A pyrrolsulfonyl derivative, and its preparation method and application

Abstract

The present invention relates to a new type of pyrrole sulfonyl derivatives, a preparation method thereof, a pharmaceutical composition containing the derivatives, and the use thereof in pharmaceutical preparation. Specifically, the structure of the pyrrole sulfonyl derivatives is shown in formula (I), and the pyrrole sulfonyl derivatives exhibit excellent gastric acid secretion inhibition and potassium ion competitive acid blocker activity.

Description

Technical Field

[0001] The present invention relates to a new type of pyrrole sulfonyl derivatives, a preparation method thereof, a pharmaceutical composition containing the derivatives, and the use of the derivatives as therapeutic agents, especially as gastric acid secretion inhibitors and potassium ion competitive acid blockers (P-CABs). Background Art

[0002] Gastrointestinal diseases include Helicobacter pylori infection, gastroesophageal reflux, peptic ulcer, duodenal ulcer, gastric ulcer and esophagitis. Long-term gastrointestinal diseases can gradually develop into gastrointestinal cancer. Among the six most common cancers in the world, five are related to the digestive tract, including gastric cancer, liver cancer, esophageal cancer, intestinal cancer and pancreatic cancer. The exact pathogenesis of this disease is still unclear in the medical community, but inhibiting gastric acid secretion has become the recognized first choice for treating such diseases.

[0003] In 1987, the first proton pump inhibitor (PPI) omeprazole was successfully developed by AstraZenaca and first launched in Sweden. It is the world's first proton pump inhibitor used in clinical practice and has the strongest effect in inhibiting gastric acid. It is used to treat duodenal ulcers, Zollinger-Ellison syndrome, gastric ulcers and reflux esophagitis. Subsequently, several PPIs products were launched around the world. After years of clinical application, PPIs have become the first choice for the treatment of gastric acid-related diseases. Proton Pump is also called gastric acid pump. Its essence is H + / K + -ATPase (H + / K + -ATPase), which is the gastric secretion of H + The final common pathway is present on the cell membrane of the secretory tubules of the gastric parietal cells, which uses ATP degradation to provide energy for H and K + The first generation of PPIs has a significant inhibitory effect on basal, nocturnal gastric acid, gastric acid secretion stimulated by pentagastrin, and test meals. However, due to limitations in pharmacokinetics and pharmacodynamics, including bioavailability, the effect of administration time on drug efficacy, slow nocturnal acid breakthrough (NAB), instability under acidic conditions (often needing to be prepared into enteral preparations, which take several hours to show effects), and dependence on CYP450 enzymes (significant individual differences in the inhibitory effect of gastric acid secretion), the therapeutic effect and clinical application are affected. Compared with the first generation of PPIs, the new generation of PPIs has obvious advantages in the treatment of gastroesophageal reflux disease (GERD) and other acid-related diseases.

[0004] Potassium-Competitive Acid Blockers (P-CABs) are a new type of acid inhibitors that competitively and reversibly bind to H + Inhibit H + / K + -ATPase activity, and its mechanism of action is significantly different from that of traditional PPIs, so it can be called an acid pump blocker. P-CABs are lipophilic, weakly alkaline, have a high dissociation constant, a long half-life, are stable in acidic conditions, are not primarily metabolized by CYP2C19, and have good tolerance and dependence. In an acidic environment, P-CABs immediately ionize, and the ionized form inhibits H + / K + -ATPase, inhibits H + Transport and acid secretion into the gastric cavity, without the need for microcapsules and microtubules concentrated in the gastric parietal cells and acid activation, can quickly increase the pH value in the stomach, and the enzyme activity is restored after dissociation. After oral administration, humans and animals can absorb it rapidly and reach the peak plasma concentration. Clinical and animal experiments have also shown that P-CABs are faster than PPIs or histamine receptor 2 (Histamine receptor 2, H2) blockers, have a stronger effect on increasing pH, and the blood drug concentration is linearly related to the oral dosage, indicating that this type of drug can achieve the optimal acid suppression state relatively easily and has obvious advantages. Takeda's Vonoprazan Fumarate was approved in Japan in December 2014; it was approved for import in China in December 2019, and some P-CABs preparations have entered clinical research.

[0005] A series of patent applications for P-CABs have been disclosed, including W02005041961, W02006134460, W02009041447 or W02010021149, etc.

[0006] Although a series of P-CABs drugs or compounds have been disclosed, there is still a need to develop new compounds with richer structural types, better efficacy and greater safety. After continuous efforts, the present invention designs compounds having a structure shown in general formula (I), and finds that compounds having such a structure exhibit excellent effects and good safety. Summary of the invention

[0007] In order to solve the above problems in the prior art, the object of the present invention is to provide a new pyrrole sulfonyl derivative, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, so as to screen out compounds having excellent performance in terms of effectiveness, safety and selectivity for use as gastric acid secretion inhibitors and potassium ion competitive acid blockers (P-CABs).

[0008] Another object of the present invention is to provide a method for preparing the derivative, its pharmaceutically acceptable salt, its tautomer or its stereoisomer.

[0009] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0010] A pyrrole sulfonyl derivative, its tautomer or stereoisomer, and a pharmaceutically acceptable salt thereof, wherein the structure of the pyrrole sulfonyl derivative is as shown in formula (I):

[0011]

[0012] in:

[0013] Ring A is selected from phenyl or pyridyl;

[0014] T is selected from a chemical bond, -O-, -S(O) L -, -NH- or -S-;

[0015] R1 is selected from C 1-6 Alkyl, C 1-6 Alkyl-C(=O)R a 、-C(=O)R a , the C 1-6 The alkyl group is optionally further substituted with 1-3 3-7 membered heterocycloalkyl groups, 3-7 membered cycloalkyl groups, 5-8 membered aryl groups, 5-8 membered heteroaryl groups, C 1-6 Alkoxy, halogen, -NH2, C 2-6 Alkynyl, C 2-6 Alkenyl, deuterium substituted;

[0016] R a Selected from H, -OH, C 1-6 Alkyl, -NH-C 1-6 alkyl, 3-7 membered heterocycloalkyl, 3-7 membered cycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 1-6 wherein the alkyl group is optionally further substituted with 1-3 -NH2, C 1-6 Alkoxy, -OH, 3-7 membered heterocycloalkyl, 3-7 membered cycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl;

[0017] Heterocycloalkyl, cycloalkyl, aryl, heteroaryl may further be substituted with 1-3 C 1-6 Alkyl, halogen, -(C=O)NR c R d replaced by;

[0018] R2 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, cyano, C 2-6 Alkynyl, C 2-6 Alkenyl, -OC 1-6 Alkyl-OC 1-6 Alkyl, -NR c R d ;

[0019] R3 is selected from halogen, 5-8 membered aryl, 5-8 membered heteroaryl, cyano, C 2-6 Alkynyl, C 2-6 Alkenyl, -OC 1-6 Alkyl-OC 1-6 Alkyl, -NR c R d ;

[0020] Or two R3 together with the carbon atom to which they are attached form a fused ring aromatic group, wherein the aromatic group, heteroaryl group and fused ring aromatic group may be further optionally substituted by 1-3 C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 2-6 Alkynyl, C 2-6 Alkenyl, cyano, -OC 1-6 Alkyl-OC 1-6 Alkyl, -NR c R d replaced by;

[0021] R4 is selected from C 1-6 Alkyl-NH-C 1-6 Alkyl; the alkyl group is optionally further substituted by 1-3 halogens or deuterium;

[0022] The R c , R d Independently selected from C 1-6 Alkyl, C 3-7 of a cycloalkyl group;

[0023] n is selected from 0, 1, 2, 3;

[0024] L is selected from 1 and 2.

[0025] In some embodiments, the structure of the pyrrole sulfonyl derivative is as shown in formula (II):

[0026]

[0027] wherein T is selected from a chemical bond, -O-, -NH- or -S-;

[0028] m is selected from 0, 1, 2, and 3.

[0029] In some preferred embodiments, R a Selected from C 1-6 Alkyl, -NH-C 1-6 Alkyl, 3-7 membered heterocycloalkyl, 3-7 membered cycloalkyl, C 2-6 Alkynyl, C 2-6 Alkenyl, -OH, C 1-6 wherein the alkyl group is optionally further substituted with 1-3 -NH2, C 1-6 Alkoxy, -OH, 3-7 membered heterocycloalkyl, 3-7 membered cycloalkyl;

[0030] The heterocycloalkyl and cycloalkyl groups are optionally further substituted with 1-3 C 1-6 Alkyl substituted.

[0031] More preferably, R a Selected from C 1-6 Alkoxy, C 1-6 Alkyl-OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -NH-C 1-6 Alkyl-C 1-6 Alkoxy,

[0032] In some embodiments, T is selected from -O-, -NH-, or -S-; R1 is selected from C 1-6 Alkyl, the alkyl group is optionally further substituted with 1-3 3-7 membered heterocycloalkyl groups, 3-7 membered cycloalkyl groups, C 1-6 Alkoxy, halogen, -NH2, C 2-6 Alkynyl, C 2-6 Substituted with alkenyl.

[0033] In some preferred embodiments, T is selected from -O-, -NH- or -S-; R1 is selected from C 1-6 Alkyl, wherein the alkyl is optionally substituted with 1 to 3 -NH2 groups.

[0034] Preferably, ring A is selected from phenyl;

[0035] R2 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, cyano, C 2-6 Alkynyl, C 2-6 alkenyl;

[0036] R3 is selected from halogen;

[0037] R4 is selected from C 1-6 Alkyl-NH-C 1-6 Alkyl; the alkyl group is optionally further substituted by 1-3 halogens or deuterium.

[0038] Preferably, the pyrrole sulfonyl derivative is selected from any one of the following structures:

[0039]

[0040]

[0041]

[0042] In another aspect, the present invention provides a pharmaceutical composition, comprising the pyrrole sulfonyl derivatives, pharmaceutically acceptable salts thereof, tautomers or stereoisomers thereof and pharmaceutically acceptable carriers and / or excipients as described above.

[0043] In another aspect, the present invention provides a pyrrole sulfonyl derivative as described in the first aspect, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, or a pharmaceutical composition as described in the third aspect for use in the preparation of a gastric acid secretion inhibitor, H + / K + - Use in ATPase inhibitors or potassium ion competitive acid blockers.

[0044] The present invention provides a use of the above-mentioned pyrrole sulfonyl derivatives, their pharmaceutically acceptable salts, their tautomers or their stereoisomers, or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating or preventing the following diseases: peptic ulcer, Zollinger-Ellison syndrome, gastric erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett's esophagitis, functional dyspepsia, Helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, ulcers caused by nonsteroidal anti-inflammatory drugs, hyperacidity caused by postoperative stress, or ulcers caused by postoperative stress; or in the preparation of drugs for inhibiting upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress. The pyrrole sulfonyl derivatives provided by the present invention have small toxic and side effects and excellent safety; at the same time, they have good pharmacokinetic properties, a longer half-life, and a more sustained acid suppression effect, and are expected to have a better improvement effect on the nocturnal acid breakthrough phenomenon.

[0045] Explanation of terms

[0046] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0047] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, and more preferably includes 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, condensed and bridged rings. Cycloalkyls can be optionally substituted or unsubstituted.

[0048] "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic non-aromatic heterocyclic radical containing 3-12 ring atoms, wherein at least one of the ring atoms is a heteroatom, such as an oxygen, nitrogen, sulfur atom, etc. Preferably, it has a 3-7-membered monocyclic or 7-10-membered bicyclic or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl. The heterocyclyl group may be optionally substituted or unsubstituted.

[0049] "Heterocycloalkyl" refers to a heterocycloalkyl having 1 to 3 heteroatoms as ring atoms, the remaining ring atoms being carbon, the heteroatoms being selected from oxygen, sulfur and nitrogen, and the ring may be a 3-6 membered ring optionally containing 1-2 unsaturated bonds. Heterocycloalkyl groups include but are not limited to

[0050] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferably, aryl is C5-C 10 Aryl, more preferably phenyl and naphthyl, most preferably phenyl. Aryl can be substituted or unsubstituted. The "aryl" can be fused with heteroaryl, heterocyclic or cycloalkyl, wherein the aryl ring is connected to the parent structure, non-limiting examples include but are not limited to:

[0051]

[0052] "Heteroaryl" refers to an aromatic 5 to 8-membered monocyclic or 9 to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. The embodiment of "heteroaryl" includes, but is not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl and benzisoxazolyl. Heteroaryl may be optionally substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:

[0053]

[0054] "Fused ring aryl" refers to an unsaturated, aromatic cyclic group containing 8-10 ring carbon atoms, formed by two or more cyclic structures sharing two adjacent atoms, preferably "9-10 membered fused ring aryl", non-limiting examples include but are not limited to:

[0055]

[0056] "Optional" means that the event described can but does not have to occur. For example, "A is optionally substituted by 1 to more R2" includes the situation that the A group can be substituted by 1 to more R2 or not substituted by R2.

[0057] The present invention provides a pyrrole sulfonyl derivative with a new structure. The test results show that the pyrrole sulfonyl derivative exhibits excellent gastric acid secretion inhibition and potassium ion competitive acid blocker (P-CABs) activity, and can be used to prepare drugs for treating or preventing peptic ulcer, Zollinger-Ellison syndrome, gastric erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett's esophagitis, functional dyspepsia, Helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, ulcers caused by nonsteroidal anti-inflammatory drugs, hyperacidity caused by postoperative stress, or ulcers caused by postoperative stress; or in the preparation of drugs for inhibiting upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress. The pyrrole sulfonyl derivative provided by the present invention has small toxic and side effects and excellent safety; at the same time, it has good pharmacokinetic properties, a longer half-life, and a more sustained acid suppression effect, and is expected to have a better improvement effect on the nocturnal acid breakthrough phenomenon. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1Instruct voltage program for manual patch clamp hERG current testing. DETAILED DESCRIPTION

[0059] The method of the present invention is described below by means of specific embodiments to make the technical solution of the present invention easier to understand and grasp, but the present invention is not limited thereto. 1 H NMR spectra were measured using a Bruker instrument (400 MHz), and chemical shifts were expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0060] The mass spectrum was obtained by LC / MS using ESI as the ionization method.

[0061] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods, and commercially available materials and reagents are used directly without further purification.

[0062] CD3OD: deuterated methanol

[0063] CDCl3: deuterated chloroform

[0064] DMSO-d6: deuterated dimethyl sulfoxide

[0065] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.

[0066] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0067] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C-30°C.

[0068] Preparation of intermediates

[0069] Synthesis of intermediate Int 2

[0070]

[0071] Step 1: Synthesis of 1-(5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine (Int 2-1)

[0072] At room temperature, compound Int 1 (3.8 g, 20.1 mmol) was dissolved in 30% methylamine alcohol solution (20 mL), stirred for 1 hour, and then NaBH4 (2.3 g, 60.3 mmol) was added in batches, and stirring was continued for 1 hour. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4.1 g of a yellow solid, with a yield of 97.6%.

[0073] Step 2: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int2)

[0074] At room temperature, compound Int 2-1 (4.1 g, 20.6 mmol) was dissolved in dichloromethane (50 mL), and triethylamine (11 mL, 78.9 mmol) and Boc2O (9.0 g, 41.2 mmol) were added respectively. The mixture was reacted at room temperature for 2 hours, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (n-hexane / ethyl acetate) to obtain 5.2 g of a white solid with a yield of 82.5%.

[0075] Synthesis of intermediate Int 3

[0076]

[0077] Synthesis of tert-butyl ((1-((5-bromopyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int3)

[0078] In an ice bath, compound Int 2 (3.0 g, 9.87 mmol) was dissolved in DMF (40 ml), and then NaH (789 mg, 19.71 mmol) was added, stirred for half an hour, and then compound Int 3-1 (3.03 g, 11.83 mmol) was added, and stirring was continued for 2 h. After the reaction was complete, ethyl acetate (150 mL) was added for dilution, and the mixture was washed twice with saturated brine (100 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (PE / EA=3:1) gave 4.5 g of a yellow oily compound with a yield of 87.2%.

[0079] Synthesis of intermediate Int 4

[0080]

[0081] Synthesis of tert-butyl ((1-((3-bromophenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int 4)

[0082] At room temperature, compound Int 2 (3 g, 9.86 mmol) was dissolved in DMF (50 mL), cooled to 0°C, sodium hydride (600 mg, 14.8 mmol) was added, and after stirring at room temperature for 10 minutes, 3-bromobenzenesulfonyl chloride (3 g, 11.8 mmol) was added. The reaction was continued for 1 hour, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (n-hexane / ethyl acetate) to obtain 4.8 g of a white solid with a yield of 93.0%.

[0083] Example 1

[0084] Synthesis of 1-(5-(2-fluorophenyl)-1-((5-(3-methoxypropoxy)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (I-1)

[0085]

[0086] Step 1: Synthesis of 3-bromo-5-(3-methoxypropoxy)pyridine (1-2)

[0087] At room temperature, compound 1-1 (4.0 g, 22.99 mmol), potassium carbonate (4.77 g, 34.48 mmol) and DMF (50 mL) were added to a 100 mL single-mouth bottle in sequence. Stir at room temperature for 0.5 h. 3-methoxypropyl bromide (3.87 g, 25.29 mmol) was added to the reaction system. After the addition was completed, react at room temperature for 12 h. After the reaction was complete, water (100 mL) was slowly added for liquid extraction. The aqueous phase was extracted 3 times with ethyl acetate (80 mL × 3). The organic phases were combined, and the organic phase was washed 3 times with water (100 mL × 3) and once with saturated brine (100 mL × 1). Drying over anhydrous sodium sulfate. Filter, concentrate the filtrate, and purify the crude product by column chromatography (PE / EA = 3:1) to obtain yellow solid compound 1-2 (4.2 g, yield: 72.4%, purity: >95%).

[0088] Step 2: Synthesis of 3-(benzylthio)-5-(3-methoxypropoxy)pyridine (1-3)

[0089] At room temperature, compound 1-2 (4.2 g, 17.07 mmol), benzyl mercaptan (2.2 mL, 20.48 mmol), xantphos (0.82 g, 3.4 mmol), Pd2(dba)3 (0.65 g, 1.70 mmol), DIEA (6.2 mL, 34.14 mmol), and toluene (200 mL) were added to a 250 mL single-mouth bottle in sequence. Under nitrogen protection, the reaction was carried out at 135°C overnight. After the reaction was complete, the mixture was filtered, and the filter cake was washed twice with ethyl acetate (50 mL×2). The organic phases were combined and dried, and the crude product was separated and purified by column chromatography (PE / EA=5:1) to obtain a brown oil compound 1-3 (4.2 g, yield 85.04%).

[0090] Step 3: Synthesis of 5-(3-methoxypropoxy)pyridine-3-sulfonic acid (1-4)

[0091] At 0°C, compound 1-3 (1.2 g, 4.16 mmol), NaClO (60 mL), HCl (12N, 60 mL) and H2O (60 mL) were added to a 250 mL single-mouth bottle. The reaction was stirred at 0°C for 0.5 h. After the reaction was complete, the reaction solution was poured into ice water (200 mL), extracted with chloroform (150 mL×3), the combined organic phases were washed with saturated brine (130 mL×1), the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain yellow oily compound 1-4 (1.1 g, crude product).

[0092] Step 4: Synthesis of 5-(3-methoxypropoxy)pyridine-3-sulfonyl chloride (1-5)

[0093] Compound 1-4 (1.0 g, 3.86 mmol) and thionyl chloride (10 mL) were added to a 25 mL single-necked bottle at room temperature, stirred at room temperature for 1 hour, and concentrated under reduced pressure to obtain compound 1-5 (1.1 g, crude product) as a yellow oil.

[0094] Step 5: Synthesis of 5-(2-fluorophenyl)-1-((5-(3-methoxypropoxy)pyridin-3-yl)sulfonyl)-1H-pyrrole-3-carbaldehyde (1-6)

[0095] At room temperature, NaH (169.13 mg, 4.23 mmol, purity: 60%), compound Int 1 (400 mg, 2.11 mmol) and THF (10 mL) were added to a 25 mL single-mouth bottle. The mixture was stirred at room temperature for half an hour, and then compound 1-5 (1.1 g, crude product) was added, and stirring was continued for 2 hours. After the reaction was completed, a saturated aqueous solution of ammonium chloride (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and washed with saturated brine (30 mL × 1), and the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Yellow solid compound 1-6 (0.11 g, yield 6.33%) was obtained by column chromatography (DCM / MeOH = 20:1).

[0096] Step 6: Synthesis of 1-(5-(2-fluorophenyl)-1-((5-(3-methoxypropoxy)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (I-1)

[0097] Compound 1-6 (110 mg, 0.26 mmol) and a methanol solution of methylamine (32.6 mg, wt: 30% content) were added to a 25 mL single-mouth bottle and dissolved in methanol (2 mL). The mixture was stirred at room temperature for 2 h, then cooled in an ice bath, and sodium borohydride (14.92 mg, 0.42 mmol) was added and stirred for 2 hours. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate (6 mL × 2). The organic phases were combined and washed with saturated brine (10 mL × 1). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 30 mg of brown-yellow viscous compound I-1 was obtained by column chromatography purification (DCM / MeOH = 10: 1). The yield was 26.33%, and the purity was >95%, [M+H] + :434.2.

[0098] 1 H NMR: (400MHz, CDCl3) δ8.44(s, 1H), 8.24(s, 1H), 7.45-7.39(m, 2H), 7.23-7.05(m, 4H), 6.34(s, 1H), 4 .02 (t, J=6.4Hz, 2H), 3.73 (s, 2H), 3.55 (t, J=6.4Hz, 2H), 3.39 (s, 3H), 2.51 (s, 3H), 2.09-2.06 (m, 2H).

[0099] Example 2

[0100] Synthesis of 1-(5-(2-fluorophenyl)-1-((5-(3-methoxypropoxy)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (I-2)

[0101]

[0102] Step 1: Synthesis of methyl 2-(3-bromophenoxy)acetate (2-2)

[0103] At room temperature, compound 2-1 (5.0 g, 28.90 mmol), potassium carbonate (5.9 g, 43.35 mmol) and DMF (50 mL) were added to a 100 mL single-mouth bottle in sequence. Stir at room temperature for 0.5 h. Methyl bromoacetate (3.76 g, 34.68 mmol) was added to the reaction system. After the addition was completed, the reaction was allowed to proceed at room temperature for 12 h. After the reaction was complete, water (100 mL) was slowly added, and the aqueous phase was extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed with water (100 mL × 3), washed with saturated brine (100 mL × 1), and dried over anhydrous sodium sulfate. Filter, concentrate the filtrate, and purify the crude product by column chromatography (PE / EA = 3:1) to obtain yellow solid compound 2-2 (6 g, yield: 84.7%).

[0104] Step 2: Synthesis of methyl 2-(3-(benzylthio)phenoxy)acetate (2-3)

[0105] At room temperature, compound 2-2 (3.0 g, 12.24 mmol), benzyl mercaptan (1.7 mL, 14.69 mmol), xantphos (0.82 g, 3.4 mmol), Pd2(dba)3 (0.65 g, 1.70 mmol), DIEA (6.2 mL, 34.14 mmol), and toluene (200 mL) were added to a 250 mL single-mouth bottle in sequence. Under nitrogen protection, the reaction was carried out at 135°C overnight. After the reaction was complete, the mixture was filtered, and the filter cake was washed twice with ethyl acetate (50 mL×2). The organic phases were combined and dried, and the crude product was separated and purified by column chromatography (PE / EA=5:1) to obtain a brown oil compound 2-3 (1.5 g, yield 42.5%).

[0106] Step 3: Synthesis of methyl 2-(3-(chlorosulfonyl)phenoxy)acetate (2-4)

[0107] At 0°C, compound 2-3 (1.3 g, 4.51 mmol), dichlorohydantoin (1.78 g, 9.02 mmol), AcOH (0.65 mL) and H2O (0.65 mL) were added to a 100 mL single-mouth bottle. The reaction was stirred at 0°C for 0.5 h. After the reaction was complete, the reaction solution was poured into ice water (200 mL), extracted with dichloromethane (150 mL × 3), the combined organic phases were washed with saturated brine (130 mL × 1), the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain yellow oily compound 2-4 (0.35 g, crude product).

[0108] Step 4: Synthesis: methyl 2-(3-((2-(2-fluorophenyl)-4-formyl-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetate (2-5)

[0109] At room temperature, NaH (20.30 mg, 0.42 mmol, purity: 60%), compound Int 1 (80 mg, 0.42 mmol) and THF (2 mL) were added to a 25 mL single-mouth bottle. The mixture was stirred at room temperature for half an hour, and then compound 2-4 (0.11 g, 0.51 mmol) was added, and stirring was continued for 2 hours. After the reaction was completed, a saturated aqueous solution of ammonium chloride (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 mL × 2). The organic phases were combined and washed with saturated brine (3 mL × 1), and the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The yellow solid compound 2-5 (0.1 g, yield 61.16%) was obtained by column chromatography (DCM / MeOH = 20:1).

[0110] Step 5: Synthesis of 1-(5-(2-fluorophenyl)-1-((5-(3-methoxypropoxy)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (I-2)

[0111] Compound 2-5 (100 mg, 0.24 mmol) and a methanol solution of methylamine (31.66 mg, wt: 30% content) were added to a 25 mL single-mouth bottle and dissolved in methanol (3 mL). The mixture was stirred at room temperature for 2 h, then cooled in an ice bath, and sodium borohydride (13.60 mg, 0.36 mmol) was added and continued to stir for 2 hours. After the reaction was completed, a saturated aqueous solution of ammonium chloride (6 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (6 mL × 2). The organic phases were combined and washed with saturated brine (10 mL × 1). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by column chromatography (DCM / MeOH = 10: 1) to give 11 mg of brown-yellow viscous solid compound I-2 with a yield of 10.62%, purity: >95%, [M+H] + :434.1.

[0112] 1 H NMR: (400MHz, CDCl3) δ7.42-7.41(m, 2H), 7.33-7.31(m, 1H), 7.18-7.05(m, 5H) , 6.90(s, 1H), 6.30(s, 1H), 4.56(s, 2H), 3.82(s, 3H), 3.71(s, 2H), 2.49(s, 3H).

[0113] Example 3

[0114] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (I-3)

[0115]

[0116] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-methoxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (3-1)

[0117] At room temperature, compound Int 2 (1 g, 3.29 mmol) was dissolved in DMF (15 mL), cooled to 0 ° C, sodium hydride (197 mg, 4.93 mmol) was added, and after stirring at room temperature for 10 minutes, 3-methoxybenzenesulfonyl chloride (815 mg, 3.94 mmol) was added. The reaction was continued for 1 hour, and water (15 mL) was added to quench the reaction, and extracted with ethyl acetate (40 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (n-hexane / ethyl acetate) to obtain 1.5 g of a yellow oil with a yield of 96.2%.

[0118] Step 2: Synthesis of 3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenol hydrobromide (3-2)

[0119] At room temperature, compound 3-1 (1.4 g, 2.95 mmol) was dissolved in dichloromethane (14 mL), cooled to 0°C, and 1M BBr3 dichloromethane solution (14 mL, 14.0 mmol) was slowly added dropwise. Stirred at room temperature for 2 hours. Concentrated under reduced pressure to obtain 1.3 g of a red solid with a yield of 100%.

[0120] Step 3: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (3-3)

[0121] At room temperature, compound 3-2 (1.2 g, 2.72 mmol) was dissolved in dichloromethane (25 mL), and triethylamine (826 mg, 8.16 mmol) and Boc2O (594 mg, 2.72 mmol) were added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (n-hexane / ethyl acetate) to obtain 1.1 g of a yellow oil with a yield of 87.8%.

[0122] Step 4: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (3-4)

[0123] At room temperature, compound 3-3 (100 mg, 0.217 mmol) was dissolved in DMF (2 mL), potassium carbonate (60 mg, 0.434 mmol) and 1-chloro-3-methoxypropane (29 mg, 0.261 mmol) were added, heated to 100°C for overnight reaction, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (n-hexane / ethyl acetate) to obtain 50 mg of a yellow oil with a yield of 87.8%.

[0124] Step 5: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(3-methoxypropoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (I-3)

[0125] At room temperature, compound 3-4 (50 mg, 0.094 mmol) was dissolved in 4M hydrochloric acid / 1,4-dioxane (2 mL) and reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the crude product was slurried with dichloromethane / methanol to obtain 20 mg of a white solid. Yield: 45.5%, purity: >95%, [M+H] + :433.2.

[0126] 1 H NMR: (400MHz, DMSO-d6) δ9.82 (s, 2H), 7.66 (s, 1H), 7.39-7.35 (m, 1H), 7.25-7.22 (m, 1H), 7.12-7.04 (m, 4H), 7.01-6.97 (m, 1H), 6 .86 (s, 1H), 6.58 (s, 1H), 3.99 (s, 2H), 3.93 (t, J=6.0Hz, 2H), 3.52 (t, J=6.0Hz, 2H), 3.36 (s, 3H), 2.55 (s, 3H), 2.03-1.98 (m, 2H).

[0127] Example 4

[0128] Synthesis of 2-(((3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)amino)-N-methylacetamide (I-4)

[0129]

[0130] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-nitrophenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (4-2)

[0131] In an ice bath, compound Int 2 (1.0 g, 3.29 mmol) was dissolved in DMF (15 mL), and then NaH (263 mg, 6.58 mmol) was added and stirred for half an hour. Then compound 4-1 (1.1 g, 4.98 mmol) was added and stirred for 2 h. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE / EA=3:1) to obtain 1.1 g of a yellow oily compound with a yield of 68.75%.

[0132] Step 2: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-nitrophenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (4-3)

[0133] At room temperature, compound 4-2 (1.0 g, 2.04 mmol) was dissolved in EA (15 mL), and then Pd / C (100 mg) was added. Under H2 system, the mixture was stirred for 4 h. After the reaction was completed, it was filtered and concentrated to obtain 800 mg of a yellow oily compound. The next step was carried out directly without further purification.

[0134] Step 3: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-((2-(methylamino)-2-oxoethyl)amino)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (4-5)

[0135] At room temperature, compound 4-3 (200 mg, 0.43 mmol) was dissolved in DMF (15 mL), and then compound 4-4 (330 mg, 2.17 mmol), potassium carbonate (361 mg, 2.62 mmol) and potassium iodide (72 mg, 0.43 mmol) were added in sequence, and then stirred at 60 ° C for 48 h. After the reaction was completed, water was added to the reaction solution for dilution, extracted with ethyl acetate, dried with anhydrous sodium sulfate, concentrated, and purified by reverse phase preparation to obtain 180 mg of a white solid compound with a yield of 78.26%.

[0136] Step 4: Synthesis of 2-(((3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)amino)-N-methylacetamide (I-4)

[0137] At room temperature, compound 4-5 (180 mg, 0.34 mmol) was dissolved in dichloromethane (5 mL) solution, TFA (5 mL) was added, and stirred for 2 h. After the reaction was complete, the mixture was concentrated and purified by reverse phase preparation to obtain 120 mg of a white solid compound with a yield of 82.19% and a purity of >95%, [M+H] + :431.2.

[0138] 1 H NMR: (400MHz, CD3OD) δ7.70 (s, 1H), 7.48-7.46 (m, 1H), 7.22-7.03 (m, 4H), 6.86 (d, J=7.6Hz, 1H), 6. 75(d, J=7.6Hz, 1H), 6.46(s, 1H), 6.37(s, 1H), 4.09(s, 2H), 3.68(s, 2H), 2.74(s, 3H), 2.72(s, 3H).

[0139] Example 5

[0140] Synthesis of N-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)-2-methoxyacetamide (I-5)

[0141]

[0142] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(2-methoxyacetamido)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (5-2)

[0143] Compound 4-3 (180 mg, 0.4 mmol), compound 5-1 (86 mg, 0.8 mmol), TEA (122 mg, 1.2 mmol), THF (3 mL) were added to the sealed tube, stirred, replaced with nitrogen 3 times, and reacted at 25°C overnight. TLC spot plate monitoring showed that the reaction was complete and new spots were generated (PE / EA=3:1, Rf=0.3). 30 mL of water was added, and ethyl acetate (30 mL×2) was used for extraction. The organic phases were combined, washed once with saturated brine (30 mL), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure at 45°C, and separated by column chromatography (PE / EA=3:1) to obtain 110 mg of colorless oil.

[0144] Step 2: Synthesis of N-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)-2-methoxyacetamide (I-5)

[0145] At room temperature, compound 5-2 (110 mg) and dichloromethane (4 mL) were added to the reaction bottle, stirred to dissolve, and 4M hydrochloric acid / 1,4-dioxane (2 mL) was added. The reaction was allowed to react for 1 h at room temperature. The reaction was complete and a new spot was generated (DCM / MeOH=10:1, Rf=0.2). Sodium bicarbonate aqueous solution was added to adjust the pH to 8, and ethyl acetate (5 mL×2) was used for extraction. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and separated by TLC to obtain 40 mg of an off-white solid with a purity of >95%, [M+H] + :432.1.

[0146] 1 H NMR: (400MHz, CD3OD) δ7.95 (s, 1H), 7.85-7.75 (m, 1H), 7.56 (s, 1H), 7.48-7.38 (m, 2H) , 7.21-7.02(m, 4H), 6.32(s, 1H), 4.06(s, 2H), 3.71(s, 2H), 3.50(s, 3H), 2.45(s, 3H).

[0147] Example 6

[0148] Synthesis of 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N-methylacetamide hydrochloride (I-6)

[0149]

[0150] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(2-(methylamino)-2-oxoethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (6-2)

[0151] At 0°C, DMF (2 mL), potassium carbonate (54.02 mg, 66.83 μmol), compound 3-3 (60.00 mg, 130.29 μmol) and compound 6-1 (54.02 mg, 30.40 μmol) were added to a single-mouth bottle in sequence and stirred at room temperature for 12 h. After the reaction was complete, it was quenched with water (10 mL) under an ice bath, then extracted with ethyl acetate (5 mL × 2), the combined organic phases were washed with saturated brine (5 mL × 1), the organic phases were dried over anhydrous sodium sulfate, and filtered to obtain 60 mg of a brown oily liquid with a yield of 86.30%.

[0152] Step 2: Synthesis of 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N-methylacetamide hydrochloride (I-6)

[0153] Under nitrogen protection, compound 6-2 (60 mg, 112.87 μmol), dichloromethane (1 mL), and 4M hydrochloric acid / 1,4-dioxane (0.5 mL) were added to a single-mouth bottle in sequence and stirred at room temperature for 4 h. Solid precipitated. After the reaction was complete, the solid was filtered and collected to obtain 21 mg of off-white solid, with a yield of 24.64% and a purity of 95.00%. [M+H] + :432.1.

[0154] 1 H NMR: (400MHz, CD3OD) δ7.76 (s, 1H), 7.48-7.44 (m, 1H), 7.42-7.40 (m, 1H), 7.30-7.29 (m, 1H), 7.18-7.16 (m, 1H), 7.12-7.08(m, 3H), 6.96-6.95(m, 1H), 6.39(s, 1H), 4.45(s, 2H), 4.09(s, 2H), 2.80(s, 3H), 2.70(s, 3H).

[0155] Example 7

[0156] Synthesis of 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetic acid hydrochloride (I-7)

[0157]

[0158] Step 1: Synthesis of tert-butyl 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetate (7-2)

[0159] At 0°C, DMF (3 mL), potassium carbonate (90.00 mg, 651.44 μmmol), and compound 3-3 (100.00 mg, 217.15 μmol) were added to a single-mouth bottle in sequence, stirred for 30 min, and compound 7-1 (54.83 mg, 260.58 μmol) was slowly added, and stirred at room temperature for 12 h. After the reaction was complete, it was quenched with water (10 mL) under an ice bath, and then extracted with ethyl acetate (5 mL × 2), the organic phases were combined and washed with saturated brine (5 mL × 1), and the organic phases were dried over anhydrous sodium sulfate and filtered to obtain 100 mg of a brown oily liquid with a yield of 80.00%.

[0160] Step 2: Synthesis of 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetic acid hydrochloride (I-7)

[0161] Under nitrogen protection, compound 7-2 (100 mg, 174.02 μmol), dichloromethane (1 mL) and 4M hydrochloric acid / 1,4-dioxane (0.5 mL) were added to a single-mouth bottle in sequence and stirred at room temperature for 4 h. After the reaction was complete, n-hexane (3 mL) was added and solid precipitated. The solid was collected to obtain 39 mg of brown solid, with a yield of 54.00%, a purity of 95.00%, [M+H] + :419.1.

[0162] 1 H NMR: (400MHz, CD3OD) δ7.76 (s, 1H), 7.51-7.40 (m, 3H), 7.21-7.10 (m, 4H), 6.94-6.93 (m, 1H), 6.40 (s, 1H), 4.67 (s, 2H), 4.10 (s, 2H), 2.88 (s, 3H).

[0163] Example 8

[0164] Synthesis of 3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)-N-(2-methoxyethyl)benzamide (I-8)

[0165]

[0166] Step 1: Synthesis of 3-(benzylthio)benzoic acid (8-2)

[0167] At room temperature, compound 8-1 (4.5 g, 29 mmol), sodium hydroxide (2.32 g, 58.00 mmol) and benzyl chloride (7.34 g, 58.00 mmol), ethanol (100 mL), and water (300 mL) were added to a 500 mL single-mouth bottle in sequence. After the addition was completed, the reaction was carried out at 60°C for 12 h. After the reaction was complete, the reaction solution was concentrated, and the pH was adjusted to 4 with HCl solution (1N). Solids were precipitated, filtered, collected, and dried to obtain compound 8-2 (3.6 g, yield: 50.49%, white solid).

[0168] Step 2: Synthesis of 3-(benzylthio)-N-(2-methoxyethyl)benzamide (8-3)

[0169] At room temperature, compound 8-2 (3.6 g, 5.67 mmol), 2-methoxyethylamine (3.35 g, 43.92 mmol), HATU (8.39 g, 21.96 mmol), DIEA (5.67 g, 43.92 mmol), and DMF (200 mL) were added to a 500 mL single-mouth bottle in sequence. The mixture was reacted overnight at room temperature under nitrogen protection. After the reaction was complete, water (600 ml) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 8-3 (3.5 g, yield 90.06%, yellow oil).

[0170] Step 3: Synthesis of 3-((2-methoxyethyl)carbamoyl)benzenesulfonic acid (8-4)

[0171] At 0°C, compound 8-3 (900 mg, 2.99 mmol), NaClO (45 mL), HCl (12N, 45 mL) and H2O (45 mL) were added to a 100 mL single-mouth bottle. The reaction was stirred at 0°C for 0.5 h. After the reaction was complete, the reaction solution was poured into ice water (150 ml), chloroform (150 mL × 3 extractions), the combined organic phases were washed with saturated brine (130 mL × 1), the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain yellow oily compound 8-4 (1.0 g, crude product).

[0172] Step 4: Synthesis of 3-((2-methoxyethyl)carbamoyl)benzene-1-sulfonyl chloride (8-5)

[0173] Compound 8-4 (1.0 g, 3.86 mmol) and thionyl chloride (5 ml) were added to a 25 mL single-necked bottle at room temperature, stirred at room temperature for 1 hour, and concentrated under reduced pressure to obtain compound 8-5 (1.0 g, crude product) as a yellow oil.

[0174] Step 5: Synthesis of 3-((2-(2-fluorophenyl)-4-formyl-1H-pyrrol-1-yl)sulfonyl)-N-(2-methoxyethyl)benzamide (8-6)

[0175] At room temperature, NaH (211 mg, 5.24 mmol, purity: 60%), compound Int1 (500 mg, 2.64 mmol) and DMF (10 ml) were added to a 25 mL single-mouth bottle. The mixture was stirred at room temperature for half an hour, and then compound 8-5 (1.0 g, crude product) was added. The mixture was stirred for 2 hours. After the reaction was completed, a saturated aqueous solution of ammonium chloride (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and washed with saturated brine (30 mL × 1). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. A yellow solid compound (0.35 g, yield 38.66%) was obtained by column chromatography (DCM / EA = 20:1).

[0176] Step 6: Synthesis of 3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)-N-(2-methoxyethyl)benzamide (I-8)

[0177] Compound 8-6 (150 mg, 0.47 mmol) and a methanol solution of methylamine (39.56 mg, wt: 30% content) were added to a 25 mL single-mouth bottle and dissolved in methanol (2 ml). The mixture was stirred at room temperature for 2 h, then cooled in an ice bath, and sodium borohydride (15.78 mg, 0.42 mmol) was added and continued to stir for 2 hours. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate (6 mL × 2). The organic phases were combined and washed with saturated brine (10 mL × 1). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 57 mg of a brown solid compound was obtained by reverse phase preparation, with a yield of 36.2%, a purity of 95.00%, and [M+H] + :446.2.

[0178] 1 H NMR: (400MHz, CDCl3) δ8.06 (d, J=7.6Hz, 1H), 7.79 (s, 1H), 7.77 (d, J=6.4Hz, 1H), 7.56-7.39 (m, 4H), 7.17-7.12 (m, 2H), 7.07-7. 02 (m, 1H), 6.80-6.77 (m, 1H), 6.29 (s, 1H), 3.73 (s, 3H), 3.65 (t, J=5.2Hz, 2H), 3.57 (t, J=5.2Hz, 2H), 3.39 (s, 3H), 2.51 (s, 3H).

[0179] Example 9

[0180] Synthesis of 3-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)propan-1-amine hydrochloride (I-9)

[0181]

[0182] Step 1: Synthesis of tert-butyl (3-(3-bromophenoxy)propyl)carbamate (9-2)

[0183] At room temperature, compound 9-1 (5 g, 28.9 mmol) was dissolved in DMF (100 mL), and potassium carbonate (12 g, 86.8 mmol), potassium iodide (4.8 g, 28.9 mmol), and tert-butyl (3-bromopropyl) carbamate (9 g, 37.8 mmol) were added respectively. The mixture was heated to 60°C and stirred overnight. Water (100 mL) was added, and stirring was continued for 1 hour. The mixture was filtered, and the filter cake was washed with n-hexane and dried to obtain 9.4 g of a white solid with a yield of 97.9%.

[0184] Step 2: Synthesis of tert-butyl (3-(3-(benzylthio)phenoxy)propyl)carbamate (9-3)

[0185] At room temperature, compound 9-2 (5 g, 15.1 mmol) was added to a 100 mL single-mouth bottle, dissolved in toluene (50 mL), and then Pd2(dba)3 (700 mg, 0.755 mmol), xantphos (440 mg, 0.755 mmol), DIEA (3.9 g, 30.2 mmol), and benzyl mercaptan (2.1 g, 16.6 mmol) were added respectively. After N2 substitution, the mixture was heated to reflux and stirred overnight. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (n-hexane / ethyl acetate) to obtain 5.2 g of a yellow oil with a yield of 92.8%.

[0186] Step 3: Synthesis of tert-butyl (3-(3-(chlorosulfonyl)phenoxy)propyl)carbamate (9-4)

[0187] At 0°C, compound 9-3 (2.1 g, 5.62 mmol) was dissolved in acetonitrile (90 mL), and water (4.5 mL), acetic acid (4.5 mL), and 1,3-dichloro-5,5-dimethylhydantoin (2.2 g, 11.2 mmol) were added respectively. The mixture was reacted at 0°C for 1 hour. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (n-hexane / ethyl acetate) to obtain 1.5 g of a white solid with a yield of 76.5%.

[0188] Step 4: Synthesis of tert-butyl (3-(3-((2-(2-fluorophenyl)-4-formyl-1H-pyrrol-1-yl)sulfonyl)phenoxy)propyl)carbamate (9-5)

[0189] At room temperature, compound Int 1 (1 g, 5.29 mmol) was dissolved in DMF (40 mL), cooled to 0°C, sodium hydride (254 mg, 6.35 mmol) was added, heated to 50°C and stirred for 30 minutes, and a DMF solution (10 mL) of compound 9-4 (2 g, 5.72 mmol) was added dropwise. Then, the mixture was heated to 70°C and reacted overnight, water (50 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (n-hexane / ethyl acetate) to obtain 1.1 g of a yellow oil with a yield of 42.3%.

[0190] Step 5: Synthesis of tert-butyl (3-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)propyl)carbamate (9-6)

[0191] At room temperature, compound 9-5 (1.1 g, 2.19 mmol) was dissolved in methanol (10 mL), 30% methylamine alcohol solution (250 mg, 2.41 mmol) was added, stirred for 1 hour, cooled to 0°C, sodium borohydride (100 mg, 2.63 mmol) was added, and the reaction was continued for 30 minutes. Water (30 mL) was added to quench the reaction, and ethyl acetate (200 mL) was used for extraction. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 1 g of a yellow oil, with a yield of 90.9%.

[0192] Step 6: Synthesis of 3-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)propan-1-amine hydrochloride (I-9)

[0193] At room temperature, compound 9-6 (100 mg, 0.193 mmol) was dissolved in 1,4-dioxane (2 mL), and 4M hydrochloric acid / 1,4-dioxane (0.5 mL) was added. The mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure, and slurried with ethyl acetate to obtain 50 mg of a white solid, with a yield of 52.9%, a purity of 95.00%, [M+H] + :618.2.

[0194] 1H NMR: (400MHz, DMSO-d6)δ9.27(br s, 2H), 8.07 (s, 3H), 7.82 (d, J=1.6Hz, 1H), 7.56-7.47 (m, 2H), 7.31-7.21 (m, 3H), 7.11-7.04 (m, 2H), 6.92-6.9 1 (m, 1H), 6.54 (d, J=2.0Hz, 1H), 4.06-4.05 (m, 2H), 3.98 (s, 2H), 3.33 (s, 3H), 2.95 (s, 2H), 2.05-2.01 (m, 2H).

[0195] Example 10

[0196] Synthesis of (E)-2-cyano-1-((1-((3-(3-((E)-2-cyano-3-methylguanidino)propoxy)phenyl)sulfonyl)-5-(2-fluorophenyl)-1-hydrogen-3-yl)methyl)-1,3-dimethylguanidine (I-10)

[0197]

[0198] At room temperature, compound I-9 (250 mg, 0.510 mmol) was dissolved in DMF (5 mL), and 10-1 (132 mg, 1.02 mmol), triethylamine (258 mg, 2.55 mmol), and silver trifluoromethanesulfonate (226 mg, 1.02 mmol) were added respectively. The mixture was heated to 50 ° C and stirred overnight. Water (10 mL) was added and the mixture was stirred for 1 hour. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (DCM / MeOH=10:1) to obtain 20 mg of a yellow solid with a yield of 6.8%.

[0199] 1 H NMR: (400MHz, DMSO-d6) δ7.53-7.44(m, 3H), 7.27-7.18(m, 3H), 7.13-7.10(m, 2H), 7.05-6.95(m, 3H), 6.85(s, 1H), 6.31(s, 1H), 4.39 (s, 2H), 3.94 (t, J=4.8Hz, 2H), 3.26-3.25 (m, 2H), 2.92-2.91 (m, 3H), 2.84 (s, 3H), 2.67-2.66 (m, 3H), 1.90 (t, J=6.0Hz, 2H).

[0200] Embodiment 11

[0201] Synthesis of 1-(5-(2-fluorophenyl)-1-((5-(methylthio)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (I-11)

[0202]

[0203] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((5-(methylthio)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (11-1)

[0204] At room temperature, compound Int 3 (100 mg, 0.191 mmol) was dissolved in toluene (2 mL), and sodium thiomethoxide (20 mg, 0.286 mmol), Pd2(dba)3 (18 mg, 0.019 mmol), xantphos (12 mg, 0.019 mmol) and DIEA (50 mg, 0.381 mmol) were added in sequence. After N2 replacement, the reaction solution was sealed, heated to 120 ° C and stirred overnight. After the reaction was complete, the solvent was concentrated, and the mixture was separated and purified by column chromatography (petroleum ether / ethyl acetate = 5:1-2:1) to obtain 50 mg of a yellow oil with a yield of 53.40%. [M+H] + :492.6.

[0205] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((5-(methylthio)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (I-11)

[0206] At room temperature, compound 11-1 (50 mg, 0.102 mmol) was dissolved in 1,4-dioxane (3 mL), and 4M hydrochloric acid / 1,4-dioxane (3 mL) was added. After reacting at room temperature for 1 hour, the solvent was concentrated, and the crude product was purified by slurrying with n-hexane / ethyl acetate to obtain 30 mg of a white solid with a yield of 91.57% and a purity of 95%. [M+H] + :392.6.

[0207] 1 H NMR: (400MHz, DMSO-d6) δ 9.48-9.47 (m, 2H), 8.77 (d, J = 2.4Hz, 1H), 8.34 (d, J = 2.0Hz, 1H), 7.90 (d, J = 2.4Hz, 1H), 7.57-7.52 (m, 1H), 7.50-7.49 (m, 1H), 7.28-7.23 (m, 2H), 7.14-7.10 (m, 1H), 6.64 (d, J=2.0Hz, 1H), 3.98-3.96 (m, 2H), 2.52 (s, 3H), 2.47-2.46 (m, 3H).

[0208] Example 12

[0209] Synthesis of (E)-N-(3,7-dimethyloctyl-2,6-dien-1-yl)-3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-)pyrrol-1-yl)sulfonyl)aniline hydrogen chloride (I-12)

[0210]

[0211] Step 1: Synthesis of tert-butyl (E)-((1-((3-((3,7-dimethyloctyl-2,6-dien-1-yl)amino)phenyl)sulfonyl)-5-(2-fluorophenyl)-)1H-pyrrol-3-yl)methyl)(methyl)carbamate (12-2)

[0212] At room temperature, compound 4-3 (250 mg, 0.55 mmol), 12-1 (120 mg, 0.55 mmol) and potassium carbonate (150 mg, 1.09 mmol) were dissolved in DMF (5 mL) and stirred at room temperature overnight. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA = 3:1) to obtain 50 mg of a colorless oily compound with a yield of 15.43%, [M+H] + :596.3.

[0213] Step 2: Synthesis of (E)-N-(3,7-dimethyloctyl-2,6-dien-1-yl)-3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-)pyrrol-1-yl)sulfonyl)aniline hydrochloride (I-12)

[0214] At room temperature, compound 12-2 (50 mg, 0.084 mmol) was dissolved in dichloromethane (2 mL) solution, and then 4M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. Concentration gave 34 mg of brown solid compound, yield 72.34%, purity: 95%, [M+H] + :496.2.

[0215] 1H NMR: (400MHz, DMSO-d6) δ9.34 (br, 1H), 7.72 (s, 1H), 7.53-7.48 (m, 1H), 7.24 -7.16 (m, 3H), 7.07 (t, J=6.4Hz, 1H), 6.86 (d, J=8.0Hz, 1H), 6.62-6.59 (m, 2H ), 6.54 (s, 1H), 5.15 (t, J=6.0Hz, 1H), 4.91 (t, J=6.0Hz, 1H), 3.97 (s, 2H), 3. 56 (d, J=8.0Hz, 2H), 2.48 (s, 3H), 1.99 (t, J=6.0Hz, 2H), 1.66-1.48 (M, 11H).

[0216] Embodiment 13

[0217] N-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)pyrrolidine-2-carboxamide dihydrochloride

[0218] Synthesis of (I-13)

[0219]

[0220] Step 1: Synthesis of 2-tert-butyl 2-[3-[4-(tert-butoxy)carbonyl](methyl)amino}methyl)-2-(2-fluorophenyl)-1H-pyrrolidin-1-yl]sulfonyl}phenyl)carbamoyl-1-carboxylate (13-2)

[0221] At room temperature, compound 4-3 (200 mg, 0.44 mmol), 13-1 (113 mg, 0.53 mmol) and HATU (200 mg, 0.53 mmol) were added to THF (10 mL), triethylamine (0.2 mL, 1.32 mmol) was added, and stirred at 40°C overnight. After the reaction was completed, the reaction system was concentrated under reduced pressure, and purified by column chromatography (PE / EA=2:1) ​​to obtain 80 mg of a yellow oil with a yield of 62.5%, [M+H] + :557.1.

[0222] Step 2: Synthesis of N-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)pyrrolidine-2-carboxamide dihydrochloride) (I-13)

[0223] At room temperature, compound 13-2 (40 mg, 0.06 mmol) was dissolved in dichloromethane (5 mL) solution, and then 4M hydrochloric acid / 1,4-dioxane (1.4 mL) was added and stirred at room temperature for 2 h. Concentration gave a brown compound 20 mg, yield 75.19%, purity: 95%, [M+H] + :457.2.

[0224] 1 H NMR: (400MHz, CD3OD) δ7.89 (t, J=2.0Hz, 1H), 7.85-7.81 (m, 1H), 7.79 (d, J=2.0Hz, 1H), 7.48 (t, J=8.0Hz, 2H), 7.27-7.22 (m, 1H), 7.18 (d, J=7.6Hz, 1H), 7.11 (d, J=7.2 Hz, 1H), 7.08 (d, J = 9.1 Hz, 1H), 6.41 (d, J = 2.0 Hz, 1H), 4.44 (d, J = 8.0 Hz, 1H), 4.13 (s, 2H), 2.73 (s, 3H), 2.59-2.56 (m, 2H), 2.17-2.14 (m, 2H), 2.06-2.03 (m, 2H). Example 14

[0225] Synthesis of N-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)-1-methylpyrrolidine-2-carboxamide hydrochloride (I-14)

[0226]

[0227] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(1-methylpyrrolidine-2-carboxamido)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (14-2)

[0228] At room temperature, compound 14-1 (73.1 mg, 0.57 mmol) and HATU (248 mg, 0.65 mmol) were added to DMF (10 mL), and DIPEA (141 mg, 1.1 mmol) was added. The mixture was stirred at room temperature for 1 h, and 4-3 (200 mg) was added. The mixture was stirred overnight. After the reaction was completed, the reaction system was concentrated under reduced pressure, and purified by column chromatography (PE / EA=2:1) ​​to obtain 80 mg of a yellow oil with a yield of 31.84%, [M+H] + :571.3.

[0229] Step 2: Synthesis of N-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)-1-methylpyrrolidine-2-carboxamide hydrochloride (I-14)

[0230] At room temperature, compound 14-2 (80 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL) solution, and then 4M hydrochloric acid / 1,4-dioxane (1.0 mL) was added and stirred at room temperature for 2 h. Concentration gave 60 mg of a brown compound with a yield of 84.5% and a purity of 95%, [M+H] + :471.2.

[0231] 1 H NMR: 1 H NMR (400MHz, CD3OD) δ7.91 (s, 1H), 7.84 (d, J=8.0Hz, 1H), 7.79 (s, 1H), 7.51-7.47 (m, 2H), 7.26 (d, J=8.0Hz, 1H), 7.17 (t, J=7.6Hz, 1H), 7.14-7. 04(m, 2H), 6.42(s, 1H), 4.29(t, J=8.4Hz, 1H), 4.13(s, 2H), 3.03(s, 3H) , 2.73(s, 3H), 2.33-2.28(m, 2H), 2.24-2.08(m, 3H), 2.07-2.00(m, 1H).

[0232] Embodiment 15

[0233] Synthesis of N-cyclopropyl-2-((3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)amino)acetamide hydrogen chloride salt (I-15)

[0234]

[0235] Step 1: Synthesis of tert-butyl ((1-((3-((2-(cyclopropylamino)-2-oxoethyl)amino)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (15-2)

[0236] Compound 4-3 (200 mg, 0.44 mmol) was dissolved in DMF (5 mL) solution, and compound 15-1 (76 mg, 0.57 mmol), sodium carbonate (116 mg, 1.09 mmol) and potassium iodide (15 mg, 0.09 mmol) were added in sequence, and then stirred at 90 ° C overnight, cooled to room temperature, added with water (20 mL), extracted with ethyl acetate (15 mL × 2), combined organic phases, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, separated and purified by column chromatography (PE / EA = 1: 1) to obtain 100 mg of colorless oily compound with a yield of 41.32%, [M+H] + :557.2.

[0237] Step 2: Synthesis of N-cyclopropyl-2-((3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)amino)acetamide hydrochloride (I-15)

[0238] At room temperature, compound 15-2 (100 mg, 0.27 mmol) was dissolved in dichloromethane (2 mL) solution, and then 4M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. Concentration gave 57 mg of a white compound with a yield of 60.64% and a purity of 95%, [M+H] + :457.2.

[0239] 1 H NMR: (400MHz, CD3OD) δ7.73 (s, 1H), 7.49-7.44 (m, 1H), 7.24-7.05 (m, 4H), 6.89 (d, J = 8.4Hz, 1H), 6.76 (d, J = 8.0Hz, 1H), 6 .59(s, 1H), 6.40(s, 1H), 4.12(s, 2H), 3.71(s, 2H), 2.74(s, 3H), 2.69-2.63(m, 1H), 0.76-0.71(m, 2H), 0.51-0.47(m, 2H).

[0240] Example 16

[0241] Synthesis of (S)-2-amino-N-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)-3-phenylpropanamide dichloride (I-16)

[0242]

[0243] Step 1: Synthesis of tert-butyl (S)-((1-((3-(2-amino-3-phenylpropionamido)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (16-2)

[0244] At room temperature, compound 16-1 (225 mg, 0.85 mmol), HATU (323 mg, 0.85 mmol) were added to a 50 ml single-mouth bottle, and DMF (6 mL) was added to dissolve. After stirring for 30 min, 4-3 (300 mg, 0.65 mmol), DMF (4 ml) and DIPEA (211 mg, 1.63 mmol) were added, and the reaction was continued to stir at room temperature overnight. After the reaction was completed, water (40 mL) was added, and the mixture was extracted with ethyl acetate (60 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA = 2:1) to obtain 218 mg of a yellow solid with a yield of 47.23%, [M-100 + H] + :607.22.

[0245] Step 2: Synthesis of (S)-2-amino-N-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)-3-phenylpropanamide dichloride (I-16)

[0246] At room temperature, compound 16-2 (210 mg, 0.14 mmol) was dissolved in dichloromethane (3 mL) solution, and then 4M hydrochloric acid / 1,4-dioxane (3 mL) was added and stirred at room temperature for 3 h. Concentration gave 195 mg of a black purple solid compound. Yield 96.59%, purity>95%, [M-100+H] + :507.2.

[0247] 1 H NMR: (400MHz, DMSO-d6) δ11.34(s, 1H), 9.16(s, 2H), 8.29(s, 3H), 7.66-7.60(m, 2H), 7.50(s, 1H), 7.27-7.21(m, 2H), 7.09-7.00(m, 5H) , 6.93-6.89(m, 2H), 6.79-6.74(m, 1H), 6.34(s, 1H), 4.15-4.06(s, 1H), 3.73(s, 2H), 3.03-2.99(m, 1H), 2.92-2.87(m, 1H), 2.53(s, 3H).

[0248] Embodiment 17

[0249] Synthesis of (S)-1-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)benzoyl)-N,N-dimethylpyrrolidine-2-carboxamide (I-17)

[0250]

[0251] Step 1: Synthesis of methyl 3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)benzoate (17-2)

[0252] Compound Int 2 (2.0 g, 6.58 mmol) was dissolved in DMF (30 mL) solution, cooled to room temperature, sodium hydride (395 mg, 9.86 mmol) was added to the reaction solution, and stirred for 30 minutes under an ice-water bath. Compound 17-1 (1.85 g, 7.87 mmol) was then slowly added to the reaction system and continued to stir for 2 h. After the reaction was completed, the reaction system was quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate (40 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (PE / EA = 5:1) gave 2.3 g of a yellow oily compound with a yield of 69.70%, [M+H] + :503.2.

[0253] Step 2: Synthesis of 3-(((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)benzoic acid (17-3)

[0254] At room temperature, compound 17-2 (2.2 g, 4.38 mmol) was dissolved in methanol (20 mL), NaOH (350 mg, 8.75 mmol) was dissolved in water (10 mL), and then the aqueous solution was added dropwise to the methanol solution and stirred at room temperature for two hours. The methanol solvent was removed by concentration, and the pH was adjusted to 6 with 1N hydrochloric acid aqueous solution, extracted with dichloromethane, and concentrated to obtain 2.0 g of a light red solid compound with a yield of 93.46%, [M+H] + :488.2.

[0255] Step 3: Synthesis of tert-butyl (S)-((1-((3-(2-(dimethylcarbamoyl)pyrrolidine-1-carbonyl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl) (methyl)carbamate (17-5)

[0256] At room temperature, compound 17-3 (200 mg, 0.41 mmol) was dissolved in DMF (5 mL), HATU (187 mg, 0.49 mmol) was added, and the mixture was stirred for 1 hour. Then DIEA (106 mg, 0.82 mmol) and compound 17-4 (70 mg, 0.49 mmol) were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, EA was used for extraction, concentration was performed, and 200 mg of a light yellow oily compound was obtained by reverse phase purification, with a yield of 80.00%, [M+H] + :613.2.

[0257] Step 4: Synthesis of (S)-1-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)benzoyl)-N,N-dimethylpyrrolidine-2-carboxamide (I-17)

[0258] At room temperature, compound 17-5 (200 mg, 0.33 mmol) was dissolved in dichloromethane (2 mL) solution, and then 4M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. Concentration was performed and 80 mg of a yellow compound was obtained by reverse phase preparation, with a yield of 47.90%, a purity of 95%, [M+H] + :513.2.

[0259] 1 H NMR: (400MHz, DMSO-d6) δ7.85 (d, J=7.4Hz, 1H), 7.69-7.63 (m, 2H), 7.60-7.4 2(m, 4H), 7.25-7.20(m, 2H), 7.14-7.08(m, 1H), 6.48(s, 0.6H), 6.46(s, 0.4H) , 4.93-4.90(m, 0.6H), 4.63-4.60(m, 0.4H), 3.82(s, 2H), 3.63-3.52(m, 2H), 3.10(s, 3H), 2.87(s, 3H), 2.41(s, 3H), 2.33-2.23(m, 1H), 1.92-1.72(m, 3H).

[0260] Embodiment 18

[0261] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(methylthio)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (I-18)

[0262]

[0263] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(methylthio)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (18-1)

[0264] Compound Int 4 (500 mg, 0.96 mmol), sodium thiomethoxide (88 mg, 1.26 mmol), Pd2(dba)3 (175 mg, 0.19 mmol), xantphos (111 mg, 0.19 mmol) and DIEA (494 mg, 3.83 mmol) were dissolved in toluene (15 mL), and the mixture was sealed and reacted overnight at 100 ° C under nitrogen protection. After the reaction was completed, water (30 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and purified by column chromatography (PE / EA = 5:1) to obtain 390 mg of a yellow oil with a yield of 83.33%, [M+H] + :491.1.

[0265] Step 2: 1-(5-(2-fluorophenyl)-1-((3-(methylthio)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (I-18)

[0266] At room temperature, compound 18-1 (70 mg, 0.14 mmol) was dissolved in dichloromethane (2 mL) solution, and then 4M hydrochloric acid / 1,4-dioxane solution (4 mL) was added and stirred at room temperature for 2 h. Concentration gave 28 mg of brown solid compound. Yield 45.90%, [M+H] + :391.1.

[0267] 1 H NMR (400MHz, CD3OD) δ7.78 (s, 1H), 7.54-7.45 (m, 2H), 7.41 (t, J = 7.6Hz, 1H), 7.28 (d, J = 6.8Hz, 1H), 7.2 1(t,J=8.8Hz,1H),7.13-7.08(m,3H),6.41(m,3H),6.41(s,1H),4.11(s,2H),2.72(s,3H),2.44(s,3H).

[0268] Embodiment 19

[0269] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(methylsulfinyl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (I-19)

[0270]

[0271] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(methylsulfinyl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (19-1)

[0272] Compound 18-1 (150 mg, 0.31 mmol) was dissolved in dichloromethane (5 mL), and m-CPBA (75 mg, 0.37 mmol) was added and stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction solution for dilution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and purified by column chromatography (DCM / MeOH = 20:1) to obtain 97 mg of a yellow oil with a yield of 62.58%, [M+H] + :507.1

[0273] Step 2: 1-(5-(2-fluorophenyl)-1-((3-(methylsulfinyl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (I-19)

[0274] At room temperature, compound 19-1 (97 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL) solution, and then 2M hydrochloric acid / ethyl acetate solution (4 mL) was added and stirred at room temperature for 2 h. Concentration gave 80 mg of brown solid compound. Yield 94.12%, [M+H] + :407.1.

[0275] 1 H NMR (400MHz, CD3OD) δ7.79 (s, 0.6H), 7.59-7.47 (m, 3.4H), 7.43-7.34 (m, 1H), 7.31-7.27 (m, 1H), 7.23-7.18 (m, 1H), 7.13-7. 08(m,2H),6.52(s,0.4H),6.41(m,0.6H),4.11(s,1.3H),4.07(m,0.7H),2.72(s,2H),2.67(s,1H),2.52(s,1H),2.43(s,2H).

[0276] Embodiment 20

[0277] Synthesis of 2-(((3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)thio)-N-methylacetamide hydrochloride (I-20)

[0278]

[0279] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-((4-methoxybenzyl)thio)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (20-1)

[0280] At room temperature, compound Int 4 (500 mg, 0.96 mmol) was dissolved in toluene (10 mL), and 4-methoxybenzyl mercaptan (178 mg, 1.15 mmol), Pd2(dba)3 (132 mg, 0.14 mmol), Xantphos (83 mg, 0.14 mmol) and DIEA (370 mg, 2.87 mmol) were added in sequence. After N2 replacement, the temperature was raised to 110 ° C and stirred overnight. After the reaction was complete, the solvent was concentrated and purified by column chromatography (PE / EA=10:1) to obtain 470 mg of a yellow oil with a yield of 82.60%, [M+H] + :597.2.

[0281] Step 2: Synthesis of 3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)benzenethiol trifluoroacetate (20-2)

[0282] At room temperature, compound 20-1 (410 mg, 0.69 mmol) was dissolved in TFA (10 mL), Et3SiH (1 mL) was added, and the mixture was heated to 110°C and stirred overnight. The solvent was concentrated to obtain 250 mg of a yellow oil, [M+H] + :376.6.

[0283] Step 3: Synthesis of tert-butyl ((1-((3-((tert-butoxycarbonyl)thio)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (20-3)

[0284] At room temperature, compound 20-2 (250 mg, 0.66 mmol) was dissolved in DCM (5 mL), and triethylamine (350 mg, 3.46 mmol) and Boc2O (300 mg, 1.37 mmol) were slowly added. The reaction was continued overnight at room temperature, the solvent was concentrated, and the product was separated and purified by column chromatography (PE / EA=5:1) to obtain 380 mg of a yellow oil with a yield of 96.29%, [M+H] + :577.3.

[0285] Step 4: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-mercaptophenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (20-4)

[0286] At room temperature, compound 20-3 (150 mg, 0.26 mmol) and potassium carbonate (90 mg, 0.65 mmol) were added to methanol (5 mL), reacted at room temperature overnight, extracted with DCM, dried, and filtered. The filtrate was concentrated to obtain 140 mg of a yellow oil, [M+H] + :477.3.

[0287] Step 5: tert-Butyl ((5-(2-fluorophenyl)-1-((3-((2-(methylamino)-2-oxoethyl)thio)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (20-6)

[0288] At room temperature, compound 20-4 (140 mg, 0.29 mmol), potassium iodide (10 mg, 0.06 mmol) and potassium carbonate (101 mg, 0.73 mmol) were added to DMF (4 mL), and 20-5 (45 mg, 0.29 mmol) was added. The mixture was reacted at 60°C overnight. The mixture was extracted with ethyl acetate, the solvent was concentrated, and the mixture was purified by column chromatography (PE / EA=1:1) to obtain 90 mg of a yellow oil with a yield of 56.25%, [M+H] + :547.2.

[0289] Step 6: 2-(((3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)thio)-N-methylacetamide hydrochloride (I-20)

[0290] At room temperature, compound 20-6 (90 mg, 0.16 mmol) was dissolved in 1,4-dioxane (3 mL), and 4M hydrochloric acid / 1,4-dioxane (3 mL) was added. After reacting at room temperature for 1 hour, the solvent was concentrated and the crude product was purified by Hex / EtOAc slurry to obtain 17 mg of a white solid with a yield of 21.52%, [M+H-HCl] + :447.3.

[0291] 1 H NMR (400MHz, CD3OD) δ7.78(s,1H),7.66(d,J=7.6Hz,1H),7.52-7.48(m,1H),7.42(t,J=7.6Hz,1H),7.38(s,1H),7.28(d, J=8.0Hz,1H),7.19(t,J=7.6Hz,1H),7.11-7.05(m,2H),6.42(s,1H),4.13(s,2H),3.65(s,2H),2.73(s,3H),2.72(s,3H).

[0292] Embodiment 21

[0293] Synthesis of 1-(5-(2-fluorophenyl)-1-((5-((methyl-D3)thio)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (I-21)

[0294]

[0295] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((5-((4-methoxybenzyl)thio)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (21-1)

[0296] At room temperature, compound Int 3 (3 g, 5.72 mmol) was dissolved in toluene (30 mL), and 4-methoxybenzyl mercaptan (1.06 g, 6.86 mmol), Pd2(dba)3 (525 mg, 0.572 mmol), Xantphos (333 mg, 0.572 mmol) and DIEA (1.48 g, 11.45 mmol) were added in sequence. After N2 replacement, the temperature was raised to 110 ° C and stirred overnight. After the reaction was complete, the solvent was concentrated and purified by column chromatography (PE / EA = 5: 1-2: 1) to obtain 3 g of yellow oil with a yield of 87.73%, [M+H] + :598.3.

[0297] Step 2: Synthesis of 5-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)pyridine-3-thiol trifluoroacetate (21-2)

[0298] At room temperature, compound 21-1 (3 g, 5.02 mmol) was dissolved in TFA (30 mL), Et3SiH (8 mL) was added, and the mixture was heated to 110°C and stirred overnight. The solvent was concentrated to obtain 2.5 g of a yellow oil with a yield of 100%, [M+H-TFA] + :377.6.

[0299] Step 3: tert-Butyl((1-((5-((tert-butoxycarbonyl)thio)pyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (21-3)

[0300] At room temperature, compound 21-2 (2.5 g, 5.09 mmol) was dissolved in DCM (30 mL), and triethylamine (2.1 g, 20.35 mmol) and Boc2O (2.8 g, 12.72 mmol) were slowly added. The reaction was continued overnight at room temperature, the solvent was concentrated, and the product was separated and purified by column chromatography (PE / EA=5:1) to obtain 2.3 g of a yellow oil with a yield of 78.19%, [M+H]+ :578.3.

[0301] Step 4: tert-Butyl ((5-(2-fluorophenyl)-1-((5-thiopyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (21-4)

[0302] Compound 21-3 (2.3 g, 3.98 mmol) and potassium carbonate (2.3 g, 16.64 mmol) were added to methanol (50 mL) at room temperature and reacted overnight at room temperature. After concentrating the solvent, ethyl acetate (30 mL) was added and filtered. The filtrate was concentrated to obtain 1.5 g of a yellow oil with a yield of 78.89%. [M+H] + :478.3.

[0303] Step 5: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((5-((methyl-D3)thio)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (21-6)

[0304] Compound 21-4 (50 mg, 0.11 mmol), 21-5 (31 mg, 0.22 mmol), K2CO3 (30 mg, 0.22 mmol) were added to a 25 mL single-mouth bottle, dissolved with 5 mL of N,N-dimethylformamide, and stirred at room temperature overnight. After the reaction was completed, 20 mL of water was added for washing, and ethyl acetate (40 mL × 2) was used for extraction. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. TLC preparation (hex / EA = 2:1) gave 25 mg of a light yellow oil with a yield of 48.07%, [M-56+H] + :439.17.

[0305] Step 6: Synthesis of 1-(5-(2-fluorophenyl)-1-((5-((methyl-D3)thio)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (I-21)

[0306] Compound 21-6 (25 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL) in a 50 mL single-mouth bottle, and 2 M hydrochloric acid / ethyl acetate (4 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was directly spin-dried, and then dissolved with a small amount of DCM. Hexane was added to precipitate the solid, and the mixture was directly dried to obtain 16 mg of a red solid compound. The yield was 72.72%, [M+H] + :395.25.

[0307] 1H NMR (400MHz, CD3OD) δ8.68(s,1H),8.37(s,1H),7.82(d,J=2.0Hz,1H),7.55-7.50(m,1H),7.45(d,J=2 .0Hz,1H),7.22(t,J=7.6Hz,1H),7.17–7.09(m,2H),6.46(d,J=2.0Hz,1H),4.11(s,2H),2.71(s,3H).

[0308] Embodiment 22

[0309] Synthesis of 1-(5-(2-fluorophenyl)-1-((5-(isopropylthio)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (I-22)

[0310]

[0311] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((5-(isopropylthio)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (22-2)

[0312] Compound 21-4 (50 mg, 0.11 mmol), 22-1 (31 mg, 0.22 mmol), K2CO3 (30 mg, 0.22 mmol) were added to a 25 mL single-mouth bottle, dissolved with 5 mL of N,N-dimethylformamide, and stirred overnight at room temperature. After the reaction was completed, 20 mL of water was added for washing, and ethyl acetate (40 mL × 2) was used for extraction. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. TLC preparation (hex / EA = 2:1) gave 30 mg of a light yellow oil with a yield of 54.98%, [M-56+H] + :464.16.

[0313] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((5-(isopropylthio)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (I-22)

[0314] Compound 22-2 (25 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL) in a 50 mL single-mouth bottle, and 2 M hydrochloric acid / ethyl acetate (4 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was directly spin-dried, and then dissolved with a small amount of DCM. N-hexane was added to precipitate the solid, and the mixture was directly dried to obtain 14 mg of a reddish brown solid compound. The yield was 63.98%, [M+H] + :420.30.

[0315] 1H NMR (400MHz, CD3OD) δ8.75(s,1H),8.41(s,1H),7.83(s,1H),7.61(s,1H),7.52(d,J=7.2Hz,1H),7.22(t, J=7.6Hz,1H),7.15-7.10(m,2H),6.47(s,1H),4.10(s,2H),3.54-3.31(m,1H),2.71(s,3H),1.28(s,6H).

[0316] Embodiment 23

[0317] Synthesis of 1-(1-((5-(ethylthio)pyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylformamide hydrochloride (I-23)

[0318]

[0319] Step 1: tert-Butyl ((1-((5-(ethylthio)pyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (23-1)

[0320] At room temperature, compound 21-4 (200 mg, 0.231 mmol) and potassium carbonate (96 mg, 0.691 mmol) were added to DMF (4 mL), and ethyl bromide (51 mg, 0.461 mmol) was added. The reaction was continued overnight at room temperature, the solvent was concentrated, and the product was separated and purified by column chromatography (PE / EA=5:1) to obtain 80 mg of a yellow oil with a yield of 68.40%, [M+H] + :506.3.

[0321] Step 2: 1-(1-((5-(Ethylthio)pyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylformamide hydrochloride (I-23)

[0322] At room temperature, compound 23-1 (80 mg, 0.158 mmol) was dissolved in 1,4-dioxane (3 mL), and 4M hydrochloric acid / 1,4-dioxane (3 mL) was added. After reacting at room temperature for 1 hour, the solvent was concentrated and the crude product was purified by Hex / EtOAc slurry to obtain 50 mg of a white solid with a yield of 71.52%, [M+H-HCl] + :406.3.

[0323] 1H NMR (400MHz, DMSO-d6) δ9.18(s,2H),8.80(d,J=2.0Hz,1H),8.36(d,J=2.0Hz,1H),7.88(d,J=1.6Hz,1H),7.58-7.52(m,2H),7.27-7. 23(m,2H),7.14-7.10(m,1H),6.60(d,J=2.0Hz,1H),3.99(t,J=5.2Hz,2H),3.06(q,J=7.2Hz,2H),2.5(s,3H),1.22(t,J=7.2Hz,3H).

[0324] Embodiment 24

[0325] Synthesis of 1-((5-((difluoromethyl)thio)pyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl-N-methylformamide (I-24)

[0326]

[0327] Step 1: tert-Butyl ((1-((5-(difluoromethylthio)pyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (24-1)

[0328] At room temperature, compound 21-4 (500 mg, 0.576 mmol) and potassium carbonate (320 mg, 2.30 mmol) were added to DMF (10 mL), and difluoroiodomethane (205 mg, 1.15 mmol) was added. The reaction was continued overnight at room temperature, the solvent was concentrated, and the mixture was separated and purified by C18 reverse phase column to obtain 110 mg of a yellow oil with a yield of 36.28%, [M+H] + :528.3.

[0329] Step 2: 1-((5-((difluoromethyl)thio)pyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl-N-methylformamide (I-24)

[0330] At room temperature, compound 24-1 (110 mg, 0.209 mmol) was dissolved in 1,4-dioxane (3 mL), 4M hydrochloric acid / 1,4-dioxane (3 mL) was added, and the reaction was carried out at room temperature for 1 hour. The solvent was concentrated, saturated Na2CO3 solution (5 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was washed with water (10 mL) and saturated brine (10 mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 70 mg of a yellow oil with a yield of 78.47%, [M+H] + :428.3.

[0331] 1 H NMR (400MHz, CDCl3) δ8.87(d,J=1.6Hz,1H),8.65(d,J=2.0Hz,1H),7.86(d,J=2.0Hz,1H),7.45-7.36(m,2 H),7.20-7.13(m,2H),7.06-7.02(m,1H),6.84(t,J=56.0Hz,1H),6.35(s,1H),3.70(s,2H),2.48(s,3H).

[0332] Embodiment 25

[0333] Synthesis of N-((5-(2-fluorophenyl)-1-((3-(methylthio)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)methane-D3-amine (I-25)

[0334] Step 1: Synthesis of (3-bromobenzenesulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (25-1)

[0335] In an ice bath, compound Int 1 (2.0 g, 10.58 mmol) was dissolved in DMF (15 mL), sodium hydride (635 mg, 15.87 mmol) was added, and the mixture was stirred for 30 minutes. Then, compound 3-bromobenzenesulfonyl chloride (3.3 g, 12.69 mmol) was added to the reaction system, and stirring was continued for 2 h. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and washed with saturated brine (50 mL × 1), and the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (PE / EA = 3:1) gave 3.8 g of a brown oily compound.

[0336] Step 2: Synthesis of 5-(2-fluorophenyl)-1-((3-(methylthio)phenyl)sulfonyl)-1H-pyrrole-3-carbaldehyde (25-2)

[0337] Compound 25-1 (270 mg, 0.66 mmol), sodium thiomethoxide (60 mg, 0.86 mmol), Pd2(dba)3 (121 mg, 0.13 mmol), Xantphos (76 mg, 0.13 mmol), DIPEA (342 mg, 2.64 mmol) were added to a 50 mL single-mouth bottle, dissolved with 5 mL of toluene, and heated at 100 ° C under nitrogen protection for overnight reaction. After the reaction was completed, the filter was filtered, and the filter cake was washed with EA several times. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. 145 mg of yellow-green oil was obtained by silica gel column chromatography (hex / EA=5:1), with a yield of 58.47%, and an ion current [M+H] + :376.15.

[0338] Step 2: Synthesis of N-((5-(2-fluorophenyl)-1-((3-(methylthio)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)methane-D3-amine (I-25)

[0339] Compound 25-2 (145 mg, 0.38 mmol) and deuterated methylamine (82 mg, 1.16 mmol) were added to a 25 mL single-mouth bottle, dissolved with dichloromethane (6 mL) and methanol (2 mL), stirred at room temperature for 30 min, added sodium triacetoxyborohydride (246 mg, 1.16 mmol) and a drop of glacial acetic acid under ice bath conditions, and warmed to room temperature for overnight reaction. After the reaction was completed, 15 mL of water was added to quench the reaction, and DCM 40 mL × 2 was used for extraction. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. TLC preparation (DCM / MeOH = 10:1) gave 130 mg of a yellow-white solid. Yield 85.52%, ion current [M+H] + :394.23.

[0340] 1 H NMR(400MHz,CD3OD)δ7.73(d,J=2.0Hz,1H),7.52–7.46(m,2H),7.39(m,J=7.8,2.4Hz,1H),7.28 –7.24(m,1H),7.18(s,1H),7.12–7.05(m,3H),6.39(d,J=2.0Hz,1H),4.03(s,2H),2.41(s,3H).

[0341] Embodiment 26

[0342] Synthesis of (5-(2-fluorophenyl)-1-((3-(2-methoxyethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (I-26)

[0343]

[0344] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(2-methoxyethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (26-1)

[0345] At room temperature, compound 3-3 (100 mg, 0.22 mmol), 2-bromoethyl methyl ether (45 mg, 0.33 mmol), potassium carbonate (61 mg, 0.44 mmol) were added to DMF (5 mL) and stirred at room temperature overnight. After the reaction was completed, 10 mL of water was added, stirred for 5 min, and 10 mL of ethyl acetate was added to extract twice to obtain an organic phase, which was concentrated under reduced pressure and purified by column chromatography (PE / EA=10:1) to obtain 80 mg of a yellow oil with a yield of 70.18%, [M+H]+: 419.3.

[0346] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(2-methoxyethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (I-26)

[0347] At room temperature, compound 26-1 (80 mg, 0.15 mmol) was dissolved in DCM (5 mL) solution, and then 4 M hydrochloric acid / 1,4-dioxane (1 mL) was added and stirred at room temperature overnight. Water (5 mL) was added to the reaction system, and pH was adjusted to 8 by saturated sodium bicarbonate aqueous solution, and extracted with DCM (10 mL × 3), and the organic phases were combined and concentrated to obtain 50 mg of brown oil, with a yield of 78.13%, [M+H] + :419.2.

[0348] 1 H NMR (400MHz, CD3OD) δ7.53(d,J=2.0Hz,1H),7.49-7.43(m,1H),7.38(t,J=8.0Hz,1H),7.21(d,J=8.4Hz,1H),7.16(t,J=7.6Hz,1H) ,7.14-7.05(m,3H),6.92(t,J=2.4Hz,1H),6.32(d,J=2.0Hz,1H),4.09-4.02(m,2H),3.77-3.68(m,4H),3.43(s,3H),2.45(s,3H).

[0349] Embodiment 27

[0350] Synthesis of 1-(1-((3-(azetidin-3-ylmethoxy)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine trifluoroacetate (I-27)

[0351]

[0352] Step 1: Synthesis of tert-butyl 3-((3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)methyl)azetidine-1-carboxylate (27-2)

[0353] Compound 3-3 (100 mg, 0.22 mmol), 27-1 (109 mg, 0.44 mmol) and potassium carbonate (75 mg, 0.54 mmol) were dissolved in DMF (3 mL) and stirred at room temperature overnight. After the reaction was completed, water (25 mL) was added to dilute the reaction solution, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (PE / EA = 3:1) to obtain 106 mg of a yellow oil with a yield of 77.94%, [M+H] +: 630.3.

[0354] Step 2: Synthesis of 1-(1-((3-(azetidin-3-ylmethoxy)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine trifluoroacetate (I-27)

[0355] At room temperature, compound 27-2 (106 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL) solution, and then trifluoroacetic acid (1 mL) was added and stirred at room temperature for 2 h. Concentration and reverse phase preparation gave 24 mg of white solid compound. Yield 21.82%, [M+H] + :430.2.

[0356] 1 H NMR (400MHz, CD3OD) δ7.78(d,J=2.0Hz,1H),7.53-7.44(m,2H),7.33(d,J=8.0Hz,1H),7.21-7.08(m,4H),7.01(t ,J=1.2Hz,1H),6.41(d,J=1.6Hz,1H),4.26(t,J=10.8Hz,2H),4.11-4.08(m,4H),3.40-3.34(m,1H),2.73(s,3H).

[0357] Embodiment 28

[0358] Synthesis of 3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)-N-(oxetan-2-ylmethyl)aniline (I-28)

[0359]

[0360] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-((oxetan-2-ylmethyl)amino)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (28-2)

[0361] Compound Int 4 (100 mg, 0.19 mmol), 28-1 (34 mg, 0.38 mmol), XphosPdG2 (16 mg, 0.02 mmol) and K2CO3 (80 mg, 0.576 mmol) were added to a 50 mL sealed tube, and toluene (6 mL) was added to dissolve, and the mixture was reacted at 100 ° C overnight under nitrogen protection. After the reaction was completed, water (10 mL) was added for washing, and the mixture was extracted with ethyl acetate (20 mL×2), and the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by column chromatography (PE / EA=2:1) ​​to obtain 91 mg of a light yellow oil with a yield of 89.51%, [M-100+H] + :430.30.

[0362] Step 2: Synthesis of 3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)-N-(oxetan-2-ylmethyl)aniline (I-28)

[0363] At room temperature, compound 28-2 (91 mg, 0.17 mmol) was dissolved in EA (4 mL) solution, placed in an ice bath under nitrogen protection, and 0.5 mL of trimethylsilyl iodide was slowly added, and the reaction was continued for 2 h. After the reaction was completed, 10 mL of methanol was added and stirred at room temperature for 10 min, and then directly dried by rotation, 10 mL of water was added, saturated NaHCO3 was added dropwise to adjust pH = 7, and extracted with DCM (30 mL × 2), the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by rotation, and TLC preparation (DCM / MeOH = 8:1) was performed to obtain 54 mg of yellow-white solid compound. Yield 73.09%, [M+H] + :430.30.

[0364] 1H NMR(400MHz, DMSO-d6)δ7.72(s,1H),7.51(q,J=7.2Hz,1H),7.30(t,J=8.0Hz,1H),7 .28-7.15(m,2H),7.10(t,J=7.2Hz,1H),6.78(d,J=8.4Hz,1H),6.68(d,J=7.6Hz,1H) ,6.44(s,1H),6.35(s,1H),5.03(s,1H),4.40(s,1H),3.98(s,2H),3.23(s,1H),3.1 7(s,2H),2.98(d,J=10.2Hz,1H),2.51(s,3H),2.05-2.00(m,1H),1.93–1.87(m,1H).

[0365] Embodiment 29

[0366] Synthesis of 3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)-N-(oxetan-2-ylmethyl)aniline (I-29)

[0367]

[0368] Step 1: Synthesis of 1-((5-bromopyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (29-1)

[0369] Compound Int 1 (600 mg, 3.17 mmol) was added to a 50 mL single-mouth bottle, dissolved with DMF (10 mL), and NaH (191 mg, 4.76 mmol, 60% wt) was added under ice bath conditions. The reaction was carried out under nitrogen protection for 30 min, and Int 3-1 (1.06 g, 4.12 mmol) was added, and the reaction was continued under ice bath for 3 h. After the reaction was completed, water (40 mL) was added for washing, and ethyl acetate (80 mL × 2) was used for extraction. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. 1.04 g of yellow-white solid was obtained by silica gel column chromatography (hex / EA = 5:1), with a yield of 79.81%, [M+H] + :411.05.

[0370] Step 2: Synthesis of N-((1-((5-bromopyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)methane-D3-amine (29-2)

[0371] Compound 29-1 (50 mg, 0.12 mmol) and deuterated methylamine hydrochloride (17 mg, 0.24 mmol) were added to a 50 mL single-mouth bottle, dissolved with dichloromethane (3 mL) and methanol (1 mL), stirred at room temperature for 30 min, added sodium triacetoxyborohydride (78 mg, 0.36 mmol) and a drop of glacial acetic acid under ice bath conditions, and heated to room temperature for overnight reaction. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with DCM (30 mL × 2), the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. TLC preparation (DCM / MeOH = 10:1) gave 40 mg of a yellow oil. The yield was 76.92%.

[0372] Step 3: Synthesis of N-((5-(2-fluorophenyl)-1-((5-(methylthio)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)methyl)methane-D3-amine (I-29)

[0373] Compound 29-2 (40 mg, 0.09 mmol), sodium thiomethoxide (9 mg, 0.12 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), Xantphos (11 mg, 0.02 mmol) were added to a 20 mL sealed tube, dissolved in 5 mL of toluene, and DIPEA (25 mg, 0.19 mmol) was added. After blowing nitrogen for 2 min, the mixture was heated at 80 ° C for overnight reaction. After the reaction was completed, 10 mL of water was added to quench the reaction, and the mixture was extracted with EA (20 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. TLC preparation (DCM / MeOH = 8:1) gave 8 mg of a yellow oil. Yield 21.62%, product ion current [M+H] + :395.23.

[0374] 1 H NMR(400MHz, CDCl3) δ8.56(d,J=2.4Hz,1H),8.36(d,J=2.0Hz,1H),7.43-7.38(m,2H),7.3 7(s,1H),7.20-7.10(m,2H),7.05(t,J=8.8Hz,1H),6.32(s,1H),3.67(s,2H),2.43(s,3H).

[0375] Embodiment 30

[0376] Synthesis of 2-(((5-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)pyridin-3-yl)thio)-N-methylacetamide hydrochloride (I-30)

[0377]

[0378] Step 1: Synthesis of methyl tert-butyl ((5-(2-fluorophenyl)-1-((5-((2-(methylamino)-2-oxoethyl)thio)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (30-2)

[0379] Compound 21-4 (150 mg, 0.32 mmol), 6-1 (96 mg, 0.64 mmol), K2CO3 (90 mg, 0.64 mmol), KI (12 mg, 0.06 mmol) were added to a 25 mL single-mouth bottle, dissolved with N, N-dimethylformamide (5 mL), and reacted at 60 ° C overnight under nitrogen protection. After the reaction was completed, it was cooled to room temperature, diluted with water (25 mL), extracted with ethyl acetate (50 mL × 2), and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. TLC preparation (hex / EA = 1:1) gave 103 mg of a light yellow oil with a yield of 59.54%, [M-100 + H] + :449.20.

[0380] Step 2: Synthesis of 2-(((5-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)pyridin-3-yl)thio)-N-methylacetamide hydrochloride (I-30)

[0381] Compound 30-2 (100 mg, 0.18 mmol) was dissolved in dichloromethane (3 mL) in a 25 mL single-mouth bottle, and 4 M hydrochloric acid / dioxane solution (4 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was directly spin-dried, and then dissolved with a small amount of DCM. N-hexane was added to precipitate the solid, and the mixture was directly dried to obtain 55 mg of a reddish brown solid compound. The yield was 62.51%, [M+H] + :449.22.

[0382] 1 H NMR (400MHz, CD3OD) δ8.79(s,1H),8.34(s,1H),7.81(s,2H),7.56–7.49(m,1H),7.21(t,J=7. 6Hz,1H),7.15–7.08(m,2H),6.46(s,1H),4.13(s,2H),3.70(s,2H),2.74(s,3H),2.71(s,3H).

[0383] Embodiment 31

[0384] Synthesis of 1-(5-(2-fluorophenyl)-1-(3-((methyl-D3)thio)benzenesulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine hydrochloride (I-31)

[0385]

[0386] Compound I-31 was synthesized according to the method of Example 21.

[0387] 1 H NMR (400MHz, CD3OD) δ7.78 (s, 1H), 7.55-7.54 (m, 2H), 7.41 (t, J = 7.6Hz, 1H), 7.29-7.26 ( m,1H),7.21(t,J=7.6Hz,1H),7.19-7.08(m,3H),6.41(s,1H),4.11(s,2H),2.71(s,3H).

[0388] H + / K + -ATPase biological evaluation

[0389] The following in vitro screening assay was used to determine the effects of the compounds of the present invention on H + / K + -Inhibition of ATPase activity.

[0390] Experimental materials and instruments:

[0391] ATP, malachite green, valinomycin, ammonium molybdate

[0392] No K + Buffer: 50 mM Tris-HCl pH 6.5, 5 mM magnesium chloride, 10 μM valinomycin

[0393] Contains K + Buffer: 50 mM Tris-HCl pH 6.5, 5 mM magnesium chloride, 10 μM valinomycin, 20 S D mM KCl

[0394] MLG colorimetric solution: 0.1% w / v malachite green, 1.5% w / v ammonium molybdate, 0.2% v / v Tween-20

[0395] Rabbit gastric mucosal microsomes (rich in H + / K +-ATPase), the extraction method is sucrose gradient centrifugation: the rabbit stomach is washed with tap water and 3MNaCl solution respectively, and then the surface water is removed with filter paper. Pre-cooled homogenization buffer (4ml / g tissue) is added, and homogenization is carried out in a tissue homogenizer for 2-5 minutes. After homogenization, if there are larger tissue particles, they can be removed by centrifugation (600g, 10min), and then the supernatant is transferred to a clean centrifuge tube. After centrifugation at 20000g for 30min, the supernatant is transferred to a clean centrifuge tube, and further centrifuged at 100000g for 90min, and the precipitate is collected; the precipitate is suspended with the homogenate, blown evenly, and the protein concentration is measured by Bradford method, and the concentration is adjusted to 10mg / mL; 7.5% Ficoll layering liquid is added in equal proportions, and after centrifugation at 100000g for 60min, the middle layer (H + / K + -ATPaseenriched gastric membranes) in a clean centrifuge tube, dilute 4-5 times with homogenate, continue centrifugation at 100000g for 90 min, collect the precipitate; suspend the precipitate with homogenate, homogenize evenly, measure the protein concentration with Bradford method, adjust the concentration to 22.5 mg / mL, and freeze at -80℃ for later use.

[0396] Experimental procedures

[0397] 45 μL buffer (containing K + 5 μL of gastric mucosal microsomes (H + / K + -ATPase), then add 5 μL 5mM ATP to start the reaction, pre-react at 37°C for 30 min. Add 15 μL malachite green solution to terminate the reaction, balance at room temperature for 20 min, and read the absorbance value at 620 nm.

[0398] At the same time, the reaction with the same volume but without KCl was performed as background and subtracted when calculating the enzyme activity.

[0399] Compound IC 50 The values ​​were calculated by the inhibition rate at different concentrations. + / K + -ATPase has obvious inhibitory activity, IC 50 The concentration of the active ingredient is 20 to 100 nM, preferably 20 to 50 nM. The control group 1 is selected from Vonoprazan, the preparation method of which is based on patent CN101300229A; the control group 2 is selected from the following structural formula.

[0400]

[0401] IC of some compounds of the present invention 50 Value (H + / K + -ATPase) are shown in Table 1 below:

[0402] Table 1:

[0403]

[0404] Conclusion: The compounds of the present invention have an + / K + -ATPase has obvious inhibitory activity.

[0405] In vitro cytotoxicity assay

[0406] Using Dulbecco's modified Eagle's medium (DMEM; Invitrogen), the cell line HepG2 derived from human liver cancer was cultured and passaged at 5% and 37°C. The cells in the logarithmic growth phase were collected, counted, and resuspended with complete medium. The cell concentration was adjusted to the appropriate concentration (determined according to the results of the cell density optimization test), inoculated into a 96-well plate, and 75μL / well of cell suspension was added according to the following platemap. The test compound was diluted to the corresponding action concentration set with the culture medium, and added to the cells according to the platemap 25μL / well. The action concentration of the test compound started from 100uM, 4-fold gradient dilution, a total of 9 concentrations, and 2 replicates. The cells were placed in a 37°C, 100% relative humidity, 5% CO2 incubator and incubated for 24h. 50μL / well CellTiterGlo RT was added and incubated in the dark for 30min. After gentle shaking, the detection was performed in Envision and the inhibition rate was calculated.

[0407] The inhibition rate of the drug on the growth of each cell was calculated according to the following formula: Cell growth inhibition rate % = (1-As / Ac)×100.

[0408] As: OA of sample (cells + CTG + test compound),

[0409] Ac: OA of normal growing cell control (cells+CTG+DMSO).

[0410] IC was calculated using the software Graphpad Prism 6 and the formula XY-analysis / Nonlinearregression (curve fit) / Dose response-Inhibition / log (inhibitor) vs. response-Variable slope (four parameters). 50 Curve fitting and calculation of IC 50 The IC value of the compound of the present invention was found to be 50 Greater than 20μM, with low cytotoxicity.

[0411] Liver microparticle stability test

[0412] Prepare liver microsomes of the desired species (e.g., mouse, rat, dog, monkey, or human). Prepare 10 mM concentration of sample and positive control stock solutions using DMSO as the diluent. Then dilute all stock solutions to a working concentration of 0.25 mM with 70% acetonitrile. The cofactor used in this study is the NADPH regeneration system, which consists of 6.5 mM NADP, 16.5 mM G-6-P, and 3 U / mL G-6-PD. The quenching reagent is an acetonitrile solution containing tolbutamide and propranolol. The buffer used in this study is 100 mM potassium phosphate buffer. A mixture containing 0.2 mg / mL liver microsomal protein and 1 μM test article / positive control is incubated in 100 mM potassium phosphate buffer.

[0413] 80 μL of each incubation solution was added to 300 μL of quenching reagent to precipitate protein, and the sample was taken at 0 minutes. After vortexing the sample, 20 μL of NADPH regeneration system was added. 520 μL of each incubation solution was added to 130 μL of NADPH regeneration system to initiate the reaction. The final incubation conditions for 650 μL were: 0.2 mg / mL microsomal protein, 1 μM band / positive control, 1.3 mM NADP, 3.3 mM glucose 6 phosphate, 0.6 U / mL glucose 6 phosphate dehydrogenase. The mixture was placed in a 37 ° C water bath and gently shaken. 100 μL of the mixture was taken at 5, 10, 30, and 60 minutes, respectively, and placed on a 96-well plate containing 300 μL of quenching reagent to precipitate protein, and centrifuged (5000 × g, 10 minutes). 80 μL of the supernatant was added to a 96-well detection plate pre-added with 160D μL ultrapure water and analyzed by LC-MS / MS.

[0414] The experiment found that the compound of the present invention in liver microsomes T 1 / 2 (min)>80min, preferably T 1 / 2 (min)>100min, with good liver microparticle metabolic stability.

[0415] Pharmacokinetic experiments

[0416] The compound under study is administered orally or intravenously (solvent 5% DMSO + 10% Solutol (HS-15) + 85% saline) to animals (such as mice, rats, dogs or monkeys) once, and blood is collected at fixed time points. Immediately after blood sampling, gently invert the test tube at least 5 times to ensure adequate mixing and then place on ice. The blood is anticoagulated with heparin and then centrifuged at 8000pm for 5 minutes to separate the serum from the red blood cells. The serum is aspirated with a pipette and transferred to a 2mL polypropylene tube, labeled with the name of the compound and the time point, and stored in a -40°C refrigerator before LC-MS analysis for testing. High-concentration samples are diluted with blank plasma for determination. After sample processing, the substances in the plasma are quantitatively analyzed by LCMS / MS. The plasma concentration / time curve obtained in this way is used to calculate pharmacokinetic parameters using a validated pharmacokinetic computer program. The experiment found that the compounds of the present invention all have good pharmacokinetic properties.

[0417] Study on the function of hERG potassium channel

[0418] Test system

[0419] Cells: Chinese hamster ovary (CHO) cell line, CHO-hERG cells were used in this experiment.

[0420] Cell culture medium and culture conditions: The complete culture medium is F12 medium supplemented with 10% fetal bovine serum and 1% Selective antibiotics (G418), 89 μg / mL hygromycin B (HB). The recovery medium is F12 medium supplemented with 10% fetal bovine serum. CHO-hERG cells are grown in a high humidity incubator at 37°C (±2°C) and 5% CO2 (4% to 8%). Cells are revived with recovery medium and passaged with complete medium. Cells used for patch clamp experiments are replaced with recovery medium at the last passage.

[0421] Extracellular and intracellular fluid components:

[0422] Reagents External solution (mM) Internal fluid (mM) <![CDATA[CaCl2]]> 2 5.37 <![CDATA[MgCl2]]> 1 1.75 KCl 4 120 NaCl 145 - Glucose 10 - HEPES 10 10 EGTA - 5 <![CDATA[Na2ATP]]> - 4 pH 7.3-7.4 7.2-7.3

[0423] Test methods

[0424] (1) Collect CHO-hERG cells in the exponential growth phase and resuspend them in ECS for later use.

[0425] (2) Manual patch clamp test

[0426] hERG currents were recorded under whole-cell patch clamp technique at room temperature. The output signal of the patch clamp amplifier was converted to digital and filtered at 2.9 kHz. Data were collected using Patchmaster Pro software.

[0427] The cells were placed in a cell recording tank on the stage of an inverted microscope, and a cell in the recording tank was randomly selected for testing. The perfusion system was fixed on the stage of an inverted microscope and the cells were continuously perfused with ECS.

[0428] Manual patch clamp recording microelectrodes were prepared using capillary glass tubes filled with intracellular fluid. On the day of the patch clamp experiment, electrodes were prepared using borosilicate glass tubes (BF150-117-10, SUTTER INSTRUMENT USA). The resistance of the electrodes after filling with ICS was between 2 and 5 MΩ.

[0429] The clamping voltage is -80mV. The first step is to depolarize to +60mV and maintain for 850ms to open the hERG channel. Then, the voltage is set to -50mV and maintained for 1275ms to generate a rebound current or tail current. The peak value of the tail current will be measured and used for analysis. Finally, the voltage is restored to the clamping voltage (-80mV). During the experiment, this command voltage program is repeated every 15s. The manual patch clamp hERG current test command voltage program is as follows Figure 1 shown.

[0430] At the beginning of recording of the perfusion of the solvent control working solution, monitor the tail current peak until more than 3 scanning curves are stabilized, then the test sample / positive control working solution to be tested can be perfused until the inhibitory effect of the test sample / positive control working solution on the hERG current peak reaches a stable state. Generally, the basic coincidence of the peak values ​​of the three most recent consecutive current curves is used as the criterion for judging whether it is in a stable state. After reaching a stable state, continue to perfuse the next concentration of the test sample. One or more test samples / positive controls, or multiple concentrations of the same drug, can be tested on one cell. Different test samples / positive controls need to be rinsed with solvent control working solution until the hERG current returns to more than 80% of the size before the addition of the drug. The standard deviation of the inhibition rate of each recorded cell at the same concentration shall not exceed 15%.

[0431] The positive control cisapride was tested at a concentration of 0.1 μM, and the cells were assayed in duplicate. According to scientific literature reports, 0.1 μM cisapride inhibits hERG current by more than 50%. (Milnes, JT, et al.).

[0432] (3) Manual patch clamp data acceptance criteria

[0433] Sealing standard: After the whole-cell mode is formed, the clamping voltage (-80mV) is applied, and the cell membrane related parameters (Cm, Rm and Ra) can be recorded. A good whole-cell recording should meet the following conditions: path resistance (Rs) is less than 10MΩ; membrane resistance (Rm) is greater than 500MΩ and membrane capacitance (Cm) is less than 100pF.

[0434] Current size: The peak current amplitude before the test article / positive control is between 400pA and 5000pA. Otherwise, the cell is discarded.

[0435] Leakage current: At a clamp voltage of -80mV, the absolute value of the leakage current should be less than 200pA. The current amplitude will be corrected using the leakage current at -80mV. Scans with leakage currents greater than 200pA cannot be used for analysis.

[0436] Data analysis

[0437] For each cell, the inhibition percentage of each concentration of the test article and positive control was calculated from the recorded current response using the following formula: (1 – peak tail current recorded after perfusion of the test article / positive control / peak tail current (starting current) recorded after perfusion of the vehicle control) × 100%.

[0438] For each concentration, all cell inhibition percentages were recorded and averaged, IC 50 The values ​​were obtained from the concentration-effect curves by the Hill fitting method.

[0439] Test results

[0440] The results of the inhibition of hERG current by some compounds of the present invention are shown in Table 2 below;

[0441] Table 2:

[0442] serial number <![CDATA[hERG IC 50 ]]> I-5 ++ I-18 ++ I-19 ++ I-21 + I-25 ++ I-31 ++ Control group 1 +

[0443] Note: IC 50 >20μM is +++, 20μM>IC 50 >10μM is ++, 10μM>IC 50 >1μM is +.

[0444] The experiment found that the compound of the present invention has a higher hERG IC 50 This indicates that the compound of the present invention has a low risk of cardiotoxicity.

[0445] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0446] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A pyrrolsulfonyl derivative and a pharmaceutically acceptable salt thereof, characterized in that: The pyrrole sulfonyl derivative is selected from any one of the following structures: 、 、 、 、 、 、 。 2. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the pyrrole sulfonyl derivative according to claim 1, and a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and / or excipient.

3. The pyrrole sulfonyl derivative according to claim 1, its pharmaceutically acceptable salt or the pharmaceutical composition according to claim 2 in the preparation of gastric acid secretion inhibitor, H + / K + - Use in ATPase inhibitors or potassium ion competitive acid blockers.

4. Use of the pyrrole sulfonyl derivatives and pharmaceutically acceptable salts thereof according to claim 1 or the pharmaceutical composition according to claim 2 in the preparation of drugs for treating or preventing the following diseases: peptic ulcer, Zollinger-Ellison syndrome, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett's esophagitis, functional dyspepsia, Helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, ulcers caused by nonsteroidal anti-inflammatory drugs, hyperacidity caused by postoperative stress, or ulcers caused by postoperative stress.

5. Use of the pyrrole sulfonyl derivatives and pharmaceutically acceptable salts thereof according to claim 1 or the pharmaceutical composition according to claim 2 in the preparation of drugs for treating or preventing the following diseases: use in the preparation of drugs for inhibiting upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress.

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