobenzenesulfonamide(I D -6) [ka] HPLC:98.9%, LC-MS(m / z):347.11(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.67(dt,J=11.6,5.8Hz,2H),7.63(d,J=2.0Hz,1H),7.57(s,1H),7.51(d,J=3.0Hz,1H), 7.16-7.08(m,3H),6.85(dd,J=8.5,2.0Hz,1H),6.49(dd,J=3.1,1.8Hz,1H),3.80(s,2H).

[0238] N-(4-(aminomethyl)-2-(1H-pyrazole-3-yl)phenyl)thiophene-3-sulfonamide(I D -7) [ka] HPLC:97.9%, LC-MS(m / z):335.11(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.96(s,1H),7.71(s,1H),7.65(s,1H),7.55-7.46(m,1H),7.40(d,J=8.4Hz, 1H), 7.14(d,J=4.9Hz,1H),7.07(d,J=8.0Hz,1H),6.70(s,1H),3.84(s,2H).

[0239] N-(5-(aminomethyl)-2-(1H-pyrazole-3-yl)phenyl)thiophene-3-sulfonamide(I D -8) [ka] HPLC:97.6%, LC-MS(m / z)335.16(M+H)+, 1 H NMR(400MHz,DMSO)δ 8.10(d,J=1.9Hz,1H),7.70(dd,J=9.0,4.8Hz,2H),7.59-7.49(m,2H),7.17 (d,J=5.1Hz,1H),6.96(d,J=7.8Hz,1H),6.77(d,J=1.6Hz,1H),3.84(s,2H).

[0240] Example 4 Compound I E Synthesis of: N-(3-(furan-2-yl)-4-(thiophen-3-sulfonamide)benzyl)acetamide(I E ) [ka] Compound I D Compound I (66.8 mg, 0.2 mmol) was dissolved in 10 mL of dichloromethane solution, and acetic anhydride (26.5 mg, 0.26 mmol) and triethylamine (60.7 mg, 0.6 mmol) were added. The mixture was reacted overnight at room temperature. After the reaction was complete, the solvent was evaporated, and the residue was separated by column chromatography to obtain the white solid compound I. E (35.1 mg, 46.6%) was obtained. HPLC:98.8%, LC-MS(m / z):377.08(M+H)+, 1H NMR(400MHz,CDCl3)δ 7.70(dd,J=3.0,1.2Hz,1H),7.62(d,J=8.3Hz,1H),7.49(d,J=1.2Hz,1H),7.31(d,J=1.7Hz,1H),7.22-7 .16(m,2H),6.99(dd,J=5.2,1.2Hz,1H),6.49-6.38(m,2H),4.40(d,J=5.8Hz,2H),2.04(d,J=3.1Hz,3H).

[0241] Example 5 Compound I B Synthesis of: Stage 1: N-(4-cyano-2-(furan-2-yl)phenyl)-N-methylthiophen-3-sulfonamide(VII-1) [ka] Intermediate V-30 (1.3 g, 3.93 mmol) and potassium carbonate (2.2 g, 15.9 mmol) are dissolved in 20 mL of acetonitrile solution, iodomethane (1.7 g, 12.0 mmol) is added, and the mixture is reacted at 75°C for 3 hours. After the reaction is complete, the solvent is evaporated and the residue is separated by column chromatography to obtain the off-white solid intermediate VII-1 (0.7 g, 2.0 mmol). 1 H NMR(400MHz,DMSO)δ 8.33-8.29(m,1H),8.27(d,J=1.8Hz,1H),7.90(dd,J=5.1,2.9Hz,2H),7.77(dd,J=8.3,1.8Hz,1H),7.34(dd ,J=5.1,0.9Hz,1H),7.23(d,J=3.4Hz,1H),6.99(d,J=8.3Hz,1H),6.74(dd,J=3.3,1.7Hz,1H),3.18(s,3H).

[0242] Stages 2-4: N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)-N-methylthiophen-3-sulfonamide(I B ) [ka] I A Using a method similar to that used for the synthesis of -1, compound I, an off-white solid, was synthesized. B (90 mg, 36.5%) is obtained. HPLC:99.1%, LC-MS(m / z)363.15(M+H)+, 1 H NMR(400MHz,DMSO)δ 8.27(dt,J=8.2,4.1Hz,1H),7.95(d,J=1.7Hz,1H),7.90(dd,J=5.1,3.0Hz,1H),7.85(d,J=1.4Hz,1H),7.37-7.28(m, 2H), 7.14(d,J=3.4Hz,1H),6.75(d,J=8.1Hz,1H),6.71(dd,J=3.4,1.8Hz,1H),3.92(s,2H),3.17(s,3H),2.44(s,3H).

[0243] Example 6 Compound I F Synthesis of: N-(4-(aminomethyl)-2-(furan-2-yl)phenyl)-N-methylthiophen-3-sulfonamide(I F ) [ka] I D Using a method similar to the synthesis of compound I, an off-white solid was synthesized. F (35.6 mg, 31.3%) was obtained. HPLC:99.4%, LC-MS(m / z)349.11(M+H)+, 1 H NMR(400MHz,DMSO)δ 8.26(dd,J=2.9,1.2Hz,1H),7.91-7.86(m,2H),7.82(s,1H),7.35(dd,J=5.1,1.2Hz,1H),7.23(dd,J= 8.1,1.7Hz,1H),7.11(d,J=3.3Hz,1H),6.68(t,J=5.6Hz,2H),3.79(s,2H),3.16(s,3H),2.33(s,2H).

[0244] Example 7 Compound I G Synthesis of: 4-(furan-2-yl)-3-(benzenesulfonamide)methyl(I G ) [ka] Using a method similar to that used for the synthesis of V-1, the yellow solid compound I was synthesized. G (810 mg, 32.1%) was obtained. HPLC:98.9%, LC-MS(m / z)358.08(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.84(dd,J=21.9,11.2Hz,3H),7.70(d,J=7.7Hz,2H),7.64(t,J=7.2Hz,1H),7.5 5(t,J=7.5Hz,2H),7.42(s,1H),7.17(d,J=3.3Hz,1H),6.63(s,1H),3.84(s,3H).

[0245] Example 8 Compound I H Synthesis of: N-(2-(furan-2-yl)-5-(hydroxymethyl)phenyl)benzenesulfonamide (I H ) [ka] Compound I G Dissolve (500 mg, 1.4 mmol) in 10 mL of anhydrous tetrahydrofuran solution, and under nitrogen gas protection conditions, add lithium aluminum tetrahydride (213 mg, 5.6 mmol) at 0°C and react at room temperature for 1 hour. After the reaction is complete, sequentially add 213 μL of water, 213 μL of aqueous sodium hydroxide solution (15% wt), and 639 μL of water to the system, filter, evaporate and dry the filtrate, and separate the residue by column chromatography to obtain compound I, a yellow oily substance. H (270 mg, 58.6%) was obtained. HPLC:97.0%, LC-MS(m / z):330.11(M+H)+, 1H NMR(400MHz,DMSO)δ 9.66(s,1H),7.71(dd,J=5.2,3.3Hz,3H),7.64(ddd,J=6.4,4.2,2.5Hz,2H),7.55(dd,J=10.4,4.7Hz,2H),7.26(dd, J=8.1,1.6Hz,1H),6.94(d,J=2.9Hz,2H),6.57(dd,J=3.4,1.8Hz,1H),5.22(t,J=5.7Hz,1H),4.40(d,J=5.5Hz,2H).

[0246] Example 9 Compound I J Synthesis of: N-(4-((dimethylamino)methyl)-2-(furan-2-yl)phenyl)thiophen-3-sulfonamide(I J -1) [ka] N-(2-(furan-2-yl)-4-(hydroxymethyl)phenyl)thiophene-3-sulfonamide (1.68 g, 5 mmol) is dissolved in 50 mL of dichloromethane solution, and triphenylphosphine (1.97 g, 7.5 mmol) and carbon tetrabromide (2.49 g, 7.5 mmol) are added under ice bath conditions. The mixture is reacted at room temperature for 2 hours, the solvent is evaporated, and the residue is dissolved in 20 mL of N,N-dimethylformamide solution. Dimethylamine hydrochloride (0.82 g, 10 mmol) and potassium carbonate (0.83 g, 6 mmol) are added, and the mixture is reacted overnight at 80°C. After workup, water is added to the system, and it is extracted three times with ethyl acetate. The mixture is washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by column chromatography to obtain compound I, a yellow solid. J -1 (105 mg, 5.8%) is obtained. HPLC:96.6%, LC-MS(m / z):363.08(M+H)+, 1H NMR(500MHz,DMSO)δ 8.00(dd,J=2.9,1.2Hz,1H),7.71(t,J=3.5Hz,1H),7.70-7.63(m,2H),7.24-7.20(m,1H) ,7.11-7.07(m,2H),6.90(t,J=8.1Hz,1H),6.60-6.56(m,1H),3.50(s,2H),2.23(s,6H).

[0247] N-(4-((3-fluoroazetidine-1-yl)methyl)-2-(furan-2-yl)phenyl)thiophene-3-sulfonamide(I J -2) [ka] I J Using a method similar to that used for the synthesis of -1, the yellow solid compound I was synthesized. J -2 (84 mg, 4.1%) was obtained. HPLC:98.3%, LC-MS(m / z):393.09(M+H)+, 1 H NMR(500MHz,DMSO)δ 8.04(dd,J=2.9,1.1Hz,1H),7.77-7.67(m,2H),7.61(d,J=1.6Hz,1H),7.23(dd,J=5.1,1.2Hz,1H),7.09(dd,J=8.1,1.7Hz,1H),7.01(d,J= 3.3Hz,1H),6.84(d,J=8.1Hz,1H),6.59(dd,J=3.3,1.8Hz,1H),3.63(s,2H),3.60-3.48(m,2H),3.14(d,J=22.3Hz,2H),2.05-1.92(m,1H).

[0248] Example 10 Compound I P Synthesis of: 4-(furan-2-yl)-N-methyl-3-(phenylsulfonamide)benzamide(I P -1) [ka] Compound I G(0.71g, 2 mmol) is dissolved in 10 mL of ethanol solution, and a methylamine ethanol solution (2 mL, 30-33 wt%) is added. The mixture is reacted at 60°C for 4 hours. After post-treatment, the residue is subjected to column chromatography (petroleum ether:ethyl acetate = 1:3) to obtain compound I, which is a yellow solid. P -1 (64 mg, 9.0%) was obtained. HPLC:97.7%, LC-MS(m / z):357.09(M+H)+, 1 H NMR(400MHz,DMSO)δ 9.83(s,1H),8.46(d,J=4.5Hz,1H),7.81-7.71(m,3H),7.66(d,J=7.7Hz,2H),7.61(t,J=7.2Hz ,1H),7.51(dd,J=13.8,5.9Hz,3H),7.05(d,J=3.3Hz,1H),6.58(s,1H),2.74(d,J=4.4Hz,3H).

[0249] I P The following compounds are obtained using the same method as in the synthesis of -1. 4-(furan-2-yl)-3-(benzenesulfonamide)benzamide(I P -2) [ka] HPLC:98.2%, LC-MS(m / z):343.11(M+H)+, 1 H NMR(400MHz,DMSO)δ 9.79(s,1H),7.94(s,1H),7.76(d,J=8.2Hz,1H),7.70(d,J=8.5Hz,2H),7.62(d,J=8.2Hz,2H),7.57( t,J=6.9Hz,1H),7.52-7.42(m,3H),7.33(s,1H),7.03(d,J=3.5Hz,1H),6.55(dt,J=2.9,1.4Hz,1H).

[0250] N-(2-(furan-2-yl)-5-(hydrazinocarbonyl)phenyl)benzenesulfonamide (I P -3) [ka] HPLC:97.5%, LC-MS(m / z):358.04(M+H)+, 1 H NMR(400MHz,DMSO)δ 9.77(s,2H),7.73-7.71(m,1H),7.69(s,2H),7.66-7.62(m,2H),7.58(t,J=7.4Hz,1H),7 .48(t,J=7.8Hz,2H),7.43(s,1H),7.04(d,J=3.4Hz,1H),6.58-6.52(m,1H),4.47(s,2H).

[0251] Example 11 Compound I K Synthesis of: 4-(furan-2-yl)-3-(benzenesulfonamide)benzoic acid (I K ) [ka] Compound I G (0.36 g, 1 mmol) is dissolved in 10 mL of tetrahydrofuran solution, 10 mL of lithium hydroxide aqueous solution (50% wt) is added, and the mixture is reacted overnight at 50°C. After the reaction is complete, the solvent is evaporated and dried, an appropriate amount of dilute hydrochloric acid is added to the system to adjust the pH to 3-4, the mixture is extracted three times with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by column chromatography to obtain compound I, a white solid. K (0.12g, 34.9%) is obtained. HPLC:99.1%, LC-MS(m / z):344.06(M+H)+, 1 H NMR(400MHz,DMSO)δ 12.99(s,1H),9.89(s,1H),7.84(dd,J=21.9,11.2Hz,3H),7.70(d,J=7.7Hz,2H),7.64( t,J=7.2Hz,1H),7.55(t,J=7.5Hz,2H),7.42(s,1H),7.17(d,J=3.3Hz,1H),6.63(s,1H).

[0252] Example 12 Compound I Q Synthesis of: Stage 1: 3-Nitro-4-(1H-pyrrole-1-yl)methyl benzoate (XIII-1) [ka] Methyl 4-fluoro-3-nitrobenzoate (2.0 g, 10.0 mmol), pyrrole (2 g, 29.8 mmol), and sodium hydroxide (0.56 g, 14.0 mmol) were dissolved in 5 mL of anhydrous dimethyl sulfoxide solution and reacted overnight at 50°C under nitrogen gas protection. After workup, water was added to the system, extracted with ethyl acetate, dried over sodium sulfate, the solvent was evaporated, and the residue was separated by column chromatography to obtain the yellow solid intermediate XIII-1 (700 mg, 28.3%). 1 H NMR(400MHz,DMSO)δ 8.51(d,J=3.2Hz,1H),8.38-8.25(m,1H),7.84(dd,J=8.1,5.3Hz,1H),7.06(d,J=2.3Hz,2H),6.36(d,J=2.2Hz,2H),3.96(s,3H).

[0253] Stage 2: 3-amino-4-(1H-pyrrole-1-yl)methyl benzoate (XIV-1) [ka] Intermediate XIII-1 (0.7 g, 2.84 mmol) is dissolved in 20 mL of a mixed solution of ethanol and water (v / v=1:1). Iron powder (0.8 g, 14.2 mmol) and ammonium chloride (0.76 g, 14.2 mmol) are added to the system, and the mixture is reacted at 75°C for 1 hour. Workup: The mixture is filtered, the filtrate is concentrated, extracted with dichloromethane, dried over sodium sulfate, the solvent is evaporated, and the mixture is subjected to column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a yellow solid XIV-1 (540 mg, 87.8%). 1H NMR(400MHz,DMSO)δ 7.56(d,J=1.3Hz,1H),7.27(dd,J=8.1,1.5Hz,1H),7.20(d,J=8.1Hz,1H),7.03(s,2H),6.33(s,2H),5.23(s,2H),3.88(s,3H).

[0254] Stages 3-4: N-(5-(hydroxymethyl)-2-(1H-pyrrole-1-yl)phenyl)benzenesulfonamide (XVI-1) [ka] I H Using a method similar to that used for the synthesis of the previous compound, a yellow solid intermediate XVI-1 (270 mg, 58.6%) was obtained. 1 H NMR(400MHz,DMSO)δ 7.90(dd,J=8.3,1.4Hz,1H),7.71-7.61(m,4H),7.57(t,J=7.7Hz,2H),7.49(d,J=8.3Hz,1H),7.03(s,2H),6.27(s,2H),3.84(s,3H).

[0255] Stage 5: N-(5-formyl-2-(1H-pyrrole-1-yl)phenyl)benzenesulfonamide (XVII-1) [ka] Intermediate XVI-1 (270 mg, 0.82 mmol) is dissolved in 10 mL of anhydrous dichloromethane solution, and 204 mg of pyridinium chlorochromate (204 mg, 0.95 mmol) is added. The mixture is reacted at room temperature for 1 hour. After the reaction is complete, the mixture is filtered by suction, the filtrate is evaporated and dried, and the residue is separated by column chromatography to obtain intermediate XVII-1 (160 mg, 59.8%), a yellow oily substance. 1H NMR(500MHz,DMSO)δ 10.06(s,1H),9.90(s,1H),7.87(dd,J=8.2,1.8Hz,1H),7.70-7.60(m,3H), 7.53(ddd,J=8.3,6.5,2.8Hz,4H),7.01(t,J=2.2Hz,2H),6.32-6.19(m,2H).

[0256] Stage 6: N-(5-((methylamino)methyl)-2-(1H-pyrrole-1-yl)phenyl)benzenesulfonamide (I Q -1) [ka] I A Using a method similar to that used for the synthesis of -1, compound I, a white solid, was synthesized. Q -1 (130 mg, 77.7%) was obtained. HPLC:99.2%, LC-MS(m / z):342.15(M+H)+, 1 H NMR(500MHz,DMSO)δ 7.63(dd,J=8.6,7.0Hz,2H),7.44-7.35(m,3H),7.27(d,J=1.8Hz,1H),7.07(d,J=8.0Hz,1H),6.9 5(t,J=2.1Hz,2H),6.83(dd,J=8.0,1.7Hz,1H),6.09(t,J=2.1Hz,2H),3.74(s,2H),2.33(s,3H).

[0257] I Q The following compounds are obtained using the same method as in the synthesis of -1. N-(5-((methylamino)methyl)-2-(1H-pyrazolyl-1-yl)phenyl)benzenesulfonamide(I Q -2) [ka] HPLC:99.5%, LC-MS(m / z):343.10(M+H)+, 1H NMR(400MHz,DMSO)δ 8.53(s,1H),7.70(s,1H),7.63(d,J=7.2Hz,2H),7.54(d,J=8.2Hz,1H),7.49(s,1H),7.4 0(dt,J=23.4,7.0Hz,3H),6.91(d,J=8.0Hz,1H),6.43(s,1H),3.87(s,2H),2.41(s,3H).

[0258] N-(5-((methylamino)methyl)-2-(2H-1,2,3-triazole-2-yl)phenyl)benzenesulfonamide (I Q -3) [ka] HPLC:98.9%, LC-MS(m / z):344.09(M+H)+, 1 H NMR(400MHz,DMSO)δ 8.03(s,2H),7.62(d,J=7.5Hz,2H),7.50(s,1H),7.44(t,J=7.1Hz,1H),7.37(t,J= 7.5Hz,2H),7.32(d,J=8.1Hz,1H),6.94(d,J=8.1Hz,1H),3.84(s,2H),2.38(s,3H).

[0259] N-(5-((methylamino)methyl)-2-(1H-1,2,3-triazole-1-yl)phenyl)benzenesulfonamide(I Q -4) [ka] HPLC:97.5%, LC-MS(m / z):344.05(M+H)+, 1 H NMR(400MHz,DMSO)δ 8.65(s,1H),7.85(s,1H),7.76-7.68(m,2H),7.56-7.46(m,2H),7.39(d,J=4.7Hz,3H),6.81(d,J=7.8Hz,1H),3.97(s,2H),2.48(s,3H).

[0260] Example 13 Compound I RSynthesis of: Stage 1: 2-(4-amino-3-bromophenyl)acetonitrile (XVIII-1) [ka] P-aminophenylacetonitrile (5.0 g, 37.83 mmol) is dissolved in 50 mL of acetonitrile solution, N-bromosuccinimide (6.7 g, 37.83 mmol) is added to the system, and the reaction is allowed to proceed at room temperature for 30 minutes. The completion of the reaction of the starting materials is monitored by TLC. Workup: The solvent is evaporated and subjected to column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain the title compound, intermediate XVIII-1 (7.3 g, 91.4%), a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ 7.40(d,J=1.7Hz,1H),7.09(dd,J=8.2,1.9Hz,1H),6.79(d,J=8.2Hz,1H),3.65(s,2H).

[0261] Stages 2-4: N-(4-(2-aminoethyl)-2-(furan-2-yl)phenyl)thiophen-3-sulfonamide(I R ) [ka] I A Using a method similar to that used for the synthesis of -1, the light brown solid compound I was synthesized. R (2.1g, 90.22%) is obtained. HPLC:98.0%, LC-MS(m / z):349.07(M+H)+, 1H NMR(400MHz,DMSO)δ8.08(dd,J=3.0,1.3Hz,1H),7.77(d,J=1.2Hz,1H),7.75(dd,J=5.1,3.0Hz,1H),7.62(d,J=2.0Hz,1H),7.29(dd,J=5.1,1.3 Hz,1H),7.14(dd,J=8.2,2.0Hz,1H),7.05(d,J=3.4Hz,1H),6.88(d,J=8.2Hz,1H),6.62(dd,J=3.4,1.8Hz,1H),3.06(s,2H),2.97-2.89(m,2H).

[0262] Example 14 Compound I S Synthesis of: Stage 1: 3-(furan-2-yl)-4-(thiophen-3-sulfonamide)phenylethylcarbamate t-butyl (XX-1) [ka] Compound I R (600 mg, 1.72 mmol) is dissolved in 35 mL of a mixed solution of dichloromethane / methanol (vol / vol = 6:1), and di-t-butyl dicarbonate (530 mg, 2.43 mmol) is added. The mixture is reacted overnight at room temperature. After the reaction is complete, the solvent is evaporated and the residue is separated by column chromatography to obtain a colorless oily intermediate XX-1 (520 mg, 67.40%). 1 H NMR(400MHz,DMSO)δ 8.06(dd,J=3.0,1.3Hz,1H),7.77-7.72(m,2H),7.56(d,J=1.9Hz,1H),7.27(dd,J=5.1,1.2Hz,1H),7.09-7.01(m,2H),6.92(t,J= 5.4Hz,1H),6.83(d,J=8.1Hz,1H),6.62(dd,J=3.4,1.8Hz,1H),3.17(dd,J=13.5,6.6Hz,2H),2.72(t,J=7.2Hz,2H),1.38(s,9H).

[0263] Stage 2: N-(2-(furan-2-yl)-4-(2-(methylamino)ethyl)phenyl)thiophen-3-sulfonamide(I S ) [ka] Intermediate XX-1 (520 mg, 1.16 mmol) is dissolved in 30 mL of tetrahydrofuran solution, lithium aluminum tetrahydride (221 mg, 5.82 mmol) is added at 0°C, and the reaction is carried out overnight at 80°C. After the reaction is complete, 221 μL of water, 221 μL of aqueous sodium hydroxide solution (10% wt), and 221 μL of water are sequentially added to the system, filtered by suction, the filtrate is evaporated and dried, and the residue is separated by column chromatography to obtain compound I, a light brown solid. S (70 mg, 16.65%) is obtained. HPLC:97.3%, LC-MS(m / z):363.10(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.79(d,J=1.9Hz,1H),7.64(s,1H),7.53-7.47(m,2H),7.41(d,J=3.2Hz,1H),7.19-7.15(m,1H),7.12(d,J=8.3Hz ,1H),6.84(dd,J=8.3,2.1Hz,1H),6.55(dd,J=3.2,1.8Hz,1H),3.01-2.93(m,2H),2.78-2.71(m,2H),2.50(s,3H).

[0264] Example 15 Compound I U Synthesis of: Stage 1: N-(4-((t-butylsulfoxide)imino)methyl)-2-(furan-2-yl)phenyl)-N-methylbenzenesulfonamide (XXII-1) [ka] Intermediate N-(4-formyl-2-(furan-2-yl)phenyl)-N-toluenesulfonamide (VIII-2) (682.8 mg, 2.0 mmol), t-butylsulfenamide (266.6 mg, 2.2 mmol), and copper sulfate (478.8 mg, 3.0 mmol) were dissolved in 30 mL of anhydrous 1,2-dichloroethane solution, heated to 85°C, and reacted overnight. After the reaction was complete, the system was cooled to room temperature, filtered by suction, the filtrate was concentrated, and the residue was separated by column chromatography to obtain the off-white solid intermediate XXII-1 (683.4 mg, 76.9%). 1 H NMR(400MHz,DMSO)δ 8.64(s,1H),8.43(d,J=1.8Hz,1H),7.88(d,J=1.3Hz,1H),7.81(ddd,J=14.7,7.9,4.7Hz,4H),7.72(t,J=7.6 Hz,2H),7.22(d,J=3.4Hz,1H),6.89(d,J=8.2Hz,1H),6.74(dd,J=3.4,1.8Hz,1H),3.19(s,3H),1.24(s,9H).

[0265] Stage 2: N-(4-(1-(t-butylsulfoxide)amino)ethyl)-2-(furan-2-yl)phenyl)-N-toluenesulfonamide (XXIII-1) [ka] Intermediate XXII-1 (666.8 mg, 1.5 mmol) is dissolved in 30 mL of anhydrous tetrahydrofuran solution, and 1.5 mL of methylmagnesium bromide tetrahydrofuran solution (1 M / L, 1.5 mmol) is slowly added dropwise at -78°C. After the addition is complete, the temperature is slowly raised to -20°C and the reaction is allowed to proceed for 6 hours. After the reaction is complete, an aqueous solution of amine chloride is added to the system under ice bath conditions to quench it, water is added, the mixture is extracted three times with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by column chromatography to obtain the yellow solid intermediate XXIII-1 (425.4 mg, 61.6%). 1H NMR(400MHz,DMSO)δ 7.95(d,J=1.7Hz,1H),7.85-7.76(m,4H),7.72(t,J=7.6Hz,2H),7.28(dt,J=12.4,6.2Hz,1H),7.14(d,J=3.4Hz,1 H),6.73-6.65(m,2H),5.84(d,J=7.3Hz,1H),4.52-4.42(m,1H),3.16(s,3H),1.46(d,J=6.8Hz,3H),1.18(s,9H).

[0266] Stage 3: N-(4-(1-aminoethyl)-2-(furan-2-yl)phenyl)-N-toluenesulfonamide (I U -1) [ka] Intermediate XXIII-1 (368.5 mg, 0.8 mmol) is dissolved in 20 mL of ethanol solution, and 2 mL of hydrochloric acid in ethanol solution (2 M / L, 4.0 mmol) is added. The mixture is reacted at 60°C for 2 hours. After the reaction is complete, the solvent is evaporated, water is added to the residue, and an appropriate amount of sodium bicarbonate aqueous solution is added to adjust the pH to 8-9. The mixture is extracted three times with ethyl acetate, washed with water, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by column chromatography to obtain compound I, an off-white solid. U -1 (180.1 mg, 63.2%) was obtained. HPLC:99.1%, LC-MS(m / z): 357.62(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.90(d,J=1.6Hz,1H),7.83-7.74(m,4H),7.70(t,J=7.6Hz,2H),7.24(dd,J=8.2,1.7Hz,1H),7.12(d,J=3.3Hz, 1H),6.69(dd,J=3.3,1.7Hz,1H),6.61(d,J=8.2Hz,1H),4.13-3.95(m,1H),3.14(s,3H),1.28(d,J=6.6Hz,3H).

[0267] I U The following compounds are obtained using the same method as in the synthesis of -1. N-(4-(1-aminoethyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I U -2) [ka] HPLC:99.3%, LC-MS(m / z):343.52(M+H)+, 1 H NMR(400MHz,CDCl3)δ 7.57(t,J=7.2Hz,3H),7.43(dd,J=14.5,7.0Hz,2H),7.35(d,J=1.7Hz,1H),7.32-7.24(m,3H),6 .40(dd,J=3.2,1.8Hz,1H),6.34(d,J=3.3Hz,1H),4.09(q,J=6.5Hz,1H),1.36(d,J=6.6Hz,3H).

[0268] N-(4-(1-aminopropyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I U -3) [ka] HPLC:99.1%, LC-MS(m / z):357.55(M+H)+, 1 H NMR(400MHz,CDCl3)δ 7.78-7.69(m,4H),7.56-7.45(m,3H),7.29(d,J=3.0Hz,1H),7.17-7.11(m,1H),7.06(d,J=8.4H) z,1H),6.59(dd,J=3.3,1.8Hz,1H),4.10-4.00(m,1H),1.98-1.73(m,2H),0.78(t,J=7.4Hz,3H).

[0269] N-(4-(1-aminobutyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I U -4) [ka] HPLC:99.3%, LC-MS(m / z):371.45(M+H)+, 1H NMR(400MHz,DMSO)δ 7.79-7.69(m,4H),7.51(dq,J=14.4,7.1Hz,3H),7.28(d,J=2.9Hz,1H),7.15(d,J=6.9Hz,1H),7.05(d,J=8.4Hz,1H),6.60(dd, J=3.2,1.8Hz,1H),4.14(dd,J=9.1,5.9Hz,1H),1.92-1.69(m,2H),1.18(ddd,J=32.6,16.7,8.4Hz,2H),0.86(t,J=7.3Hz,3H).

[0270] N-(4-(1-amino-2-methylpropyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I U -5) [ka] HPLC:99.1%, LC-MS(m / z):371.62(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.78-7.67(m,4H),7.57-7.44(m,3H),7.29(d,J=2.7Hz,1H),7.11-7.01(m,2H),6.59(dd,J=3.3,1.8Hz ,1H),3.86(d,J=8.4Hz,1H),2.06(td,J=14.5,7.5Hz,1H),1.02(d,J=6.6Hz,3H),0.73(d,J=6.7Hz,3H).

[0271] N-(4-(amino(cyclopropyl)methyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I U -6) [ka] HPLC:99.0%, LC-MS(m / z):369.62(M+H)+, 1H NMR(400MHz,DMSO)δ 7.75(dd,J=6.5,2.6Hz,3H),7.67(s,1H),7.51(d,J=2.9Hz,1H),7.46-7.38(m,3H),7.16(d,J=8.4Hz,1H),7.06-6.97(m,1H),6. 58(d,J=1.8Hz,1H),3.43(d,J=9.6Hz,1H),1.28(s,1H),0.65(t,J=6.9Hz,1H),0.58-0.45(m,2H),0.31(dd,J=14.4,8.5Hz,1H).

[0272] N-(4-(amino(phenyl)methyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I U -7) [ka] HPLC:99.2%, LC-MS(m / z):405.52(M+H)+, 1 H NMR(400MHz,DMSO)δ 8.23(s,3H),7.78(s,1H),7.77-7.71(m,3H),7.58-7.46(m,5H),7.42(t,J=7.6Hz,2H),7.34(t,J=7.2Hz,1 H),7.23(d,J=2.8Hz,1H),7.15(d,J=8.5Hz,1H),7.00(d,J=8.4Hz,1H),6.60(d,J=1.8Hz,1H),5.46(s,1H).

[0273] N-(4-(1-amino-2-phenylethyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I U -8) [ka] HPLC:99.5%, LC-MS(m / z):419.71(M+H)+, 1H NMR(400MHz,DMSO)δ 8.48(s,3H),7.74-7.66(m,4H),7.54(t,J=7.1Hz,1H),7.48(t,J=7.4Hz,2H),7.24(t,J=7.2Hz,2H),7.19(d,J=7.0Hz,2H),7.10(d,J =7.2Hz,3H),6.95(d,J=8.4Hz,1H),6.59-6.54(m,1H),4.42(dd,J=9.2,5.9Hz,1H),3.28-3.20(m,1H),3.08(dd,J=13.5,9.6Hz,1H).

[0274] N-(5-(1-aminoethyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I U -9) [ka] HPLC:99.2%, LC-MS(m / z):343.51(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.77(d,J=3.4Hz,2H),7.61(d,J=6.5Hz,2H),7.46(d,J=2.3Hz,1H),7.40(s,3H),7.28( s,1H),6.79(d,J=8.1Hz,1H),6.53(s,1H),4.07(d,J=6.4Hz,1H),1.33(d,J=6.4Hz,3H).

[0275] Example 16 Compound I V Synthesis of: Stages 1-2: N-(4-acetyl-2-(furan-2-yl)phenyl)benzenesulfonamide (XXV-1) [ka] Using a method similar to that used for the synthesis of V-1, we obtained the intermediate XXV-1. 1H NMR(400MHz,CDCl3)δ 8.33(s,1H),8.04(s,1H),7.86(d,J=8.2Hz,1H),7.75(d,J=8.1Hz,3H),7.60(s,1H) ,7.54(t,J=7.1Hz,1H),7.42(t,J=7.3Hz,2H),6.57(d,J=11.6Hz,2H),2.60(s,3H).

[0276] Stage 3: N-(2-(furan-2-yl)-4-(1-(methylamino)ethyl)phenyl)benzenesulfonamide (I V -1) [ka] Intermediate XXV-1 (682.8 mg, 2 mmol) is dissolved in 20 mL of dichloromethane solution, and 1 mL of ethanol solution of methylamine (30-33% wt) and tetraethoxytitanium (456.2 mg, 2 mmol) are added. The mixture is reacted overnight at room temperature. The next day, sodium borohydride (151.3 mg, 4 mmol) is slowly added under ice water conditions, and the mixture is reacted at room temperature for 4 hours. After the reaction is complete, water is added to the system, and the mixture is extracted three times with dichloromethane. The mixture is washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by column chromatography to obtain compound I, a white solid. V -1 (165.1 mg, 23.2%) was obtained. HPLC:99.0%, LC-MS(m / z):357.40(M+H)+, 1 H NMR(400MHz,CDCl3)δ 7.62(dd,J=12.1,7.9Hz,3H),7.52-7.43(m,2H),7.35(dd,J=16.8,4.8Hz,3H),7.27(dd,J=8.4,1.9Hz,1H),6 .45(dd,J=3.3,1.8Hz,1H),6.40(d,J=3.3Hz,1H),3.68(q,J=6.5Hz,1H),2.32(s,3H),1.39(d,J=6.6Hz,3H).

[0277] I V The following compounds are obtained using the same method as in the synthesis of -1. N-(2-(furan-2-yl)-5-(1-(methylamino)ethyl)phenyl)benzenesulfonamide (I V -2) [ka] HPLC:99.0%, LC-MS(m / z):357.45(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.74(d,J=6.6Hz,2H),7.65(dd,J=9.3,4.5Hz,2H),7.52-7.41(m,3H),7.30(d,J=3.1Hz,1H),7.07(s,1H),6 .95(d,J=8.1Hz,1H),6.56(dd,J=3.2,1.8Hz,1H),3.72(q,J=6.4Hz,1H),2.18(s,3H),1.26(d,J=6.7Hz,3H).

[0278] Example 17 Compound I W Synthesis of: Stage 1: 2-(4-(furan-2-yl)-3-(phenylsulfonamide)phenyl)pyrrolidine-1-carboxylate t-butyl(XXVII-1) [ka] Using a method similar to that used for the synthesis of V-1, the intermediate for XXVII-1 is obtained. 1 H NMR(400MHz,DMSO)δ 9.71(s,1H),7.69(dd,J=22.9,16.6Hz,5H),7.56(d,J=29.8Hz,2H),7.13(t ,J=13.5Hz,1H),7.01(t,J=10.5Hz,1H),6.59(d,J=17.1Hz,2H),4.80-4.47 (m,1H),3.37(d,J=11.6Hz,1H),3.21(s,1H),2.16(d,J=48.0Hz,1H),1.81- 1.69(m,1H),1.51(d,J=11.7Hz,1H),1.40(s,3H),1.27(s,1H),1.14(s,6H).

[0279] Stage 2: N-(2-(furan-2-yl)-5-(pyrrolidine-2-yl)phenyl)benzenesulfonamide (I W ) [ka] Intermediate XXVI-1 (234.3 mg, 0.5 mmol) is dissolved in 30 mL of ethyl acetate solution, 1 mL of hydrochloric acid in ethanol solution (2 M / L, 2.0 mmol) is added, and the mixture is reacted at room temperature for 3 hours. After the reaction is complete, the solvent is evaporated, water is added to the residue, an appropriate amount of sodium bicarbonate aqueous solution is added to adjust the pH to 8-9, the mixture is extracted three times with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by column chromatography to obtain compound I, an off-white solid. W (70.0 mg, 38.0%) was obtained. HPLC:99.1%, LC-MS(m / z):368.34(M+H)+, 1 H NMR(400MHz,DMSO)δ 7.75(dd,J=7.3,1.9Hz,2H),7.61(d,J=9.9Hz,2H),7.41(dd,J=12.4,5.0Hz,4H),7.19(s,1H),6.85(d,J=8.0Hz,1H),6.54(dd,J=3.0 ,1.7Hz,1H),4.20-4.14(m,1H),3.10(t,J=7.2Hz,2H),2.13(td,J=12.0,7.2Hz,1H),1.92-1.84(m,2H),1.66(dq,J=17.5,8.8Hz,1H).

[0280] Example 18 TRPA1 inhibitory activity In this example, the inhibitory activity of several example-prepared compounds of the present invention against transient receptor potential channel protein A1 (TRPA1) is tested. Here, the positive control compound is the compound of formula A (WO2010075353). [ka]

[0281] The method is as follows: Test method using Ion Works Barracuda (IWB) automated patch-clamp detection: HEK293 cells stably expressing mTRPA1 are placed in a T175 culture flask using DMEM medium containing 15 g / mL Blasticidin S HCl, 200 g / mL Hygromycin B, and 10% FBS serum. The cells are cultured in an incubator at 37°C and 5% CO2. Once the cell density reaches ~80%, the culture medium is removed, the cells are rinsed once with calcium-magnesium-free phosphate buffer (PBS), 3 mL of Trypsin is added and digestion is carried out for 2 minutes, and 7 mL of medium is added to stop digestion. The cells are collected in a 15 mL centrifuge tube, centrifuged at 800 rpm for 3 minutes, the supernatant is removed, and the cells are resuspended in an appropriate volume of extracellular fluid until the cell density reaches 2-3 × 10⁶. 6 The solution is controlled to a concentration of / mL and used for IWB experiments. Extracellular solution (in mM): 140 NaCl, 5 KCl, 1 MgCl2, 10 HEPES, 0.5 EGTA, 10 Glucose (pH 7.4). Intracellular solution (in mM): 140 CsCl, 10 HEPES, 5 EGTA, 0.1 CaCl2, 1 MgCl2 (pH 7.2). Amphotericin B and DMSO for the day of the experiment are freshly prepared at 28 mg / mL and adjusted to a final concentration of 0.1 mg / mL using the intracellular solution.

[0282] In the IWB experiment, a population patch clamp (PPC) plate is used, and the entire detection process is completed automatically by the instrument. Specifically, extracellular fluid is added to 384 wells of the PPC plate, intracellular fluid is added to the plenum below the PPC plate, then 6L of cell fluid is added and a sealing test is performed. Finally, the intracellular fluid in the plenum is replaced with amphotericin B-containing intracellular fluid, and after holes are made in the sealed cells, a whole-cell recording mode is formed. The sampling frequency for recording the TPRA1 current is 10kHz, the cells are clamped to 0mV, and the voltage stimulation command (channel protocol) is a 300ms ramp voltage from -100mV to +100mV, applied every 10 seconds, and the mTRPA1 current is induced by 300M AITC.

[0283] Data recording and export of current amplitude measurements are performed by IWB software (version 2.5.3, Molecular Devices Corporation, Union City, CA). Data statistics are not recorded for holes with a seal impedance of less than 20 MΩ. Raw current data is corrected by the software for leakage subtraction, and TRPA1 current amplitude is measured at +100 mV. Each PPC plate in the experiment has dose-effect data of HC030031 as a positive control, e.g., IC of HC030031 50 The IC values ​​obtained from each plate in the past 50 If the value exceeds three times the average, remeasure. Dose-effect curve and IC of the compound. 50 The model is fitted and calculated using GraphPad Prism 5.02 (GraphPad Software, San Diego, CA).

[0284] Experimental results The IonWorks Barracuda (IWB) automated patch clamp detection test method allows for the detection of ICs of several compounds of the present invention. 50 The inhibitory activity was tested, and the activity data is shown in Table 2. [Table 2] Here, activity: (μM): 50≦IC 50 <100:+ 20≦IC 50 <50:++ 10≦IC 50 <20:+++ 5≦IC 50 <10:++++ 1 ≤ IC 50 <5:+++++ I C 50 <1:++++++

[0285] The results indicate that the compound of the present invention exhibits potent inhibitory activity against TRPA1.

[0286] Example 19 WI S This study investigates the therapeutic effects of compounds prepared in several examples of the present invention on 2,4-dinitrobenzenesulfonic acid (DNBS)-induced ulcerative colitis (corresponding to Crohn's disease) in tar rats.

[0287] Experimental process 1. Laboratory animals Animal species and strain: Wistar rat Medication history: No medication history Sex, weight: Male, approximately 150g Breeder / Supplier: Shanghai SLAC ANIMAL Adaptation period: 5 days Room: Room in a common area Indoor temperature: 20~26℃ Indoor relative humidity: 40-70% Lighting: Fluorescent lighting, 12-hour on (08:00~20:00) and 12-hour off. Animal feeding: 2-4 rats per cage (same dose group) Food: Unlimited access to feed (sterilized by radiation, Xietong Shengwu, Jiangsu Province, China) Water: Unlimited access to drinking water (reverse osmosis and autoclaved). A total of 80 Wistar rats were purchased from Shanghai SLAC ANIMAL, 10 of which were used as reserve animals to select animals within an appropriate weight range to be included in the group in order to control for variations in disease levels due to weight fluctuations.

[0288] 2. Grouping Based on the animals' weight, 70 animals are randomly grouped and screened using BioBook software to ensure that the weight values ​​of the animals in each group are similar and to reduce deviations. [Table 3]

[0289] 3. Experimental Design 3.1. Dissolve the DNBS powder in 30% ethanol to obtain a final concentration of 60 mg / mL. 3.2. Induction of Proctitis: Rats were fasted for 40 hours prior to the experiment, and 5% glucose saline was subcutaneously injected during the fasting period. On day 0 of the experiment, the fasted rats were anesthetized by intraperitoneal injection of zoletil and 5 mg / kg xylazine. In groups G2 to G7, a flexible tube was inserted from the anus to the left bend of the colorectum, and proctitis was induced in the rats using a DNBS enema. The normal control group (G1) was similarly given an enema of 30% ethanol.

[0290] 3.3. Administration Plan: After inducing DNBS in animals in groups G1 and G2, administer the vehicle. After inducing DNBS in animals in group G3, administer 300 mg / kg of orsalazine sodium. After inducing DNBS in animals in groups G4 to G7, administer 10 mg / kg of the compound of the present invention to each group. Refer to Table 3 for administration time, specific dosage, and administration route. Administration will begin on modeling day 0 and continue for 7 days, with the animals being sacrificed on day 6.

[0291] 3.4. Detection Indicators: After the experiment, all animals are euthanized by inhaling excess CO2 and dislocating the cervical vertebrae. The abdominal cavity is opened and the colorectum is removed. The length of the colorectum is immediately measured. The colorectum is then cut in half lengthwise, thoroughly cleaned, and the weight and ulcer area of ​​the colorectum are recorded. A photograph of the entire body is taken, and the colorectal injury of the rats is visually evaluated according to Table 4. [Table 4]

[0292] 3.5. Experimental Observation The animals' health status, as well as their overall response to surgery and medication, will be observed daily.

[0293] 4.Statistical analysis Experimental data are statistically expressed as mean ± standard error. Statistical analysis is performed using Graphpad Prism, SPSS, or Sigmaplot software. Specific data are displayed in graph format. P < 0.05 is considered statistically distinct.

[0294] Experimental results In the experimental observations, none of the animals exhibited any abnormal appearance or behavior. Inflammatory colitis was induced in Wistar rats by intracolonic injection of DNBS according to the experimental protocol. Colitis is characterized by a significant shortening of colon length, a significant increase in colon weight, a significant increase in colonic ulcer area, and a significant increase in gross colonic injury score. Colon length, weight, and ulcer area data for each group of animals are shown in Table 5 and Figure 1. Gross colonic injury score data for each group of animals are shown in Table 6 and Figure 1. Representative colorectal photographs of each group of animals are shown in Figure 2.

[0295] The experimental results show that the positive drug orsalazine sodium can significantly reduce the colon weight and ulcer area in model mice. Compound I of the present invention A -51, I A-30, I D -5, I A -55 significantly inhibits colonic shortening in model mice and significantly reduces intestinal weight, ulcer area, and gross colon injury score. The efficacy of each compound in the present invention at a dose of 10 mg / kg is neither stronger nor weaker than that of the positive control group at a dose of 300 mg / kg, indicating that the compounds in the present invention have a strong therapeutic effect on DNBS-induced colitis in rats, and that the effective dose is low. [Table 5] [Table 6]

[0296] In summary, Compound I of the present invention A -51, I A -30, I D -5, I A -55 exhibits good preventive and therapeutic effects against DNBS-induced colitis in rats and can be developed as a treatment for Crohn's disease.

[0297] Example 20 This study investigates the efficacy of compounds prepared in several examples of the present invention against DSS (dextran sulfate sodium)-induced inflammatory bowel disease (corresponding to ulcerative colitis) in C57BL / 6 mice.

[0298] Experimental process 1. Laboratory animals Animal species and strain: C57BL / 6 mouse Medication history: No medication history Sex and weight: Female, approximately 18-20g Breeder / Supplier: Shanghai SLAC ANIMAL Adaptation period: 7 days Room: SPF room Indoor temperature: 20~26℃ Indoor relative humidity: 40-70% Lighting: Fluorescent lighting, 12-hour on (08:00~20:00) and 12-hour off. Animal feeding: 2-5 mice per cage (same dose group) Food: Unlimited access to feed (sterilized by irradiation, Shanghai SLAC ANIMAL, China) Water: Unlimited access to drinking water (tap water purified using an ultrapure water filtration system) A total of 80 C57BL / 6 mice were purchased from Shanghai SLAC ANIMAL, with 10 of them being used as reserve animals to select animals within the appropriate weight range during grouping. All reserve animals were not subjected to medication or modeling procedures and were euthanized at the end of the experiment.

[0299] 2. Grouping Based on their body weight, 70 animals were screened on day 3 and randomly grouped using BioBook software. The weight values ​​of the animals in each group were checked to ensure similarity and reduce deviations. Specific grouping information is shown in Table 7 below. [Table 7]

[0300] 3. Experimental Design 3.1. Dissolve an appropriate amount of DSS powder in a high-pressure sterilized drinking water vehicle to prepare a 3% DSS solution. 3.2. Induction of Colitis: On day 3, 70 mice are randomly divided into seven groups according to Table 7. From day 0 to day 4, mice in groups 2-7 are given a 3% DSS-containing aqueous solution for 5 days, after which they are allowed to drink normal water freely (from day 5 until before necropsy). The day on which the DSS drinking water is first given is counted as day 0. The DSS solution is wrapped in an opaque, dark-colored bag to protect it from light. The DSS solution is replaced once every 2 days.

[0301] 3.3. Dosage Plan: Refer to Table 7. 3.4. Assessment of enteritis: (1) Mouse weight, feces, and bleeding status Changes in body weight, fecal matter, and bleeding were recorded daily for all groups of mice. Three scores were created according to Table 8 below, and these were summed up to create the daily disease activity index (DAI) score. [Table 8]

[0302] (2) Weight and length of the intestines After blood collection, the animals are euthanized by cervical dislocation after excessive CO2 ingestion. The abdominal cavity is cut open, the mouse's colorectum is removed, the surrounding tissue is removed, and the longitudinal length from the ileocecal valve to the anus is measured. The colorectum is dissected, the fecal contents are scored, the intestinal contents are washed, a photograph of the entire colon is taken, and it is weighed. (3)ELISA analysis We will analyze the colorectal inflammatory factors TNF-α and IL-10 in each group using a commercially available ELISA analysis kit.

[0303] 3.5. Experimental Observation The animals' health status, as well as their overall response to DSS and drugs, will be observed daily. Any abnormal appearances or behaviors related to the onset of disease will be recorded in detail in the Pengli Biological Experiment Observation Log.

[0304] 4.Statistical analysis The data is statistically represented as mean ± standard error. Statistical analysis is performed using Graphpad Prism and SPSS software. The specific data is displayed in graph format. A value of P < 0.05 indicates that the data is considered statistically distinct.

[0305] Experimental results In the experimental observations, none of the animals exhibited any abnormal appearance or behavior. This experiment induced acute colitis in C57BL / 6 mice by systematically administering DSS drinking water according to the experimental protocol. Animals administered DSS drinking water exhibited clinical symptoms of acute colitis, such as weight loss, diarrhea, and bloody stools, and showed shortening of the intestinal length and increase in intestinal weight at necropsy. The DAI score data for each group of animals is shown in Figure 3, the colorectal weight and length results for each group of animals are shown in Figure 4, and the ELISA analysis results for the colorectal inflammatory factors TNF-α and IL-10 in each group of animals are shown in Figure 5.

[0306] The experimental results show that the positive drug Cyclosporine A exhibited clear therapeutic effects in multiple indicators, indicating that this model was successfully constructed. Compound I of the present invention A -51, I A -30, I D -5, I A -55 can significantly reduce the DAI score, decrease colorectal weight, and increase colorectal length in model mice, while simultaneously significantly reducing the levels of colorectal inflammatory factors TNF-α and IL-10 in animals in each group. The efficacy of each compound in the present invention at a dose of 10 mg / kg is neither stronger nor weaker than that of the positive control group at a dose of 60 mg / kg, indicating that the compounds in the present invention have a good therapeutic effect against DSS-induced inflammatory bowel disease in C57BL / 6 mice.

[0307] In summary, Compound I of the present invention A -51, I A -30, I D -5, I A -55 exhibits good preventive and therapeutic effects against DSS-induced inflammatory bowel disease in C57BL / 6 mice and can be developed as a therapeutic agent for ulcerative colitis.

[0308] Example 21 The efficacy of compounds prepared in several examples of the present invention will be tested in an acetic acid-induced writhing pain model in ICR mice. The mouse acetate-induced agony model is a classic model for evaluating the efficacy of drugs in the treatment of visceral pain and inflammatory pain.

[0309] Experimental process 1. Laboratory animals Animal species and strain: ICR mouse Medication history: None Sex, age, weight: Male, 8 weeks old, 20-25g Breeder / Supplier: Shanghai SLAC ANIMAL Adaptation period: 7 days or more Room: Standard room Room temperature: 19~26℃ Relative humidity: 40-70% Lighting cycle: Fluorescent lighting, 12 hours on (08:00~20:00) and 12 hours off. Animal feeding: 5 animals per group / cage Food: Ad libitum (irradiated feed, Shanghai SLAC ANIMAL, China) Water: Free access (tap water filtered by a Mol ultrapure water system) A total of 70 mice were purchased from Shanghai SLAC ANIMAL. The animals were SPF grade and approximately 7 weeks old at the time of purchase.

[0310] 2. Grouping Based on the animals' weight, the BioBook random assignment function randomly assigns animals to each treatment group, achieving an approximate average weight for each group and reducing the deviation between groups. [Table 9]

[0311] 3. Experimental Design 3.1. Within 12 hours prior to use, prepare a 0.6% glacial acetic acid solution by mass / volume using 0.9% physiological saline. 3.2. Administration Procedure: Animals in Group G1 were orally administered 0.9% physiological saline, while animals in Groups G2 to G6 were specifically administered the compounds of the present invention according to the administration schedule in Table 9. 3.3. Modeling treatment: Animals in group G1 were orally administered 0.9% physiological saline, and one hour later, 0.6% glacial acetic acid was injected intraperitoneally to induce a pain response (10 ml / kg). For animals in groups G2 to G8, different groups after administration were injected intraperitoneally with 0.6% glacial acetic acid to induce a pain response (10 ml / kg) according to the plan designed in Table 9.

[0312] 3.4. Measurement: Record the weight of all mice before the modeling treatment. Perform and record the wriggling test immediately after acetic acid treatment. The behavioral observation period will last 20 minutes. One person will count the number of wriggles (a standard wriggle consists of abdominal muscle contraction, body extension, and hind limb extension). After the test, slaughter the animals with CO2. 3.5. Experimental Observation: Daily health monitoring of animals and general responses to drug treatments will be conducted. All abnormal health and behavioral symptoms will be recorded.

[0313] 4.Statistical analysis Experimental data are statistically expressed as mean ± standard error. Statistical analysis is performed using Graphpad Prism, SPSS, or Sigmaplot software. Specific data are displayed in graph format. P < 0.05 is considered statistically significant.

[0314] Experimental results The statistics of the number of writhing episodes in each experimental group are shown in Figure 6. As can be seen from Figure 6, the compound I of the present invention is compared to the G1 model group. A -51, I A -30, I D -5, I A -55 significantly reduced the number of writhing episodes in model mice, and its efficacy is essentially equivalent to 200 mpk aspirin, which exhibits potent analgesic activity. In summary, Compound I of the present invention A -51, I A -30, I D -5, I A -55 has good analgesic effects and can be developed as a drug for pain treatment.

[0315] Example 22 The antagonistic activity of compounds prepared in several examples of the present invention against the chemokine receptor CCR9 will be investigated.

[0316] Experimental process 1. Test drug and positive control drug 1.1. Test drug Name: See Table 10 for details. Storage instructions: Store in the refrigerator, away from light. Preparation concentrations: 10mM, 1mM, 100μM, 10μM, 1μM, 100nM, 10nM, DMSO. Working concentrations: 100 μM, 10 μM, 1 μM, 100 nM, 10 nM, 1 nM, 100 pM, DMSO.

[0317] 1.2. Positive control: Vercirnon (CCR9 antagonist) Name: Vercirnon Storage instructions: Store in a sealed container away from light at -80°C. Preparation concentrations: 10mM, 1mM, 100μM, 10μM, 1μM, 100nM, 10nM, DMSO. Working concentrations: 100 μM, 10 μM, 1 μM, 100 nM, 10 nM, 1 nM, 100 pM, DMSO.

[0318] 1.3. CCL25 (CCR9 agonist) Name: CCL25 Storage instructions: Store in a sealed container away from light at -80°C. Preparation concentration: 15 μM. Working concentration: 150nM.

[0319] 2. Reagents and equipment: 2.1. Main reagents: DMEM medium (GIBCO), dimethyl sulfoxide (Sigma), FLUO-4, AM (Invitrogen) 2.2. Main equipment: Flexstation-3 (Molecular Devices)

[0320] 3. Grouping and dosage setting: 3.1. Rationale for determining the dosage: I C 50 Set up the test concentration gradient of the compound and set up the duplicated well according to the test requirements. 3.2. Dosage setting and grouping: For each test substance, eight concentrations are set, and three duplicate wells are set for each concentration.

[0321] 4. Experimental principles and methods: Experimental principle: By establishing cell lines that are simultaneously transfected with the target receptor and G16, the activation of the Gα16 protein is triggered after the receptor is activated, which in turn activates phospholipase C (PLC) to produce IP3 and DAG. IP3 then binds to IP3 receptors on the endoplasmic reticulum and mitochondria of the cell, thereby causing intracellular calcium release. Therefore, measuring changes in intracellular calcium can be used as a method to detect the activation state of the target receptor. Fluo-4 / AM is a calcium fluorescent probe indicator used to measure calcium ions. As a nonpolar lipid-soluble compound, after entering the cell, the AM group is dissociated under the action of cellular lipolytic enzymes, releasing Fluo-4. Since Fluo-4 is a polar molecule and cannot easily pass through the lipid bilayer, Fluo-4 remains in the cell for a long period. Ultimately, the activation bell of the G protein can be reflected by measuring the excited fluorescence intensity. If the screened compound can stimulate the target receptor, the calcium flow response can be significantly increased. Conversely, if the screened compound can antagonize the target receptor, the calcium flow response can be significantly decreased.

[0322] Experimental procedure: 1. Inoculate cells that stably express the target receptor / Gα16 into a 96-well plate and culture overnight. 2. Aspirate the culture medium from the wells containing the cells, add 40 μl / well of the freshly prepared dye, and incubate at a constant temperature of 37°C for 40 minutes. 3. Dilute the test drug with calcium buffer and mix it uniformly. Antagonism mode: 4. Aspirate and discard the dye, wash once with freshly prepared calcium buffer, and then replace with 50 μl of calcium buffer dissolved in the test drug. 5. Detect the sample using the FlexStation II instrument. After 15 seconds, the instrument automatically adds 25 μl of calcium buffer dissolved in a known agonist, and finally read the fluorescence value at 525 nm.

[0323] 5. Data processing and statistical analysis: Antagonism mode The cellular response rate (%Response) for each sample at each concentration condition is calculated using the following formula.

number

number

number

number

[0324] 6. Experimental results: The test results are shown in Table 10. The results indicate that the antagonistic activity of the compound of the present invention against the chemokine receptor CCR9 is IC2. 50 It was found to be greater than 10 μM, which indicates that the compound of the present invention does not have chemokine receptor CCR9 antagonistic activity. Similarly, the compounds of the present invention were also tested for antagonistic activity against other chemokine receptors such as CCR1 to CCR10, and the test results showed that none of the compounds of the present invention possess chemokine receptor antagonistic activity. Therefore, the compounds of the present invention are used to treat inflammatory bowel disease not through chemokine receptor antagonism, but through a novel drug action mechanism, namely, inhibition of the ion channel TRPA1. [Table 10]

[0325] All documents referenced in this invention are cited as references in this application, as if each document were cited individually. Furthermore, after reading the above teachings of this invention, persons skilled in the art can make various changes or modifications to the invention, and these equivalent forms are also included within the scope defined by the claims appended to this application.

Claims

1. A compound of formula Z, or an optical isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 In the formula, R Ａ , R Ｂ , R Ｃ Each of these is independently a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, Ar is a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 3- to 10-membered heteroaryl group, a 3- to 10-membered heterocycloalkane ring fused C6-C10 aryl group, a substituted or unsubstituted C6-C10 aryl-substituted or unsubstituted C1-C6 alkyl-, or a substituted or unsubstituted 3- to 10-membered heteroaryl-substituted or unsubstituted C1-C6 alkyl-. X １ , X ２ , X ３ , X ４ and labeled a, b, c, d and e 【Chemistry 2】 It forms a furan ring, thiophene ring, pyrrole ring, thiazole ring, pyrazole ring, isoxazole ring, oxazole ring, imidazole ring, or triazole ring. R １ is hydrogen, a substituted or unsubstituted C1-C6 alkyl group, R ２ is hydrogen, a substituted or unsubstituted C1-C10 alkyl group, n is 0, 1, 2, or 3. Here, the aforementioned "any substitution" refers to the substitution of one or more hydrogen atoms on a ring or group with substituents selected from the group consisting of C1-C8 alkyl groups, C3-C8 cycloalkyl groups, C1-C8 haloalkyl groups, C3-C8 halocycloalkyl groups, halogens, nitro groups, -CN groups, hydroxyl groups, mercapto groups, amino groups, C1-C4 carboxyl groups, C2-C4 ester groups, C2-C4 amide groups, C1-C8 alkoxy groups, C1-C8 alkylthio groups, C1-C8 haloalkoxy groups, C1-C8 haloalkylthio groups, C6-C12 aryl groups, 5-10 membered heteroaryl groups, and 5-10 membered heterocycloalkyl groups. The compound is characterized in that the heteroaryl group, the heterocycloalkane ring, and the heterocycloalkyl group each independently have one, two, three, or four heteroatoms selected from N, O, and S.

2. Ar is characterized by being a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 3- to 8-membered heteroaryl group, a 3- to 8-membered heterocycloalkane ring fused C6-C10 aryl group, a substituted or unsubstituted C6-C10 aryl-substituted or unsubstituted C1-C4 alkyl-, or a substituted or unsubstituted 3- to 8-membered heteroaryl-substituted or unsubstituted C4 alkyl-. The compound according to claim 1.

3. Ar is characterized by being a substituted or unsubstituted C6-C10 aryl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group. The compound according to claim 1.

4. Ar is characterized by being a phenyl group, halophenyl group, methoxyphenyl group, trifluoromethoxyphenyl group, trifluoromethylphenyl group, methylphenyl group, naphthyl group, dihydrofuran fusion phenyl group, benzothiazolyl group, pyridinyl group, halopyridinyl group, imidazolyl group, methylimidazolyl group, thienyl group, halothienyl group, or benzyl group. The compound according to claim 1.

5. R １ R is hydrogen, C1-C4 alkyl group, ２ It is characterized by being hydrogen and a C1-C4 alkyl group. The compound according to claim 1.

6. The aforementioned "any substitution" refers to the substitution of one or more hydrogen atoms on a ring or group with substituents selected from the group consisting of C1-C8 alkyl groups, C1-C8 haloalkyl groups, halogens, C1-C8 alkoxy groups, and C1-C8 haloalkoxy groups. The compound according to claim 1.

7. The aforementioned "any substitution" refers to the substitution of one, two, three, or four hydrogen atoms on a ring or group with substituents selected from the group consisting of C1-C6 alkyl groups, C1-C6 haloalkyl groups, halogens, C1-C6 alkoxy groups, and C1-C6 haloalkoxy groups. The compound according to claim 1.

8. Compounds characterized by being selected from the following group: 【Transformation 3】 【Chemistry 4】 【Transformation 5】 。

9. A pharmaceutical composition, The pharmaceutical composition is characterized by comprising the compound described in claim 1, an optical isomer thereof, a racemate thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. A method for preparing a compound of formula Z described in claim 1, an optical isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof, The above method includes one of methods 1 to 3, Method 1: 【Transformation 6】 Method 2: 【Transformation 7】 Method 3: 【Transformation 8】 Here, X １ , X ２ , X ３ , X ４ , R １ , R ２ n and Ar are as defined in claim 1, R ３ and R ５ A method for preparing a compound of formula Z according to claim 1, or an optical isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that each of them independently comprises hydrogen, a substituted or unsubstituted C1-C6 alkyl group.

11. The use of a compound according to any one of claims 1 to 8, an optical isomer thereof, a racemic mixture thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, The use is characterized by being used (a) to prepare an inhibitor of transient receptor potential channel protein TRPA1, and / or (b) to prepare a drug for the prevention and / or treatment of a disease associated with transient receptor potential channel protein TRPA1.

12. The disease associated with the transient receptor potential channel protein TRPA1 is characterized by being selected from the group consisting of inflammatory bowel disease, irritable bowel syndrome, pain, inflammation, or a combination thereof. The use described in claim 11.

13. The inflammatory bowel disease is characterized by including Crohn's disease and / or ulcerative colitis. The use described in claim 12.

14. The pain is characterized by including visceral pain, acute inflammatory pain, chronic inflammatory pain, neuropathic pain, myofibrogia, headache, neuralgia, or pain due to cancer. The use described in claim 12.

15. An in vitro, non-therapeutic, and non-diagnostic method for inhibiting the activity of transient receptor potential channel proteins, The method is characterized by comprising the step of contacting a transient receptor potential channel protein or a cell expressing the protein with a compound according to any one of claims 1 to 8, an optical isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, thereby inhibiting the activity of the transient receptor potential channel protein.

Images