N-substituted phenylsulfonamide compounds and their uses

Abstract

This invention relates to N-substituted phenylsulfonamide compounds and their uses. Specifically, this invention provides a compound of formula I, or an optical isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof. The compound of this invention exhibits excellent inhibitory activity against transient receptor potential channel proteins and excellent therapeutic effects on diseases related to transient receptor potential channel proteins, such as inflammatory bowel disease, irritable bowel syndrome, pain, and inflammation.

Description

Technical Field

[0001] This invention relates to the fields of medicinal chemistry and pharmacotherapeutic science, and more specifically to an N-substituted phenylsulfonamide compound and its uses. Background Technology

[0002] Transient receptor potential ankyrin 1 (TRPA1), also known as ANKTM1, is a member of the transient receptor potential (TRP) channel family. TRPA1 is primarily distributed on primary sensory neurons of the dorsal root nerve (DRG), trigeminal nerve (TG), and vagus nerve (VG), and is found in both peptidotropic (rich in neuropeptides CGRP and SP, and neurotrophic factor receptor TrkA) and non-peptidotropic neurons (co-expressing purine receptors P2X3, Neuroturin, Artemin, G protein-coupled receptors of the Mrg family, and GFR from the GDNF receptor family). α1 and GFR α2 TRPA1 is expressed in all systems. In terms of distribution across human systems, TRPA1 is highly expressed in the gastrointestinal system, peripheral nervous system, respiratory system, and urinary system. When these organs and tissues experience functional abnormalities, the expression and function of TRPA1 channels usually also become abnormal simultaneously.

[0003] Inflammatory bowel disease (IBD) is a chronic inflammatory disease characterized by erosions or ulcers in the intestinal mucosa. It is mainly divided into two categories: ulcerative colitis (UC) and Crohn's disease (CD). The former primarily affects the colon, while the latter can affect any segment of the gastrointestinal tract, with diarrhea and abdominal pain being the most common symptoms. Currently, the pathogenesis of IBD is not fully understood. Commonly used treatments include four main classes: 5-aminosalicylic acids, glucocorticoids, antibiotics, and immunosuppressants. These drugs have drawbacks such as tolerance, limited applicability, and poor treatment efficacy. Studies have shown that TRPA1 plays an important role in gastrointestinal regulation. TRPA1 immune responses have been detected in inhibitory motor neurons, descending interneurons, cholinergic neurons, and intrinsic sensory neurons in the cecum and colon of mice. Increasing evidence demonstrates that TRPA1 is expressed in intrinsic sensory neurons of the intestinal and submucosal nerve plexuses, as well as in the surface epithelial cells of the colonic mucosa. Studies of biopsy materials from patients with active and inactive CD and UC have revealed significant upregulation of TRPA1 mRNA. Other studies have reported increased TRPA1 expression in colonic strictures in CD patients, including surgical and endoscopic findings. In in vivo models of colitis induced by DNBS, TNBS, or DSS, administration of the selective TRPA1 inhibitor HC-030031, or knockout of the TRPA1 gene, significantly reduced colitis symptoms in animals. Therefore, TRPA1 inhibitors could be used for the treatment of IBD.

[0004] In animal models of irritable bowel syndrome (IBS), pancreatic inflammation, and gastric mucosal injury, TRPA1 expression was found to be significantly upregulated. In rodent models, TRPA1 and TRPV1 together promote stress-induced visceral hyperalgesia, i.e., IBS. In acute pancreatitis models, TRPA1 and TRPV1 have a synergistic effect, jointly regulating the transition from acute inflammation and hyperalgesia phenotypes to chronic inflammation and hyperalgesia phenotypes. Furthermore, in a rat model of acute gastric mucosal injury, the TRPA1 antagonist HC-030031 also showed positive results.

[0005] Visceral pain, a primary visceral sensation, is often caused by stimuli such as mechanical traction, spasm, ischemia, or inflammation of the viscera. TRPA1's involvement in the regulation of visceral hypersensitivity has been confirmed through various animal models of visceral hypersensitivity, such as colitis, rectal dilatation, or stress. Neurogenic pain is a pain syndrome caused by damage or disease of the central or peripheral nervous system, mainly manifested as hyperalgesia, atypical hyperalgesia, and spontaneous pain. Unlike inflammatory pain, neurogenic pain is not related to the vascular response at the central stage of inflammation, but depends on damage and dysfunction of the nervous system, often caused by peripheral nerve damage. In recent years, increasing research has shown that the TRPA1 channel plays an important role in various types of neurogenic pain, such as diabetic neuropathy and chemotherapy-induced neuropathy. Recent studies have also shown that TRPA1 has a mediating role in toothache, migraine, and other types of pain; administration of TRPA1 antagonists can significantly alleviate pain symptoms.

[0006] Inflammation is a defensive response of living tissue with a vascular system to damaging factors. Stimulation by inflammatory mediators such as prostaglandins, serotonin, and bradykinin is a major cause of localized pain in inflammatory conditions. Inflammatory pain is a common symptom of certain chronic diseases, and effective treatments are still lacking clinically. Animal studies have shown that TRPA1 participates in the inflammatory response and plays an important role in inflammatory pain; the use of TRPA1-specific blockers can significantly reduce inflammatory pain responses in rats. The pathogenesis of asthma and cough is becoming increasingly clear with ongoing research. Current research indicates that TRPA1 plays a crucial role in the development of asthma and cough. Compounds that induce asthma and cough, whether endogenous or exogenous factors, can activate TRPA1. TRPA1 antagonists can alleviate asthma symptoms and block airway hyperresponsiveness.

[0007] Given the widespread distribution and expression of TRPA1 in the human body, its functional importance is self-evident. In addition to the physiological functions involved by TRPA1 mentioned above, the development of TRPA1 inhibitors for various indications has been reported, including chronic obstructive pulmonary disease, cough suppression, antipruritic effects, allergic rhinitis, ear diseases, antidiabetic applications, and urinary incontinence. TRPA1 is a novel therapeutic target for inflammatory bowel disease, irritable bowel syndrome, pain, and inflammation, but there are currently no marketed drugs targeting this specific target.

[0008] Inflammatory bowel disease, irritable bowel syndrome, and pain are among the refractory diseases. Therefore, there is an urgent need in this field to develop a therapeutic drug targeting TRPA1 to improve the treatment effect of these diseases. Summary of the Invention

[0009] The purpose of this invention is to provide a novel compound targeting TRPA1 and its uses.

[0010] In a first aspect, the present invention provides a compound of formula I, or an optical isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

[0011]

[0012] In the formula:

[0013] Ar represents substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 3-12 heteroaryl, 3-12 heterocyclic alkyl cyclopentadienyl C6-C12 aryl, substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C8 alkyl-, or substituted or unsubstituted 3-12 heteroaryl-substituted or unsubstituted C1-C8 alkyl-.

[0014] X 1 X 2 X 3 and X 4 Each can be independently represented by C, O, S, or N;

[0015] The labels are a, b, c, d, and e. It can be a single bond or a double bond;

[0016] R 1 It is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, or halogen;

[0017] R 2 It is hydrogen, substituted or unsubstituted C1-C10 alkyl, or substituted or unsubstituted C3-C10 cycloalkyl;

[0018] A is Substituted or unsubstituted C2-C6 ester group, substituted or unsubstituted C2-C6 carboxyl group, substituted or unsubstituted C2-C6 amide group, substituted or unsubstituted 3-8 membered heterocyclic alkyl group, or substituted or unsubstituted 2HN-HN-C(O)-.

[0019] m can be 0, 1, 2, or 3;

[0020] Y 1 Let N be the number of people in the group.

[0021] Y 2 For O or S;

[0022] Y 3 It can be NH, O, or S;

[0023] Y 4 For O or S;

[0024] Y 5 Let N be the number of people in the group.

[0025] R 3 and R 4 Each of these can be independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C3 alkyl-, substituted or unsubstituted C2-C6 acyl, or R 3 R 4 With adjacent Y 1 They are linked together to form substituted or unsubstituted 3-8 membered heterocyclic alkyl groups;

[0026] R 5 It is hydrogen, substituted or unsubstituted C1-C6 alkyl, hydroxyl, mercapto or substituted or unsubstituted C1-C6 alkoxy;

[0027] n is 0, 1, 2, 3, 4 or 5;

[0028] Wherein, any “substitution” refers to one or more (preferably 1, 2, 3, 4, 5 or 6) hydrogen atoms on a ring or group being replaced by a substituent selected from the group consisting of: C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C3-C8 halocycloalkyl, halogen, nitro, -CN, hydroxyl, mercapto, amino, C1-C4 carboxyl, C2-C4 ester, C2-C4 amide, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 haloalkoxy, C1-C8 haloalkylthio, C6-C12 aryl, 5-10 heteroaryl, 5-10 heterocyclic alkyl;

[0029] The heterocyclic rings of the heteroaryl, heterocyclic alkyl, and heterocyclic alkyl groups each independently have 1 to 4 (preferably 1, 2, 3, or 4) heteroatoms selected from N, O, and S.

[0030] In another preferred embodiment, Ar is a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted 3-10 heteroaryl, a 3-10 heterocyclic cyclodextrin C6-C10 aryl, a substituted or unsubstituted C6-C10 aryl-substituted or unsubstituted C1-C6 alkyl-, or a substituted or unsubstituted 3-10 heteroaryl-substituted or unsubstituted C1-C6 alkyl-.

[0031] In another preferred embodiment, Ar is a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted 3-8 heteroaryl, a 3-8 heterocyclic cyclohexane cyclohexane C6-C10 aryl, a substituted or unsubstituted C6-C10 aryl-substituted or unsubstituted C1-C4 alkyl-, or a substituted or unsubstituted 3-8 heteroaryl-substituted or unsubstituted C1-C4 alkyl-.

[0032] In another preferred embodiment, Ar is a substituted or unsubstituted C6-C8 aryl, a substituted or unsubstituted 5-8 heteroaryl, a 5-8 heterocyclic cyclopentadienyl C6-C8 aryl, a substituted or unsubstituted C6-C8 aryl-substituted or unsubstituted C1-C3 alkyl-, or a substituted or unsubstituted 5-8 heteroaryl-substituted or unsubstituted C1-C3 alkyl-.

[0033] In another preferred embodiment, Ar is a substituted or unsubstituted C6-C10 aryl group, or a substituted or unsubstituted 3-8 nucleotide (preferably 5-8 nucleotide) heteroaryl group.

[0034] In another preferred embodiment, Ar is phenyl, halophenyl, methoxyphenyl, trifluoromethoxyphenyl, trifluoromethylphenyl, methylphenyl, naphthyl, dihydrofuranophenyl, benzothiazolyl, pyridyl, halopyridyl, imidazolyl, methylimidazolyl, thiophene, halothiophene, or benzyl.

[0035] In another preferred embodiment, Ar is phenyl or thiophene.

[0036] In another preferred embodiment, the halophenyl is a monohalophenyl or a dihalophenyl.

[0037] In another preferred embodiment, the dihydrofuranophenyl is...

[0038] In another preferred embodiment, the substituents in the Ar are selected from the group consisting of halogens (preferably fluorine), C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy.

[0039] In another preferred embodiment, R 1 It is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, or halogen.

[0040] In another preferred embodiment, R 1 It is hydrogen, substituted or unsubstituted C1-C2 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, or halogen.

[0041] In another preferred embodiment, R 1 It is hydrogen, substituted or unsubstituted C1-C4 alkyl, preferably hydrogen.

[0042] In another preferred embodiment, R 1 It consists of hydrogen and methyl groups.

[0043] In another preferred embodiment, R 2 It is hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C7 cycloalkyl.

[0044] In another preferred embodiment, R 2It is hydrogen, substituted or unsubstituted C1-C4 alkyl, preferably hydrogen.

[0045] In another preferred embodiment, R 2 It can be hydrogen or methyl.

[0046] In another preferred embodiment, A is... Substituted or unsubstituted C2-C4 ester group, substituted or unsubstituted C1-C4 carboxyl group, substituted or unsubstituted C1-C4 amide group, or substituted or unsubstituted 2HN-HN-C(O)-.

[0047] In another preferred embodiment, A is... Methyl ester group, ethyl ester group, formic acid group, acetamide group, formamide group, or 2HN-HN-C(O)-.

[0048] In another preferred embodiment, A is...

[0049] In another preferred embodiment, A is...

[0050] In another preferred embodiment, Y 3 Let N be the number of elements in the array.

[0051] In another preferred embodiment, m is 0, 1, or 2.

[0052] In another preferred embodiment, R 3 and R 4 Each is independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C4 acyl, or R 3 R 4 With adjacent Y 1 They are linked together to form substituted or unsubstituted 3-6 membered heterocyclic alkyl groups.

[0053] In another preferred embodiment, R 3 and R 4 Each of these can be independently hydrogen, substituted or unsubstituted C1-C2 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C4 acyl, or R. 3 R 4 With adjacent Y 1 They are linked together to form substituted or unsubstituted 3-6 membered heterocyclic alkyl groups.

[0054] In another preferred embodiment, R 3 and R 4 Each of the following is independent: hydrogen, methyl, trifluoromethyl-methyl-, ethyl, cyclopropyl, cyclobutyl, acetyl, or R 3 R 4 With adjacent Y 1They are linked together to form substituted or unsubstituted nitrogen-containing heterocyclic butyl groups.

[0055] In another preferred embodiment, when A is At that time, R 3 It is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C4 acyl, R 4 For hydrogen, R is preferred. 3 R 4 Both are hydrogen.

[0056] In another preferred embodiment, when A is At that time, R 3 The following are the possible meanings: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C3 alkyl-, R 5 It is hydrogen, substituted or unsubstituted C1-C6 alkyl.

[0057] In another preferred embodiment, when A is At that time, R 3 R is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl. 5 It is hydrogen, substituted or unsubstituted C1-C6 alkyl.

[0058] In another preferred embodiment, R 5 It is hydrogen, hydroxyl, mercapto, or a substituted or unsubstituted C1-C4 alkoxy group.

[0059] In another preferred embodiment, R 5 It can be hydrogen, hydroxyl, mercapto, or methoxy.

[0060] In another preferred embodiment, R 3 R 4 With adjacent Y 1 They are linked together to form halo-nitrogen heterocyclic butyl groups.

[0061] In another preferred example, X 1 X 2 X 3 and X 4 Each can be independently represented by C, O, S, or N.

[0062] In another preferred example, X 1 It can be C, O, S, or N.

[0063] In another preferred example, X 2 It can be C, O, S, or N.

[0064] In another preferred example, X 3It can be C, O, S, or N.

[0065] In another preferred example, X 4 It can be C, O, S, or N.

[0066] In another preferred example, X 1 X 2 X 3 and X 4 One or more (2 or 3) of them are O, S or N, and the rest are C.

[0067] In another preferred embodiment, the labels are a, b, c, d, and e. Each can be a single bond or a double bond independently.

[0068] In another preferred example, the one labeled a It can be a single bond or a double bond.

[0069] In another preferred example, the one labeled b It can be a single bond or a double bond.

[0070] In another preferred embodiment, labeled c It can be a single bond or a double bond.

[0071] In another preferred example, the one labeled d It can be a single bond or a double bond.

[0072] In another preferred example, the one labeled e It can be a single bond or a double bond.

[0073] In another preferred example, X 1 X 2 X 3 X 4 With the labels a, b, c, d and e It forms aromatic rings or heteroaromatic rings.

[0074] In another preferred embodiment, each of the heterocyclic aromatic rings has 1 to 4 (preferably 1, 2, 3 or 4) heteroatoms selected from N, O and S.

[0075] In another preferred example, X 1 X 2 X 3 X 4 With labels a, b, c, d and e It forms furan rings, thiophene rings, pyrrole rings, thiazole rings, pyrazole rings, isoxazole rings, oxazole rings, imidazole rings, and triazole rings.

[0076] In another preferred embodiment, n is 0, 1, 2, 3, or 4.

[0077] In another preferred embodiment, any “substitution” refers to the substitution of one or more (preferably 1, 2, 3, 4, 5 or 6) hydrogen atoms on a ring or group by a substituent selected from the group consisting of: C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C3-C8 halocycloalkyl, halogen, nitro, -CN, hydroxyl, mercapto, amino, C1-C4 carboxyl, C2-C4 ester, C2-C4 amide, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 haloalkylthio, C6-C12 aryl, 5-10 heteroaryl, 5-10 heterocyclic alkyl.

[0078] In another preferred embodiment, any “substitution” refers to the substitution of one or more (preferably 1, 2, 3, 4, 5 or 6) hydrogen atoms on a ring or group by a substituent selected from the group consisting of: C1-C4 alkyl, C3-C8 cycloalkyl, C1-C4 haloalkyl, C3-C8 halocycloalkyl, halogen, nitro, -CN, hydroxyl, mercapto, amino, C1-C4 carboxyl, C2-C4 ester, C2-C4 amide, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 haloalkoxy, C1-C4 haloalkylthio, C6-C12 aryl, 5-10 heteroaryl, and 5-10 heterocyclic alkyl.

[0079] In another preferred embodiment, the heteroaryl, heterocyclic alkyl, and heterocyclic rings each independently have 1 to 4 (preferably 1, 2, 3, or 4) heteroatoms selected from N, O, and S.

[0080] In another preferred embodiment, the compound has the structure of formula I-1:

[0081]

[0082] In another preferred embodiment, the compound has the structure of formula I-2:

[0083]

[0084] In another preferred embodiment, the compound has the structure of formula I-3:

[0085]

[0086] In another preferred embodiment, the compound has the structure of formula I-4:

[0087]

[0088] In another preferred embodiment, the compound has the structure of formula I-5:

[0089]

[0090] In another preferred embodiment, the compound has the structure of formula I-6:

[0091]

[0092] In another preferred embodiment, the compound has the structure of formula I-7:

[0093]

[0094] In another preferred embodiment, the compound has the structure of formula I-8:

[0095]

[0096] In another preferred embodiment, the compound has a structure of formula Z:

[0097]

[0098] Among them, R 1 R 2 X 1 X 2 X 3 X 4 Ar, a, b, c, d, e, n are as described above;

[0099] R A R B R C Each is independently hydrogen, substituted or unsubstituted C1-C6 alkyl.

[0100] In another preferred embodiment, R 1 R 2 X 1 X 2 X 3 X 4 Ar, A, a, b, c, d, e, and n are each independently the corresponding functional groups in the compounds prepared in the examples.

[0101] In another preferred embodiment, the compound is selected from the group consisting of:

[0102]

[0103]

[0104]

[0105]

[0106] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I as described in the first aspect of the present invention, or an optical isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof; and a pharmaceutically acceptable carrier.

[0107] In another preferred embodiment, the dosage form of the pharmaceutical composition is an oral formulation, an injectable formulation, or a topical formulation.

[0108] In another preferred embodiment, the dosage form of the pharmaceutical composition is a solid dosage form, a liquid dosage form, or a semi-solid dosage form.

[0109] In another preferred embodiment, the dosage form of the pharmaceutical composition is a tablet, injection, infusion, ointment, gel, solution, microsphere, or film.

[0110] A third aspect of the present invention provides a method for preparing a compound of formula I as described in the first aspect of the present invention, or an optical isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, characterized in that the method comprises:

[0111]

[0112] Among them, X 1 X 2 X 3 X 4 R 1 R 2 , n, Ar and R 3 The definition is as defined above.

[0113] In another preferred embodiment, the method includes:

[0114]

[0115] Among them, X 1 X 2 X 3 X 4 R 1 R 2 , n, Ar and R 3 The definition is as defined above. In another preferred embodiment, the method includes:

[0116]

[0117] Among them, X 1 X 2 X 3 X 4 R 1 R 2 , n, Ar and R 3The definition is as defined above. In another preferred embodiment, the method includes:

[0118]

[0119] Among them, X 1 X 2 X 3 X 4 R 1 R 2 , n, Ar and R 3 The definition is as defined above.

[0120] In another preferred embodiment, the method includes:

[0121]

[0122] Among them, X 1 X 2 X 3 X 4 R 1 n, Ar, R 3 and R 4 The definition is as defined above.

[0123] In another preferred embodiment, the method includes:

[0124]

[0125] Among them, X 1 X 2 X 3 X 4 R 1 n, Ar, R 3 and R 4 The definition is as defined above.

[0126] In another preferred embodiment, the method includes:

[0127]

[0128] Among them, X 1 X 2 X 3 X 4 R 1 The definitions of , n and Ar are as defined above.

[0129] In a fourth aspect, the present invention provides the use of a compound of formula I as described in the first aspect of the present invention, or an optical isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a pharmaceutical composition as described in the second aspect of the present invention, for (a) the preparation of an inhibitor of transient receptor potential channel protein TRPA1; and / or (b) the preparation of a medicament for the prevention and / or treatment of diseases associated with transient receptor potential channel protein TRPA1.

[0130] In another preferred embodiment, the diseases associated with the transient receptor potential channel protein TRPA1 are selected from the group consisting of inflammatory bowel disease, irritable bowel syndrome, pain, inflammation, or combinations thereof.

[0131] In another preferred embodiment, the inflammatory bowel disease includes Crohn's disease and / or ulcerative colitis.

[0132] In another preferred embodiment, the pain includes visceral pain, acute inflammatory pain, chronic inflammatory pain, neurogenic pain, myofibromyalgia, headache, neuralgia, or pain caused by cancer.

[0133] In another preferred embodiment, the prevention and / or treatment of inflammatory bowel disease includes one or more methods selected from the group consisting of:

[0134] (i) Improves ulcers;

[0135] (ii) Improves intestinal obstruction;

[0136] (iii) Improves intestinal adhesions;

[0137] (iv) Increased intestinal wall thickening; and / or

[0138] (v) Reduce the level of intestinal inflammatory factors.

[0139] In another preferred embodiment, the prevention and / or treatment of Crohn's disease and / or ulcerative colitis includes one or more methods selected from the group consisting of:

[0140] (i) Improves ulcers;

[0141] (ii) Improves intestinal obstruction;

[0142] (iii) Improves intestinal adhesions;

[0143] (iv) Increased intestinal wall thickening; and / or

[0144] (v) Reduce the level of intestinal inflammatory factors.

[0145] In another preferred embodiment, the inflammatory factors are selected from the group consisting of TNF-α, IL-10, or combinations thereof.

[0146] In a fifth aspect, the present invention provides an in vitro non-therapeutic and non-diagnostic method for inhibiting the activity of transient receptor potential channel proteins, comprising the steps of: contacting the transient receptor potential channel protein or cells expressing said protein with a compound of formula I as described in the first aspect of the present invention, or an optical isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, thereby inhibiting the activity of the transient receptor potential channel protein.

[0147] A sixth aspect of the present invention provides a method for inhibiting transient receptor potential channel protein (TRPA1) or for preventing and / or treating diseases associated with TRPA1, comprising the steps of administering to a desired subject a compound of formula I as described in the first aspect of the present invention, or an optical isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a pharmaceutical composition as described in the second aspect of the present invention.

[0148] In a seventh aspect, the present invention provides a compound, said compound being represented by any one of the following formulas II-1 to II-6:

[0149]

[0150] In the formula:

[0151] Ar represents substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 3-12 heteroaryl, 3-12 heterocyclic alkyl cyclopentadienyl C6-C12 aryl, substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C8 alkyl-, or substituted or unsubstituted 3-12 heteroaryl-substituted or unsubstituted C1-C8 alkyl-.

[0152] X 1 X 2 X 3 and X 4 Each can be independently represented by C, O, S, or N;

[0153] The labels are a, b, c, d, and e. It can be a single bond or a double bond;

[0154] R 1 It is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, or halogen;

[0155] R 2 It is hydrogen, substituted or unsubstituted C1-C10 alkyl, or substituted or unsubstituted C3-C10 cycloalkyl;

[0156] n is 0, 1, 2, 3, 4 or 5;

[0157] Wherein, any “substitution” refers to one or more (preferably 1, 2, 3, 4, 5 or 6) hydrogen atoms on a ring or group being replaced by a substituent selected from the group consisting of: C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C3-C8 halocycloalkyl, halogen, nitro, -CN, hydroxyl, mercapto, amino, C1-C4 carboxyl, C2-C4 ester, C2-C4 amide, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 haloalkoxy, C1-C8 haloalkylthio, C6-C12 aryl, 5-10 heteroaryl, 5-10 heterocyclic alkyl;

[0158] The heterocyclic rings of the heteroaryl, heterocyclic alkyl, and heterocyclic alkyl groups each independently have 1 to 4 (preferably 1, 2, 3, or 4) heteroatoms selected from N, O, and S.

[0159] In another preferred embodiment, the intermediate is selected from the group consisting of:

[0160]

[0161] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0162] Figure 1 Compound I of the present invention A -51、I A -30、I D -5、I A -55 Results of colon length (A), colon weight (B), ulcer area (C), and macroscopic colon injury score (D) in a DNBS-induced rat colitis model.

[0163] Figure 2 Compound I of the present invention A -51、I A -30、I D -5、I A -55 Representative colorectal photographs of animals in each group in the DNBS-induced rat colitis model (A: blank control group, B: model-solvent group, C: oxalazine sodium group, D: compound I) A Group -51, E is compound I A Group -30, F is compound I D Group -5, G is compound I A -55 groups).

[0164] Figure 3 Compound I of the present invention A-51、I A -30、I D -5、I A -55 is the DAI score result in a DSS-induced inflammatory bowel disease model in C57BL / 6 mice.

[0165] Figure 4 Compound I of the present invention A -51、I A -30、I D -5、I A Effects of -55 on colorectal weight and length in a DSS-induced inflammatory bowel disease model in C57BL / 6 mice.

[0166] Figure 5 Compound I of the present invention A -51、I A -30、I D -5、I A -55 ELISA analysis results of colorectal inflammatory factors TNF-α and IL-10 in a DSS-induced inflammatory colitis model of C57BL / 6 mice.

[0167] Figure 6 Compound I of the present invention A -51、I A -30、I D -5 and I A -55 Results of writhing count in an acetic acid-induced writhing pain model in ICR mice. Detailed Implementation

[0168] Through extensive and in-depth research, the inventors have unexpectedly developed, for the first time, a compound of formula I, or its optical isomer, its racemic mixture, or its pharmaceutically acceptable salt. Experiments show that the compound of formula I of this invention has a significant inhibitory effect on TRPA1. The compound of formula I of this invention can effectively treat inflammatory bowel disease, irritable bowel syndrome, pain, and inflammation associated with the TRPA1 target. Based on this, the present invention was completed.

[0169] the term

[0170] As used herein, the terms “comprising,” “including,” and “containing” are used interchangeably and include not only closed definitions but also semi-closed and open definitions. In other words, the terms include “consisting of” and “substantially consisting of”.

[0171] As used herein, the terms “transient receptor potential ankyrin 1”, “TRPA1”, and “transient receptor potential ankyrin A1” are used interchangeably.

[0172] It should be understood that those skilled in the art can select the substituents and substitution patterns on the compounds of the present invention to produce chemically stable compounds that can be synthesized using techniques known in the art and the methods described below. If substituted by more than one (or more) substituent groups, it should be understood that these groups can be on the same carbon or on different carbons, as long as a stable structure is produced.

[0173] As used herein, the term “substitution” or “substituted” refers to a compound in which a hydrogen atom on a group is replaced by a non-hydrogen group, but the substitution must satisfy the valence requirement and the substitution produces a chemically stable compound, i.e., a compound that does not spontaneously undergo transformations such as cyclization or elimination.

[0174] As used in this article, "R1", "R1", and "R" are... 1 The meanings of "" are the same and they can be used interchangeably. Other similar definitions have the same meaning.

[0175] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight and branched groups. When an alkyl group is preceded by a carbon number qualifier (e.g., C1-C10 alkyl), it means that the alkyl group contains 1 to 10 carbon atoms. For example, C1-C4 alkyl means an alkyl group containing 1 to 4 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0176] In this invention, the term "halogen" refers to F, Cl, Br, or I.

[0177] In this invention, the term "halogenated" refers to being replaced by a halogen.

[0178] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more (preferably 1, 2, 3 or 4) hydrogen atoms are replaced by a halogen, the alkyl group and the halogen being as defined above. When an alkyl group is preceded by a carbon number limit (e.g., C1-C6 haloalkyl), it means that the alkyl group contains 1 to 6 carbon atoms. For example, C1-C6 haloalkyl refers to a haloalkyl group containing 1 to 6 carbon atoms. Representative examples include, but are not limited to, -CF3, -CHF2, monofluoroisopropyl, difluorobutyl, or similar groups.

[0179] As used herein, the term "cycloalkyl" refers to a cyclic group having a saturated or partially saturated monocyclic, bicyclic, or polycyclic (fused, bridged, or spirocyclic) ring. When a cycloalkyl group is preceded by a carbon number limitation (e.g., C3-C12), it means that the cycloalkyl group has 3-12 ring carbon atoms. In some preferred embodiments, the term "C3-C8 cycloalkyl" refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having 3-8 ring carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which monocyclic rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Fused cycloalkyl" refers to an all-carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms. These groups may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Representative examples of cycloalkyl groups are as follows, including but not limited to:

[0180]

[0181] As used herein, the term "halocycloalkyl" refers to a cycloalkyl group in which one or more (preferably 1, 2, 3, or 4) hydrogen atoms are replaced by a halogen, the cycloalkyl group and the halogen being as defined above. When a carbon number limitation is specified before the cycloalkyl group (e.g., C3-C8 haloalkyl), it means that the cycloalkyl group contains 3-8 cyclic carbon atoms. For example, C3-C8 haloalkyl refers to a halocycloalkyl group containing 3-6 carbon atoms. Representative examples include, but are not limited to, monofluorocyclopropyl, monochlorocyclobutyl, monofluorocyclopentyl, difluorocycloheptyl, or similar groups.

[0182] The term "alkoxy" refers to an RO- group, where R is an alkyl group, and the alkyl group is as defined above herein. When the alkoxy group is preceded by a carbon number qualifier, such as C1-C8 alkoxy groups, it means that the alkyl group in the alkoxy group has 1-8 carbon atoms. Representative examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, or similar groups.

[0183] As used herein, the term "alkathio" refers to an RO- group, where R is an alkyl group, and the alkyl group is as defined above. When the alkathio group is preceded by a carbon number qualifier, such as C1-C8 alkathio, it means that the alkyl group in the alkathio group has 1-8 carbon atoms. Representative examples of alkathio groups include, but are not limited to: methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, or similar groups.

[0184] As used herein, the term "haloalkoxy" refers to a haloalkyl group -O-, as defined above. For example, C1-C6 haloalkoxy refers to a haloalkoxy group containing 1-6 carbon atoms, and representative examples include, but are not limited to, monofluoromethoxy, monofluoroethoxy, difluorobutoxy, or similar groups.

[0185] As used herein, the term "haloalkylthio" refers to a haloalkyl-S-, as defined above, for example, C1-C6 haloalkylthio refers to a haloalkylthio containing 1-4 carbon atoms, representative examples including but not limited to, monofluoromethylthio, monofluoroethylthio, difluorobutylthio, or similar groups.

[0186] The term "heterocyclic alkane" refers to a fully saturated or partially unsaturated ring (including, but not limited to, 3-7 membered monocyclic rings, 7-11 membered bicyclic rings, or 8-16 membered tricyclic systems) in which at least one heteroatom is present in a ring containing at least one carbon atom. When a member is specified before the heterocycle, it refers to the number of ring atoms in the heterocycle; for example, a 3-16 membered heterocycle refers to a heterocycle with 3-16 ring atoms. Each heterocycle containing heteroatoms may have one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from nitrogen, oxygen, or sulfur atoms, wherein the nitrogen or sulfur atom may be oxidized or quaternized. The heterocycle may be attached to any heteroatom or carbon residue in a ring or ring system molecule. Typical monocyclic heterocyclic alkanes include, but are not limited to, azathiobutane rings, oxacyclobutane rings, imidazoline rings, imidazoline rings, tetrahydrofuran rings, piperidine rings, piperazine rings, 2-oxopiperazine rings, 2-oxopiperidine rings, 4-piperidinone rings, tetrahydropyran rings, morpholine rings, thiomorpholine rings, thiomorpholine sulfoxide rings, thiomorpholine sulfone rings, 1,3-dioxane rings, and tetrahydro-1,1-dioxothiophene rings. Polycyclic heterocyclic alkanes include spirocyclic, fused, and bridged heterocyclic rings; the spirocyclic, fused, and bridged heterocyclic rings involved may optionally be connected to other rings via single bonds, or may be further cyclically linked to other cycloalkane rings or heterocyclic rings via any two or more atoms on the ring.

[0187] The term "heterocyclic alkyl" refers to a fully saturated or partially unsaturated cyclic group (including, but not limited to, 3-7 membered monocyclic, 7-11 membered bicyclic, or 8-16 membered tricyclic systems) in which at least one heteroatom is present in a ring with at least one carbon atom. When a heterocyclic alkyl group is preceded by a number, it refers to the number of ring atoms in the heterocyclic alkyl group; for example, a 3-16 membered heterocyclic alkyl group refers to a heterocyclic alkyl group having 3-16 ring atoms. Each heterocyclic ring containing a heteroatom may have one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from nitrogen, oxygen, or sulfur atoms, wherein the nitrogen or sulfur atom may be oxidized or quaternized. Heterocyclic alkyl groups may be attached to any heteroatom or carbon atom residue in a ring or cyclic molecule. Typical monocyclic heterocyclic alkyl groups include, but are not limited to, azazolinyl, oxazolinyl, imidazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinosulfoxide, thiomorpholinosulfone, 1,3-dioxane, and tetrahydro-1,1-dioxothiophene. Polycyclic heterocyclic alkyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; the spirocyclic, fused-ring, and bridged-ring heterocyclic alkyl groups involved may optionally be connected to other groups by single bonds, or further cyclically linked to other cycloalkane rings or heterocycles by any two or more atoms on the ring.

[0188] The term "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic ring (i.e., a ring sharing adjacent carbon atom pairs) with a conjugated π-electron system. It is an aromatic cyclic hydrocarbon compound. When the aromatic ring is preceded by a carbon atom number limit, such as a C6-C12 aromatic ring, it means that the aromatic ring has 6-12 ring carbon atoms, such as benzene and naphthalene rings. The aromatic ring can be fused to other carbon rings (including saturated or unsaturated rings), but it cannot contain heteroatoms such as nitrogen, oxygen, or sulfur. The point of connection to the parent ring must be on a carbon atom of a ring with a conjugated π-electron system. Representative aromatic rings are benzene and naphthalene rings, or similar rings.

[0189] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon pairs) group with a conjugated π-electron system. It is an aromatic cyclic hydrocarbon compound group. When the aryl group is preceded by a carbon number limit, such as C6-C12 aryl, it means that the aryl group has 6-12 ring carbon atoms, for example, phenyl and naphthyl. The aryl ring can be fused to other cyclic groups (including saturated or unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur. The point of attachment to the parent group must be on a carbon atom of a ring with a conjugated π-electron system. The following are representative examples of aryl groups, including but not limited to:

[0190]

[0191] The term "heteroaromatic ring" refers to an aromatic heterocycle having one to several (preferably 1, 2, 3, or 4) heteroatoms. It can be a monocyclic ring (monocyclic) or a polycyclic ring (bicyclic, tricyclic, or polycyclic) fused together or covalently linked. Each heterocycle 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 a member is specified before "heteroaromatic ring," it refers to the number of ring atoms in the heteroaromatic ring. For example, a 5-12 member heteroaromatic ring refers to a heteroaromatic ring having 5-12 ring atoms. Representative 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 tetrazolium rings.

[0192] The term "heteroaryl" refers to an aromatic heterocyclic group having one to several (preferably 1, 2, 3, or 4) heteroatoms. These heteroatoms can be monocyclic (monocyclic) or polycyclic (bicyclic, tricyclic, or polycyclic) fused together or covalently linked. Each heterocycle containing a heteroatom 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 a member is specified before "heteroaryl," it refers to the number of ring atoms in the heteroaryl group. For example, a 5-12 member heteroaryl refers to a heteroaryl group having 5-12 ring atoms. Representative examples include, but are not limited to: pyrrole, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and tetrazolyl.

[0193] As used herein, the term “carboxyl” refers to a group having a -COOH group or an alkyl-COOH group, where alkyl is as defined above, for example, “C2-C4 carboxyl” refers to a group with a -C1-C3 alkyl-COOH structure. Representative examples of carboxyl groups include (but are not limited to): -COOH, -CH2COOH, -C2H4COOH, or similar groups.

[0194] As used herein, the term "ester group" refers to an R-CO-O- or -CO-OR group, where R is an alkyl group and the alkyl group is as defined above herein. 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. Representative examples of ester groups include, but are not limited to: CH3COO-, C2H5COO-, C3H8COO-, (CH3)2CHCOO-, -COOCH3, -COOC2H5, -COOC3H8, or similar groups.

[0195] As used herein, the term "amide group" refers to an R-CO-N- or -CO-NR group, where R is an alkyl group and the alkyl group is as defined above herein. For example, "C2-C4 amide group" refers to a group with a C1-C3 alkyl-CO-N- structure or a group with a -CO-N-C1-C3 alkyl structure. Representative 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.

[0196] As used herein, the term "amino" means -NH2, either alone or as part of other substituents.

[0197] As used herein, the term "nitro" means -NO2, either alone or as part of other substituents.

[0198] As used herein, the term "hydroxyl" means -OH, either alone or as part of other substituents.

[0199] As used herein, the term "thiol" means -SH, either alone or as part of other substituents.

[0200] In this specification, all substituents should be interpreted as unsubstituted unless explicitly described herein as “substituted.” The term “substituted” means that one or more hydrogen atoms on a particular group are replaced by a particular substituent. The particular substituent is the substituent described accordingly above, or the substituent appearing in the various examples. Preferably, the substitution refers to the substitution of one or more (preferably 1, 2, 3, 4, 5, or 6) hydrogen atoms on a ring or group by a substituent selected from the group consisting of: C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C3-C8 halocycloalkyl, halogen, nitro, -CN, hydroxyl, mercapto, amino, C1-C4 carboxyl, C2-C4 ester, C2-C4 amide, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 haloalkoxy, C1-C8 haloalkylthio, C6-C12 aryl, 5-10 heteroaryl, 5-10 heterocyclic alkyl;

[0201] In this invention, the term "prevention" refers to a method of preventing the onset of a disease and / or its accompanying symptoms or protecting a subject from acquiring a disease. As used herein, "prevention" also includes delaying the onset of a disease and / or its accompanying symptoms and reducing the subject's risk of contracting the disease.

[0202] The “treatment” described in this invention includes delaying and halting the progression of disease, or eliminating disease, and does not require 100% inhibition, eradication, and reversal. In some embodiments, compared to levels observed in the absence of the compositions, packaging, food packaging, or health supplement packaging, or combination of active ingredients described in this invention, the compositions or pharmaceutical compositions of this invention reduce, inhibit, and / or reverse disease associated with the transient receptor potential channel protein TRPA1 by, for example, at least about 10%, at least about 30%, at least about 50%, or at least about 80%.

[0203] Active ingredients

[0204] As used herein, “compound of the present invention,” “N-substituted phenylsulfonamide compound of the present invention,” or “compound of formula I” are used interchangeably to refer to a compound of formula I, or an optical isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. It should be understood that the term also includes mixtures of the foregoing components.

[0205] This invention provides a compound of formula I, or an optical isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

[0206]

[0207] In the formula:

[0208] Ar represents substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 3-12 heteroaryl, 3-12 heterocyclic alkyl cyclopentadienyl C6-C12 aryl, substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C8 alkyl-, or substituted or unsubstituted 3-12 heteroaryl-substituted or unsubstituted C1-C8 alkyl-.

[0209] X 1 X 2 X 3 and X 4 Each can be independently represented by C, O, S, or N;

[0210] The labels are a, b, c, d, and e. It can be a single bond or a double bond;

[0211] R 1 It is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, or halogen;

[0212] R 2 It is hydrogen, substituted or unsubstituted C1-C10 alkyl, or substituted or unsubstituted C3-C10 cycloalkyl;

[0213] A is Substituted or unsubstituted C2-C6 ester group, substituted or unsubstituted C2-C6 carboxyl group, substituted or unsubstituted C2-C6 amide group, or substituted or unsubstituted 2HN-HN-C(O)-; m is 0, 1, 2 or 3;

[0214] Y 1 Let N be the number of people in the group.

[0215] Y 2 For O or S;

[0216] Y 3 It can be NH, O, or S;

[0217] Y 4 For O or S;

[0218] Y 5 Let N be the number of people in the group.

[0219] R 3 and R 4 Each is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C6 acyl, or R 3 R 4 With adjacent Y 1 They are linked together to form substituted or unsubstituted 3-8 membered heterocyclic alkyl groups;

[0220] R 5 It is a hydrogen, hydroxyl, mercapto, or substituted or unsubstituted C1-C6 alkoxy group;

[0221] n is 0, 1, 2, 3, 4 or 5;

[0222] Wherein, any “substitution” refers to one or more (preferably 1, 2, 3, 4, 5 or 6) hydrogen atoms on a ring or group being replaced by a substituent selected from the group consisting of: C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C3-C8 halocycloalkyl, halogen, nitro, -CN, hydroxyl, mercapto, amino, C1-C4 carboxyl, C2-C4 ester, C2-C4 amide, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 haloalkoxy, C1-C8 haloalkylthio, C6-C12 aryl, 5-10 heteroaryl, 5-10 heterocyclic alkyl;

[0223] The heterocyclic rings of the heteroaryl, heterocyclic alkyl, and heterocyclic alkyl groups each independently have 1 to 4 (preferably 1, 2, 3, or 4) heteroatoms selected from N, O, and S.

[0224] Preferably, the compound of formula I is as described in the first aspect of the present invention.

[0225] The term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are salts formed by the compounds of the present invention with acids, including (but 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, benzenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid. A preferred class of salts are metal salts formed by the compounds of the present invention with bases, including (but not limited to): inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphate; and organic bases such as ammonia, triethylamine, and diethylamine.

[0226] The compounds of Formula I described in this invention can be converted into their pharmaceutically acceptable salts by conventional methods. For example, a solution of the corresponding acid can be added to a solution of the above-mentioned compound, and after complete salt formation, the solvent can be removed to obtain the corresponding salt of the compound described in this invention.

[0227] The preferred compounds of this invention are as described in the specific compounds prepared in the embodiments of this application.

[0228] Representatively, the compounds described in this invention are selected from Table 1 below:

[0229] Table 1

[0230]

[0231]

[0232]

[0233] Preparation method

[0234] The present invention also provides compound I represented by formula I. A ~I W Preparation method of .

[0235] The present invention also provides a method for preparing intermediates IV to XXVII for preparing the above-mentioned compounds.

[0236] The specific synthesis strategies are as follows:

[0237] I A ~I F Synthesis:

[0238]

[0239] Among them, X 1 X 2 X3 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.

[0240] Substituted iodobenzene II, substituted or unsubstituted five-membered heteroarylboronic acid III, tetra-triphenylphosphine palladium, and sodium carbonate were dissolved in a mixed solution of toluene, methanol, and water. The mixture was heated under reflux overnight under nitrogen protection. After the reaction was complete, the solvent was evaporated to dryness, water was added to the system, 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 intermediate IV.

[0241] Intermediate IV, or a substituted or unsubstituted sulfonyl chloride, was dissolved in a mixed solution of pyridine and tetrahydrofuran. The solution was then sealed and reacted overnight at 50-100°C. After the reaction was complete, the solvent was evaporated, and the residue was separated by column chromatography to obtain intermediate V.

[0242] Intermediate V was dissolved in tetrahydrofuran solution, and appropriate amounts of acetic acid and Raney nickel were added. The mixture was reacted at 50-100°C for 1-2 hours. After the reaction was completed, Raney nickel was removed by filtration, the filtrate was evaporated to dryness, and the residue was separated by column chromatography to obtain intermediate VI.

[0243] Intermediate VI was dissolved in an ethanol solution, and a substituted amine was 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 compound I. C .

[0244] Intermediate VI was dissolved in an ethanol solution, and a substituted amine was added. The mixture was reacted overnight at room temperature. On the second day, sodium borohydride was added in portions, and the reaction was carried out for 1 hour each time. After the reaction was complete, the solvent was evaporated, and the residue was separated by column chromatography to obtain compound I. A .

[0245] Intermediate V was dissolved in ammonia-methanol solution, Raney nickel was added, hydrogen gas was bubbled through, and the reaction was carried out overnight at room temperature. After the reaction was completed, Raney nickel was removed by filtration, the filtrate was evaporated to dryness, and the residue was separated by column chromatography to obtain compound I. D .

[0246] Compound I D The compound was dissolved in dichloromethane solution, and triethylamine and acetic anhydride were added. The mixture was reacted overnight at room temperature. After the reaction was complete, the solvent was evaporated to dryness, and the residue was separated by column chromatography to obtain compound I. E .

[0247] Intermediate V was dissolved in acetonitrile solution, and potassium carbonate and substituted alkyl iodine were added. The mixture was reacted at 60-80°C for three hours. After the reaction was completed, the solvent was evaporated, and the residue was separated by column chromatography to obtain intermediate VII.

[0248] Intermediate VII was dissolved in tetrahydrofuran solution, and appropriate amounts of acetic acid and Raney nickel were added. The mixture was reacted at 50-100°C for 1-2 hours. After the reaction was completed, Raney nickel was removed by filtration, the filtrate was evaporated to dryness, and the residue was separated by column chromatography to obtain intermediate VIII.

[0249] Intermediate VIII was dissolved in ethanol, and a substituted amine was added. The mixture was reacted overnight at room temperature. The next day, sodium borohydride was added in portions, and the reaction was allowed to proceed for 1 hour each time. After the reaction was complete, the solvent was evaporated, and the residue was separated by column chromatography to obtain compound I. B .

[0250] Intermediate VII was dissolved in ammonia-methanol solution, Raney nickel was added, hydrogen gas was bubbled through, and the reaction was carried out overnight at room temperature. After the reaction was completed, Raney nickel was removed by filtration, the filtrate was evaporated to dryness, and the residue was separated by column chromatography to obtain compound I. F .

[0251] I G I H I J I K and I P Synthesis:

[0252]

[0253] Among them, 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 this invention above.

[0254] The substituted iodobenzene IX, substituted or unsubstituted five-membered heteroarylboronic acid III, tetra-triphenylphosphine palladium, and sodium carbonate were dissolved in a mixed solution of toluene, methanol, and water. The mixture was heated under reflux overnight under nitrogen protection. After the reaction was complete, the solvent was evaporated to dryness, water was added to the system, 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 intermediate X.

[0255] Intermediate X, or a substituted or unsubstituted sulfonyl chloride, was dissolved in a mixed solution of pyridine and tetrahydrofuran. The mixture was then sealed and reacted overnight at 50-100°C. After the reaction was complete, the solvent was evaporated, and the residue was separated by column chromatography to obtain compound I. G .

[0256] Compound I GDissolved in tetrahydrofuran solution, under nitrogen protection, lithium aluminum hydride was added in batches under ice bath conditions, and the reaction was carried out at room temperature for 1-4 hours. Post-treatment involved adding water, sodium hydroxide aqueous solution, and water sequentially to the system, followed by filtration. The filtrate was evaporated to dryness, and the residue was separated by column chromatography to obtain compound I. H .

[0257] Compound I H Dissolved in dichloromethane solution, triphenylphosphine and carbon tetrabromide were added under ice bath conditions, and the reaction was carried out at room temperature for 1-4 hours. After the reaction was completed, the solvent was evaporated to dryness, and the residue was dissolved in N,N-dimethylformamide solution. A substituted amine and potassium carbonate were added, and the reaction was carried out overnight at 60-90°C. After the reaction was completed, water was added to the system, 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 compound I. J .

[0258] Compound I G Dissolved in ethanol solution, a substituted amine was added, and the reaction was carried out overnight at 60-100°C. After the reaction was complete, the solvent was evaporated to dryness, and the residue was separated by column chromatography to obtain compound I. P .

[0259] Compound I G Dissolved in tetrahydrofuran solution, lithium hydroxide aqueous solution was added, and the reaction was carried out overnight at 40-60℃. After the reaction was completed, the solvent was evaporated to dryness, and the pH was adjusted to 3-4 by adding an appropriate amount of dilute hydrochloric acid. 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 compound I. K .

[0260] I Q Synthesis:

[0261]

[0262] Among them, 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 this invention above.

[0263] The substituted fluorobenzene XI and the substituted or unsubstituted five-membered nitrogen-containing heterocyclic compound XII were dissolved in dimethyl sulfoxide solution, sodium hydroxide was added, and the reaction was carried out overnight at 40-80°C under nitrogen protection. After the reaction was completed, water was added to the system, 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 intermediate XIII.

[0264] Intermediate XIII was dissolved in a mixed solution of ethanol and water, and iron powder and ammonium chloride were added. The mixture was reacted at 60-80°C for 1 hour. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, extracted three times with dichloromethane, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to obtain intermediate XIV.

[0265] Intermediate XIV, along with substituted or unsubstituted sulfonyl chloride, was dissolved in a mixed solution of pyridine and tetrahydrofuran. The solution was then sealed and reacted overnight at 50-100°C. After the reaction was complete, the solvent was evaporated, and the residue was separated by column chromatography to obtain intermediate XV.

[0266] Intermediate XV was dissolved in tetrahydrofuran solution under nitrogen protection, and lithium aluminum hydride was added in an ice bath. The reaction was carried out at room temperature for 1-4 hours. For post-treatment, water, sodium hydroxide aqueous solution, and water were added sequentially to the system. The mixture was filtered, the filtrate was evaporated to dryness, and the residue was separated by column chromatography to obtain intermediate XVI.

[0267] Intermediate XVI was dissolved in dichloromethane solution, and pyridinium chlorochromate was added. The mixture was reacted at room temperature for 1 hour. After post-treatment, the mixture was filtered, the filtrate was evaporated to dryness, and the residue was separated by column chromatography to obtain intermediate XVII.

[0268] Intermediate XVII was dissolved in ethanol solution, and a substituted amine was added. The reaction was carried out overnight at room temperature. On the second day, sodium borohydride was added to the system in portions, and the reaction was carried out for 1 hour each time. After the reaction was completed, the solvent was evaporated to dryness, and the residue was separated by column chromatography to obtain compound I. Q .

[0269] I R and I S Synthesis:

[0270]

[0271] Among them, X 1 X 2 X 3 X 4 R 1 The definitions of , n, and Ar are as described in the first aspect of this invention above.

[0272] The amino-substituted phenylacetonitrile was dissolved in acetonitrile solution, and N-bromosuccinimide was added. The reaction was carried out at room temperature for 0.5–2 hours. After the reaction was completed, the solvent was evaporated, and the residue was separated by column chromatography to obtain intermediate XVIII.

[0273] Intermediate XVIII, substituted or unsubstituted five-membered heteroarylboronic acid III, tetra-triphenylphosphine palladium, and sodium carbonate were dissolved in a mixed solution of toluene, methanol, and water. The mixture was heated under reflux overnight under nitrogen protection. After the reaction was complete, the solvent was evaporated to dryness, water was added to the system, 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 intermediate XIX.

[0274] Intermediate XIX, along with substituted or unsubstituted sulfonyl chloride, was dissolved in a mixed solution of pyridine and tetrahydrofuran. The solution was then sealed and reacted overnight at 50-100°C. After the reaction was complete, the solvent was evaporated, and the residue was separated by column chromatography to obtain intermediate XX.

[0275] Intermediate XX was dissolved in ammonia-methanol solution, Raney nickel was added, hydrogen gas was bubbled through, and the reaction was carried out overnight at room temperature. After the reaction was completed, Raney nickel was removed by filtration, the filtrate was evaporated to dryness, and the residue was separated by column chromatography to obtain compound I. R .

[0276] Compound I R The product was dissolved in a mixed solution of dichloromethane and methanol, and di-tert-butyl dicarbonate was 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 intermediate XXI.

[0277] Intermediate XXI was dissolved in tetrahydrofuran solution, and under nitrogen protection, lithium aluminum hydride was added in an ice bath and reacted overnight at 60-80°C. For post-treatment, water, sodium hydroxide aqueous solution, and water were added sequentially to the system. The mixture was filtered, the filtrate was evaporated to dryness, and the residue was separated by column chromatography to obtain compound I. S .

[0278] I U Synthesis:

[0279]

[0280] Among them, X 1 X 2 X 3 X 4 R 1 The definitions of , n, and Ar are as described in the first aspect of this invention above.

[0281] Intermediate VIII, tert-butylsulfonamide, and copper sulfate were dissolved in 30 mL of anhydrous 1,2-dichloroethane solution and heated to react overnight. After the reaction was completed, the system was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was separated by column chromatography to obtain intermediate XXII.

[0282] Intermediate XXII was dissolved in anhydrous tetrahydrofuran solution, and a tetrahydrofuran solution of methyl magnesium bromide was slowly added dropwise at -78°C. After the addition was complete, the temperature was slowly raised to -20°C to allow the reaction to proceed. After the reaction was completed, an aqueous solution of ammonium chloride was added to quench the reaction under ice bath conditions. Water was then added, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to obtain intermediate XXIII.

[0283] Intermediate XXIII was dissolved in an ethanol solution, and an ethanol solution of hydrochloric acid was added. The reaction was carried out at 60°C. After the reaction was completed, the solvent was evaporated to dryness, water was added to the residue, and an appropriate amount of sodium bicarbonate aqueous solution was added to adjust the pH to 8-9. The residue was extracted 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 compound I. U .

[0284] I V Synthesis:

[0285]

[0286] Among them, X 1 X 2 X 3 X 4 R 1 The definitions of , n, and Ar are as described in the first aspect of this invention above.

[0287] Using a method similar to that used to synthesize intermediate V, intermediate XXV was obtained.

[0288] Intermediate XXV was dissolved in dichloromethane solution, and an ethanol solution of methylamine and tetraethoxytitanium were added. The mixture was reacted overnight at room temperature. Sodium borohydride was slowly added under ice-water bath conditions, and the reaction was continued at room temperature. After the reaction was complete, water was added to the system, and the mixture was extracted with dichloromethane, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to obtain compound I. V .

[0289] I W Synthesis:

[0290]

[0291] Among them, X 1 X 2 X 3 X 4 R 1 The definitions of , n, and Ar are as described in the first aspect of this invention above.

[0292] Using a method similar to that used for synthesizing intermediate V, intermediate XXVII was obtained.

[0293] Intermediate XXVII was dissolved in ethyl acetate solution, and an ethanol solution of hydrochloric acid was added. The reaction was carried out at room temperature. After the reaction was completed, the solvent was evaporated to dryness, water was added to the residue, and an appropriate amount of sodium bicarbonate aqueous solution was added to adjust the pH to 8-9. The residue was extracted 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 compound I. W .

[0294] Transient receptor potential channel protein (TRP)

[0295] Transient receptor potential channel proteins are a superfamily of proteins consisting of important cation channels located on the cell membrane. Transient receptor potential channel proteins include several subfamilies, such as TRPA1, TRPC, TRPM, TRPV, TRPML, and TRPP.

[0296] Studies have found that the TRPA1 channel protein is associated with diseases such as inflammatory bowel disease, pain, irritable bowel syndrome, and inflammation, and TRPA1 is a target for the treatment of these diseases.

[0297] use

[0298] The present invention also provides a method for inhibiting the transient receptor potential channel protein TRPA1, and a method for treating diseases related to TRPA1.

[0299] The compounds of this invention can be used to inhibit transient receptor potential channel protein TRPA1, thereby preventing or treating diseases associated with transient receptor potential channel protein TRPA1.

[0300] In this invention, examples of diseases associated with the transient receptor potential channel protein TRPA1 include (but are not limited to): inflammatory bowel disease, pain, irritable bowel syndrome, and inflammation. Representative examples of inflammatory bowel disease include ulcerative colitis and Crohn's disease; examples of pain include (but are not limited to): visceral pain, acute inflammatory pain, chronic inflammatory pain, neurogenic pain, fibromyalgia, headache, neuralgia, or pain caused by cancer.

[0301] 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, for example, in an in vitro culture system, contacting the transient receptor potential channel protein TRPA1 or cells expressing the transient receptor potential channel protein with the compound of the present invention, thereby inhibiting the activity of the transient receptor potential channel protein TRPA1.

[0302] The present invention also 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 the compound described in this invention to the desired subject.

[0303] Preferably, the objects include humans and non-human mammals (rodents, rabbits, monkeys, livestock, dogs, cats, etc.).

[0304] Crohn's disease

[0305] Crohn's disease is an inflammatory bowel disease that causes inflammation of the gastrointestinal tract. It can occur at any age, but typically 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. Crohn's disease can occur anywhere in the gastrointestinal tract, from the mouth to the anus.

[0306] Ulcerative colitis

[0307] Ulcerative colitis is a chronic, nonspecific inflammatory disease of the rectum and colon with an unclear etiology. The lesions are mainly limited to the mucosa and submucosa of the large intestine. Clinical manifestations primarily include diarrhea, bloody and mucous stools, and abdominal pain, often recurring and persistent.

[0308] Composition and method of application

[0309] This invention provides a composition for inhibiting the activity of the transient receptor potential channel protein TRPA1. The composition includes (but is not limited to): pharmaceutical compositions, food compositions, dietary supplements, beverage compositions, etc.

[0310] Typically, the composition is a pharmaceutical composition comprising a compound as described in this invention, and a pharmaceutically acceptable carrier.

[0311] In this invention, the dosage form of the pharmaceutical composition includes (but is not limited to) oral preparations, injections, and topical preparations.

[0312] Representative examples include (but are not limited to): tablets, injections, infusions, ointments, gels, solutions, microspheres, and films.

[0313] 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 must have sufficient purity and sufficiently low toxicity. "Compatibility" refers to the ability of the components in a pharmaceutical composition and the active ingredient of the drug, as well as the interactions between them, to not significantly reduce the drug's efficacy.

[0314] It should be understood that the carrier described in this invention is not particularly limited and can be any material commonly used in the art, prepared by conventional methods, or purchased from the market. Pharmaceutically acceptable examples of carriers include cellulose and its derivatives (such as methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium dodecyl sulfate), buffers, chelating agents, thickeners, pH adjusters, transdermal penetration enhancers, colorants, flavoring agents, stabilizers, antioxidants, preservatives, antibacterial agents, pyrogen-free water, etc.

[0315] In addition to the active pharmaceutical ingredient, liquid dosage forms typically contain inert diluents commonly used in the art, such as water or other solvents, 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, castor oil, and sesame oil, or mixtures thereof. Besides these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers, and suspending agents.

[0316] The pharmaceutical formulation should be matched with the route of administration. The pharmaceutical formulation of this invention can also be used with other synergistic therapeutic agents (including before, during, or after administration). When using the pharmaceutical composition or formulation, a safe and effective amount of the drug is administered to the desired subject (such as a human or non-human mammal), said safe and effective amount generally being at least about 10 micrograms per kilogram of body weight, and in most cases not exceeding about 8 milligrams per kilogram of body weight, preferably about 10 micrograms per kilogram of body weight to about 1 milligram per kilogram of 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, which are within the scope of the skill of a skilled physician.

[0317] The main advantages of this invention include:

[0318] (a) This invention provides a class of compounds of formula I with novel structures and excellent TRPA1 inhibitory activity.

[0319] (b) The compounds of the present invention have excellent therapeutic effects on inflammatory bowel disease.

[0320] (c) The compounds of the present invention have excellent analgesic effects.

[0321] (d) The compounds of this invention have low toxicity and high efficacy, thus providing a large safety window.

[0322] (e) The compounds of the present invention have good drug-like properties.

[0323] (f) The compounds of the present invention have excellent pharmacokinetic properties.

[0324] (g) The compounds of the present invention are suitable for oral administration.

[0325] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0326] Example 1

[0327] Compound I A Synthesis:

[0328] Step 1: 3-Amino-4-(furan-2-yl)benzonitrile (IV-1)

[0329]

[0330] 3-Amino-4-iodobenzonitrile (244.0 mg, 1 mmol), furan-2-boronic acid (123.1 mg, 1.1 mmol), tetrakis(triphenylphosphine)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 (v / v / v = 9:3:1) and refluxed overnight. After the reaction was complete, the solvent was evaporated to dryness, 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 give intermediate IV-1, an off-white solid (172.0 mg, 93.4%).

[0331] 1 H NMR(400MHz, CDCl3) δ7.69(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).

[0332] Step 2: N-(5-cyano-2-(furan-2-yl)phenyl)-4-fluorobenzenesulfonamide (V-1)

[0333]

[0334] 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 (volume / volume = 1:1) mixture, and the mixture was 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 give intermediate V-1 as a yellow solid (94.8 mg, 55.4%).

[0335] 1 H NMR (500MHz, DMSO) δ10.13(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).

[0336] Step 3: 4-Fluoro-N-(5-formyl-2-(furan-2-yl)phenyl)benzenesulfonamide (Intermediate VI-1)

[0337]

[0338] Intermediate V-1 (68.5 mg, 0.2 mmol) was dissolved in 12 mL of a tetrahydrofuran / acetic acid (volume / volume = 5:1) mixed solution. An appropriate amount of Raney nickel aqueous solution was added to the system, hydrogen gas was introduced, and the reaction was carried out at 60 °C for one hour. After the reaction was complete, Raney nickel was removed by filtration, the filtrate was evaporated to dryness, and the residue was separated by column chromatography to obtain intermediate VI-1, a yellow solid (32.9 mg, 47.6%).

[0339] 1 H NMR (400MHz, DMSO) δ10.11(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).

[0340] Steps 4-5: 4-Fluoro-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (Compound I) A -1)

[0341]

[0342] Intermediate VI-1 (27.6 mg, 0.08 mmol) was dissolved in an ethanol solution, and 1 mL of an ethanol solution of methylamine (30-33 wt%) was added. The reaction was allowed to proceed overnight, followed by the addition of sodium borohydride (3.0 mg, 0.08 mmol). After the reaction was complete, the solvent was evaporated to dryness, and the residue was separated by column chromatography to obtain compound I. A -1, white solid (14.0 mg, 48.7%).

[0343] HPLC: 99.1%; LC-MS (m / z): 361.10 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.82–7.66(m,2H),7.66–7.54(m,2H),7.38(d,J=3.1Hz,1H),7.25(d,J=1.5Hz,1 H),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).

[0344] Take synthetic I A Using a similar method, the following compounds were obtained:

[0345] 2-Fluoro-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -2)

[0346]

[0347] HPLC: 99.0%; LC-MS (m / z): 361.09 (M+H) + ; 1 H NMR(400MHz,DMSO)δ7.74(td,J=7.6,1.5Hz,1H),7.64–7.55(m,2H),7.51(s,1H),7.43–7.30(m,2H),7.1 3(dd,J=15.1,7.9Hz,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).

[0348] 3-Fluoro-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -3)

[0349]

[0350] HPLC: 98.9%; LC-MS (m / z): 361.11 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.64–7.55(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).

[0351] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -4)

[0352]

[0353] HPLC: 99.4%; LC-MS (m / z): 343.10 (M+H) + ; 1 H NMR(400MHz,DMSO)δ7.75–7.66(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).

[0354] 2-Methoxy-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -5)

[0355]

[0356] HPLC: 98.8%; LC-MS (m / z): 373.11 (M+H) + ; 1H NMR (400MHz, DMSO) δ7.75(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),7.15–7.0 8(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).

[0357] 4-Methoxy-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -6)

[0358]

[0359] HPLC: 97.9%; LC-MS (m / z): 373.16 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.67–7.56 (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).

[0360] 4-Chloro-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -7)

[0361]

[0362] HPLC: 99.4%; LC-MS (m / z): 377.11 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.72–7.66(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).

[0363] 2-Trifluoromethoxy-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -8)

[0364]

[0365] HPLC: 96.9%; LC-MS (m / z): 427.10 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.93–7.87(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).

[0366] 4-Trifluoromethoxy-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -9)

[0367]

[0368] HPLC: 98.8%; LC-MS (m / z): 427.19 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.82–7.75(m,2H),7.61(dd,J=11.1,4.5Hz,2H),7.34(t,J=10.5Hz,3H),7.3 0(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).

[0369] 4-Methyl-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -10)

[0370]

[0371] HPLC: 98.7%; LC-MS (m / z): 357.13 (M+H) + ; 1H NMR (400MHz, DMSO) δ7.62(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).

[0372] 2,4-Difluoro-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -11)

[0373]

[0374] HPLC: 99.6%; LC-MS (m / z): 379.10 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.72 (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).

[0375] 2,6-Difluoro-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -12)

[0376]

[0377] HPLC: 99.1%; LC-MS (m / z): 379.11 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.51 (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).

[0378] 4-Trifluoromethyl-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -13)

[0379]

[0380] HPLC: 98.5%; LC-MS (m / z): 411.10 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.88(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).

[0381] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)naphthalene-2-sulfonamide (I) A -14)

[0382]

[0383] HPLC: 97.9%; LC-MS (m / z): 393.13 (M+H) + ; 1 H NMR (500MHz, DMSO) δ8.33(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).

[0384] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)-2,3-dihydrobenzofuran-5-sulfonamide (I) A -15)

[0385]

[0386] HPLC: 97.7%; LC-MS (m / z): 385.14 (M+H) + ; 1H NMR (400MHz, DMSO) δ7.67(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,1H),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).

[0387] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzothiazole-6-sulfonamide (I) A -16)

[0388]

[0389] HPLC: 99.3%; LC-MS (m / z): 400.07 (M+H) + ; 1 H NMR (400MHz, DMSO) δ9.46(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=8.1Hz,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).

[0390] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)pyridine-3-sulfonamide (I) A -17)

[0391]

[0392] HPLC: 99.6%; LC-MS (m / z): 344.11 (M+H) + ; 1H NMR (400MHz, DMSO) δ8.83 (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).

[0393] 6-Chloro-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)pyridine-3-sulfonamide (I) A -18)

[0394]

[0395] HPLC: 98.1%; LC-MS (m / z): 378.06 (M+H) + ; 1 H NMR (500MHz, DMSO) δ8.55(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).

[0396] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)-1-methyl-1H-imidazol-4-sulfonamide (I) A -19)

[0397]

[0398] HPLC: 98.5%; LC-MS (m / z): 347.12 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.79–7.71(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).

[0399] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)thiophene-2-sulfonamide (I) A -20)

[0400]

[0401] HPLC: 98.9%; LC-MS (m / z): 349.06 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.66–7.58(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).

[0402] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)thiophene-3-sulfonamide (I) A -twenty one)

[0403]

[0404] HPLC: 99.0%; LC-MS (m / z): 349.08 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.96(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).

[0405] 5-Chloro-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)thiophene-2-sulfonamide (I) A -twenty two)

[0406]

[0407] HPLC: 96.9%; LC-MS (m / z): 383.03 (M+H) + ; 1H NMR (400MHz, DMSO) δ7.74–7.65(m,2H),7.40(s,1H),7.32(d,J=1.6Hz,1H),7.23(d,J=4.0Hz,1 H), 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).

[0408] 5-Bromo-N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)thiophene-2-sulfonamide (I) A -twenty three)

[0409]

[0410] HPLC: 97.4%; LC-MS (m / z): 426.99 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.73 –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).

[0411] N-(2-(furan-2-yl)-5-((methylamino)methyl)phenyl)-1-phenylmethanesulfonamide (I) A -twenty four)

[0412]

[0413] HPLC: 97.8%; LC-MS (m / z): 357.16 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.68–7.61(m,2H),7.33–7.24(m,6H),7.13(d,J=3.4Hz,1H),7.03 (d, J=7.9Hz, 1H), 6.51 (dd, J=3.2, 1.8Hz, 1H), 4.31 (s, 2H), 3.81 (s, 2H), 2.42 (s, 3H).

[0414] N-(2-(furan-2-yl)-5-((2,2,2-trifluoroethyl)amino)methyl)phenyl)benzenesulfonamide (I) A -25)

[0415]

[0416] HPLC: 99.3%; LC-MS (m / z): 411.10 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.72(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).

[0417] N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -26)

[0418]

[0419] HPLC: 98.8%; LC-MS (m / z): 343.16 (M+H) + ; 1 H NMR(400MHz,DMSO)δ7.77–7.62(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).

[0420] 4-Fluoro-N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -27)

[0421]

[0422] HPLC: 99.2%; LC-MS (m / z): 361.14 (M+H) + ; 1 H NMR (500MHz, MeOD) δ7.67(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).

[0423] 2-Fluoro-N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -28)

[0424]

[0425] HPLC: 97.0%; LC-MS (m / z): 361.09 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.70–7.64(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).

[0426] N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-2-sulfonamide (I) A -29)

[0427]

[0428] HPLC: 98.1%; LC-MS (m / z): 349.07 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.74(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).

[0429] N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide (I) A -30)

[0430]

[0431] HPLC: 98.4%; LC-MS (m / z): 349.09 (M+H) + ; 1H NMR (500MHz, CDCl3) δ7.70–7.65(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).

[0432] N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)pyridine-3-sulfonamide (I) A -31)

[0433]

[0434] HPLC: 98.6%; LC-MS (m / z): 344.11 (M+H) + ; 1 H NMR (400MHz, DMSO) δ8.80(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).

[0435] N-(4-((ethylamino)methyl)-2-(furan-2-yl)phenyl)thiophene-3-sulfonamide (I) A -32)

[0436]

[0437] HPLC: 99.3%; LC-MS (m / z): 363.09 (M+H) + ; 1H NMR (500MHz, DMSO) δ7.77(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).

[0438] N-(4-((cyclopropylamino)methyl)-2-(furan-2-yl)phenyl)thiophene-3-sulfonamide (I) A -33)

[0439]

[0440] HPLC: 99.4%; LC-MS (m / z): 375.09 (M+H) + ; 1 H NMR (500MHz, DMSO) δ7.98(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).

[0441] N-(4-((cyclobutylamino)methyl)-2-(furan-2-yl)phenyl)thiophene-3-sulfonamide (I) A -34)

[0442]

[0443] HPLC: 96.9%; LC-MS (m / z): 389.09 (M+H) + ; 1H NMR (500MHz, CDCl3) δ7.69–7.64(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).

[0444] N-(5-((methylamino)methyl)-2-(5-methylfuran-2-yl)phenyl)benzenesulfonamide (I) A -35)

[0445]

[0446] HPLC: 96.8%; LC-MS (m / z): 357.12 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.70–7.64(m,2H),7.57(d,J=8.0Hz,1H),7.48–7.38(m,3H),7.18(s,1H),7.11(s ,1H),6.96(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).

[0447] N-(3-(furan-2-yl)-4-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -36)

[0448]

[0449] HPLC: 97.5%; LC-MS (m / z): 343.13 (M+H) + ; 1H NMR (400MHz, CD3OD) δ7.83–7.78(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).

[0450] N-(4-(furan-2-yl)-3-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -37)

[0451]

[0452] HPLC: 99.2%; LC-MS (m / z): 343.03 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.78–7.71(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).

[0453] N-(4-(furan-2-yl)-2-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -38)

[0454]

[0455] HPLC: 97.6%; LC-MS (m / z): 343.06 (M+H) + ; 1H NMR (400MHz, DMSO) δ7.82–7.73(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).

[0456] N-(3-(furan-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -39)

[0457]

[0458] HPLC: 98.4%; LC-MS (m / z): 343.17 (M+H) + ; 1 H NMR (500MHz, DMSO) δ7.83–7.78(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),7.36(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).

[0459] N-(5-(furan-2-yl)-2-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -40)

[0460]

[0461] HPLC: 99.0%; LC-MS (m / z): 343.14 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.80(dd,J=6.6,3.0Hz,2H),7.68(d,J=1.2Hz,1H),7.48–7.39(m,4H),7.09(d,J=7.8H z, 1H), 6.98 (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).

[0462] 4-Fluoro-N-(2-(furan-3-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -41)

[0463]

[0464] HPLC: 96.7%; LC-MS (m / z): 361.20 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.95(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).

[0465] N-(2-(furan-3-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -42)

[0466]

[0467] HPLC: 97.7%; LC-MS (m / z): 343.10 (M+H) + ; 1 H NMR (400MHz, DMSO) δ8.32 (s, 1H), 7.72–7.64 (m, 2H), 7.62 (t, J = 1.7Hz, 1H), 7.50–7.3 5(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).

[0468] N-(2-(furan-3-yl)-5-((methylamino)methyl)phenyl)thiophene-3-sulfonamide (I) A -43)

[0469]

[0470] HPLC: 97.9%; LC-MS (m / z): 349.08 (M+H) + ; 1H NMR (400MHz, DMSO) δ7.97(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=8.1Hz,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).

[0471] N-(2-(furan-3-yl)-5-((methylamino)methyl)phenyl)thiophene-2-sulfonamide (I) A -44)

[0472]

[0473] HPLC: 96.6%; LC-MS (m / z): 349.07 (M+H) + ; 1 H NMR (400MHz, CD3OD) δ7.70(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).

[0474] 4-Fluoro-N-(5-((methylamino)methyl)-2-(thiophen-2-yl)phenyl)benzenesulfonamide (I) A -45)

[0475]

[0476] HPLC: 98.5%; LC-MS (m / z): 377.11 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.66 (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=3.3Hz,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).

[0477] N-(2-(thiophen-2-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -46)

[0478]

[0479] HPLC: 99.2%; LC-MS (m / z): 359.08 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.72(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).

[0480] N-(2-(thiophen-2-yl)-5-((methylamino)methyl)phenyl)thiophen-2-sulfonamide (I) A -47)

[0481]

[0482] HPLC: 98.9%; LC-MS (m / z): 365.05 (M+H) + ; 1 H NMR (400MHz, CD3OD) δ7.67(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).

[0483] N-(2-(thiophen-2-yl)-5-((methylamino)methyl)phenyl)thiophen-3-sulfonamide (I) A -48)

[0484]

[0485] HPLC: 97.4%; LC-MS (m / z): 365.07 (M+H) + ; 1H NMR (400MHz, CD3OD) δ7.87(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).

[0486] N-(2-(thiophen-3-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -49)

[0487]

[0488] HPLC: 96.7%; LC-MS (m / z): 359.08 (M+H) + ; 1 H NMR(400MHz,DMSO)δ7.68(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).

[0489] N-(5-((methylamino)methyl)-2-(1H-pyrrolo-2-yl)phenyl)benzenesulfonamide (I) A -50)

[0490]

[0491] HPLC: 98.8%; LC-MS (m / z): 342.12 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.79–7.69(m,2H),7.50(d,J=8.0Hz,1H),7.44–7.31(m,3H),7.2 4(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).

[0492] N-(5-((methylamino)methyl)-2-(thiazolyl-2-yl)phenyl)benzenesulfonamide (I) A -51)

[0493]

[0494] HPLC: 98.1%; LC-MS (m / z): 360.10 (M+H) + ; 1 H NMR (400MHz, DMSO) δ8.20(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).

[0495] N-(5-((methylamino)methyl)-2-(1H-pyrazolyl-4-yl)phenyl)benzenesulfonamide (I) A -52)

[0496]

[0497] HPLC: 99.4%; LC-MS (m / z): 343.12 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.97 (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).

[0498] N-(2-(3,5-dimethylisoxazol-4-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -53)

[0499]

[0500] HPLC: 97.3%; LC-MS (m / z): 372.34 (M+H) + ; 1 H NMR(400MHz,DMSO)δ7.73(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).

[0501] N-(5-((methylamino)methyl)-2-(1H-pyrazolyl-5-yl)phenyl)benzenesulfonamide (I) A -54)

[0502]

[0503] HPLC: 96.0%; LC-MS (m / z): 343.16 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.81(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), 7.44 (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).

[0504] N-(5-((methylamino)methyl)-2-(1H-pyrazolyl-3-yl)phenyl)benzenesulfonamide (I) A -55)

[0505]

[0506] HPLC: 97.4%; LC-MS (m / z): 343.19 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.81(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), 7.44 (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).

[0507] N-(2-(1-methyl-1H-pyrazole-4-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -56)

[0508]

[0509] HPLC: 97.8%; LC-MS (m / z): 357.13 (M+H) + ; 1H NMR (400MHz, DMSO) δ8.05(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).

[0510] N-(5-((methylamino)methyl)-2-(1,3,5-trimethyl-1H-pyrazole-4-yl)phenyl)benzenesulfonamide (I) A -57)

[0511]

[0512] HPLC: 98.1%; LC-MS (m / z): 385.16 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.77(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).

[0513] N-(2-(3,5-dimethyl-1H-pyrazol-4-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -58)

[0514]

[0515] HPLC: 98.5%; LC-MS (m / z): 371.15 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.82(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).

[0516] N-(5-((methylamino)methyl)-2-(5-methylthiazolyl-2-yl)phenyl)benzenesulfonamide (I)A -59)

[0517]

[0518] HPLC: 99.3%; LC-MS (m / z): 374.19 (M+H) + ; 1 H NMR (400MHz, DMSO) δ8.09 (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).

[0519] N-(2-(1-methyl-1H-imidazol-5-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -60)

[0520]

[0521] HPLC: 99.4%; LC-MS (m / z): 357.13 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.64(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).

[0522] N-(2-(1H-imidazol-5-yl)-5-((methylamino)methyl)phenyl)benzenesulfonamide (I) A -61)

[0523]

[0524] HPLC: 98.3%; LC-MS (m / z): 343.13 (M+H) + ; 1H NMR(400MHz,DMSO)δ8.00(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).

[0525] N-(2-(furan-2-yl)-5-((2,2,2-trifluoroethyl)amino)methyl)phenyl)benzenesulfonamide (I) A -62)

[0526]

[0527] HPLC: 99.3%; LC-MS (m / z): 411.35 (M+H) + ; 1 H NMR(400MHz, DMSO)δ9.66(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).

[0528] Example 2

[0529] Compound I C Synthesis:

[0530] N-(2-(furan-2-yl)-5-((hydroxyimino)methyl)phenyl)benzenesulfonamide (I) C -1)

[0531]

[0532] Intermediate VI-4 (65.5 mg, 0.2 mmol) was dissolved in 10 mL of ethanol solution, and 1 mL of hydroxylamine aqueous solution (50 wt%) was added. The reaction was carried out overnight at room temperature. After the reaction was completed, the solvent was evaporated to dryness, and the residue was separated by column chromatography to obtain compound I. C -1, yellow solid (32.9 mg, 47.6%).

[0533] HPLC: 99.2%; LC-MS (m / z): 343.13 (M+H) + ; 1H NMR (500MHz, DMSO) δ11.33(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).

[0534] Take synthetic I C Using a similar method, the following compounds were obtained:

[0535] N-(2-(furan-2-yl)-5-((methoxyimino)methyl)phenyl)benzenesulfonamide (I) C -2)

[0536]

[0537] HPLC: 97.5%; LC-MS (m / z): 357.01 (M+H) + ; 1 H NMR (400MHz, DMSO) δ9.76 (s, 1H), 8.02 (d, J = 5.7Hz, 2H), 7.73 (dd, J = 19.4, 9.4Hz, 5H), 7.6 1(t,J=7.2Hz,1H),7.52(t,J=7.6Hz,2H),7.06(d,J=3.3Hz,1H),6.59(s,1H),3.74(s,3H).

[0538] Example 3

[0539] Compound I D Synthesis:

[0540] N-(5-(aminomethyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I) D -1)

[0541]

[0542] Intermediate V-4 (64.9 mg, 0.2 mmol) was dissolved in 5 mL of ammonia-methanol solution, and an appropriate amount of Raney nickel aqueous solution was added. Hydrogen gas was bubbled through the solution, and the mixture was left to stand overnight at room temperature. Post-treatment: Raney nickel was removed by vacuum filtration, the filtrate was evaporated to dryness, and the residue was separated by column chromatography to obtain compound I. D -1, white solid (44.3 mg, 63.8%).

[0543] HPLC: 99%; LC-MS (m / z): 329.10 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.71 (dd, J=7.7, 1.4Hz, 2H), 7.61 (d, J=8.1Hz, 2H), 7.39 (q, J=6.2 Hz, 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).

[0544] Take synthetic I D Using a similar method, the following compounds were obtained:

[0545] N-(5-(aminomethyl)-2-(furan-2-yl)phenyl)-4-fluorobenzenesulfonamide (I) D -2)

[0546]

[0547] HPLC: 98.7%; LC-MS (m / z): 347.09 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.74(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).

[0548] N-(5-(aminomethyl)-2-(furan-2-yl)phenyl)thiophene-3-sulfonamide (I) D -3)

[0549]

[0550] HPLC: 99.3%; LC-MS (m / z) 335.04 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.81–7.75(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).

[0551] N-(4-(aminomethyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I) D -4)

[0552]

[0553] HPLC: 98.2%; LC-MS (m / z): 329.15 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.70–7.64(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).

[0554] N-(4-(aminomethyl)-2-(furan-2-yl)phenyl)thiophene-3-sulfonamide (I) D -5)

[0555]

[0556] HPLC: 97.5%; LC-MS (m / z): 335.06 (M+H) + ; 1 H NMR (400MHz, DMSO) δ8.09(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=8.2,1.5 Hz, 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).

[0557] N-(4-(aminomethyl)-2-(furan-2-yl)phenyl)-4-fluorobenzenesulfonamide (I) D -6)

[0558]

[0559] HPLC: 98.9%; LC-MS (m / z): 347.11 (M+H) + ; 1H NMR (400MHz, DMSO) δ7.67(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).

[0560] N-(4-(aminomethyl)-2-(1H-pyrazol-3-yl)phenyl)thiophene-3-sulfonamide (I D -7)

[0561]

[0562] HPLC: 97.9%; LC-MS (m / z): 335.11 (M+H) + ; 1 H NMR(400MHz,DMSO)δ7.96(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).

[0563] N-(5-(aminomethyl)-2-(1H-pyrazol-3-yl)phenyl)thiophene-3-sulfonamide (I D -8)

[0564]

[0565] HPLC: 97.6%; LC-MS (m / z) 335.16 (M+H) + ; 1 H NMR(400MHz,DMSO)δ8.10(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).

[0566] Example 4

[0567] Compound I E Synthesis:

[0568] N-(3-(furan-2-yl)-4-(thiophen-3-sulfonyl)benzyl)acetamide (I) E )

[0569]

[0570] Compound I D Compound I 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 reaction was carried out overnight at room temperature. After the reaction was completed, the solvent was evaporated, and the residue was separated by column chromatography to obtain compound I. E White solid (35.1 mg, 46.6%).

[0571] HPLC: 98.8%; LC-MS (m / z): 377.08 (M+H) + ; 1 H NMR (400MHz, CDCl3) δ7.70(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,1 H),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).

[0572] Example 5

[0573] Compound I B Synthesis:

[0574] Step 1: N-(4-cyano-2-(furan-2-yl)phenyl)-N-methylthiophene-3-sulfonamide (VII-1)

[0575]

[0576] Intermediate V-30 (1.3 g, 3.93 mmol) and potassium carbonate (2.2 g, 15.9 mmol) were dissolved in 20 mL of acetonitrile solution, and iodomethane (1.7 g, 12.0 mmol) was added. The mixture was reacted at 75 °C for three hours. After the reaction was complete, the solvent was evaporated, and the residue was separated by column chromatography to give intermediate VII-1, an off-white solid (0.7 g, 2.0 mmol).

[0577] 1H NMR (400MHz, DMSO) δ8.33–8.29(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).

[0578] Steps 2-4: N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)-N-methylthiophene-3-sulfonamide (I) B )

[0579]

[0580] Using synthetic I A -1. Using a similar method, compound I was obtained. B Off-white solid (90 mg, 36.5%).

[0581] HPLC: 99.1%; LC-MS (m / z) 363.15 (M+H) + ; 1 H NMR (400MHz, DMSO) δ8.27(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).

[0582] Example 6

[0583] Compound I F Synthesis:

[0584] N-(4-(aminomethyl)-2-(furan-2-yl)phenyl)-N-methylthiophene-3-sulfonamide (I) F )

[0585]

[0586] Using synthetic I D Compound I was obtained using a similar method. FOff-white solid (35.6 mg, 31.3%).

[0587] HPLC: 99.4%; LC-MS (m / z) 349.11 (M+H) + ; 1 H NMR(400MHz, DMSO)δ8.26(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).

[0588] Example 7

[0589] Compound I G Synthesis:

[0590] 4-(furan-2-yl)-3-(benzenesulfonamide)methyl benzoate (I) G )

[0591]

[0592] Compound I was obtained using a method similar to that used in the synthesis of V-1. G Yellow solid (810 mg, 32.1%).

[0593] HPLC: 98.9%; LC-MS (m / z) 358.08 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.84 (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),3.84(s,3H).

[0594] Example 8

[0595] Compound I H Synthesis:

[0596] N-(2-(furan-2-yl)-5-(hydroxymethyl)phenyl)benzenesulfonamide (I) H )

[0597]

[0598] Compound I G (500 mg, 1.4 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran solution. Under nitrogen protection, lithium aluminum hydride (213 mg, 5.6 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 1 hour. The reaction was accepted, and 213 μL of water, 213 μL of sodium hydroxide aqueous solution (15% wt), and 639 μL of water were added sequentially to the system. The mixture was filtered, the filtrate was evaporated to dryness, and the residue was separated by column chromatography to obtain compound I. H Yellow oily substance (270 mg, 58.6%).

[0599] HPLC: 97.0%; LC-MS (m / z): 330.11 (M+H) + ; 1 H NMR (400MHz, DMSO) δ9.66(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).

[0600] Example 9

[0601] Compound I J Synthesis:

[0602] N-(4-((dimethylamino)methyl)-2-(furan-2-yl)phenyl)thiophene-3-sulfonamide (I) J -1)

[0603]

[0604] N-(2-(furan-2-yl)-4-(hydroxymethyl)phenyl)thiophene-3-sulfonamide (1.68 g, 5 mmol) was dissolved in 50 mL of dichloromethane solution. Triphenylphosphine (1.97 g, 7.5 mmol) and carbon tetrabromide (2.49 g, 7.5 mmol) were added under ice bath conditions, and the reaction was carried out at room temperature for 2 hours. The solvent was evaporated to dryness, and the residue was dissolved in 20 mL of N,N-dimethylformamide solution. Dimethylamine hydrochloride (0.82 g, 10 mmol) and potassium carbonate (0.83 g, 6 mmol) were added, and the reaction was carried out overnight at 80 °C. For post-treatment, water was added to the system, 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 compound I. J-1, yellow solid (105 mg, 5.8%).

[0605] HPLC: 96.6%; LC-MS (m / z): 363.08 (M+H) + ; 1 H NMR (500MHz, DMSO) δ8.00 (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).

[0606] N-(4-((3-fluorozacricyclobutan-1-yl)methyl)-2-(furan-2-yl)phenyl)thiophene-3-sulfonamide (I) J -2)

[0607]

[0608] Take synthetic I J -1. Using a similar method, compound I was obtained. J -2, yellow solid (84 mg, 4.1%).

[0609] HPLC: 98.3%; LC-MS (m / z): 393.09 (M+H) + ; 1 H NMR (500MHz, DMSO) δ8.04(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).

[0610] Example 10

[0611] Compound I P Synthesis:

[0612] 4-(furan-2-yl)-N-methyl-3-(benzenesulfonyl)benzamide (I) P -1)

[0613]

[0614] Compound I G (0.71 g, 2 mmol) was dissolved in 10 mL of ethanol solution, and a methylamine ethanol solution (2 mL, 30-33 wt%) was added. The mixture was reacted at 60 °C for 4 hours. After post-treatment, the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 1:3) to give compound I. P -1, yellow solid (64 mg, 9.0%).

[0615] HPLC: 97.7%; LC-MS (m / z): 357.09 (M+H) + ; 1 H NMR(400MHz, DMSO) δ9.83(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).

[0616] Take synthetic I P Using a similar method, the following compounds were obtained:

[0617] 4-(furan-2-yl)-3-(benzenesulfonamide)benzamide (I) P -2)

[0618]

[0619] HPLC: 98.2%; LC-MS (m / z): 343.11 (M+H) + ; 1 H NMR (400MHz, DMSO) δ9.79 (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).

[0620] N-(2-(furan-2-yl)-5-(hydrazine carbonyl)phenyl)benzenesulfonamide (I) P -3)

[0621]

[0622] HPLC: 97.5%; LC-MS (m / z): 358.04 (M+H) + ; 1 H NMR (400MHz, DMSO) δ9.77(s,2H),7.73–7.71(m,1H),7.69(s,2H),7.66–7.62(m,2H),7.58(t,J=7.4 Hz,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).

[0623] Example 11

[0624] Compound I K Synthesis:

[0625] 4-(furan-2-yl)-3-(benzenesulfonamide)benzoic acid (I K )

[0626]

[0627] Compound I G (0.36 g, 1 mmol) was dissolved in 10 mL of tetrahydrofuran solution, and 10 mL of lithium hydroxide aqueous solution (50% wt) was added. The reaction was carried out overnight at 50 °C. After the reaction was completed, the solvent was evaporated to dryness, and the pH was adjusted to 3-4 by adding an appropriate amount of dilute hydrochloric acid. 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 into compound I by column chromatography. K White solid (0.12 g, 34.9%).

[0628] HPLC: 99.1%; LC-MS (m / z): 344.06 (M+H) + ; 1 H NMR (400MHz, DMSO) δ12.99(s,1H),9.89(s,1H),7.84(dd,J=21.9,11.2Hz,3H),7.70(d,J=7.7Hz,2 H), 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).

[0629] Example 12

[0630] Compound I Q Synthesis:

[0631] Step 1: Methyl 3-nitro-4-(1H-pyrrolo-1-yl)benzoate (XIII-1)

[0632]

[0633] 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 protection. After post-treatment, water was added to the system, followed by extraction with ethyl acetate, drying to sodium sulfate, evaporation of the solvent, and separation of the residue by column chromatography to give intermediate XIII-1, a yellow solid (700 mg, 28.3%).

[0634] 1 H NMR (400MHz, DMSO) δ8.51 (d, J = 3.2 Hz, 1H), 8.38–8.25 (m, 1H), 7.84 (dd, J = 8.1, 5.3 Hz, 1H), 7.06 (d, J = 2.3 Hz, 2H), 6.36 (d, J = 2.2 Hz, 2H), 3.96 (s, 3H).

[0635] Step 2: Methyl 3-amino-4-(1H-pyrrolo-1-yl)benzoate (XIV-1)

[0636]

[0637] Intermediate XIII-1 (0.7 g, 2.84 mmol) was dissolved in 20 mL of a mixture 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) were added to the system, and the mixture was reacted at 75 °C for one hour. Post-treatment: The filtrate was filtered, concentrated, extracted with dichloromethane, dried over sodium sulfate, and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to give XIV-1, a yellow solid (540 mg, 87.8%).

[0638] 1 H NMR (400MHz, DMSO) δ7.56 (d, J = 1.3 Hz, 1H), 7.27 (dd, J = 8.1, 1.5 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.03 (s, 2H), 6.33 (s, 2H), 5.23 (s, 2H), 3.88 (s, 3H).

[0639] Steps 3-4: N-(5-(hydroxymethyl)-2-(1H-pyrrolo-1-yl)phenyl)benzenesulfonamide (XVI-1)

[0640]

[0641] Take synthetic I H A similar method yielded intermediate XVI-1, a yellow solid (270 mg, 58.6%).

[0642] 1 H NMR (400MHz, DMSO) δ7.90 (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).

[0643] Step 5: N-(5-formyl-2-(1H-pyrrolo-1-yl)phenyl)benzenesulfonamide (XVII-1)

[0644]

[0645] Intermediate XVI-1 (270 mg, 0.82 mmol) was dissolved in 10 mL of anhydrous dichloromethane solution, and 204 mg of pyridinium chlorochromate (204 mg, 0.95 mmol) was added. The reaction was carried out at room temperature for 1 hour. After the reaction was accepted, the mixture was filtered, the filtrate was evaporated to dryness, and the residue was separated by column chromatography to obtain intermediate XVII-1, a yellow oil (160 mg, 59.8%).

[0646] 1 H NMR(500MHz,DMSO)δ10.06(s,1H),9.90(s,1H),7.87(dd,J=8.2,1.8Hz,1H),7.70–7.6 0(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).

[0647] Step 6: N-(5-((methylamino)methyl)-2-(1H-pyrrolo-1-yl)phenyl)benzenesulfonamide (I) Q -1)

[0648]

[0649] Take synthetic I A -1. Using a similar method, compound I was obtained. Q -1, white solid (130 mg, 77.7%).

[0650] HPLC: 99.2%; LC-MS (m / z): 342.15 (M+H) +; 1 H NMR (500MHz, DMSO) δ7.63(dd,J=8.6,7.0Hz,2H),7.44–7.35(m,3H),7.27(d,J=1.8Hz,1H),7.07(d,J=8.0H z, 1H), 6.95 (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).

[0651] Take synthetic I Q Using a similar method, the following compounds were obtained:

[0652] N-(5-((methylamino)methyl)-2-(1H-pyrazolyl-1-yl)phenyl)benzenesulfonamide (I) Q -2)

[0653]

[0654] HPLC: 99.5%; LC-MS (m / z): 343.10 (M+H) + ; 1 H NMR (400MHz, DMSO) δ8.53(s,1H),7.70(s,1H),7.63(d,J=7.2Hz,2H),7.54(d,J=8.2Hz,1H),7.49( s,1H),7.40(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).

[0655] N-(5-((methylamino)methyl)-2-(2H-1,2,3-triazol-2-yl)phenyl)benzenesulfonamide (I) Q -3)

[0656]

[0657] HPLC: 98.9%; LC-MS (m / z): 344.09 (M+H) + ; 1 H NMR (400MHz, DMSO) δ8.03 (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).

[0658] N-(5-((methylamino)methyl)-2-(1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide (I) Q -4)

[0659]

[0660] HPLC: 97.5%; LC-MS (m / z): 344.05 (M+H) + ; 1 H NMR(400MHz,DMSO)δ8.65(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).

[0661] Example 13

[0662] Compound I R Synthesis:

[0663] Step 1: 2-(4-amino-3-bromophenyl)acetonitrile (XVIII-1)

[0664]

[0665] p-Aminophenylacetonitrile (5.0 g, 37.83 mmol) was dissolved in 50 mL of acetonitrile solution. N-bromosuccinimide (6.7 g, 37.83 mmol) was added to the system, and the reaction was carried out at room temperature for 30 minutes. The reaction was monitored by TLC until the starting material was completely reacted. Post-treatment: The solvent was evaporated to dryness, and column chromatography (petroleum ether: ethyl acetate = 4:1) was performed to give the title compound, a pale yellow solid intermediate XVIII-1 (7.3 g, 91.4%).

[0666] 1 H NMR (400MHz, CDCl3) δ7.40 (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).

[0667] Steps 2-4: N-(4-(2-aminoethyl)-2-(furan-2-yl)phenyl)thiophene-3-sulfonamide (I) R )

[0668]

[0669] Take synthetic I A-1. Using a similar method, compound I was obtained. R Light brown solid (2.1 g, 90.22%).

[0670] HPLC: 98.0%; LC-MS (m / z): 349.07 (M+H) + ; 1 H 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=5.1,1.3Hz,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).

[0671] Example 14

[0672] Compound I S Synthesis:

[0673] Step 1: 3-(furan-2-yl)-4-(thiophene-3-sulfonamide)phenethylcarbamate tert-butyl ester (XX-1)

[0674]

[0675] Compound I R (600 mg, 1.72 mmol) was dissolved in 35 mL of a mixture of dichloromethane / methanol (volume / volume = 6:1), and di-tert-butyl dicarbonate (530 mg, 2.43 mmol) was 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 give intermediate XX-1, a colorless oil (520 mg, 67.40%).

[0676] 1H NMR (400MHz, DMSO) δ8.06(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).

[0677] Step 2: N-(2-(furan-2-yl)-4-(2-(methylamino)ethyl)phenyl)thiophene-3-sulfonamide (I) S )

[0678]

[0679] Intermediate XX-1 (520 mg, 1.16 mmol) was dissolved in 30 mL of tetrahydrofuran solution. Lithium aluminum hydride (221 mg, 5.82 mmol) was added at 0 °C, and the reaction was carried out overnight at 80 °C. After the reaction was complete, 221 μL of water, 221 μL of sodium hydroxide aqueous solution (10% wt), and 221 μL of water were added sequentially to the system. The mixture was filtered, the filtrate was evaporated to dryness, and the residue was separated by column chromatography to obtain compound I. S Light brown solid (70 mg, 16.65%).

[0680] HPLC: 97.3%; LC-MS (m / z): 363.10 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.79(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).

[0681] Example 15

[0682] Compound I U Synthesis:

[0683] Step 1: N-(4-((tert-butyl sulfoxide)imino)methyl)-2-(furan-2-yl)phenyl)-N-methylbenzenesulfonamide (XXII-1)

[0684]

[0685] Intermediate N-(4-formyl-2-(furan-2-yl)phenyl)-N-toluenesulfonamide (VIII-2) (682.8 mg, 2.0 mmol), tert-butylsulfinamide (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 and heated to 85 °C overnight. After the reaction was completed, the system was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was separated by column chromatography to give intermediate XXII-1, an off-white solid (683.4 mg, 76.9%).

[0686] 1 H NMR (400MHz, DMSO) δ8.64(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),7.7 2(t,J=7.6Hz,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).

[0687] Step 2: N-(4-(1-(tert-butyl sulfoxide)amino)ethyl)-2-(furan-2-yl)phenyl)-N-toluenesulfonamide (XXIII-1)

[0688]

[0689] Intermediate XXII-1 (666.8 mg, 1.5 mmol) was dissolved in 30 mL of anhydrous tetrahydrofuran solution. 1.5 mL of a tetrahydrofuran solution of methyl magnesium bromide (1 M / L, 1.5 mmol) was slowly added dropwise at -78 °C. After the addition was complete, the temperature was slowly raised to -20 °C and the reaction was carried out for 6 hours. After the reaction was completed, the mixture was quenched with an aqueous solution of ammonium chloride under ice bath conditions. Water was added, 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 intermediate XXIII-1, a yellow solid (425.4 mg, 61.6%).

[0690] 1H NMR (400MHz, DMSO) δ7.95(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,1H),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).

[0691] Step 3: N-(4-(1-aminoethyl)-2-(furan-2-yl)phenyl)-N-toluenesulfonamide (I) U -1)

[0692]

[0693] Intermediate XXIII-1 (368.5 mg, 0.8 mmol) was dissolved in 20 mL of ethanol solution, and 2 mL of hydrochloric acid in ethanol solution (2 M / L, 4.0 mmol) was added. The reaction was carried out at 60 °C for 2 hours. After the reaction was completed, the solvent was evaporated to dryness, water was added to the residue, and an appropriate amount of sodium bicarbonate aqueous solution was added to adjust the pH to 8-9. The residue 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 compound I. U -1, off-white solid (180.1 mg, 63.2%).

[0694] HPLC: 99.1%; LC-MS (m / z): 357.62 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.90(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).

[0695] Using synthetic I U Using a similar method, the following compounds were obtained:

[0696] N-(4-(1-aminoethyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I) U -2)

[0697]

[0698] HPLC: 99.3%; LC-MS (m / z): 343.52 (M+H) + ; 1 H NMR (400MHz, CDCl3) δ7.57(t,J=7.2Hz,3H),7.43(dd,J=14.5,7.0Hz,2H),7.35(d,J=1.7Hz,1H),7.32–7.2 4(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).

[0699] N-(4-(1-aminopropyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I) U -3)

[0700]

[0701] HPLC: 99.1%; LC-MS (m / z): 357.55 (M+H) + ; 1 H NMR (400MHz, CDCl3) δ7.78–7.69(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=8.4Hz,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).

[0702] N-(4-(1-aminobutyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I) U -4)

[0703]

[0704] HPLC: 99.3%; LC-MS (m / z): 371.45 (M+H) + ; 1H NMR (400MHz, DMSO) δ7.79–7.69(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).

[0705] N-(4-(1-amino-2-methylpropyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I) U -5)

[0706]

[0707] HPLC: 99.1%; LC-MS (m / z): 371.62 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.78–7.67(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).

[0708] N-(4-(amino(cyclopropyl)methyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I) U -6)

[0709]

[0710] HPLC: 99.0%; LC-MS (m / z): 369.62 (M+H) + ; 1H NMR (400MHz, DMSO) δ7.75(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).

[0711] N-(4-(amino(phenyl)methyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I) U -7)

[0712]

[0713] HPLC: 99.2%; LC-MS (m / z): 405.52 (M+H) + ; 1 H NMR (400MHz, DMSO) δ8.23(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,1H),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).

[0714] N-(4-(1-amino-2-phenylethyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I) U -8)

[0715]

[0716] HPLC: 99.5%; LC-MS (m / z): 419.71 (M+H) + ; 1H NMR (400MHz, DMSO) δ8.48(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).

[0717] N-(5-(1-aminoethyl)-2-(furan-2-yl)phenyl)benzenesulfonamide (I) U -9)

[0718]

[0719] HPLC: 99.2%; LC-MS (m / z): 343.51 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.77(d,J=3.4Hz,2H),7.61(d,J=6.5Hz,2H),7.46(d,J=2.3Hz,1H),7.40(s,3 H),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).

[0720] Example 16

[0721] Compound I V Synthesis:

[0722] Step 1-2: N-(4-acetyl-2-(furan-2-yl)phenyl)benzenesulfonamide (XXV-1)

[0723]

[0724] Using a method similar to that used to synthesize V-1, the intermediate XXV-1 was obtained.

[0725] 1H NMR (400MHz, CDCl3) δ8.33(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).

[0726] Step 3: N-(2-(furan-2-yl)-4-(1-(methylamino)ethyl)phenyl)benzenesulfonamide (I) V -1)

[0727]

[0728] Intermediate XXV-1 (682.8 mg, 2 mmol) was dissolved in 20 mL of dichloromethane solution, and 1 mL of methylamine in ethanol (30-33% wt) and tetraethoxytitanium (456.2 mg, 2 mmol) were added. The reaction was carried out overnight at room temperature. The next day, sodium borohydride (151.3 mg, 4 mmol) was slowly added under ice-water bath conditions, and the reaction was carried out for four hours at room temperature. After the reaction was completed, water was added to the system, and the mixture was extracted three times with dichloromethane, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to obtain compound I. V -1, white solid (165.1 mg, 23.2%).

[0729] HPLC: 99.0%; LC-MS (m / z): 357.40 (M+H) + ; 1 H NMR (400MHz, CDCl3) δ7.62(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).

[0730] Using synthetic I V Using a similar method, the following compounds were obtained:

[0731] N-(2-(furan-2-yl)-5-(1-(methylamino)ethyl)phenyl)benzenesulfonamide (I) V -2)

[0732]

[0733] HPLC: 99.0%; LC-MS (m / z): 357.45 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.74(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).

[0734] Example 17

[0735] Compound I W Synthesis:

[0736] Step 1: 2-(4-(furan-2-yl)-3-(benzenesulfonyl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (XXVII-1)

[0737]

[0738] Using a method similar to that used in the synthesis of V-1, intermediate XXVII-1 was obtained.

[0739] 1 H NMR (400MHz, DMSO) δ9.71 (s, 1H), 7.69 (dd, J = 22.9, 16.6Hz, 5H), 7.56 (d, J = 29.8 Hz,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).

[0740] Step 2: N-(2-(furan-2-yl)-5-(pyrrolidone-2-yl)phenyl)benzenesulfonamide (I) W )

[0741]

[0742] Intermediate XXVI-1 (234.3 mg, 0.5 mmol) was dissolved in 30 mL of ethyl acetate solution, and 1 mL of hydrochloric acid in ethanol solution (2 M / L, 2.0 mmol) was added. The mixture was reacted at room temperature for 3 hours. After the reaction was complete, the solvent was evaporated to dryness, water was added to the residue, and an appropriate amount of sodium bicarbonate aqueous solution was added to adjust the pH to 8-9. 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 compound I. W Off-white solid (70.0 mg, 38.0%).

[0743] HPLC: 99.1%; LC-MS (m / z): 368.34 (M+H) + ; 1 H NMR (400MHz, DMSO) δ7.75(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).

[0744] Example 18

[0745] TRPA1 inhibitory activity

[0746] In this embodiment, the inhibitory activity of compounds prepared in some embodiments of the present invention against transient receptor potential channel protein A1 (TRPA1) was tested. The positive control compound used was compound A (WO2010075353):

[0747]

[0748] The method is as follows:

[0749] The assay method using the IonWorks Barracuda (IWB) automated patch-clamp assay: HEK293 cells stably expressing mTRPA1 were cultured in DMEM medium containing 15 g / mL Blasticidin S HCl, 200 g / mL Hygromycin B, and 10% FBS serum in T175 culture flasks at 37°C in a 5% CO2 incubator. When the cell density reached approximately 80%, the culture medium was removed, and the cells were washed once with calcium- and magnesium-free phosphate-buffered saline (PBS). 3 mL of Trypsin was added for digestion for 2 minutes, followed by 7 mL of culture medium to terminate the digestion. The cells were then collected in 15 mL centrifuge tubes and centrifuged at 800 rpm for 3 minutes. After removing the supernatant, the cells were resuspended in an appropriate volume of extracellular fluid to maintain a cell density of 2-3 × 10⁶ cells / min. 6 Amphotericin B was prepared at a concentration of 28 mg / mL using DMSO on the day of the experiment, and then further prepared to a final concentration of 0.1 mg / mL using intracellular fluid. Extracellular fluid formulation (in mM): 140 NaCl, 5 KCl, 1 MgCl2, 10 HEPES, 0.5 EGTA, 10 Glucose (pH 7.4); Intracellular fluid formulation (in mM): 140 CsCl, 10 HEPES, 5 EGTA, 0.1 CaCl2, 1 MgCl2 (pH 7.2).

[0750] IWB experiments used a population patch clamp (PPC) plate. The entire detection process was automated. Extracellular fluid was added to the 384 wells of the PPC plate, followed by intracellular fluid in the plenum. Then, 6 L of cell culture was added for sealing. Finally, the intracellular fluid in the plenum was replaced with intracellular fluid containing amphotericin B, allowing the sealed cells to perforate and form a whole-cell recording mode. The sampling frequency for recording TPRA1 current was 10 kHz, with cells clamped at 0 mV. The voltage stimulation command (channel protocol) was a ramp voltage from -100 mV to +100 mV applied every 10 s over 300 ms. The mTRPA1 current was induced by 300 M AITC.

[0751] Data logging and current amplitude measurement export were performed using IWB software (version 2.5.3, Molecular Devices Corporation, Union City, CA). Holes with sealing impedance below 20 MΩ were not recorded. Raw current data were corrected for omissions using the software; the TRPA1 current amplitude was measured at +100 mV. Each PPC board in the experiment included a dose-effect data set for HC030031 as a positive control, such as the IC of HC030031. 50 The value exceeds the IC obtained on each board in the past. 50 A repeat test will be conducted when the value is three times the average. Compound dose-response curves and IC50 values ​​are also required. 50 Fitting calculations were performed using GraphPad Prism 5.02 (GraphPad Software, San Diego, CA).

[0752] Experimental results

[0753] Some compounds of the present invention were tested using the IonWorks Barracuda (IWB) automated patch clamp assay method, and IC analysis was performed. 50 The inhibitory activity test results are shown in Table 2.

[0754] Table 2. Inhibitory activity data (IC50) of some compounds of the present invention against TRPA1 50 (μM)

[0755] serial number <![CDATA[IC 50 (μM)]]> serial number <![CDATA[IC 50 (μM)]]> serial number <![CDATA[IC 50 (μM)]]> serial number <![CDATA[IC 50 (μM)]]> <![CDATA[I A -1]]> +++++ <![CDATA[I A -2]]> +++++ <![CDATA[I A -3]]> +++++ <![CDATA[I A -4]]> +++++ <![CDATA[I A -5]]> +++++ <![CDATA[I A -6]]> ++++ <![CDATA[I A -7]]> ++++ <![CDATA[I A -8]]> +++ <![CDATA[I A -9]]> ++ <![CDATA[I A -10]]> +++++ <![CDATA[I A -11]]> +++++ <![CDATA[I A -12]]> ++++ <![CDATA[I A -13]]> +++ <![CDATA[I A -14]]> + <![CDATA[I A -15]]> +++++ <![CDATA[I A -16]]> ++++ <![CDATA[I A -17]]> ++++ <![CDATA[I A -18]]> +++ <![CDATA[I A -20]]> +++++ <![CDATA[I A -21]]> +++++ <![CDATA[I A -22]]> ++ <![CDATA[I A -23]]> +++ <![CDATA[I A -24]]> ++ <![CDATA[I A -25]]> ++ <![CDATA[I A -26]]> +++++ <![CDATA[I A -27]]> +++++ <![CDATA[I A -28]]> +++++ <![CDATA[I A -29]]> ++++++ <![CDATA[I A -30]]> ++++++ <![CDATA[I A -31]]> ++++ <![CDATA[I A -32]]> ++++++ <![CDATA[I A -33]]> +++++ <![CDATA[I A -34]]> +++++ <![CDATA[I A -35]]> +++++ <![CDATA[I A -36]]> ++ <![CDATA[I A -39]]> ++ <![CDATA[I A -40]]> + <![CDATA[I A -41]]> ++++ <![CDATA[I A -42]]> +++++ <![CDATA[I A -43]]> +++++

[0756] <![CDATA[I A -44]]> +++++ <![CDATA[I A -45]]> +++++ <![CDATA[I A -46]]> +++++ <![CDATA[I A -47]]> +++++ <![CDATA[I A -48]]> +++++ <![CDATA[I A -49]]> +++++ <![CDATA[I A -50]]> ++ <![CDATA[I A -51]]> ++++++ <![CDATA[I A -52]]> ++ <![CDATA[I A -53]]> ++++ <![CDATA[I A -54]]> +++++ <![CDATA[I A -55]]> ++++++ <![CDATA[I A -56]]> +++ <![CDATA[I A -57]]> ++ <![CDATA[I A -58]]> + <![CDATA[I A -59]]> ++++ <![CDATA[I A -61]]> +++ <![CDATA[I B ]]> ++++++ <![CDATA[I C -1]]> ++ <![CDATA[I D -1]]> ++++++ <![CDATA[I D -2]]> +++++ <![CDATA[I D -3]]> ++++++ <![CDATA[I D -4]]> +++++ <![CDATA[I D -5]]> ++++++ <![CDATA[I D -6]]> +++++ <![CDATA[I D -7]]> +++++ <![CDATA[I D -8]]> +++++ <![CDATA[I E ]]> ++ <![CDATA[I F ]]> ++++++ <![CDATA[I H ]]> ++ <![CDATA[I J -1]]> +++++ <![CDATA[I J -2]]> +++++ <![CDATA[I Q -1]]> +++++ <![CDATA[I Q -2]]> +++++ <![CDATA[I Q -3]]> +++++ <![CDATA[I Q -4]]> ++++ <![CDATA[I R ]]> +++++ <![CDATA[I S ]]> +++++ Compound A + <![CDATA[I A -62]]> + <![CDATA[I U -1]]> +++++ <![CDATA[I U -2]]> +++++ <![CDATA[I U -3]]> ++++++ <![CDATA[I U -4]]> ++++++ <![CDATA[I U -5]]> ++++++ <![CDATA[I U -6]]> ++++++ <![CDATA[I U -7]]> +++++ <![CDATA[I U -8]]> +++ <![CDATA[I U -9]]> ++++++ <![CDATA[I V -1]]> +++++ <![CDATA[I V -2]]> +++++ <![CDATA[I W ]]> +++++

[0757] Activity (μM):

[0758] 50≤IC 50 <100:+

[0759] 20≤IC 50 <50:++

[0760] 10≤IC 50 <20:+++

[0761] 5≤IC 50 <10:++++

[0762] 1≤IC 50 <5: +++++

[0763] IC 50 <1:++++++

[0764] The results showed that the compounds of the present invention exhibited potent inhibitory activity against TRPA1.

[0765] Example 19

[0766] The therapeutic effects of compounds prepared in some embodiments of the present invention on ulcerative colitis (corresponding to Crohn's disease) induced by 2,4-dinitrobenzenesulfonic acid (DNBS) in Wistar rats were investigated.

[0767] Experimental process

[0768] 1. Laboratory animals

[0769] Animal species and strain: Wistar rat

[0770] Medication history: No history of medication administration

[0771] Sex and weight: Male, approximately 150g

[0772] Breeder / Supplier: Shanghai Slack Laboratory Animal Breeding Co., Ltd.

[0773] Adaptation period: 5 days

[0774] Room: Standard Area Room

[0775] Indoor temperature: 20–26℃

[0776] Indoor relative humidity: 40-70%

[0777] Lighting: Fluorescent lighting, 12 hours of lighting (08:00-20:00) and 12 hours without lighting.

[0778] Animal housing: 2-4 rats per cage (same drug administration group)

[0779] Food: Unlimited access to feed (irradiated sterilized, Jiangsu Xietong Pharmaceutical Biotechnology Co., Ltd., China)

[0780] Water: Unlimited access to drinking water (treated by reverse osmosis and autoclaving)

[0781] A total of 80 Wistar rats were purchased from Shanghai Slack Laboratory Animal Breeding Co., Ltd., of which 10 were reserved as reserve animals to select animals of suitable weight range for inclusion in the group, in order to control the fluctuation of disease severity caused by weight fluctuation.

[0782] 2. Grouping

[0783] Based on animal weight, 70 animals were randomly grouped using BioBook software to ensure that the weight values ​​of animals in each group were similar, thereby reducing bias.

[0784] Table 3. Animal grouping and administration methods

[0785]

[0786] 3. Experimental Design

[0787] 3.1 Dissolve DNBS powder in 30% ethanol to a final concentration of 60 mg / mL.

[0788] 3.2 Induction of colitis: Rats were fasted for 40 hours before the experiment, and during the fasting period, they were subcutaneously injected with 5% glucose saline. On day 0 of the experiment, fasted rats were anesthetized by intraperitoneal injection of acetaminophen and 5 mg / kg toluidine. In groups G2-G7, a soft tube was inserted through the anus into the left flexure of the colon and rectum, and DNBS was used to induce colitis in rats. The normal control group (G1) was enemaed with 30% ethanol in the same way.

[0789] 3.3 Dosing regimen: Animals in groups G1 and G2 were administered the drug via solvent after DNBS induction. Group G3 was administered 300 mg / kg of oxalazine sodium after DNBS induction. Groups G4 through G7 were administered 10 mg / kg of the compound of this invention after DNBS induction. The dosing time, specific dosage, and route of administration are detailed in Table 3. Dosing began on day 0 of model establishment and continued for 7 consecutive days. Animals were sacrificed on day 6.

[0790] 3.4 Detection Indicators: After the experiment, all animals were euthanized by inhaling excessive CO2 and dislocating their cervical vertebrae. The abdominal cavity was opened, the colon and rectum were removed, and the length of the colon and rectum was immediately measured. The colon and rectum were longitudinally dissected, rinsed clean, and the weight and ulcer area of ​​the colon and rectum were recorded. A whole photograph was taken, and the colorectal injury of the rats was macroscopically assessed according to Table 4.

[0791] Table 4. Macroscopic assessment of rat colon injury scores

[0792]

[0793]

[0794] 3.5 Experimental Observation

[0795] Observe the animal's health status and overall response to surgery and medication daily.

[0796] 4. Statistical Analysis

[0797] Experimental data are presented as mean ± standard error. Statistical analysis was performed using Graphpad Prism, SPSS, or Sigmaplot software. Specific data are presented in graphical form. A p-value < 0.05 was considered statistically significant.

[0798] Experimental results

[0799] During the experimental observation, none of the animals exhibited any abnormal appearance or behavior.

[0800] According to the experimental protocol, Wistar rats were induced to develop inflammatory colitis by intracolonic perfusion with DNBS. Colitis was characterized by a significantly shortened colon, a significantly increased colon weight, a significantly enlarged colonic ulcer area, and a significantly elevated macroscopic colonic injury score. Data on colon length, weight, and ulcer area for each group are shown in Table 5. Figure 1 As shown in Table 6, the macroscopic colonic injury score data for each group of animals are presented in Table 6 and... Figure 1 As shown. Representative colorectal photographs of each group of animals are shown below. Figure 2 As shown.

[0801] The experimental results show that, in this experiment, the positive control drug oxalazine sodium significantly reduced colon weight and ulcer area in model mice. Compound I of this invention... A -51、I A -30、I D -5、I A -55 significantly inhibited colonic shortening in model mice, and significantly reduced intestinal weight, ulcer area, and macroscopic colonic injury score. Furthermore, the efficacy of each compound group at a dose of 10 mg / kg was stronger than or no weaker than that of the positive control group at 300 mg / kg, indicating that the compounds of this invention have strong therapeutic efficacy against DNBS-induced colitis in rats and have a low onset dose.

[0802] Table 5. Colon length, weight, and ulcer area

[0803]

[0804] Table 6. Macroscopic assessment of rat colon injury scores

[0805]

[0806]

[0807] In summary, compound I of the present invention A -51、I A -30、I D -5、I A -55 has a good preventive and therapeutic effect on DNBS-induced colitis in rats and can be developed into a drug for the treatment of Crohn's disease.

[0808] Example 20

[0809] This study investigated the efficacy of compounds prepared in some embodiments of the present invention against DSS (dextran sulfate sodium)-induced inflammatory bowel disease (corresponding to ulcerative colitis) in C57BL / 6 mice.

[0810] Experimental process

[0811] 1. Laboratory animals

[0812] Animal species and strain: C57BL / 6 mouse

[0813] Medication history: No history of medication administration

[0814] Sex and weight: Female, approximately 18-20g

[0815] Breeder / Supplier: Shanghai Slack Laboratory Animal Co., Ltd.

[0816] Adaptation period: 7 days

[0817] Room: SPF Room

[0818] Indoor temperature: 20–26℃

[0819] Indoor relative humidity: 40-70%

[0820] Lighting: Fluorescent lighting, 12 hours of lighting (08:00-20:00) and 12 hours without lighting.

[0821] Animal housing: 2-5 mice per cage (same drug administration group)

[0822] Food: Unlimited access to feed (irradiated sterilized, Shanghai Slack Laboratory Animal Co., Ltd., China)

[0823] Water: Unlimited access to drinking water (tap water purified by an ultrapure water filtration system)

[0824] A total of 80 C57BL / 6 mice were purchased from Shanghai Silex Laboratory Animal Technology Co., Ltd., of which 10 were reserved as reserve animals for selecting animals of suitable weight range for the experiment. All reserve animals were not given any drugs or modeling procedures and were euthanized at the end of the experiment.

[0825] 2. Grouping

[0826] Based on animal weight, 70 animals were selected on Day-3 and randomly grouped using BioBook software to ensure that the weight values ​​of animals in each group were similar, thereby reducing bias. Specific grouping information is shown in Table 7 below.

[0827] Table 7. Grouping and Dosing Regimens

[0828]

[0829]

[0830] 3. Experimental Design

[0831] 3.1 Dissolve an appropriate amount of DSS powder in autoclaved drinking water solvent to prepare a 3% DSS solution.

[0832] 3.2 Induction of Colitis: On Day 3, 70 mice were randomly divided into 7 groups according to Table 7. From Day 0 to Day 4, mice in groups 2 to 7 drank a solution containing 3% DSS for 5 days, after which they had free access to normal drinking water (from Day 5 until necropsy). The day on which DSS was first administered was counted as Day 0. The DSS solution was wrapped in an opaque dark bag to protect it from light. The DSS solution was changed every 2 days.

[0833] 3.3 Dosage regimen: See Table 7.

[0834] 3.4. Evaluation of enteritis:

[0835] (1) Mouse weight, feces, and bleeding status

[0836] Daily changes in body weight, feces, and bleeding were recorded for all groups of mice. The three scores were calculated according to Table 8 below and summed together to form the Daily Disease Activity Index (DAI) score.

[0837] Table 8. Disease Activity Index (DAI) Scores

[0838]

[0839] (2) Weight and length of intestines

[0840] After blood collection, the animals were euthanized by cervical dislocation following exposure to excessive CO2. The abdominal cavity was opened, the mouse colon and rectum were removed, the tissue surrounding the colon was removed, and the longitudinal length from the ileocecal valve to the anus was measured. The colon and rectum were dissected, the fecal contents were scored, the intestinal contents were cleaned, the entire colon was photographed, and it was weighed.

[0841] (3) ELISA analysis

[0842] Commercially available ELISA kits were used to analyze the colorectal inflammatory factors TNF-α and IL-10 in each group.

[0843] 3.5 Experimental Observation

[0844] Observe the animals' health status and overall response to DSS and drugs daily. Any abnormal appearance or behavior, except those related to disease development, are recorded in detail in the Pengli Biological Experiment Observation Sheet.

[0845] 4. Statistical Analysis

[0846] Data are presented as mean ± standard error. Statistical analysis was performed using Graphpad Prism and SPSS software. Specific data are presented in graphical form. A p-value < 0.05 was considered statistically significant.

[0847] Experimental results

[0848] During the experimental observation, none of the animals exhibited any abnormal appearance or behavior.

[0849] In this experiment, acute colitis was induced in C57BL / 6 mice by oral administration of DSS (digestive saline solution). Animals receiving DSS exhibited clinical symptoms of acute colitis, including weight loss, diarrhea, and bloody stools, as well as necropsy findings of shortened intestinal length and increased intestinal weight. DAI (Digestive Acid Injection) scores for each group are shown below. Figure 3 As shown; the results of colon and rectum weight and length for each group of animals, as follows: Figure 4 As shown; ELISA analysis results of colorectal inflammatory factors TNF-α and IL-10 in each group of animals. Figure 5 As shown.

[0850] The experimental results show that the positive control drug Cyclosporine A exhibited significant efficacy in multiple indicators, indicating that the model was successfully constructed. Compound I of this invention... A -51、I A -30、I D -5、I A -55 significantly reduced the DAI score, decreased colonic and rectal weight, and increased colonic and rectal length in model mice. It also significantly reduced the levels of colonic inflammatory factors TNF-α and IL-10 in all groups of animals. Furthermore, the efficacy of each compound group at a dose of 10 mg / kg was stronger than or no weaker than that of the positive control group at 60 mg / kg, indicating that the compounds of this invention have good therapeutic efficacy against DSS-induced inflammatory colitis in C57BL / 6 mice.

[0851] In summary, compound I of the present invention A -51、I A -30、I D -5、I A -55 has a good preventive and therapeutic effect on DSS-induced inflammatory enteritis in C57BL / 6 mice and can be developed into a drug for the treatment of ulcerative colitis.

[0852] Example 21

[0853] The efficacy of compounds prepared in some embodiments of the present invention on a writhing pain model induced by acetic acid in ICR mice was investigated.

[0854] The mouse acetic acid writhing pain model is a classic pharmacodynamic model for evaluating the efficacy of drugs in treating visceral pain and inflammatory pain.

[0855] Experimental process

[0856] 1. Laboratory animals

[0857] Animal species and strains: ICR mice

[0858] History of drug treatment: None

[0859] Sex, age, and weight: Male, 8 weeks old, 20-25g

[0860] Breeder / Supplier: Shanghai Slack Laboratory Animal Co., Ltd.

[0861] Adaptation period: no less than 7 days

[0862] Room: Standard Room

[0863] Room temperature: 19–26℃

[0864] Relative humidity: 40-70%

[0865] Light cycle: fluorescent lighting, 12 hours of lighting (08:00-20:00) and 12 hours without lighting.

[0866] Animal housing: 5 animals per cage, grouped by group.

[0867] Food: Free access (irradiated feed, Shanghai Slack Laboratory Animal Co., Ltd., China)

[0868] Water: Free access (municipal tap water filtered by the Mol Ultrapure Water System)

[0869] A total of 70 mice were imported from Shanghai Slack Laboratory Animal Co., Ltd. The animals were SPF grade and were about 7 weeks old when purchased.

[0870] 2. Grouping

[0871] Based on the animals' weight, the BioBook random assignment function is used to randomly assign the animals to various treatment groups to achieve approximately equal weight in each group and reduce inter-group bias.

[0872] Table 9. Animal grouping and administration methods

[0873]

[0874]

[0875] 3. Experimental Design

[0876] 3.1 Within 12 hours before use, prepare a 0.6% glacial acetic acid solution with 0.9% physiological saline.

[0877] 3.2 Administration treatment: Animals in group G1 were orally administered 0.9% saline; animals in groups G2-G6 were administered the compounds of the present invention according to the administration regimen in Table 9.

[0878] 3.3 Modeling treatment: Animals in group G1 were given 0.9% saline by gavage, and 1 hour later, they were injected intraperitoneally with 0.6% glacial acetic acid to induce a pain response (10 ml / kg). Animals in groups G2-G8 were injected intraperitoneally with 0.6% glacial acetic acid to induce a pain response (10 ml / kg) according to the protocol designed in Table 9 after drug administration.

[0879] 3.4 Measurement: The weight of all mice was recorded before modeling. A writhing test was performed immediately after acetic acid treatment. The behavioral observation period lasted 20 minutes. Each person counted the writhing movements (one standard writhing movement consisted of abdominal muscle contraction, body extension, and hind limb extension). Animals were euthanized with CO2 after the test.

[0880] 3.5 Experimental Observation: Observe the animals' health and general response to drug treatment daily. Record all abnormal health and behavioral manifestations.

[0881] 4. Statistical Analysis

[0882] Experimental data are presented as mean ± standard error. Statistical analysis was performed using Graphpad Prism, SPSS, or Sigmaplot software. Detailed data are presented in graphical form. A p-value < 0.05 was considered statistically significant.

[0883] Experimental results

[0884] The number of twisting motions in each experimental group is as follows: Figure 6 As shown. From Figure 6 It can be seen that, compared with the G1 model group, compound I of the present invention... A -51、I A -30、I D -5、I A -55 significantly reduced the number of writhing movements in model mice, and its efficacy was basically equivalent to that of 200 mpk aspirin, demonstrating strong analgesic activity.

[0885] 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 into a drug for pain treatment.

[0886] Example 22

[0887] The antagonistic activity of compounds prepared in some embodiments of the present invention against the chemokine receptor CCR9 was investigated.

[0888] Experimental process

[0889] 1. Test drug and positive control drug

[0890] 1.1 Test Drug

[0891] Name: See Table 10 for details

[0892] Storage method: Store away from light and refrigerate.

[0893] Drug concentrations: 10mM, 1mM, 100μM, 10μM, 1μM, 100nM, 10nM, DMSO.

[0894] Working concentrations: 100μM, 10μM, 1μM, 100nM, 10nM, 1nM, 100pM, DMSO.

[0895] 1.2 Positive control: Vercirnon (CCR9 antagonist)

[0896] Name: Vercirnon

[0897] Storage method: Protect from light, store in a sealed container at -80℃

[0898] Drug concentrations: 10mM, 1mM, 100μM, 10μM, 1μM, 100nM, 10nM, DMSO.

[0899] Working concentrations: 100μM, 10μM, 1μM, 100nM, 10nM, 1nM, 100pM, DMSO.

[0900] 1.3 CCL25 (CCR9 agonist)

[0901] Name: CCL25

[0902] Storage method: Protect from light, store in a sealed container at -80℃

[0903] Drug concentration: 15 μM.

[0904] Working concentration: 150 nM.

[0905] 2. Reagents and Instruments:

[0906] 2.1 Main reagents: DMEM medium (GIBCO); dimethyl sulfoxide (Sigma); FLUO-4, AM (Invitrogen)

[0907] 2.2 Main Instrument: Flexstation-3 (Molecular Devices)

[0908] 3. Grouping and dosage settings:

[0909] 3.1 Basis for Dosage Setting:

[0910] According to the test IC 50 As required, set the test concentration gradient of the compound and set up duplicate wells.

[0911] 3.2 Dosage setting and group:

[0912] Eight concentrations were set for all test substances, with three replicates for each concentration.

[0913] 4. Experimental principles and methods:

[0914] Experimental principle:

[0915] By establishing cell lines co-transferring the target receptor and G16, it was demonstrated that receptor activation leads to Gα16 protein activation, which in turn activates phospholipase C (PLC) to produce IP3 and DAG. IP3 binds to IP3 receptors on the endoplasmic reticulum and mitochondria, thereby releasing intracellular calcium. Therefore, measuring changes in intracellular calcium can be used to detect the activation state of the target receptor. Fluo-4 / AM is a fluorescent calcium probe indicator used to measure calcium ions. As a nonpolar, lipid-soluble compound, after entering the cell, the AM group dissociates under the action of cellular lipases, releasing Fluo-4. Because Fluo-4 is a polar molecule, it does not easily cross the lipid bilayer, allowing it to remain in the cell for a long time. Ultimately, the level of G protein activation can be reflected by measuring the intensity of the excited fluorescence. If the screened compound can stimulate the target receptor, the calcium flux response can be greatly increased. Conversely, if the screened compound can antagonize the target receptor, the calcium flux response can be greatly reduced.

[0916] Experimental steps:

[0917] 1. Seed cells that stably express the target receptor / Gα16 into 96-well plates and incubate overnight.

[0918] 2. Remove the culture medium from the wells containing cells, add 40 μl of freshly prepared dye per well, and incubate at 37°C for 40 minutes.

[0919] 3. Dilute and mix the drug to be tested with calcium buffer solution.

[0920] Antagonistic mode:

[0921] 4. Remove and discard the dye, wash once with freshly prepared calcium buffer, and then replace with 50 μl of calcium buffer containing the drug to be tested.

[0922] 5. Using a FlexStation II instrument, starting at the 15th second, the instrument automatically adds 25 μl of calcium buffer solution containing a known agonist, and finally reads the fluorescence value at 525 nm.

[0923] 5. Data processing and statistical analysis:

[0924] Antagonistic mode

[0925] The cell response rate (%Response) of each sample under each concentration condition was calculated using the following formula.

[0926]

[0927] L Sample L represents the detection signal value of the sample to be tested. Blank L represents the detection signal value indicating complete inhibition by the positive antagonist. Agonist This indicates the detection signal value after stimulation of the DMSO blank group with a positive agonist.

[0928] IC 50 The value is calculated using GraphPad Prism.

[0929] 6. Experimental Results:

[0930] The test results are shown in Table 10. The results show that the compound of this invention exhibits IC50 antagonistic activity against the chemokine receptor CCR9. 50 All values ​​were greater than 10 μM, indicating that the compounds of the present invention do not have antagonistic activity against the chemokine receptor CCR9.

[0931] Similarly, the antagonistic activity of the compounds of the present invention against other chemokine receptors, such as CCR1 to CCR10, was also tested. The test results showed that none of the compounds of the present invention possessed antagonistic activity against chemokine receptors. Therefore, the compounds of the present invention are used for the treatment of inflammatory bowel disease not through antagonism of chemokine receptors, but through a novel pharmacological mechanism, namely, inhibition of the ion channel TRPA1.

[0932] Table 10. Results of the antagonistic activity of the compounds of the present invention against the chemokine receptor CCR9.

[0933]

[0934] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of Formula I, or a racemate thereof, or a pharmaceutically acceptable salt thereof; ###0001### Formula I wherein: Ar is substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 3-8 membered heteroaryl, 3-8 membered heterocycloalkyl fused C6-C10 aryl, substituted or unsubstituted C6-C10 aryl-substituted or unsubstituted C1-C4 alkyl-, or substituted or unsubstituted 3-8 membered heteroaryl-substituted or unsubstituted C1-C4 alkyl-; m is 1, 2, or 3; n is 0, 1, 2, or 3; and wherein "substituted" means that one or more hydrogen atoms on a group are replaced with a substituent selected from the group consisting of C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C3-C8 halocycloalkyl, halogen, -CN, hydroxyl, thiol, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 haloalkoxy, C1-C8 haloalkylthio, 5-10 membered heterocycloalkyl; and wherein the heteroaryl, heterocycloalkyl, and heterocycloalkyl fused aryl groups each independently have 1-4 heteroatoms in the heteroaromatic ring selected from N, O, and S.

2. The compound of claim 1, wherein Ar is substituted or unsubstituted C6-C8 aryl, substituted or unsubstituted 5-8 membered heteroaryl, 5-8 membered heterocycloalkyl fused C6-C8 aryl, substituted or unsubstituted C6-C8 aryl-substituted or unsubstituted C1-C3 alkyl-, or substituted or unsubstituted 5-8 membered heteroaryl-substituted or unsubstituted C1-C3 alkyl-.

3. The compound of claim 1, wherein Ar is substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 3-8 membered heteroaryl. X 1 , X 2 , X 3 , X 4 form a furan ring, a thiophene ring, a pyrrole ring, a thiazole ring, a pyrazole ring, an isoxazole ring, an oxazole ring, an imidazole ring, a triazole ring with the "------" denoted by the letters a, b, c, d, and e; R 1 is hydrogen or substituted or unsubstituted C1-C6alkyl; R 2 is hydrogen or substituted or unsubstituted C1-C6alkyl; A is 4. The compound of claim 1, wherein Ar is phenyl or thienyl. Y 1 is N; Y 2 is O or S; Y 3 is NH, O or S; R 3 and R 4 each independently is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C6-C12aryl, substituted or unsubstituted C6-C12aryl-substituted or unsubstituted C1-C3alkyl-, or R 3 , R 4 and the adjacent Y 1 together with the carbon atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocycloalkyl; R 5 is hydrogen or substituted or unsubstituted C1-C6alkyl; 5. The compound of claim 1, wherein the substituents on Ar are selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy. wherein 6. The compound of claim 1, wherein: Ar is substituted or unsubstituted C6-C10 aryl; m is 1, 2, or 3; n is 0, 1, 2, or 3; and wherein "substituted" means that one or more hydrogen atoms on a group are replaced with a substituent selected from the group consisting of C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C3-C8 halocycloalkyl, halogen, -CN, hydroxyl, thiol, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 haloalkoxy, C1-C8 haloalkylthio, 5-10 membered heterocycloalkyl; and wherein the heteroaryl, heterocycloalkyl, and heterocycloalkyl fused aryl groups each independently have 1-4 heteroatoms in the heteroaromatic ring selected from N, O, and S.

7. The compound of claim 1, wherein the compound has the structure of Formula Z: ###0002### Formula Z.

8. The compound of claim 1, wherein the compound is selected from the group consisting of: ###0003### ###0004### ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ###0059### ###0060### ###0061### ###0062### ###0063### ###0064### ###0065### ###0066### ###0067### ###0068### ###0069### ###0070### ###0071### ###0072### ###0073### ###0074### ###0075### ###0076### ###0077### ###0078### ###0079### ###0080### ###0081### ###0082### ###0083### ###0084### ###0085### ###0086### ###0087### ###0088### ###0089### ###0090### ###0091### ###0092### ###0093### ###0094### ###0095### ###0096### ###0097### ###0098### ###0099### ###0100### ###0101### ###0102### ###0103### ###0104### ###0105### ###0106### ###0107### ###0108### ###0109### ###0110### ###0111### ###0112### ###0113### ###0114### ###0115### ###0116### ###0117### ###0118### ###0119### ###0120### ###0121### ###0122### ###0123### ###0124### ###0125### ###0126### ###0127### ###0128### ###0129### ###0130### ###0131### ###0132### ###0133### ###0134### ###0135### ###0136### ###0137### ###0138### ###0139### ###0140### ###0141### ###0142### ###0143### ###0144### ###0145### ###0146### ###0147### ###0148### ###0149### ###0150### ###0151### ###0152### ###0153### ###0154### ###0155### ###0156### ###0157### ###0158### ###0159### ###0160### ###0161### ###0162### ###0163### ###0164### ###0165### ###0166### ###0167### ###0168### ###0169### ###0170### ###0171### ###0172### ###0173### ###0174### ###0175### ###0176### ###0177### ###0178### ###0179### ###0180### ###0181### ###0182### ###0183### ###0184### ###0185### ###0186### ###0187### ###0188### ###0189### ###0190### ###0191### ###0192### ###0193### ###0194### ###0195### ###0196### ###0197### ###0198### ###0199### ###0200### ###0201### ###0202### ###0203### ###0204### ###0205### ###0206### ###0207### ###0208### ###0209### ###0210### ###0211### ###0212### ###0213### ###0214### ###0215### ###0216### ###0217### ###0218### ###0219### ###0220### ###0221### ###0222### ###0223### ###0224### ###0225### ###0226### ###0227### ###0228### ###0229### ###0230### ###0231### ###0232### ###0233### ###0234### ###0235### ###0236### ###0237### ###0238### ###0239### ###0240### ###0241### ###0242### ###0243### ###0244### ###0245### ###0246### ###0247### ###0248### ###0249### ###0250### ###0251### ###0252### ###0253### ###0254### ###0255### ###0256### ###0257### ###0258### ###0259### ###0260### ###0261### ###0262### ###0263### ###0264### ###0265### ###0266### ###0267### ###0268### ###0269### ###0270### ###0271### ###0272### ###0273### ###0274### ###0275### ###0276### ###0277### ###0278### ###0279### ###0280### ###0281### ###0282### ###0283### ###0284### ###0285### ###0286### ###0287### ###0288### ###0289### ###0290### ###0291### ###0292### ###0293### ###0294### ###0295### ###0296### ###0297### ###0298### ###0299### ###0300### ###0301### ###0302### ###0303### ###030 2. The compound of claim 1, wherein ​ 3. The compound of claim 1, wherein ​ 4. The compound of claim 1, wherein ​ 5. The compound of claim 1, wherein ​ ​ ​ X 1 , X 2 , X 3 , X 4 form a furan ring, a thiophene ring, a pyrrole ring, a thiazole ring, a pyrazole ring, an isoxazole ring, an oxazole ring, an imidazole ring, a triazole ring with the "------" marked as a, b, c, d and e; R 1 is hydrogen or substituted or unsubstituted C1-C6alkyl; R 2 is hydrogen or substituted or unsubstituted C1-C6alkyl; A is ​ Y 1 is N; Y 2 is O or S; Y 3 is NH, O or S; R 3 and R 4 Each of these can be independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C3 alkyl-, or R 3 R 4 With adjacent Y 1 They are linked together to form substituted or unsubstituted 3-8 membered heterocyclic alkyl groups; R 5 is hydrogen or substituted or unsubstituted C1-C6alkyl; ​ ​ ​ 7. The compound of claim 1, wherein R 1 is hydrogen, substituted or unsubstituted C1-C4alkyl; R 2 is hydrogen, substituted or unsubstituted C1-C4alkyl.

8. The compound of claim 1, wherein R 3 and R 4 each independently is hydrogen, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C3-C6cycloalkyl, or R 3 , R 4 and the adjacent Y 1 together with the carbon atom to which they are attached form a substituted or unsubstituted 3-6 membered heterocycloalkyl.

9. The compound of claim 1, wherein R 5 is hydrogen.

10. The compound of claim 1, wherein A is 11. The compound of claim 1, wherein ​ wherein R 1 , R 2 , X 1 , X 2 , X 3 , X 4 , Ar, a, b, c, d, e, n are as described in claim 1 ; R A , R B , R C each independently is hydrogen, substituted or unsubstituted C1-C6alkyl.

12. A compound, or racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that, ​ 13. A pharmaceutical composition, characterized by, ​ 14. A process for preparing a compound of formula I as claimed in claim 1, or a racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that, ​ ​ wherein R is selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C6-Ci2aryl, substituted or unsubstituted C6-Ci2aryl-substituted or unsubstituted Ci-C3alkyl-; and 3 wherein R is selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C6-Ci2aryl, substituted or unsubstituted C6-Ci2aryl-substituted or unsubstituted Ci-C3alkyl-; and ​ ​ wherein R 3 is selected from hydrogen, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C6-Ci2aryl, substituted or unsubstituted C6-Ci2aryl-substituted or unsubstituted Ci-C3alkyl-, R 2 Ci-C6-alkyl which is substituted by one or more substituents selected from the group consisting of halogen, -CN, -OH, -d-C6-alkyl, -OH ​ wherein R is a substituted or unsubstituted C1-C6alkyl group; 2 a substituted or unsubstituted C1-C6alkyl group; ​ ​ wherein R 3 is selected from substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C6-C12aryl, substituted or unsubstituted C6-C12aryl-substituted or unsubstituted C1-C3alkyl-, R 2 is hydrogen or substituted or unsubstituted C1-C6alkyl; ​ ​ wherein R is selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C6-Ci2aryl, substituted or unsubstituted C6-Ci2aryl-substituted or unsubstituted Ci-C3alkyl-; and 3 wherein R is selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C6-Ci2aryl, substituted or unsubstituted C6-Ci2aryl-substituted or unsubstituted Ci-C3alkyl-; and R 5 is hydrogen or substituted or unsubstituted C1-C6alkyl; wherein X 1 , X 2 , X 3 , X 4 , R 1 , n and Ar are as defined in claim 1, wherein "substituted" means that one or more hydrogen atoms on the group are replaced with a substituent selected from the group consisting of C1-C8alkyl, C3-C8cycloalkyl, C1-C8haloalkyl, C3-C8halocycloalkyl, halogen, -CN, hydroxyl, thiol, C1-C8alkoxy, C1-C8alkylthio, C1-C8haloalkoxy, C1-C8haloalkylthio, 5-10 membered heterocycloalkyl.

15. Use of a compound as defined in any one of claims 1-12, or a racemate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 13, wherein the use is for the treatment of a disease or disorder. Inhibitors of the transient receptor potential channel protein TRPA1 for use in the preparation of a medicament for the prevention and / or treatment of a disease associated with the transient receptor potential channel protein TRPA1.

16. Use of a compound of any one of claims 1-12, or a racemate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 13, wherein, Inhibitors of the transient receptor potential channel protein TRPA1 for use in the preparation of a medicament for the prevention and / or treatment of a disease associated with the transient receptor potential channel protein TRPA1.

17. The use according to claim 16, characterized in that, 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, or a combination thereof.

18. The use of claim 16, wherein, The inflammatory bowel disease is selected from the group consisting of Crohn's disease and / or ulcerative colitis.

19. A method of inhibiting transient receptor potential channel protein activity in vitro for non-therapeutic and non-diagnostic purposes, characterized in that, The pain is selected from the group consisting of visceral pain, acute inflammatory pain, chronic inflammatory pain, neuropathic pain, fibromyalgia, headache, neuralgia, or cancer-induced pain. The method comprises the step of contacting a transient receptor potential channel protein or a cell expressing said protein with a compound according to any one of claims 1 to 12, or a racemate thereof, or a pharmaceutically acceptable salt thereof, thereby inhibiting the activity of the transient receptor potential channel protein.

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