A pyrrolylsulfonyl derivative, and its preparation method and application

Abstract

The present invention relates to a novel pyrrole sulfonyl derivative, a method for preparing the same, a pharmaceutical composition containing the same, and the use of the same in pharmaceutical preparations. Specifically, the present invention relates to a novel pyrrole sulfonyl derivative represented by general formula (I), a method for preparing the same, a pharmaceutical composition containing the same, and the use of the same as a therapeutic agent, particularly as a gastric acid secretion inhibitor and potassium-competitive acid blocker (P-CAB).

Description

Technical Field

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

[0002] China has 120 million patients suffering from gastrointestinal diseases, including Helicobacter pylori infection, gastroesophageal reflux disease, peptic ulcers, duodenal ulcers, gastric ulcers, and esophagitis. The incidence of peptic ulcers is 10%, and that of chronic gastritis is 30%. Long-term gastrointestinal diseases can gradually develop into gastrointestinal cancer. Of the six most common cancers worldwide, five are related to the digestive tract: gastric cancer, liver cancer, esophageal cancer, intestinal cancer, and pancreatic cancer. With the development of society and changes in people's lifestyles, the incidence of gastric diseases caused by smoking, alcohol consumption, emotional stress, staying up late, medications, and the Chinese preference for spicy and sour foods is increasing. Peptic ulcers are seriously impacting people's work and daily lives. While the exact pathogenesis of peptic ulcers remains unclear, inhibiting gastric acid secretion has become the recognized treatment of choice for these conditions.

[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 were launched around the world. After years of clinical application, PPIs have become the first choice for treating gastric acid-related diseases. Proton pump, also known as gastric acid pump, is actually H + / K + -ATPase (H + / K + -ATPase), is the gastric secretion of H + The final common pathway is present on the cell membrane of the secretory tubules of gastric parietal cells, which uses ATP degradation to provide energy for H + , K + exchange, specifically H +Pumped into the gastric cavity, they create a strong acidic state in the stomach. First-generation PPIs have a significant inhibitory effect on basal and nocturnal gastric acid secretion, as well as gastric acid secretion stimulated by pentagastrin and test meals. However, limitations in pharmacokinetics and pharmacodynamics, including bioavailability, the effect of administration time on efficacy, slow onset of nocturnal acid breakthrough (NAB), instability under acidic conditions (often requiring enteral preparations that take several hours to show an effect), and dependence on CYP450 enzymes (significant individual variability in the inhibitory effect on gastric acid secretion), have impacted their therapeutic efficacy and clinical application. Compared with first-generation PPIs, new-generation PPIs offer significant 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 + And 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 secretion of acid into the gastric cavity do not require the activation of microcapsules and microtubules and acid concentrated in the gastric parietal cells, and 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 peak plasma concentration. Clinical and animal experiments have also shown that P-CABs are faster than PPIs or histamine receptor 2 (H2) blockers in onset and have a stronger effect in raising pH. The blood drug concentration is linearly correlated with the oral dosage, suggesting 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 into 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 has designed compounds having the structure represented by general formula (I) and found that compounds having such structures exhibit excellent effects, have few toxic side effects, and have good safety and metabolic stability. Summary of the Invention

[0007] In order to solve the above-mentioned problems of 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 properties in terms of efficacy, 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, characterized in that the structure of the pyrrole sulfonyl derivative is shown in formula (I):

[0011]

[0012] in:

[0013] Ring A is selected from phenyl or pyridyl, phenyl or pyridyl is optionally substituted by 1, 2 or 3 R 1 replaced by;

[0014] Ring B is selected from 3-12 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl, 3-12 membered cycloalkyl, 7-12 membered spirocyclyl, 7-12 membered cyclocyclyl, 7-12 membered bridged ring group, wherein Ring B is optionally substituted by 1, 2 or 3 R 2 substituted or oxo;

[0015] Or ring A and ring B together form a fused-ring aromatic group;

[0016] R 1 Selected from C 1-6 Alkyl, C 1-6Alkoxy, halogen, cyano, C 2-6 Alkynyl, C 2-6 Alkenyl, OC 1-6 Alkyl-OC 1-6 Alkyl, NR a R b ;

[0017] R 2 Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, cyano, C 2-6 Alkynyl, C 2-6 Alkenyl, 3-12 membered cycloalkyl, -NH2, -C(=O)R c 、-OC 1-6 Alkyl-O-C1-6 alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -OC 1-6 Alkyl-C(=O)NHR d 、 -S(=O) m -C 1-6 Alkyl, wherein alkyl, alkoxy, cycloalkyl is optionally further substituted with 1, 2 or 3 chlorines;

[0018] R3 is selected from halogen, 5-8 membered aryl, 5-8 membered heteroaryl; or two R3 together with the carbon atom to which they are attached form a fused ring aryl; wherein aryl, heteroaryl and fused ring aryl may be optionally further substituted with 1, 2 or 3 C 1-6 Alkyl, C 1-6 Alkoxy, halogen substituted;

[0019] R4 is selected from C 1-6 wherein the alkyl group may be optionally further substituted with 1, 2 or 3 deuterium or halogen;

[0020] R a 、R b 、R c 、R d Each independently selected from H, C 1-6 Alkyl, 3-12 membered cycloalkyl;

[0021] n is selected from 0, 1, 2, 3;

[0022] m is selected from 0, 1, and 2.

[0023] In some embodiments: Ring B is selected from 3-8 membered monoheterocyclyl, 7-12 membered bridged ring, 7-12 membered spiroheterocyclyl, 3-8 membered heterocyclyl and 3-8 membered heterocyclyl, 3-8 membered monoheterocyclyl and 3-8 membered monocycloalkyl, 3-8 membered monoheterocyclyl and phenyl.

[0024] In some embodiments:

[0025] Ring B is selected from:

[0026]

[0027]

[0028] Z1, Z2, and Z3 are each independently selected from C, O, S, S(=O), S(=O)2, NR e ; R e Selected from H, C 1-6 Alkyl, polyhalogenated C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, 3-12 membered cycloalkyl, -C(=O)C 1-6 alkyl;

[0029] Z4, Z5, and Z6 are each independently selected from N and C;

[0030] L and P are each independently selected from 1, 2, 3, and 4;

[0031] Ring B is optionally substituted with 1, 2 or 3 R 2 replaced.

[0032] In some embodiments:

[0033] Ring B is selected from:

[0034]

[0035] Wherein, Z1 is selected from O, S, NR e ; R e Selected from H, C 1-3 Alkyl, polyhalogenated C 1-3 Alkyl, 3-6 membered cycloalkyl, -C(=O)C 1-6 alkyl;

[0036] Ring B is optionally substituted with 1, 2 or 3 R 2 replaced.

[0037] In some preferred embodiments:

[0038] Ring B is selected from:

[0039]

[0040]

[0041] In some preferred embodiments: R 2 Selected from H, C 1-6Alkoxy, halogen; R3 is selected from halogen; R4 is C 1-6 alkyl.

[0042] The present invention provides pharmaceutically acceptable salts of pyrrole sulfonyl derivatives, which may be hydrochloride or trifluoroacetate.

[0043] Furthermore, the pyrrole sulfonyl derivatives of the present invention can be selected from any one of the following structures:

[0044]

[0045]

[0046]

[0047] On the other hand, the present invention provides a pharmaceutical composition comprising a pyrrole sulfonyl derivative, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, and a pharmaceutically acceptable carrier and / or excipient.

[0048] On the other hand, the present invention provides a pyrrole sulfonyl derivative, a pharmaceutically acceptable salt thereof, a tautomer thereof or a stereoisomer thereof or a pharmaceutical composition thereof for use in the preparation of a gastric acid secretion inhibitor, H + / K + - Use as an ATPase inhibitor or potassium ion competitive acid blocker.

[0049] The present invention provides a use of the above-described pyrrole sulfonyl derivative, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a stereoisomer thereof, or a pharmaceutical composition as described above, in preparing a medicament for treating or preventing the following diseases: peptic ulcer, Zollinger-Ellison syndrome, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett's esophagus, 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 preparing a medicament for inhibiting upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer, hemorrhagic gastritis, or invasive stress. Furthermore, the pyrrole sulfonyl derivative provided by the present invention has fewer toxic and side effects, better safety, and better metabolic stability than the prior art.

[0050] Explanation of terms

[0051] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0052] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. The cycloalkyl group comprises 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups. Cycloalkyl groups may be optionally substituted or unsubstituted.

[0053] "Spirocyclyl" refers to a polycyclic group containing two or more cyclic structures, and a carbon atom (called spiro atom) shared between the monocyclic rings. The ring may contain one or more double bonds and may contain one or more heteroatoms, including oxygen, sulfur and nitrogen, but no ring has a completely conjugated π electron aromatic system. Preferably, it is 6 to 12 members. According to the number of shared spiro atoms between the rings, the spirocyclyl is divided into a single spiro, a double spiro or a multi-spirocyclyl, preferably a single spiro and a double spirocyclyl, preferably a 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered. Non-limiting examples of "spirocyclyl" include, but are not limited to:

[0054]

[0055] "Bridged cyclic group" refers to a 5 to 18-membered polycyclic group containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, one or more rings may contain one or more heteroatoms, including oxygen, sulfur and nitrogen, but no ring has a completely conjugated π electron aromatic system, preferably 6 to 12 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cyclic groups" include but are not limited to:

[0056]

[0057] "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic non-aromatic heterocyclic group containing 3-12 ring atoms, wherein at least one ring atom is a heteroatom, such as an oxygen, nitrogen, or sulfur atom. Preferably, it has a 3- to 8-membered monocyclic ring or a 7- to 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 attached to the parent structure is the heterocyclyl. A heterocyclyl group may be optionally substituted or unsubstituted.

[0058] "Parallel ring" refers to a ring structure formed by two, three, or four ring structures sharing two adjacent atoms. Each single ring in the ring structure can be a monocyclic aryl, a monocyclic heteroaryl, a monocyclic cycloalkyl, or a monocyclic heterocycloalkyl. The paracyclic group referred to in the present invention is a saturated, unsaturated, or partially saturated paracyclic ring structure, preferably a bicyclic or tricyclic paracyclic ring group. In the present invention, the paracyclic group is a 3-20-membered, preferably a 3-15-membered paracyclic ring group. Specific examples of cyclopentyl groups include, but are not limited to, benzocyclobutenyl, 2,3-dihydro-1-H-indenyl, 1,2,3,4-tetrahydronaphthyl, 6,7,8,9-tetrahydro-5H-benzo[7]annulyl, 6,9-dihydro-5H-benzo[7]annulyl, 5,6,7,8,9,10-hexahydrobenzo[8]annulyl, 2,3-cyclopentenopyridinyl, 5,6-dihydro-4H-cyclopentyl[B]thienyl, 5,6-dihydro-4H-cyclopentyl[B]furanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, dihydroindole, 2,3-dihydrobenzo[b]thienyl, dihydrobenzopyranyl, 1, 2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1,4-benzodioxanyl, 3,4-dihydro-2H-1,4-benzoxazinyl, naphthyridinyl, naphthyl, benzofuranyl, benzothiophenyl, benzopyrrolyl, benzothiazolyl, benzoxazolyl, indazolyl, benzopyridazinyl, benzimidazolyl, indolyl, quinolinyl, isoquinolinyl, purinyl, pteridinyl,

[0059]

[0060]

[0061] wait.

[0062] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused manner. The term "aryl" includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl. Preferably, aryl is C6-C 10 Aryl, more preferably phenyl and naphthyl, most preferably phenyl. Aryl can be substituted or unsubstituted. The "aryl" can be fused with a heteroaryl, a heterocyclic group or a cycloalkyl group, wherein the aryl ring is connected to the parent structure. Non-limiting examples include but are not limited to:

[0063]

[0064] "Heteroaryl" refers to an aromatic 5 to 8 yuan monocyclic or 9 to 10 yuan bicyclic ring, which can contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulphur. 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 can 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:

[0065]

[0066] "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 a 9-10 membered fused ring aryl. Non-limiting examples include, but are not limited to:

[0067]

[0068] "Alkoxy" refers to a group (alkyl-O-). Alkyl is defined herein. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0069] "Haloalkyl" refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as described herein. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.

[0070] "Optional" means that the event it describes may but need not occur. For example, "A is optionally replaced by 1 to more R 2 The term "substituted" means that the group A can be replaced by one or more R 2 Replaced or not by R 2 Replacement situation.

[0071] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0072] The present invention provides a novel pyrrole sulfonyl derivative. Test results show that the pyrrole sulfonyl derivative exhibits excellent gastric acid secretion inhibition and potassium ion competitive acid blocker (P-CAB) activity, and can be used to prepare drugs for treating or preventing peptic ulcer, Zollinger-Ellison syndrome, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett's esophagus, 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 ulcers, acute stress ulcers, hemorrhagic gastritis, or invasive stress. The pyrrole sulfonyl derivative provided by the present invention has low toxicity and side effects, excellent safety performance, and exhibits good pharmacokinetic properties, significantly prolonged half-life, and more sustained acid suppression effect, and is expected to improve the nocturnal acid breakthrough phenomenon of proton pump inhibitor drugs in the prior art.

[0073] Figure 1 Instruct voltage program for manual patch-clamp hERG current testing. DETAILED DESCRIPTION

[0074] The method of the present invention is described below by means of specific examples 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 obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1H 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.

[0075] Mass spectra were obtained using LC / MS instrumentation, using ESI as the ionization method.

[0076] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents were commercially available or synthesized according to known methods, and commercially available materials and reagents were used directly without further purification.

[0077] CD3OD: deuterated methanol

[0078] CDCl3: deuterated chloroform

[0079] DMSO-d6: deuterated dimethyl sulfoxide

[0080] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0081] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0082] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C-30°C.

[0083] Preparation of intermediates

[0084] Synthesis of intermediate Int 1

[0085]

[0086] Step 1: Synthesis of 1-(5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine (Int 1-2)

[0087] Compound Int 1-1 (3.8 g, 20.1 mmol) was dissolved in 30% methylamine alcohol solution (20 mL) at room temperature and stirred for 1 hour. NaBH4 (2.3 g, 60.3 mmol) was then added portionwise and stirred for another 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 afford 4.1 g of a yellow solid in a 97.6% yield.

[0088] Step 2: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int1-3)

[0089] Compound Int 1-2 (4.1 g, 20.6 mmol) was dissolved in dichloromethane (50 mL) at room temperature, and triethylamine (11 mL, 78.9 mmol) and Boc2O (9.0 g, 41.2 mmol) were added, respectively. The mixture was allowed to react at room temperature for 2 hours, then concentrated under reduced pressure. 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%.

[0090] Step 3: Synthesis of tert-butyl ((1-((3-bromophenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int 1)

[0091] Compound Int 1-3 (3 g, 9.86 mmol) was dissolved in DMF (50 mL) at room temperature and cooled to 0°C. Sodium hydride (600 mg, 14.8 mmol) was added and stirred at room temperature for 10 minutes. 3-Bromobenzenesulfonyl chloride (3 g, 11.8 mmol) was then added. The reaction was continued for 1 hour, quenched by the addition of water (50 mL), and 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%.

[0092] Synthesis of intermediate Int 2

[0093]

[0094] Synthesis of tert-butyl ((1-((5-bromopyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int 2)

[0095] Compound Int 1-3 (3.0 g, 9.87 mmol) was dissolved in DMF (40 ml) under ice, followed by the addition of NaH (789 mg, 19.71 mmol). The mixture was stirred for half an hour, followed by the addition of compound Int 2-1 (3.03 g, 11.83 mmol), and stirring continued for 2 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (150 mL) and washed 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) afforded 4.5 g of a yellow oil in an 87.2% yield.

[0096] Synthesis of intermediate Int 3

[0097]

[0098] Step 1: Synthesis of 1-(5-bromo-1H-pyrrol-3-yl)-N-methylmethanamine (Int 3-2)

[0099] At room temperature, compound Int 3-1 (5.0 g, 28.74 mmol) was dissolved in a methanol solution of methylamine (50 mL), stirred at room temperature for 2 h, then cooled in an ice-water bath, sodium borohydride (2.2 g, 57.47 mmol) was added, 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 dichloromethane (100 mL × 2). The combined organic phases were washed with saturated brine (150 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5.43 g of a yellow oily compound, which was directly used for the next step without purification. [M+H] + :189.1.

[0100] Step 2: Synthesis of tert-butyl ((5-bromo-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int 3-3)

[0101] At room temperature, compound Int 3-2 (15.43 g, 28.72 mmol) and triethylamine (7.98 mL, 57.44 mmol) were dissolved in dichloromethane (50 mL), and then Boc2O (7.52 g, 34.47 mmol) was slowly added and stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (PE / EA = 5:1) to obtain 8.2 g of a colorless oily compound with a yield of 98.60%, [M+H] + :289.1.

[0102] Step 3: Synthesis of tert-butyl ((5-(2,4-difluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int 3-5)

[0103] Compound Int 3-3 (8.0 g, 27.67 mmol), Int 3-4 (8.0 g, 33.20 mmol), Pd(dppf)Cl2 (2.1 g, 2.77 mmol), and potassium carbonate (9.6 g, 69.16 mmol) were dissolved in 1,4-dioxane and water (80 / 16 mL) and stirred at 115°C for 4 h under nitrogen. After the reaction was completed, it was extracted with dichloromethane (100 mL × 2), the combined organic phases were washed with saturated brine (150 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (PE / EA = 3:1) gave 6.2 g of a brown oily compound with a yield of 69.66%, [M+H] + :323.2.

[0104] Step 4: Synthesis of tert-butyl ((1-((3-bromophenyl)sulfonyl)-5-(2,4-difluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int 3)

[0105] In an ice bath, compound Int 3-5 (2.0 g, 6.20 mmol) was dissolved in DMF (15 mL), sodium hydride (373 mg, 9.31 mmol) was added, and the mixture was stirred for 30 minutes. Compound Int 3-6 (1.9 g, 7.45 mmol) was then added to the reaction system 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 (30 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (PE / EA = 3:1) gave 3.0 g of a brown oily compound with a yield of 89.55%.

[0106] Synthesis of intermediate Int 4

[0107]

[0108] Synthesis of tert-butyl ((1-((3-bromo-5-fluorophenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int 4)

[0109] Compound Int 1-3 (1.0 g, 3.29 mmol) was dissolved in DMF (15 mL) solution, cooled to room temperature, sodium hydride (198 mg, 4.93 mmol) was added to the reaction solution, and stirred under an ice-water bath for 30 minutes. Compound I nt 4-1 (1.1 g, 3.94 mmol) was then slowly added to the reaction system, and stirring was continued for 2 h. After the reaction was completed, the reaction system was quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (PE / EA = 10: 1) gave 700 mg of a yellow oily compound with a yield of 39.54%, [M+H] + :541.1.

[0110] Synthesis of intermediate Int 5

[0111]

[0112] Step 1: Synthesis of tert-butyl ((1-((5-bromo-2-methoxyphenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (Int 5)

[0113] At room temperature, compound Int 1-3 (1000 mg, 3.29 mmol) was dissolved in DMF (10 mL). NaH (118.44 mg, 4.94 mmol) was added at 0°C. After the addition, the mixture was stirred at room temperature for 30 min, followed by the addition of Int 5-1 (1127 mg, 3.95 mmol) and stirring for 3 h. 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 882 mg of the red oily compound with a yield of 48.5%, [M+H] + :554.20.

[0114] Example 1

[0115] Synthesis of 1-(1-((3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl)sulfonyl)-5-(2-fluoro-phenyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-1)

[0116]

[0117] Step 1: Synthesis of tert-butyl ((1-((3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (1-2)

[0118] Compound Int-1 (150 mg, 0.29 mmol), 1-1 (52 mg, 0.35 mmol), Pd(OAc)2 (7 mg, 0.03 mmol), xantphos (Chinese name: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 33 mg, 0.06 mmol) and cesium carbonate (234 mg, 0.72 mmol) were added to a toluene (5 mL) solution and stirred at 110°C overnight under nitrogen protection. After the reaction was complete, ethyl acetate (20 mL) was added to dilute the mixture, washed with saturated brine (20 mL×2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by reverse phase preparative yielded 50 mg of a white solid compound with a yield of 31.44%, [M+H] + :556.2.

[0119] Step 2: Synthesis of 1-(1-((3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl)sulfonyl)-5-(2-fluoro-phenyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-1)

[0120] At room temperature, compound 1-2 (50 mg, 0.09 mmol) was dissolved in dichloromethane (2 mL) and 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added. The mixture was stirred for two hours. After the reaction was complete, the mixture was concentrated and purified by reverse phase preparative method to obtain 30 mg of a yellow solid compound with a yield of 73.17% and a purity of >95%. [M+H] + :456.2.

[0121] 1 HNMR: (400MHz, CDCl3) δ7.40-7.34(m, 2H), 7.23-7.18(m, 2H), 7.11(t, J=7.6H z, 1H), 7.05 (t, J=7.6Hz, 1H), 6.87 (d, J=8.4Hz, 1H), 6.82 (d, J=8.0Hz, 1H), 6. 69(s, 1H), 6.25(s, 1H), 3.93-3.91(m, 2H), 3.76(d, J=11.2Hz, 2H), 3.64(s, 2H ), 3.50 (d, J=11.2Hz, 2H), 2.47 (s, 3H), 2.10-2.07 (m, 2H), 1.99-1.96 (m, 2H).

[0122] Example 2

[0123] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-2)

[0124]

[0125] Step 1: Synthesis of tert-butyl 5-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2-2)

[0126] Compound Int 1 (200 mg, 0.38 mmol), 2-1 (123 mg, 0.58 mmol), Pd(OAc)2 (9 mg, 0.04 mmol), xantphos (22 mg, 0.04 mmol) and cesium carbonate (313 mg, 0.96 mmol) were added to a toluene (5 mL) solution and stirred at 110°C overnight under nitrogen. After the reaction was complete, ethyl acetate (20 mL) was added to dilute the mixture and washed with saturated brine (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (PE / EA = 2:1) gave 180 mg of a yellow oily compound with a yield of 72.00%, [M+H] + :655.2.

[0127] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-2)

[0128] At room temperature, compound 2-2 (180 mg, 0.26 mmol) was dissolved in dichloromethane (3 mL) and 4 M hydrochloric acid / 1,4-dioxane (3 mL) was added and stirred for 2 h. After the reaction was complete, the mixture was concentrated and purified by reverse phase preparative method to obtain 50 mg of a yellow solid compound with a yield of 40.32% and a purity of >95%. [M+H] + :455.2.

[0129] 1 HNMR: (400MHz, CDCl3) δ7.40-7.34(m, 2H), 7.23-7.17(m, 2H), 7.11(t, J=7.6 Hz, 1H), 7.07 (t, J=7.6Hz, 1H), 6.79 (d, J=8.4Hz, 1H), 6.70 (d, J=8.0Hz, 1H), 6 .56(s, 1H), 6.23(s, 1H), 3.64(s, 2H), 3.36-3.32(m, 2H), 3.21-3.16(m, 2H), 3 .09 (d, J=9.6Hz, 2H), 2.94-2.92 (m, 2H), 3.83 (d, J=11.2Hz, 2H), 2.47 (s, 3H).

[0130] Example 3

[0131] Synthesis of 1-(1-((3-(3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylamine dihydrochloride (III-3)

[0132]

[0133] Step 1: Synthesis of tert-butyl 8-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (3-2)

[0134] To a 100 mL reaction flask were added compound Int 1 (150 mg, 0.287 mmol), compound 3-1 (73 mg, 0.345 mmol), Pd(OAc)2 (7 mg, 0.029 mmol), xantphos (33 mg, 0.057 mmol), Cs2CO3 (234 mg, 0.718 mmol), and toluene (5 mL). The mixture was stirred, the atmosphere purged with nitrogen three times, and the temperature was raised to 110°C and stirred for 12 h. TLC monitoring indicated the reaction was complete, with the formation of a new spot (PE / EA = 3:1, Rf = 0.3). 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined and washed once with saturated brine (30 mL). The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure at 45°C, and separated by column chromatography (PE / EA = 2:1 elution) to obtain 200 mg of a colorless oil.

[0135] Step 2: Synthesis of 1-(1-((3-(3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylamine dihydrochloride (III-3)

[0136] At room temperature, compound 3-2 (200 mg) and MeOH (5 mL) were added to a reaction flask. The mixture was stirred to dissolve. 4 M hydrochloric acid / 1,4-dioxane (5 mL) was added and the mixture was allowed to react at room temperature for 1 h. TLC monitoring showed that the reaction was complete with the generation of a new spot (DCM / MeOH = 10:1, Rf = 0.2). The mixture was dried to give a light purple oil. Dichloromethane was added to precipitate a solid. The solid was filtered and dried to give 50 mg of a light purple solid with a purity >95%. [M+H] + :455.6.

[0137] 1HNMR: (400MHz, CD3OD) δ7.81 (d, J=2.0Hz, 1H), 7.54-7.47 (m, 1H), 7.39 (t, J=8.0Hz, 1H), 7.20 (t, J=7.2Hz, 2H), 7.17-7.04 (m, 2H), 6.95 (d, J=9.6Hz, 1H), 6.79 (t, J=2.0Hz, 1H), 6.43 (d, J=1.6Hz, 1H), 4.36 (s, 2H), 4.13 (s, 2H), 3.23-3.13 (m, 4H), 2.73 (s, 3H), 2.34-2.21 (m, 2H), 2.12 (d, J=7.2Hz, 2H).

[0138] Example 4

[0139] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(piperazin-1-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine dihydrochloride (III-4)

[0140]

[0141] Step 1: Synthesis of tert-butyl 4-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)piperazine-1-carboxylate (4-2)

[0142] To a 100 mL reaction flask were added compound Int 1 (150 mL, 0.287 mmol), compound 4-1 (70 mg, 0.345 mmol), Pd(OAc)2 (7 mg, 0.029 mmol), xantphos (33 mg, 0.057 mmol), Cs2CO3 (234 mg, 0.718 mmol), and toluene (5 mL). The mixture was stirred, the atmosphere purged with nitrogen three times, and the temperature was raised to 110°C and stirred for 12 h. TLC monitoring indicated the reaction was complete, with the formation of a new spot (PE / EA = 3:1, Rf = 0.3). 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined and washed once with saturated brine (30 mL). The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure at 45°C, and separated by column chromatography (PE / EA = 2:1) to yield 170 mg of a colorless oil.

[0143] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(piperazin-1-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine dihydrochloride (III-4)

[0144] Compound 4-2 (170 mg) and MeOH (5 mL) were added to a reaction flask at room temperature. The mixture was stirred until clear. 4M hydrochloric acid / 1,4-dioxane (5 mL) was added and the mixture was allowed to react at room temperature for 1 h. TLC monitoring showed that the reaction was complete with the generation of a new spot (DCM / MeOH = 10:1, Rf = 0.2). The mixture was dried to give a pale purple oil. Dichloromethane was added, and a solid precipitated. The solid was filtered and dried to give 50 mg of a pale purple solid with a purity >95%. [M+H] + :429.5.

[0145] 1 H NMR: (400MHz, CD3OD) δ7.81 (s, 1H), 7.54-7.48 (m, 1H), 7.41 (t, J=8.0Hz, 1H), 7.32 (d, J=8.0Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.15-7.08 (m, 2H), 7.05 (d, J=7.6Hz, 1H), 6.93 (s, 1H), 6.42 (s, 1H), 4.12 (s, 2H), 3.39 (s, 8H), 2.73 (s, 3H).

[0146] Example 5

[0147] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-5)

[0148]

[0149] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (5-2)

[0150] At room temperature, compound Int 1 (200 mg, 0.382 mmol) was placed in a 10 mL single-necked flask and dissolved in toluene (3 mL). 5-1 (75 mg, 0.497 mmol), Pd(OAc)2 (9 mg, 0.038 mmol), Xantphos (76 mg, 0.076 mmol), and cesium carbonate (436 mg, 1.34 mmol) were then added. After nitrogen substitution, the mixture was heated to 110°C and stirred overnight. The mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (n-hexane / ethyl acetate) to obtain 100 mg of a white solid in a 47.2% yield.

[0151] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-5)

[0152] Compound 5-2 (100 mg, 0.180 mmol) was dissolved in 4M hydrochloric acid / 1,4-dioxane (2 mL) at room temperature and reacted for 1 hour. The mixture was concentrated under reduced pressure and purified by reverse phase preparative method to obtain 30 mg of a white solid with a yield of 37.4% and a purity of >95%. [M+H] + :456.5.

[0153] 1 H NMR: (400MHz, DMSO-d6) δ7.36-7.31(m, 2H), 7.19-7.15(m, 2H), 7.10-7.06(m, 1H), 7.04 -7.00(m, 1H), 6.79-6.77(m, 1H), 6.69-6.67(m, 1H), 6.54-6.53(m, 1H), 6.23-6.22(m, 1H ), 4.00-3.96 (m, 2H), 3.68 (d, J=3.2Hz, 1H), 3.66 (d, J=3.6Hz, 1H), 3.63 (s, 2H), 3.38=3. 33 (m, 2H), 3.12 (d, J = 2.8Hz, 1H), 3.10 (d, J = 2.8Hz, 1H), 3.05 = 3.03 (m, 2H), 2.45 (s, 3H).

[0154] Example 6

[0155] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-6)

[0156]

[0157] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (6-2)

[0158] Compound Int 1 (150 mg, 0.29 mmol), 6-1 (90 mg, 0.43 mmol), Pd(dppf)Cl2 (21 mg, 0.03 mmol) and potassium carbonate (99 mg, 0.72 mmol) were dissolved in 1,4-dioxane / water (10 / 2 mL) and stirred at 110°C overnight under nitrogen. After the reaction was complete, ethyl acetate (20 mL) was added to dilute the mixture and the mixture was washed with saturated brine (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (PE / EA = 1:1) gave 130 mg of a yellow oily compound with a yield of 86.67%, [M+H] + :525.1.

[0159] Step 2: Synthesis of (5-(2-fluorophenyl)-1-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-6)

[0160] At room temperature, compound 6-2 (130 mg, 0.24 mmol) was dissolved in dichloromethane (3 mL) and 4 M hydrochloric acid / 1,4-dioxane (3 mL) was added and stirred for 2 h. After the reaction was complete, 51 mg of a white solid compound was obtained by filtration. The yield was 63.75%, the purity was >95%, and [M+H] + :460.1.

[0161] 1 H NMR: (400MHz, DMSO-d6) δ9.39 (s, 2H), 8.25 (s, 1H), 7.92-7.85 (m, 3H), 7.55-7.50 (m, 3H), 7.25-7.17 (m, 3H), 7.06 (t, J=6.0Hz, 1H), 6.56 (s, 1H), 3.97 (t, J=5.6Hz, 2H), 3.89 (s, 3H), 2.47 (t, J=5.2Hz, 3H).

[0162] Example 7

[0163] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-morpholinophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-7)

[0164]

[0165] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-morpholinophenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (7-1)

[0166] At room temperature, compound Int 1 (200 mg, 0.382 mmol) was dissolved in toluene (3 mL). Pd(OAc)2 (9 mg, 0.038 mmol), xantphos (45 mg, 0.076 mmol), cesium carbonate (374 mg, 1.15 mmol), and morpholine (50 mg, 0.573 mmol) were added. The mixture was sealed and heated to 110°C with stirring overnight. The mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (n-hexane / ethyl acetate) to obtain 80 mg of a yellow oil in a 39.6% yield.

[0167] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-morpholinophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-7)

[0168] Compound 7-1 (80 mg, 0.151 mmol) was dissolved in 4M hydrochloric acid / 1,4-dioxane (2 mL) at room temperature and allowed to react for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was adjusted to pH 9 with saturated sodium bicarbonate solution. The product was extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and then spin-dried. The crude product was slurried with DCM / MeOH to obtain 30 mg of a yellow solid with a yield of 42.9% and a purity of >95%. [M+H] + :430.1.

[0169] 1 H NMR: (400MHz, CDCl3) δ7.37-7.33(m, 2H), 7.23-7.16(m, 2H), 7.11-7.07(m, 1H), 7.04-6.98(m, 2H), 6.94-6. 92 (m, 1H), 6.81 (s, 1H), 6.24 (s, 1H), 3.81 (t, J = 4.8Hz, 4H), 3.64 (s, 2H), 3.05 (t, J = 4.8Hz, 4H), 2.45 (s, 3H)

[0170] Example 8

[0171] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-8)

[0172]

[0173] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (8-2)

[0174] To a 100 mL reaction flask were added compound Int 1 (150 mg, 0.287 mmol), compound 8-1 (36 mg, 0.345 mmol), Pd(OAc)2 (7 mg, 0.029 mmol), xantphos (33 mg, 0.057 mmol), Cs2CO3 (234 mg, 0.718 mmol), and toluene (5 mL). The mixture was stirred, the atmosphere purged with nitrogen three times, and the temperature was raised to 110°C and stirred for 12 h. TLC monitoring indicated the reaction was complete, with the formation of a new spot (PE / EA = 3:1, Rf = 0.3). 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined and washed once with saturated brine (30 mL). The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure at 45°C, and separated by column chromatography (PE / EA = 2:1) to afford 170 mg of a colorless oil.

[0175] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-8)

[0176] At room temperature, compound 8-2 (150 mg) and DCM (4 mL) were added to a reaction flask. The mixture was stirred until clear. 4 M hydrochloric acid / 1,4-dioxane (4 mL) was added and the reaction was allowed to proceed for 1 h at room temperature. TLC monitoring showed that the reaction was complete with the generation of a new spot (DC M / MeOH = 10:1, Rf = 0.2). The mixture was dried by spin drying and anhydrous ether was added. Solid precipitated, which was filtered and dried to obtain 60 mg of an off-white solid with a purity >95%. [M+H] + :442.2.

[0177] 1 H NMR: (400MHz, CD3OD) δ7.81 (s, 1H), 7.57-7.48 (m, 1H), 7.41 (t, J=8.0Hz, 1H), 7.33 (d, J=8.0Hz, 1H), 7.21 (t, J=7.6Hz, 1H), 7.16-7.09 (m, 2H), 7.06 (d, J=6.8Hz, 1H), 6.92 (s 1H), 6.42 (s, 1H), 4.12 (s, 2H), 3.79 (d, J = 14.0Hz, 2H), 3.65 (d, J = 11.6Hz, 2H), 3.27 (t, J=10.8Hz, 2H), 3.10 (t, J=10.8Hz, 2H), 3.00 (s, 3H), 2.73 (s, 3H).

[0178] Example 9

[0179] Synthesis of 1-(1-((3-(3,6-dihydro-2H-pyran-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-9)

[0180]

[0181] Step 1: Synthesis of tert-butyl ((1-((3-(3,6-dihydro-2H-pyran-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (9-2)

[0182] To a 100 mL reaction flask were added compound Int 1 (260 mg, 0.5 mmol), compound 9-1 (126 mg, 0.6 mmol), Pd(dppf)Cl2 (37 mg, 0.05 mmol), K2CO3 (174 mg, 1.25 mmol), and 1,4-dioxane / water (5 / 1 mL). The mixture was stirred, the atmosphere purged with nitrogen three times, and the temperature was raised to 100°C with stirring for 12 h. TLC monitoring indicated the reaction was complete, with the formation of a new spot (PE / EA = 3 / 1, Rf = 0.3). 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined and washed once with saturated brine (30 mL). The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure at 45°C, and separated by column chromatography (PE / EA = 2:1) to afford 200 mg of a yellow oil.

[0183] Step 2: Synthesis of 1-(1-((3-(3,6-dihydro-2H-pyran-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-9)

[0184] At room temperature, compound 9-2 (200 mg) and DCM (8 mL) were added to a reaction flask. The mixture was stirred to dissolve. 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and the mixture was allowed to react at room temperature for 1 h. TLC monitoring showed that the reaction was complete with the generation of a new spot (DCM / MeOH=10:1, Rf=0.2). Saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried. TLC separation gave 70 mg of a brown solid with a purity >95%, [M+H] + :426.5.

[0185] 1H NMR: (400MHz, CD3OD) δ7.72 (d, J=7.2, 1H), 7.57 (s, 1H), 7.50-7.41 (m, 3H), 7.36 (s, 1H), 7.16 (t, J=7.6Hz, 1H), 7 .13-7.05 (m, 2H), 6.32 (s, 1H), 6.19 (s, 1H), 4.32 (s, 2H), 3.93 (t, J=5.2Hz, 2H), 3.71 (s, 2H), 2.44-2.39 (m, 5H).

[0186] Example 10

[0187] Synthesis of 1-(5-(2-fluorophenyl)-1-((5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-10)

[0188]

[0189] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (10-1)

[0190] Compound Int 2 (200 mg, 0.38 mmol), 5-1 (95 mg, 0.58 mmol), Pd(OAc)2 (9 mg, 0.04 mmol), xantphos (22 mg, 0.04 mmol), and cesium carbonate (313 mg, 0.96 mmol) were dissolved in toluene (8 mL) and stirred at 100°C overnight under nitrogen. After the reaction was complete, ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (PE / EA = 1:1) gave 150 mg of a yellow oily compound in a yield of 43.73%.

[0191] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-10)

[0192] At room temperature, a solution of compound 10-1 (150 mg, 0.27 mmol) in dichloromethane (3 mL) was added with 4 M hydrochloric acid / 1,4-dioxane (3 mL). The mixture was stirred for two hours. After the reaction was complete, 20 mL of dichloromethane was added and the mixture was washed with water (10 mL x 3). The organic phase was filtered, the filtrate was dried over anhydrous sodium sulfate, and then concentrated. Purification by reverse phase preparative chromatography gave 20 mg of the yellow solid compound with a yield of 9.76% and a purity of >95%. [M+H] + :457.1.

[0193] 1 H NMR: (400MHz, CD3OD) δ8.11 (s, 1H), 7.87 (s, 1H), 7.52-7.46 (m, 2H), 7.21-7.09 (m, 3H), 6.79 (s, 1H), 6.34 (s, 1H), 3.9 9-3.95 (m, 2H), 3.73-3.71 (m, 2H), 3.66 (s, 2H), 3.48-3.44 (m, 2H), 3.24-3.20 (m, 2H), 3.20-3.11 (m, 2H), 2.39 (s, 3H).

[0194] Example 11

[0195] Synthesis of 1-(1-((3-(3,3-difluoroazetidin-1-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-11)

[0196]

[0197] Step 1: Synthesis of 1-(1-((3-(3,3-difluoroazetidin-1-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine (11-2)

[0198] At room temperature, compound Int 1 (0.3 g, 0.57 mmol), compound 11-1 (110 mg, 0.86 mmol), xantphos (29.00 mg, 0.05 mmol), Pd(OAc)2 (13.00 mg, 0.05 mmol), cesium carbonate (446 mg, 1.43 mmol), and toluene (12 mL) were added sequentially to a 250 mL single-necked flask. Under nitrogen protection, the mixture was reacted at 110°C overnight. After the reaction was complete, the mixture was filtered and the filter cake was washed with ethyl acetate (10 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 0.21 g of a brown oil with a yield of 84.0%, [M+H] + :436.1.

[0199] Step 2: Synthesis of 1-(1-((3-(3,3-difluoroazetidin-1-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-11)

[0200] Compound 11-2 (100 mg, 0.18 mmol), 4M hydrochloric acid / 1,4-dioxane (1 mL) and dichloromethane (3 mL) were added to a 25 mL single-necked bottle and stirred at room temperature for 2 h. After the reaction was complete, a solid precipitated and was filtered and collected to obtain 50 mg of a yellow solid compound with a yield of 48% (M+H). + :436.1.

[0201] 1 H NMR: (400MHz, CD3OD) δ8.20 (s, 1H), 8.07 (d, J=2.0Hz, 1H), 7.86 (d, J=1.6Hz, 1H), 7.59-7.56 (m, 1 H), 7.28-7.14(m, 4H), 6.98(s, 1H), 6.48(s, 1H), 4.43(t, J=1.6Hz4H), 4.37(s, 2H), 2.73(s, 3H).

[0202] Example 12

[0203] Synthesis of 1-(5-(2-fluorophenyl)-1-(isoindolin-5-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-12)

[0204]

[0205] Step 1: Synthesis of tert-butyl 5-(benzylthio)isoindoline-2-carboxylate (12-3)

[0206] To a 250 mL single-necked flask at room temperature, compound 12-1 (1.5 g, 5.03 mmol), 12-2 (1 mL, 6.04 mmol), xantphos (0.4 g, 1.7 mmol), Pd2(dba)3 (0.3 g, 0.5 mmol), DIEA (2.5 mL, 13.26 mmol), and toluene (30 mL) were added sequentially. Under nitrogen, the mixture was reacted at 135°C overnight. After completion, the mixture was filtered, and the filter cake was washed with ethyl acetate (50 mL x 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 1.3 g of the yellow viscous compound in a yield of 75.04%.

[0207] Step 2: Synthesis of tert-butyl 5-(chlorosulfonyl)isoindoline-2-carboxylate (12-4)

[0208] To a 100 mL single-necked flask at 0°C, compound 12-3 (1.3 g, 3.81 mmol), dichlorohydantoin (1.5 g, 7.6 mmol), acetic acid (0.8 mL), water (0.8 mL), and acetonitrile (13 mL) were added. The reaction was stirred at 0°C for 0.5 h. After the reaction was complete, the reaction solution was poured into ice water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 0.6 g of the compound as a yellow oil with a yield of 49.53%.

[0209] Step 3: Synthesis of tert-butyl 5-(((4-((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)isoindoline-2-carboxylate (12-5)

[0210] At room temperature, NaH (26.13 mg, 0.65 mmol, purity: 60%), compound Int 1-3 (115 mg, 0.33 mmol) and tetrahydrofuran (5 mL) were added to a 25 mL single-necked flask and stirred at room temperature for half an hour. Compound 12-4 (0.1 g, 0.32 mmol) was then added and stirred for 2 hours. After the reaction was completed, a saturated aqueous solution of ammonium chloride (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 2), and the combined organic phases were washed with saturated brine (10 mL × 1). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 0.1 g of the yellow solid compound was obtained by column chromatography (DCM / MeOH = 20:1) with a yield of 51.13%.

[0211] Step 4: Synthesis of 1-(5-(2-fluorophenyl)-1-(isoindolin-5-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-12)

[0212] Compound 12-5 (100 mg, 0.17 mmol) and 4 M hydrochloric acid / 1,4-dioxane (0.3 mL) were added to a 25 mL single-necked bottle. The mixture was stirred for 2 hours with dichloromethane (1 mL). A solid precipitated and was collected by filtration. The solid was concentrated under reduced pressure and dried to give 50 mg of a pale purple solid compound with a yield of 75% and a purity of >95%. [M+H] + :457.1.

[0213] 1H NMR: (400MHz, CDCl3) δ7.82 (s, 1H), 7.58-7.50 (m, 4H), 7.23-7.20 (m, 1H), 7.15-7.10 (m, 2H), 6.43 (s, 1H), 4.66 (s, 2H), 4.62 (s, 2H), 4.12 (s, 2H), 2.72 (s, 3H).

[0214] Example 13

[0215] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-fluoropyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-13)

[0216]

[0217] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(5-fluoropyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (13-2)

[0218] At room temperature, compound Int 1 (200 mg, 0.38 mmol), 13-1 (81 mg, 0.57 mmol), Pd(dppf)Cl2 (28 mg, 0.04 mmol), and potassium carbonate (133 mg, 0.96 mmol) were dissolved in dioxane / water (5 / 1 mL) and stirred at 100°C overnight under nitrogen. After cooling to room temperature, water (20 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 = 1:1) to afford 155 mg of the compound as a colorless oil with a yield of 75.56% and [M+H] + :540.2.

[0219] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-fluoropyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-13)

[0220] Compound 13-2 (155 mg, 0.28 mmol) was dissolved in DCM (2 mL) at room temperature, and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. Anhydrous ether (5 mL) was added to dilute the mixture, and a white solid precipitated. The solid was filtered and dried to obtain 13 mg of the target compound with a yield of 9.44% and a purity of >95%. [M+H] + :440.2.

[0221] 1H NMR: (400MHz, CD3OD) δ8.84 (s, 1H), 8.82 (s, 1H), 8.29 (d, J=9.2Hz, 1H), 8.10(d, J=8.0Hz, 1H), 7.88(s, 1H), 7.76(s, 1H), 7.74-7.66(m, 2H), 7.47-7.44(m, 1H), 7.16-7.14 (m, 2H), 7.06 (t, J=8.4Hz, 1H), 6.44 (s, 1H), 4.12 (s, 2H), 2.72 (s, 3H).

[0222] Example 14

[0223] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine trifluoroacetate (III-14)

[0224]

[0225] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (14-2)

[0226] At room temperature, compound Int 1 (200 mg, 0.38 mmol), 14-1 (71 mg, 0.57 mmol), Pd(dppf)Cl2 (28 mg, 0.04 mmol) and potassium carbonate (133 mg, 0.96 mmol) were dissolved in 1,4-dioxane / water (5 / 1 mL) and stirred at 100°C overnight under nitrogen. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with ethyl acetate (1.5 mL x 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 = 1:1) to obtain 150 mg of the compound as a colorless oil with a yield of 75.26% and [M+H] + :522.2.

[0227] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine trifluoroacetate (III-14)

[0228] Compound 14-2 (150 mg, 0.28 mmol) was dissolved in DCM (2 mL) at room temperature, and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. The mixture was diluted with water (5 mL) and adjusted to pH 8. The mixture was extracted with dichloromethane (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 reverse phase preparation (5-100% acetonitrile / water (0.1% TFA)) to give 60 mg of a white solid with a yield of 39.21% and a purity of >95%. [M+H] + :422.2.

[0229] 1 H NMR: (400MHz, CD3OD) δ8.93-8.89(m, 1H), 8.80-7.78(m, 1H), 8.47-8.37(m, 1H), 8.09-8.07(m, 1H), 7.94-7.89(m, 1H), 7.85(s , 1H), 7.78-7.65(m, 3H), 7.46-7.40(m, 1H), 7.16-7.13(m, 2H), 7.04(t, J=8.4Hz, 1H), 6.43(s, 1H), 4.12(s, 2H), 2.72(s, 3H).

[0230] Example 15

[0231] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(furan-2-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine trifluoroacetate (III-15)

[0232]

[0233] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3(furan-2-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (15-2)

[0234] At room temperature, compound Int 1 (200 mg, 0.38 mmol), 15-1 (65 mg, 0.573 mmol), Pd(dppf)2Cl 2· CH2Cl2 (32 mg, 0.038 mmol) and potassium carbonate (132 mg, 0.955 mmol) were dissolved in a solution of 1,4-dioxane and water (7.2 mL, 5 / 1). The mixture was reacted at 100°C under nitrogen for 2 hours. After the reaction was complete, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE / EA = 5:1) to give 150 mg of a white solid in a yield of 77.3%.

[0235] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(furan-2-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine trifluoroacetate (III-15)

[0236] At room temperature, compound 15-2 (150 mg, 0.294 mmol) was dissolved in 1,4-dioxane (3 mL), and 4 M hydrochloric acid / 1,4-dioxane (3 mL, 12.0 mmol) was added. The mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure, and water (10 mL) was added. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse column separation (5-100% acetonitrile / water (0.1% TFA)) to give 30 mg of a yellow oil with a yield of 19.5% and a purity of >95%. [M+H] + :411.3.

[0237] 1 HNMR: (400MHz, CDCl3) δ9.18 (s, 2H), 7.83-7.81 (m, 1H), 7.62 (d, J=1.6Hz, 1H), 7.56 (s, 1H), 7.48 (d, J=1.2Hz, 1H), 7.41-7.35 (m, 2H), 7.31-7.29 (m , 1H), 7.11-7.06 (m, 2H), 6.96 (t, J=8.8Hz, 1H), 6.62 (d, J=3.2Hz, 1H), 6.5 0-6.48 (m, 1H), 6.30 (d, J=2.0Hz, 1H), 4.00 (s, 2H), 2.61 (t, J=4.8Hz, 3H).

[0238] Example 16

[0239] Synthesis of 1-(5-(2-fluorophenyl)-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine trifluoroacetate (III-16)

[0240]

[0241] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)methyl))(methyl)carbamate (16-2)

[0242] At room temperature, compound Int 2 (500 mg, 0.95 mmol), 6-1 (209 mg, 1.43 mmol), Pd(dppf) Cl2 (70 mg, 0.09 mmol) and potassium carbonate (330 mg, 2.38 mmol) were dissolved in 1,4-dioxane / water (10 / 2 mL) and stirred at 100°C overnight under nitrogen. After cooling to room temperature, water (30 mL) was added and the mixture was extracted with ethyl acetate (30 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 (DCM / MeOH = 20:1) to obtain 480 mg of a colorless oily compound with a yield of 95.78%, [M+H] + :526.2.

[0243] Step 2: 1-(5-(2-Fluorophenyl)-1-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine trifluoroacetate (III-16)

[0244] At room temperature, compound 16-2 (450 mg, 0.86 mmol) was dissolved in DCM (4 mL), and then 4 M hydrochloric acid / 1,4-dioxane (4 mL) was added and stirred at room temperature for 2 h. Water (10 mL) was added to dilute the mixture and adjust the pH to 8. The mixture was extracted with dichloromethane (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 reverse phase preparative (TFA / H2O / MeCN) to give 380 mg of a white solid with a yield of 82.61% and a purity of >95%. [M+H] + :426. 2.

[0245] 1 H NMR: (400MHz, CD3OD) δ9.03 (s, 1H), 8.41 (s, 1H), 8.14 (s, 1H), 7.88-7.83 (m, 3H), 7.52-7.49 (m, 1 H), 7.23-7.15 (m, 2H), 7.08 (t, J=8.8Hz, 1H), 6.45 (s, 1H), 4.12 (s, 2H), 3.98 (s, 3H), 2.72 (s, 3H).

[0246] Example 17

[0247] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(thiophen-2-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-17)

[0248]

[0249] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(thiophen-2-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (17-2)

[0250] At room temperature, compound Int 1 (100 mg, 191.05 μmol), compound 17-1 (36.67 mg, 386.58 μmol), Pd(dppf)2Cl2 (0.1 g, 86.58 μmol) and potassium carbonate (66.01 mg, 477.63 μmol) were dissolved in 1,4-dioxane / water (5 / 1 mL) and reacted at 80°C overnight under nitrogen protection. After the reaction was complete, water (8 mL) was added and the mixture was extracted with ethyl acetate (10 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 80 mg of a yellow viscous solid with a yield of 79.51%. [M+H] + :527.1.

[0251] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(thiophen-2-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-17)

[0252] At room temperature, compound 17-2 (80 mg, 151.91 μmol), 4M hydrochloric acid / 1,4-dioxane (1 mL, 4N), and dichloromethane (2 mL) were added to a 10 mL single-necked vial. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Dichloromethane (1 mL) was added to dissolve the mixture, and ether (2 mL) was added with stirring. The mixture was stirred at room temperature for 0.5 hours. A purple solid precipitated. The solid was collected by filtration and dried under reduced pressure to obtain 40 mg of a purple solid with a yield of 57.12% and a purity of >95%. [M+H] + :427.5.

[0253] 1 H NMR: (400MHz, CD3OD) δ7.99-7.97 (m, 1H), 7.82 (d, J=2.0Hz, 1H), 7.68-7.67 (m, 1 H), 7.59-7.56(m, 2H), 7.54-7.52(m, 1H), 7.47-7.42(m, 2H), 7.37-7.35(m, 1H), 7.14-7.03(m,3H),6.40(s,1H),4.11(s,2H),2.70(s,3H)

[0254] Example 18

[0255] Synthesis of 1-(1-((3-(3,5-dimethylisoxazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-18)

[0256]

[0257] Step 1: Synthesis of tert-butyl ((1-((3-(3,5-dimethylisoxazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (18-2)

[0258] At room temperature, compound Int 1 (200 mg, 0.38 mmol), 18-1 (128 mg, 0.57 mmol), Pd(dppf)Cl2 (28 mg, 0.04 mmol), and potassium carbonate (132 mg, 0.95 mmol) were dissolved in 1,4-dioxane / water (5 / 1 mL) and stirred at 100°C overnight under nitrogen. After cooling to room temperature, 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 150 mg of the compound as a colorless oil with a yield of 72.82% and [M+H] + :540.2.

[0259] Step 2: 1-(1-((3-(3,5-dimethylisoxazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-18)

[0260] Compound 18-2 (150 mg, 0.28 mmol) was dissolved in DCM (2 mL) at room temperature, and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. Filtration afforded 80 mg of a brown solid with a yield of 60.61% and a purity of >95%. [M+H] + :440.2.

[0261] 1H NMR: (400MHz, CD3OD) δ7.84 (s, 1H), 7.71-7.68 (m, 1H), 7.61 (t, J=7.6Hz, 1H), 7.52-7.49(m, 1H), 7.45-7.42(m, 1H), 7.32(s, 1H), 7.16-7.14(m, 2H), 7.01(t, J=8.8 Hz, 1H), 6.44 (m, 1H), 4.12 (s, 2H), 2.74 (s, 3H), 2.37 (s, 3H), 2.20 (s, 3H).

[0262] Example 19

[0263] Synthesis of 1-(1-((3-(3-oxa-9-azaspiro[5.5]undec-9-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-19)

[0264]

[0265] Step 1: Synthesis of methyl tert-butyl((1-((3-(3-oxa-9-azaspiro[5.5]undec-9-yl)phenyl)sulfonyl)-5-(2-fluoro-phenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (19-2)

[0266] At room temperature, compound Int 1 (200 mg, 0.382 mmol), 19-1 (110 mg, 0.573 mmol), Pd(OAc)2 (9 mg, 0.038 mmol), xantphos (45 mg, 0.076 mmol) and cesium carbonate (374 mg, 1.15 mmol) were added to toluene (4 mL) and reacted at 100 ° C for 2 hours under nitrogen protection. After the reaction was complete, the mixture was filtered and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA=5:1) to give 170 mg of a white solid with a yield of 74.4%. [M+H] + :598.9.

[0267] Step 2: Synthesis of 1-(1-((3-(3-oxa-9-azaspiro[5.5]undec-9-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-19)

[0268] Compound 19-2 (170 mg, 0.284 mmol) was dissolved in 1,4-dioxane (3 mL) at room temperature, and 4M hydrochloric acid / 1,4-dioxane (3 mL) was added. The mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure, dissolved in dichloromethane, and concentrated under reduced pressure to obtain 50 mg of a gray solid with a yield of 32.9% and a purity of >95%. [M+H] + :498.9.

[0269] 1 H NMR: (400MHz, CDCl3) δ10.11(s, 2H), 8.24(s, 1H), 7.82(s, 1H), 7.70(s, 1H), 7.50(s, 1H), 7.35(br s, 2H), 7.04-6.98 (m, 3H), 6.72 (s, 1H), 3.97 (s, 2H), 3.70 (br s, 12H), 2.74 (s, 3H), 2.17 (br s, 4H).

[0270] Example 20

[0271] Synthesis of 1-(1-((5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine 2,2,2-trifluoroacetate (III-20)

[0272]

[0273] Step 1: Synthesis of tert-butyl ((1-((5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl))methyl)(methyl)carbamate (20-2)

[0274] At room temperature, compound Int 2 (200 mg, 0.38 mmol), 20-1 (140 mg, 0.57 mmol), Pd(dppf)Cl2 (28 mg, 0.04 mmol) and potassium carbonate (132 mg, 0.95 mmol) were dissolved in 1,4-dioxane / water (5 / 1 mL) and stirred at 110°C for 4 h under nitrogen. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with ethyl acetate (15 mL × 3). 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 180 mg of a colorless oily compound with a yield of 80.04% and [M+H] + :562.2.

[0275] Step 2: Synthesis of 1-(1-((5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine 2,2,2-trifluoroacetate (III-20)

[0276] Compound 20-2 (180 mg, 0.39 mmol) was dissolved in DCM (2 mL) at room temperature, and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and purified by reverse phase preparative purification (mobile phase containing trifluoroacetic acid) to give 80 mg of a white solid with a yield of 43.48% and a purity of >95%. [M+H] + :462.1.

[0277] 1 H NMR: (400MHz, CDCl3) δ9.46 (s, 2H), 8.95 (s, 1H), 8.52 (s, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.76 (s, 1H), 7.70 (s, 1H), 7. 46-7.41 (m, 1H), 7.28-7.26 (m, 1H), 7.17-7.11 (m, 2H), 7.00 (t, J=9.2Hz, 1H), 6.38 (s, 1H), 4.03 (s, 2H), 2.67 (s, 3H).

[0278] Example 21

[0279] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-21)

[0280]

[0281] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (21-2)

[0282] At room temperature, compound Int 1 (200 mg, 0.38 mmol), 21-1 (70 mg, 0.46 mmol), Pd(dppf) Cl2 (28 mg, 0.04 mmol) and potassium carbonate (132 mg, 0.95 mmol) were dissolved in 1,4-dioxane / water (5 / 1 mL) and stirred at 110°C for 4 h under nitrogen. After cooling to room temperature, water (20 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 150 mg of a colorless oily compound with a yield of 71.43% and [M+H] + :552.2.

[0283] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-21)

[0284] At room temperature, compound 21-2 (150 mg, 0.27 mmol) was dissolved in DCM (2 mL), and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to obtain 100 mg of a white solid with a yield of 75.76% and a purity of >95%. [M+H] + :452.1.

[0285] 1 H NMR: (400MHz, CD3OD) δ8.70 (s, 2H), 8.31 (s, 1H), 8.15 (d, J=7.6Hz, 1H), 7.90(s, 1H), 7.83(s, 1H), 7.77-7.69(m, 2H), 7.48-7.45(s, 1H) 7.17-7.15(m, 2H), 7.07(t, J=9.2Hz, 1H), 6.45 (s, 1H), 4.16 (s, 3H), 4.13 (s, 2H), 2.73 (s, 3H).

[0286] Example 22

[0287] Synthesis of 1-(5-(2,4-difluorophenyl)-1-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride salt (III-22)

[0288]

[0289] Step 1: Synthesis of tert-butyl ((5-(2,4-difluorophenyl)-1-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (22-1)

[0290] At room temperature, compound Int 3 (200 mg, 0.37 mmol), 6-1 (100 mg, 0.48 mmol), Pd(dppf)Cl2 (27 mg, 0.04 mmol) and potassium carbonate (128 mg, 0.92 mmol) were dissolved in 1,4-dioxane / water (5 / 1 mL) and stirred at 110°C for 4 h under nitrogen protection. After cooling to room temperature, water (20 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 150 mg of a colorless oily compound with a yield of 74.83% and [M+H] + :543.2.

[0291] Step 2: Synthesis of 1-(5-(2,4-difluorophenyl)-1-((3-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-22)

[0292] At room temperature, compound 22-1 (150 mg, 0.27 mmol) was dissolved in DCM (2 mL), and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. A white solid precipitated and was filtered to obtain the target compound 56 mg with a yield of 45.78% and a purity of >95%. [M+H] + :443.2.

[0293] 1 H NMR: (400MHz, DMSO-d6) δ9.24 (br, 2H), 8.26 (s, 1H), 7.92 (d, J=8.0Hz, 1H), 7.88 (s, 2H), 7.56-7.52 (m, 2H), 7.30-7.25 (m, 2H), 7.13-7.08 (m, 2H), 6.55 (s, 1H), 3.98 (s, 2H), 3.88 (s, 3H), 2.48 (s, 3H).

[0294] Example 23

[0295] Synthesis of 1-(5-(2,4-difluorophenyl)-1-((3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine trifluoroacetate (III-23)

[0296]

[0297] Step 1: Synthesis of tert-butyl ((5-(2,4-difluorophenyl)-1-((3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (23-1)

[0298] At room temperature, compound Int 3 (200 mg, 0.369 mmol) was dissolved in toluene (4 mL), and 5-1 (83 mg, 0.554 mmol), Pd(OAc)2 (9 mg, 0.037 mmol), xantphos (43 mg, 0.074 mmol), and cesium carbonate (361 mg, 1.11 mmol) were added sequentially. 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 product was purified by column chromatography (PE / EA = 5:1-3:1) to obtain 100 mg of a yellow oil with a yield of 47.19%. [M+H] + :574.7.

[0299] Step 2: Synthesis of 1-(5-(2,4-difluorophenyl)-1-((3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine trifluoroacetate (III-23)

[0300] At room temperature, compound 23-1 (100 mg, 0.262 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 separated and purified by reverse phase column to obtain 30 mg of colorless oil with a yield of 29.31% and a purity of >95%. [M+H] + :474.5.

[0301] 1 H NMR: (400MHz, DMSO-d6) δ8.78(s, 2H), 7.74(s, 1H), 7.36-7.28(m, 2H), 7.17-7.09(m, 2H), 6.90-6.87(m, 1H), 6.75-6.73(m, 1H), 6.44-6.43(m, 2H), 4.01-3.98(m, 2H), 3.86-3.82(m, 2H), 3.58-3.55(m, 2H), 3.34-3.30(m, 2H), 3.10-2.98(m, 4H), 2.54-2.53(m, 3H).

[0302] Example 24

[0303] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(furan-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-24)

[0304]

[0305] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(furan-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (24-2)

[0306] At room temperature, compound Int 1 (200 mg, 0.38 mmol), 24-1 (64 mg, 0.57 mmol), Pd(dppf)Cl2 (28 mg, 0.04 mmol) and potassium carbonate (132 mg, 0.96 mmol) were dissolved in 1,4-dioxane / water (5 / 1 mL) and stirred at 110°C for 4 h under nitrogen. After cooling to room temperature, water (20 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 150 mg of the compound as a colorless oil with a yield of 76.89% and [M+H] + :511.2.

[0307] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(furan-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-24)

[0308] Compound 24-2 (150 mg, 0.29 mmol) was dissolved in DCM (2 mL) at room temperature, and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. A white solid precipitated and was filtered to obtain the target compound 58 mg with a yield of 44.27% and a purity of >95%. [M+H] + :412.2.

[0309] 1H NMR: (400MHz, DMSO-d6) δ9.15 (br, 2H), 8.28 (s, 1H), 7.98 (d, J=7.6Hz, 1H), 7.87 (s, 1H), 7.81 (s, 1H), 7.60-7.56 (m, 2H), 7.5 2-7.50 (m, 1H), 7.33 (d, J=8.4Hz, 1H), 7.24-7.18 (m, 2H), 7.07 (t, J=6.0Hz, 1H), 6.93 (s, 1H), 6.53 (s, 1H), 3.99 (s, 2H), 2.49 (s, 3H).

[0310] Example 25

[0311] Synthesis of 1-(5-(2,4-difluorophenyl)-1-((3-(furan-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-25)

[0312]

[0313] Step 1: Synthesis of tert-butyl ((5-(2,4-difluorophenyl)-1-((3-(furan-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (25-1)

[0314] At room temperature, compound Int 3 (200 mg, 0.37 mmol), 24-1 (62 mg, 0.56 mmol), Pd(dppf)Cl2 (27 mg, 0.04 mmol), and potassium carbonate (128 mg, 0.92 mmol) were dissolved in 1,4-dioxane / water (5 / 1 mL) and stirred at 110°C for 4 h under nitrogen. After cooling to room temperature, water (20 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 150 mg of the compound as a colorless oil with a yield of 76.82% and [M+H] + :529.1.

[0315] Step 2: Synthesis of 1-(5-(2,4-difluorophenyl)-1-((3-(furan-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-25)

[0316] At room temperature, compound 25-1 (150 mg, 0.28 mmol) was dissolved in DCM (2 mL), and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. A white solid precipitated and was filtered to obtain the target compound 1 (8 mg) with a yield of 13.64% and a purity of >95 [M+H] + :429.1.

[0317] 1 H NMR: (400MHz, DMSO-d6) δ9.10 (br, 2H), 8.31 (s, 1H), 7.99 (d, J=8.0Hz, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.62-7.58 (m, 2H ), 7.33 (d, J=8.0Hz, 1H), 7.07 (t, J=6.0Hz, 1H), 7.12-7.09 (m, 2H), 6.95 (s, 1H), 6.53 (s, 1H), 3.99 (s, 2H), 2.49 (s, 3H).

[0318] Example 26

[0319] Synthesis of 1-(5-(2,4-difluorophenyl)-1-((3-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine trifluoroacetate (III-26)

[0320]

[0321] Step 1: Synthesis of tert-butyl ((5-(2,4-difluorophenyl)-1-((3-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (26-1)

[0322] At room temperature, compound Int 3 (200 mg, 0.37 mmol), 21-1 (68 mg, 0.44 mmol), Pd(dppf)Cl2 (27 mg, 0.04 mmol) and potassium carbonate (128 mg, 0.92 mmol) were dissolved in 1,4-dioxane / water (5 / 1 mL) and stirred at 110°C for 4 h under nitrogen. After cooling to room temperature, water (20 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 120 mg of a colorless oily compound with a yield of 57.03% and [M+H] + :570.2.

[0323] Step 2: Synthesis of 1-(5-(2,4-difluorophenyl)-1-((3-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine trifluoroacetate (III-26)

[0324] Compound 26-1 (150 mg, 0.28 mmol) was dissolved in DCM (2 mL) at room temperature, and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. The mixture was concentrated and purified by reverse phase preparative method to give 26 mg of a white solid with a yield of 21.31% and a purity of >95%. [M+H] + :470.1.

[0325] 1 HNMR: (400MHz, CD3OD) δ8.64 (br, 2H), 8.19-8.12 (m, 2H), 7.89 (s, 1H), 7.82-7.80 (m, 1H), 7.75 (t, J=8.0Hz, 1H), 7.69(d, J=7.6Hz, 1H), 7.20-7.17(m, 1H), 6.98-6.93(m, 2H), 6.46(s, 1H), 4.12(s, 3H), 4.11(s, 2H), 2.73(s, 3H).

[0326] Example 27

[0327] Synthesis of 1-(1-((3-(2,3-dihydrobenzofuran-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-27)

[0328]

[0329] Step 1: Synthesis of tert-butyl ((1-((3-(2,3-dihydrobenzofuran-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (27-2)

[0330] At room temperature, compound Int 1 (200 mg, 0.38 mmol), 27-1 (75 mg, 0.46 mmol), Pd(dppf)Cl2 (27 mg, 0.04 mmol) and potassium carbonate (132 mg, 0.95 mmol) were dissolved in 1,4-dioxane / water (5 / 1 mL) and stirred at 110°C for 4 h under nitrogen. After cooling to room temperature, water (20 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 150 mg of a yellow oily compound with a yield of 69.77% and [M+H] + :563.2.

[0331] Step 2: Synthesis of 1-(1-((3-(2,3-dihydrobenzofuran-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-27)

[0332] At room temperature, compound 27-2 (150 mg, 0.27 mmol) was dissolved in DCM (2 mL) solution, and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. Concentration gave 100 mg of a brown compound with a yield of 80.05% and a purity of >95%. [M+H] + :463.2.

[0333] 1 HNMR: (400MHz, CD3OD) δ7.86 (d, J=8.0Hz, 1H), 7.82 (s, 1H), 7.54-7.43 (m, 4H), 7.37 (s, 1H), 7.25 (d, J=8.0Hz, 1H), 7.13-7.04 (m, 3H), 6.83 (d, J=8.0Hz, 1H), 6.41 (s, 1H), 4.63 (t, J=8.8Hz, 2H), 4.11 (s, 2H), 3.29 (t, J=8.8Hz, 2H), 2.71 (s, 3H).

[0334] Example 28

[0335] Synthesis of 1-(1-((3-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-28)

[0336]

[0337] Step 1: Synthesis of tert-butyl ((1-((3-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (28-2)

[0338] At room temperature, compound Int 1 (200 mg, 0.38 mmol), 28-1 (112 mg, 0.46 mmol), Pd(dppf)Cl2 (28 mg, 0.04 mmol) and potassium carbonate (132 mg, 0.95 mmol) were dissolved in 1,4-dioxane / water (5 / 1 mL) and stirred at 110°C for 4 h under nitrogen. After cooling to room temperature, water (20 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 150 mg of the compound as a colorless oil with a yield of 70.031% and [M+H] + :561.2.

[0339] Step 2: Synthesis of 1-(1-((3-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-28)

[0340] At room temperature, compound 28-2 (150 mg, 0.27 mmol) was dissolved in DCM (2 mL) solution, and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. Concentration gave 100 mg of a white compound with a yield of 75.19% and a purity of >95%. [M+H] + :461.2.

[0341] 1 HNMR: (400MHz, CD3OD) δ8.47 (s, 1H), 8.03 (s, 1H), 7.96 (d, J=8.0Hz, 1H), 7.83 (s, 1H), 7.57 (t, J=82.8Hz, 1H), 7.57-7.42 (m, 4H), 7.16-7.06 (m, 3H), 6.41 (s, 1H), 4.11 (s, 2H), 2.71 (s, 3H).

[0342] Example 29

[0343] Synthesis of 1-(1-((3-(Benzofuran-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-29)

[0344]

[0345] Step 1: Synthesis of tert-butyl ((1-((3-(benzofuran-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (29-2)

[0346] At room temperature, compound Int 1 (200 mg, 0.38 mmol), 29-1 (75 mg, 0.46 mmol), Pd(dppf)Cl2 (27 mg, 0.04 mmol) and potassium carbonate (132 mg, 0.95 mmol) were dissolved in 1,4-dioxane / water (5 / 1 mL) and stirred at 110°C for 4 h under nitrogen. After cooling to room temperature, water (20 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 150 mg of a yellow oily compound with a yield of 69.77% and [M+H] + :561.1.

[0347] Step 2: Synthesis of 1-(1-((3-(Benzofuran-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-29)

[0348] At room temperature, compound 29-2 (150 mg, 0.27 mmol) was dissolved in DCM (2 mL) solution, and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. Concentration gave 100 mg of a yellow compound with a yield of 80.05% and a purity of >95%. [M+H] + :461.1.

[0349] 1 H NMR: (400MHz, CD3OD) δ7.97 (d, J=8.0Hz, 1H), 7.86-7.83 (m, 2H), 7.77 (s, 1H), 7.64-7.57(m, 3H), 7.50(d, J=8.0Hz, 1H), 7.46-7.39(m, 2H), 7.13-7.11(m, 2H), 7.03 (t, J=8.4Hz, 1H), 6.96 (s, 1H), 6.41 (s, 1H), 4.11 (s, 2H), 2.70 (s, 3H).

[0350] Example 30

[0351] Synthesis of 1-(5-(1H-indol-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-30)

[0352]

[0353] Step 1: Synthesis of 5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (30-3)

[0354] Compound 30-1 (500 mg, 2.87 mmol) was dissolved in DMF (10 mL) at 0°C, and NaH (230 mg, 5.75 mmol) was slowly added. After stirring for 10 minutes, 30-2 (766 mg, 4.31 mmol) was added. The reaction solution was warmed to room temperature and the reaction was continued for 1 hour. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (10 mL), then extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 5:1) to obtain 500 mg of a yellow solid with a yield of 55.40%. [M+H] + :316.1.

[0355] Step 2: Synthesis of 5-(1H-indol-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (30-5)

[0356] At room temperature, compound 30-3 (400 mg, 1.27 mmol), 30-4 (308 mg, 1.91 mmol), Pd(PPh3)4 (147 mg, 0.127 mmol), K2CO3 (528 mg, 3.82 mmol), DME (15 mL), and water (1.5 mL) were added sequentially to a single-necked flask and stirred at 80°C for 3 h. After the reaction was complete, the solvent was concentrated and the product was purified by column chromatography (PE / EA = 8:1 to 1:1) to obtain 300 mg of a yellow solid with a yield of 66.93% ([M+H] + :352.1.

[0357] Step 3: Synthesis of 1-(5-(1H-indol-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-30)

[0358] Compound 30-5 (300 mg, 0.854 mmol) was dissolved in methanol (3 mL) at room temperature, and methylamine methanol solution (0.5 mL) was added. After stirring at 30°C for 2 hours, NaBH4 (265 mg, 1.71 mmol) was added and the reaction continued for 1 hour. The mixture was concentrated under reduced pressure and purified by reverse phase column separation (0-100% ACN / H2O) to obtain 100 mg of a yellow solid with a yield of 31.76% and a purity of >95%. [M+H] + :365.2.

[0359] 1 H NMR: (400MHz, DMSO-d6) δ11.30 (s, 1H), 8.81 (d, J=4.4Hz, 1H), 8.72 (s, 2H), 7.72-7.70 (m, 2H), 7.53-7.50 (m, 1H), 7.42 (s, 1H), 7.35-7.33 (m, 1H), 7.28 (s, 1H), 6.82-6.80 (m, 1H), 6.43(s, 1H), 6.34(s, 1H), 4.01(s, 2H), 2.55(m, 3H).

[0360] Example 31

[0361] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-(2-methoxyethoxy)pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-31)

[0362]

[0363] Step 1: Synthesis of 3-bromo-5-(2-methoxyethoxy)pyridine (31-3)

[0364] Compound 31-1 (2.0 g, 11.49 mmol), 31-2 (1.6 mL, 17.24 mmol), and K2CO3 (3.9 g, 28.74 mmol) were dissolved in DMF (20 mL) at room temperature and stirred at 40°C overnight. After the reaction, water (40 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA = 5:1) to obtain 2.2 g of the white solid compound with a yield of 82.47% and [M+H] + : 232.0.

[0365] Step 2: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(5-(2-methoxyethoxy)pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (31-5)

[0366] At room temperature, compound 31-3 (200 mg, 0.86 mmol), 31-4 (263 mg, 1.03 mmol), Pd(dppf)Cl2DCM (71 mg, 0.09 mmol) and potassium acetate (169 mg, 1.72 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at 110°C for 2 h under nitrogen protection. After cooling to room temperature, compound Int 1 (200 mg, 0.38 mmol), Pd(dppf)Cl2 (28 mg, 0.04 mmol), potassium carbonate (133 mg, 0.95 mmol) and water (4 mL) were added to the reaction system, and stirred at 110°C for 2 h under nitrogen protection. After the reaction was completed, water (20 mL) was added and the mixture was extracted with ethyl acetate (15 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA = 3:1) to obtain 150 mg of a yellow oily compound with a yield of 65.90%. [M+H] + :596.2.

[0367] Step 3: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-(2-methoxyethoxy)pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-31)

[0368] At room temperature, compound 31-5 (150 mg, 0.25 mmol) was dissolved in DCM (2 mL), and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. Concentration gave 100 mg of a white compound with a yield of 75.19% and a purity of >95%. [M+H] + :461.1.

[0369] 1H NMR: (400MHz, CD3OD) δ8.71(s, 2H), 8.36(s, 1H), 8.14(s, 1H), 7.90(s, 1H), 7.82-7.69(m, 3H), 7.47-7.45(m, 1H), 7.17-7.15(m , 2H), 7.07 (t, J=9.2Hz, 1H), 6.47 (s, 1H), 4.52 (t, J=4.4Hz, 2H), 4.13 (s, 2H), 3.88 (t, J=4.4Hz, 2H), 3.44 (s, 3H), 2.73 (s, 3H).

[0370] Example 32

[0371] Synthesis of 1-(1-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-32)

[0372]

[0373] Step 1: Synthesis of tert-butyl ((1-((3-(1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (32-2)

[0374] At room temperature, compound Int 1 (500 mg, 0.96 mmol), 32-1 (214 mg, 1.91 mmol), Pd(dppf)Cl2 (70 mg, 0.10 mmol) and potassium carbonate (330 mg, 2.39 mmol) were dissolved in 1,4-dioxane / water (10 / 2 mL) and stirred at 110°C overnight under nitrogen. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with ethyl acetate (1.5 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 = 1:1) to obtain 150 mg of the white solid compound with a yield of 30.80%, [M+H] + :511.2.

[0375] Step 2: Synthesis of tert-butyl ((1-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (32-4)

[0376] At room temperature, compound 32-2 (150 mg, 0.29 mmol), 32-3 (76 mg, 0.88 mmol), Cu(OAc)2 (64 mg, 0.35 mmol), DMAP (72 mg, 0.59 mmol) and pyridine (24 mg, 0.29 mmol) were dissolved in 1,4-dioxane (8 mL) and stirred at 100°C for two days. After the reaction was completed, the mixture was cooled to room temperature, water (20 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 60 mg of the yellow oily compound with a yield of 37.09%, [M+H] + :551.2

[0377] Step 3: Synthesis of 1-(1-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-32)

[0378] At room temperature, compound 32-4 (60 mg, 0.11 mmol) was dissolved in DCM (2 mL), and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. Concentration gave 32 mg of a white solid compound with a yield of 60.38% and a purity of >95%. [M+H] + :451.1.

[0379] 1 H NMR: (400MHz, DMSO-d6) δ9.24 (br, 2H), 8.36 (s, 1H), 7.93 (d, J=8.0Hz, 1H), 7.87-7.85 (m, 2H), 7.59 (s, 1H), 7.55-7.51 (m, 2 H), 7.24-7.18 (m, 3H), 7.07 (t, J=7.6Hz, 1H), 6.53 (s, 1H), 3.98 (s, 2H), 3.78-3.75 (m, 1H), 2.48 (s, 3H), 1.11-1.00 (m, 4H).

[0380] Example 33

[0381] Synthesis of 1-(5-(2-fluorophenyl)-1-((3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-33)

[0382]

[0383] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (33-2)

[0384] At room temperature, compound Int 1 (200 mg, 0.38 mmol), 33-1 (95 mg, 0.46 mmol), Pd(dppf)Cl2 (28 mg, 0.04 mmol) and potassium carbonate (132 mg, 0.95 mmol) were dissolved in 1,4-dioxane / water (5 / 1 mL) and stirred at 110°C for 4 h under nitrogen. After cooling to room temperature, water (20 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 = 5:1) to obtain 100 mg of the yellow oily compound with a yield of 43.48% and [M+H] + :605.2.

[0385] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-33)

[0386] At room temperature, compound 33-2 (100 mg, 0.17 mmol) was dissolved in DCM (2 mL), and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. Concentration gave 51 mg of a brown solid compound with a yield of 57.30% and a purity of >95%. [M+H] + :505.1.

[0387] 1 H NMR: (400MHz, DMSO-d6) δ9.06 (br, 2H), 8.10 (d, J=8.0Hz, 1H), 7.87 (s, 1H), 7.72-7.63 (m, 3H), 7 .59-7.56(m, 3H), 7.49-7.44(m, 2H), 7.20-7.10(m, 3H), 6.54(s, 1H), 3.99(s, 2H), 2.49(s, 3H).

[0388] Example 34

[0389] Synthesis of 1-(1-((3-(1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-34)

[0390]

[0391] At room temperature, compound 32-2 (150 mg, 0.27 mmol) was dissolved in DCM (2 mL), and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. Concentration gave 123 mg of a white solid compound with a yield of 94.62% and a purity of >95%. [M+H] + :411.1.

[0392] 1 H NMR: (400MHz, CD3OD) δ8.17 (s, 2H), 7.93 (d, J=6.4Hz, 1H), 7.83 (s, 1H), 7.58 (s, 1H), 7.55 (t, J=8.0Hz, 1H), 7.48-7.40 (m, 2H), 7.16-7.04 (m, 3H), 6.41 (s, 1H), 4.12 (s, 2H), 2.71 (s, 3H).

[0393] Example 35

[0394] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-35)

[0395]

[0396] Step 1: Synthesis of 3-bromo-5-(2,2,2-trifluoroethoxy)pyridine (35-2)

[0397] Compound 31-1 (1.0 g, 5.75 mmol), 35-1 (2.0 g, 8.62 mmol), and K2CO3 (2.0 g, 14.37 mmol) were dissolved in DMF (10 mL) at room temperature and stirred overnight. After the reaction, water (30 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 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 afford 1.1 g of the compound as a yellow oil with a yield of 74.83%. [M+H] + :256.1.

[0398] Step 2: Synthesis of methyl tert-butyl ((5-(2-fluorophenyl)-1-((3-(5-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (35-3)

[0399] Compound 35-2 (200 mg, 0.78 mmol), 31-4 (258 mg, 1.02 mmol), Pd(dppf)Cl 2· DCM (64 mg, 0.08 mmol) and potassium acetate (154 mg, 1.56 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at 110°C for 2 h under nitrogen. After cooling to room temperature, compound Int 1 (200 mg, 0.38 mmol), Pd(dppf)Cl2 (28 mg, 0.04 mmol), potassium carbonate (133 mg, 0.95 mmol), and water (2 mL) were added to the reaction system and stirred at 110°C for 2 h under nitrogen. After completion of the reaction, water (20 mL) was added and the mixture was extracted with ethyl acetate (15 mL x 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 130 mg of the yellow oily compound with a yield of 54.85% and [M+H] + :620.2.

[0400] Step 3: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-35)

[0401] At room temperature, compound 35-3 (130 mg, 0.21 mmol) was dissolved in DCM (2 mL), and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. Concentration gave 73 mg of a yellow compound with a yield of 62.93% (M+H). + :520.1.

[0402] 1 H NMR: (400MHz, DMSO-d6) δ9.37 (br, 2H), 8.61 (s, 1H), 8.59 (s, 1H), 8.18 (d, J=7.6Hz, 1H), 7.99(s, 1H), 7.93(s, 1H), 7.80(s, 1H), 7.74(t, J=8.0Hz, 1H), 7.55(d, J=8.0Hz, 1H), 7.48-7.46 (m, 1H), 7.22-7.15 (m, 2H), 7.09 (t, J=7.6Hz, 1H), 6.58 (s, 1H), 5.08 (q, J=8.8Hz, 2H), 3.98 (s, 2H), 2.47 (s, 3H).

[0403] Example 36

[0404] Synthesis of 1-(1-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-36)

[0405]

[0406] Step 1: Synthesis of tert-butyl ((1-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (36-1)

[0407] At room temperature, compound Int 4 (200 mg, 0.37 mmol), 6-1 (93 mg, 0.44 mmol), Pd(dppf)Cl2 (27 mg, 0.04 mmol), and potassium carbonate (130 mg, 0.95 mmol) were dissolved in 1,4-dioxane / water (5 / 1 mL) and stirred at 110°C for 4 h under nitrogen. After cooling to room temperature, water (20 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 150 mg of the yellow oily compound with a yield of 74.89% and [M+H] + :543.2.

[0408] Step 2: Synthesis of 1-(1-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-36)

[0409] At room temperature, compound 36-1 (150 mg, 0.27 mmol) was dissolved in DCM (2 mL), and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. Concentration gave 80 mg of a yellow compound with a yield of 60.61% and a purity of >95%. [M+H] + :443.1.

[0410] 1 H NMR: (400MHz, CD3OD) δ8.15 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.69 (d, J=9.6Hz, 1 H), 7.51-7.48(m, 1H), 7.39(s, 1H), 7.20-7.06(m, 4H), 6.47(s, 1H), 4.14(s, 2H), 4.00(s, 3H), 2.73(s, 3H).

[0411] Example 37

[0412] Synthesis of 1-(1-((3-fluoro-5-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-37)

[0413]

[0414] Step 1: Synthesis of tert-butyl ((1-((3-fluoro-5-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (37-1)

[0415] At room temperature, compound Int 4 (200 mg, 0.37 mmol), 21-1 (74 mg, 0.48 mmol), Pd(dppf)Cl2 (27 mg, 0.04 mmol) and potassium carbonate (130 mg, 0.95 mmol) were dissolved in 1,4-dioxane / water (5 / 1 mL) and stirred at 110°C for 4 h under nitrogen. After cooling to room temperature, water (20 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 100 mg of a yellow oily compound with a yield of 47.62% and [M+H] + :570.2.

[0416] Step 2: Synthesis of 1-(1-((3-fluoro-5-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-37)

[0417] At room temperature, compound 37-1 (100 mg, 0.18 mmol) was dissolved in DCM (2 mL), and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. Concentration gave 40 mg of a yellow compound with a yield of 45.17% and a purity of >95%. [M+H] + :470.2.

[0418] 1H NMR: (400MHz, CD3OD) δ8.74 (s, 1H), 8.71 (s, 1H), 8.36 (s, 1H), 8.03 (d, J=9.6Hz, 1H), 7.92 (s, 1H), 7.74 (s, 1H), 7.50-7.45 ( m, 1H), 7.40 (d, J=7.2Hz, 1H), 7.21-7.19 (m, 2H), 7.10 (t, J=9.2Hz, 1H), 6.50 (s, 1H), 4.16 (s, 3H), 4.14 (s, 2H), 2.74 (s, 3H).

[0419] Example 38

[0420] Synthesis of 1-(5-(2-fluorophenyl)-1-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-38)

[0421]

[0422] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl))(methyl)carbamate (38-1)

[0423] At room temperature, compound Int 5 (200 mg, 0.36 mmol), 6-1 (90 mg, 0.43 mmol), and Pd(dppf)Cl2 (8.0 mg, 0.01 mmol) were dissolved in 1,4-dioxane (10 mL). Sodium carbonate (76 mg, 0.72 mmol) and water (2 mL) were added. Under nitrogen protection, the mixture was heated at 105°C overnight. After the reaction was completed, water (20 mL) was added and the mixture was extracted with ethyl acetate (30 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 = 1:2) to obtain 180 mg of the yellow oily compound with a yield of 89.81%. [M+H] + : 499.2.

[0424] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-38)

[0425] Compound 38-1 (180 mg, 0.33 mmol) was dissolved in DCM (3 mL) at room temperature, and then 4 M hydrochloric acid / 1,4-dioxane (5 mL) was added and stirred at room temperature for 2 h. Concentration afforded 148 mg of the compound as a pink solid, which turned gray after a short period. Yield: 92.96%, purity >95%, [M+H] + :455.2.

[0426] 1 H NMR: (400MHz, CD3OD) δ7.96-7.92(m, 1H), 7.84-7.80(m, 1H), 7.80(s, 2H), 7.26 -7.20 (m, 2H), 7.18 (d, J = 8.7Hz, 1H), 7.03-6.95 (m, 2H), 6.80 (d, J = 8.4Hz, 1H), 6.37 (d, J=2.0Hz, 1H), 4.15 (s, 2H), 4.00 (s, 3H), 3.82 (s, 3H), 2.74 (s, 3H).

[0427] Example 39

[0428] Synthesis of 1-(5-(2-fluorophenyl)-1-((2-methoxy-5-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-39)

[0429]

[0430] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((2-methoxy-5-(5-methoxypyridin-3-yl))phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (39-1)

[0431] At room temperature, compound Int 5 (200 mg, 0.36 mmol), 21-1 (66 mg, 0.43 mmol), and Pd(dppf)Cl2 (8.0 mg, 0.01 mmol) were dissolved in 1,4-dioxane (10 mL). Potassium carbonate (100 mg, 0.72 mmol) and water (2 mL) were added. Under nitrogen protection, the mixture was heated at 105°C overnight. After the reaction was completed, water (5 mL) was added and the mixture was extracted with DCM (10 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 = 1:1) to obtain 82 mg of the yellow oily compound with a yield of 39.23%. [M+H] + : 582.1.

[0432] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((2-methoxy-5-(5-methoxypyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-39)

[0433] Compound 39-1 (82 mg, 0.14 mmol) was dissolved in DCM (2 mL) at room temperature, and then 4 M hydrochloric acid / 1,4-dioxane (5 mL) was added and stirred at room temperature for 2 h. Concentration afforded 24 mg of a grayish-black solid compound. Yield: 33.09%, purity >95%, [M+H] + :482.2.

[0434] 1 H NMR: (400MHz, CD3OD) δ8.10 (s, 3H), 7.96 (s, 1H), 7.85 (s, 1H), 7.53 (d, J=9.2 Hz, 2H), 7.39 (d, J=8.2Hz, 1H), 7.24 (s, 1H), 7.11–6.79 (m, 2H), 6.41 (s, 1H), 4.17(s, 2H), 4.13(s, 3H), 3.91(s, 3H), 2.75(s, 3H).

[0435] Example 40

[0436] Synthesis of 1-(1-((3-fluoro-5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-40)

[0437]

[0438] Step 1: Synthesis of tert-butyl ((1-((3-fluoro-5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (40-1)

[0439] At room temperature, compound Int 5 (200 mg, 0.37 mmol), 5-1 (83 mg, 0.55 mmol), Pd(OAc)2 (9 mg, 0.04 mmol) and cesium carbonate (422 mg, 1.29 mmol) were dissolved in toluene (10 mL) and stirred at 110°C overnight under nitrogen. After cooling to room temperature, water (20 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 150 mg of a yellow oily compound with a yield of 69.77%, [M+H] + :574.2.

[0440] Step 2: Synthesis of 1-(1-((3-fluoro-5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-40)

[0441] At room temperature, compound 40-1 (150 mg, 0.26 mmol) was dissolved in DCM (2 mL), and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. Concentration gave 112 mg of a white compound with a yield of 4.21% and a purity of >95%. [M+H] + :475.2.

[0442] 1 H NMR: (400MHz, CD3OD) δ7.77 (s, 1H), 7.51-7.49 (m, 1H), 7.20-7.08 (m, 3H), 6.57 (d, J=12.0Hz, 1H), 6.48 (d, J=7.6Hz, 1H), 6.43 (s, 1H), 6.32 (s, 1H), 4.12 (s, 2H), 3.97-3.94(m, 2H), 3.72-3.67(m, 2H), 3.39-3.37(m, 2H), 3.13-3.11(m, 2H), 3.13-3.11(m, 4H), 2.71(s, 3H).

[0443] Example 41

[0444] Synthesis of 1-(1-((3-(3,4-dimethoxythiophen-2-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-41)

[0445]

[0446] Step 1: Synthesis of tert-butyl ((1-((3-(3,4-dimethoxythiophen-2-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (41-2)

[0447] At room temperature, compound Int1 (500 mg, 0.96 mmol), 41-1 (276 mg, 1.92 mmol), Pd(OAc)2 (22 mg, 0.10 mmol), tricyclohexylphosphine tetrafluoroborate (71 mg, 0.19 mmol), pivalic acid (49 mg, 0.48 mmol), and potassium carbonate (265 mg, 1.95 mmol) were dissolved in toluene (15 mL) and stirred at 110°C under nitrogen for 2 days. After cooling to room temperature, water (30 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 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 250 mg of the compound as a yellow oil with a yield of 44.56%, [M+H] + :587.2.

[0448] Step 2: Synthesis of 1-(1-((3-(3,4-dimethoxythiophen-2-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-41)

[0449] At room temperature, compound 41-2 (250 mg, 0.43 mmol) was dissolved in DCM (2 mL), and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. After concentration, 50 mg of a yellow compound was obtained by reverse phase preparation with a yield of 22.52% and a purity of >95%. [M+H] + :487.1.

[0450] 1 H NMR: (400MHz, CD3OD) δ7.94 (s, 1H), 7.81 (s, 1H), 7.75 (s, 1H), 7.51-7.39 (m, 3H) ,7.15-7.05(m,3H),6.56(s,1H),6.42(s,1H),4.13(s,2H),3.91(s,3H),3.81(s, 3H), 2.73(s, 3H).

[0451] Example 42

[0452] Synthesis of 1-(1-((3-(5,6-dimethoxypyridin-3-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-42)

[0453]

[0454] Step 1: Synthesis of 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (42-2)

[0455] Compound 42-1 (200 mg, 0.92 mmol), 31-4 (350 mg, 1.38 mmol), Pd(dppf)Cl2 in DCM (75.2 mg, 0.09 mmol), and potassium acetate (270 mg, 2.76 mmol) were added to 1,4-dioxane (8 mL) at room temperature. The atmosphere was replaced with nitrogen three times. Under nitrogen protection, the temperature was raised to 90°C and stirred overnight. TLC monitoring (PE / EA = 10:1) showed that the starting material had reacted completely, with new spots formed. The reaction was then proceeded directly to the next step.

[0456] Step 2: Synthesis of tert-butyl ((1-((3-(5,6-dimethoxypyridin-3-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (42-3)

[0457] At room temperature, compound 42-2 (244 mg, 0.92 mmol), Int 1 (401 mg, 0.77 mmol), Pd(dppf)Cl2 (56 mg, 0.077 mmol), and K2CO3 (212.8 mg, 1.54 mmol) were added to 1,4-dioxane (8 mL), and water (4 mL) was added and replaced three times. Under nitrogen protection, the temperature was raised to 95°C and stirred overnight. After the reaction was completed, the reaction system was concentrated under reduced pressure and column chromatography (PE / EA=2:1) ​​gave 300 mg of a yellow oil with a yield of 39.74%, [M+H] + :582.3.

[0458] Step 3: 1-(1-((3-(5,6-dimethoxypyridin-3-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-42)

[0459] Compound 42-3 (300 mg, 0.52 mmol) was dissolved in DCM (5 mL) at room temperature, followed by the addition of 4 M hydrochloric acid / 1,4-dioxane (0.65 mL) and stirring at room temperature for 2 h. After the reaction, DCM (10 mL) and water (5 mL) were added, followed by an aqueous potassium carbonate solution, and the pH was adjusted to approximately 8. The organic phase was separated and extracted with 20 mL of DCM. The combined organic phases were dried and purified by column chromatography (DCM / MeOH = 40:1) to afford 90 mg of a yellow solid with a yield of 36%. [M+H] + :482.2.

[0460] 1 HNMR: (400MHz, CD3OD) δ7.95 (s, 1H), 7.83 (s, 1H), 7.77 (s, 1H), 7.60 (t, J=7.6Hz, 1H), 7.56-7.51 (m, 2H), 7.48-7.43 (m, 1 H), 7.35(s, 1H), 7.16-7.10(m, 2H), 7.08-7.02(m, 1H), 6.40(s, 1H), 4.03(s, 3H), 4.02(s, 2H), 3.95(s, 3H), 2.65(s, 3H).

[0461] Example 43

[0462] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-(methylsulfonyl)pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-43)

[0463]

[0464] Step 1: Synthesis of (5-(methylsulfonyl)pyridin-3-yl)boronic acid ester (43-2)

[0465] Compound 43-1 (200 mg, 0.85 mmol), 31-4 (324 mg, 1.30 mmol), Pd(dppf)Cl2 in DCM (70 mg, 0.09 mmol), and potassium acetate (250 mg, 2.55 mmol) were added to 1,4-dioxane (8 mL) at room temperature. The atmosphere was replaced with nitrogen three times, the temperature was raised to 90°C, and the mixture was stirred overnight. TLC monitoring (PE / EA = 10 / 1) indicated complete reaction of the starting material with the formation of new spots. The reaction was then carried out directly to the next step. [M+H]+: 202.1.

[0466] Step 2: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(5-(methylsulfonyl)pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (43-3)

[0467] At room temperature, compound 43-2 (171 mg, 0.85 mmol), Int 1 (371 mg, 0.71 mmol), Pd(dppf)Cl2 (52 mg, 0.071 mmol), and K2CO3 (196 mg, 1.42 mmol) were added to 1,4-dioxane (8 mL). Water (4 mL) was added and the mixture was replaced with nitrogen three times. The temperature was raised to 110°C and stirred overnight. After the reaction, the reaction system was concentrated under reduced pressure and purified by column chromatography (PE / EA=5:1) to give 280 mg of a yellow oil with a yield of 65.7%. [M+H] + :544.1.

[0468] Step 3: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(5-(methylsulfonyl)pyridin-3-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-43)

[0469] Compound 43-3 (230 mg, 0.38 mmol) was dissolved in DCM (5 mL) at room temperature, followed by the addition of 4 M hydrochloric acid / 1,4-dioxane (1.0 mL) and stirring at room temperature for 2 h. After the reaction, DCM (10 mL) and water (5 mL) were added, followed by sodium bicarbonate aqueous solution, and the pH was adjusted to approximately 8. The organic phase was separated, and the aqueous phase was extracted twice with 20 mL of DCM. The combined organic phases were spin-dried and purified by thin-layer chromatography to afford 130 mg of a yellow solid with a yield of 68.4% ([M+H] + :500.08.

[0470] 1 H NMR: (400MHz, Chloroform-d) δ9.18 (s, 1H), 8.96 (s, 1H), 8.26 (s, 1H), 7.81-7.78 (m, 1H), 7.62-7.55 (m, 3H), 7.43 (s, 1H), 7.41-7.35 (m, 1H), 7.22 (d, J=7.6, 1H), 7.14 (t, J=7.6Hz, 1H), 7.01 (t, J=8.8Hz, 1H), 6.27 (s, 1H), 3.65 (s, 2H), 3.19 (s, 3H), 2.46 (s, 3H).

[0471] Example 44

[0472] Synthesis of (S)-1-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)-N,N-dimethylpyrrolidine-2-carboxamide (III-44)

[0473]

[0474] Step 1: Synthesis of tert-butyl (S)-((1-((3-(2-(dimethylcarbamoyl)pyrrolidin-1-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (44-2)

[0475] Compound Int 1 (200 mg, 0.38 mmol) 44-1 (82 mg, 0.58 mmol) Pd(OAc) 2 (10 mg, 0.04 mmol) and cesium carbonate (311 mg, 0.95 mmol) were dissolved in toluene (10 mL) and stirred at 120 ° C overnight. After the reaction was completed, it was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (PE / EA = 11:1) gave 100 mg of a yellow oily compound with a yield of 44.85%, [M+H] + :585.2.

[0476] Step 2: Synthesis of (S)-1-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)-N,N-dimethylpyrrolidine-2-carboxamide (III-44)

[0477] At room temperature, compound 44-2 (100 mg, 0.17 mmol) was dissolved in DCM (2 mL) solution, and then 4 M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. The pH of the solution was adjusted to 7, extracted with DCM, and concentrated to obtain 38 mg of a brown compound with a yield of 46.34% ([M+H] + :485.2.

[0478] 1H NMR: (400MHz, DMSO-d6) δ9.02 (br, 1H), 7.72 (s, 1H), 7.53-7.51 (m, 1H), 7.29-7.20 (m, 3H), 7.07 (t, J=8.0Hz, 1H), 6.68 (d, J=7.6Hz, 1H), 6.57 (d, J=8.0Hz, 1H), 6.48 (s, 1H), 6.31 (s, 1H), 4.61 (d, J=9.2Hz, 1H), 3.98 (s, 2H), 3.29-3.23 (m, 2H), 3. 07(s, 3H), 2.79(s, 3H), 2.49(s, 3H), 2.32-2.27(m, 1H), 2.00-1.89(m, 3H).

[0479] Example 45

[0480] Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylamine hydrochloride (III-45)

[0481]

[0482] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl))(methyl)carbamate (45-2)

[0483] Compound 32-2 (150 mg, 0.29 mmol), 45-1 (82 mg, 0.59 mmol) and potassium carbonate (122 mg, 0.88 mmol) were dissolved in DMF (5 mL) and stirred at room temperature overnight. After the reaction was complete, ethyl acetate (20 mL) was added and the mixture was washed with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography (PE / EA = 2:1) to obtain 120 mg of a yellow oily compound with a yield of 71.85%, [M+H] + :569.2.

[0484] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylamine hydrochloride (III-45)

[0485] At room temperature, compound 45-2 (120 mg, 0.21 mmol) was dissolved in 1,4-dioxane (2 mL) solution, and then 4M hydrochloric acid / 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. The reaction solution was concentrated to obtain 92 mg of a white solid compound with a yield of 86.79% (M+H). + :469.2.

[0486] 1 H NMR (400MHz, CD3OD) δ8.04 (s, 1H), 7.86 (d, J = 8.0Hz, 1H), 7.82 (s, 2H), 7.51-7.46 (m,3H),7.38(d,J=7.6Hz,1H),7.18-7.04(m,3H),6.42(s,1H),4.37(t,J=4.8Hz,2H),4.11(s, 2H), 3.81 (t, J = 4.8Hz, 2H), 3.38 (s, 3H), 2.71 (s, 3H).

[0487] Example 46

[0488] Synthesis of 1-(1-((3-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-46)

[0489]

[0490] Step 1: Synthesis of tert-butyl((1-((3-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamic acid (46-2)

[0491] In a 50 ml single-necked flask, compound Int 1 (300 mg, 0.573 mmol), 46-1 (225 mg, 0.85 mmol), Pd(OAc)2 (13 mg, 0.057 mmol), PCy3.HBF4 (42 mg, 0.115 mmol), PivOH (30 mg, 0.287 mmol), and K2CO3 (159 mg, 1.146 mmol) were added. Toluene (10 mL) was added for dissolution, and the mixture was reacted at 110°C under nitrogen overnight. After completion of the reaction, water (20 mL) was added, and the mixture was extracted with ethyl acetate (40 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (hex / EA = 1:1) to obtain 92 mg of a yellow oil with a yield of 27.46%. [M-100+H] + :485.13.

[0492] Step 2: Synthesis of 1-(1-((3-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-46)

[0493] Compound 46-2 (92 mg, 0.157 mmol) was dissolved in dichloromethane (2 mL) at room temperature, and then 4M hydrochloric acid / 1,4-dioxane (1 mL) was added and stirred at room temperature for 2 h. The solution was concentrated to obtain 86 mg of a dark gray solid compound. Yield: 95.68%, [M+H] + :483.0.

[0494] 1 H NMR (400MHz, CD3OD) δ7.97(d,J=8.4Hz,1H),7.75(s,1H),7.61(s,1H),7.47(d,J=8.0H z,1H),7.40–7.28(m,3H),7.10–7.06(m,2H),6.99(t,J=8.8Hz,1H),6.38(,1H),4.35– 4.08(m,4H),4.08(s,2H),2.68(s,3H).

[0495] Example 47

[0496] Synthesis of 1-(5-(2-fluorophenyl)-1-((3'-methoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-47)

[0497]

[0498] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3'-methoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (47-2)

[0499] At room temperature, compound Int 1 (200 mg, 0.38 mmol), compound 47-1 (69.7 mg, 0.46 mmol), potassium carbonate (105 mg, 0.76 mmol), and Pd(dppf)Cl2 (27.8 mg, 0.04 mmol) were added to 1,4-dioxane (8 mL). Water (2 mL) was added, the atmosphere was replaced with nitrogen three times, and the temperature was raised to 100°C and stirred overnight. After the reaction was completed, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and purified by column chromatography (PE / EA = 10:1) to obtain 200 mg of the compound as a pink oil with a yield of 95.24%, [M+H] + :451.28.

[0500] Step 2: Synthesis of 1-(5-(2-fluorophenyl)-1-((3'-methoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-47)

[0501] At room temperature, compound 47-2 (200 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL), and then 4M hydrochloric acid / 1,4-dioxane (1.5 mL) was added and stirred at room temperature overnight. The mixture was concentrated under reduced pressure to obtain 156 mg of a purple solid with a yield of 89.14 [M+H] + :451.21.

[0502] 1 H NMR (400MHz, CD3OD) δ7.94(d,J=7.6Hz,1H),7.82(d,J=2.0Hz,1H),7.59(d,J= 7.6Hz,1H),7.57-7.52(m,2H),7.45-7.39(m,2H),7.14-7.00(m,6H),6.41(d,J=2.0Hz,1H),4.11(s,2H),3.89(s,3H),2.71(s,3H).

[0503] Example 48

[0504] Synthesis of 1-(1-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-48)

[0505]

[0506] Step 1: Synthesis of tert-butyl ((1-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (48-2)

[0507] At room temperature, compound Int 1 (200 mg, 0.38 mmol), compound 48-1 (77.5 mg, 0.46 mmol), potassium carbonate (105 mg, 0.76 mmol), and Pd(dppf)Cl2 (27.8 mg, 0.04 mmol) were added to 1,4-dioxane (8 mL), and water (2 mL) was added. The atmosphere was replaced with nitrogen three times. Under nitrogen protection, the temperature was raised to 100°C and stirred overnight. After the reaction was completed, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and purified by column chromatography (PE / EA = 10:1) to obtain 200 mg of the yellow oily compound with a yield of 92.56%, [M+H] + :469.24.

[0508] Step 2: Synthesis of 1-(1-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-48)

[0509] At room temperature, compound 48-2 (200 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL), and then 4M hydrochloric acid / 1,4-dioxane (2.0 mL) was added and stirred at room temperature overnight. The mixture was concentrated under reduced pressure to obtain 160 mg of a purple solid with a yield of 90.52% (M+H). + :469.33.

[0510] 1H NMR (400MHz, CD3OD) δ7.95(d,J=7.6Hz,1H),7.83(d,J=2.0Hz,1H),7.60(t,J=7.6 Hz,1H),7.56(d,J=7.6Hz,1H),7.53(t,J=2.0Hz,1H),7.47-7.41(m,1H),7.13(d,J=5.6Hz,2H), 7.05(t,J=8.8Hz,1H),6.88(s,1H),6.83(m,2H),6.42(d,J=2.0Hz,1H),4.12(s,2H),3.89(s,3H), 2.72(s,3H).

[0511] Example 49

[0512] Synthesis of 1-(1-((3',5'-dimethoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-49)

[0513]

[0514] Step 1: Synthesis of methyl tert-butyl ((1-((3',5'-dimethoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-5-(2-fluoro-o-phenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (49-2)

[0515] In a 50 ml single-necked flask, compound Int 1 (200 mg, 0.38 mmol), 49-1 (91 mg, 0.50 mmol), P d(dppf)Cl2 (14 mg, 0.02 mmol), and K2CO3 (106 mg, 0.76 mmol) were added. 1,4-Dioxane (10 mL) and H2O (2 mL) were added for dissolution. The mixture was refluxed at 105°C under nitrogen overnight. After completion of the reaction, water (20 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (hex / EA = 3:1) to afford 125 mg of a light pink oil with a yield of 56.35%. [M-100+H] + :481.4.

[0516] Step 2: Synthesis of 1-(1-((3',5'-dimethoxy-[1,1'-biphenyl]-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride (III-49)

[0517] Compound 49-2 (125 mg, 0.22 mmol) was dissolved in dichloromethane (2 mL) at room temperature, followed by addition of 4M hydrochloric acid / 1,4-dioxane (5 mL) and stirring at room temperature for 2 h. The mixture was concentrated, a small amount of n-hexane was added, and the mixture was dried to afford 112 mg of a yellow-white solid. Yield: 100%, [M+H] + :481.27.

[0518] 1 H NMR (400MHz, CD3OD) δ7.90(d,J=7.6Hz,1H),7.81(d,J=2.0Hz,1H),7.587.49(m, 3H),7.41(d,J=8.4Hz,1H),7.13–7.06(m,2H),7.02(d,J=9.6Hz,1H),6.60(d,J=2.4Hz,2H), 6.56(t,J=2.4Hz,1H),6.41(d,J=1.6Hz,1H),4.09(s,2H),3.84(s,6H),2.69(s,3H).

[0519] Example 50

[0520] Synthesis of 1-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)azetidin-2-one hydrochloride (III-50)

[0521]

[0522] Step 1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-((3-(2-oxazetidin-1-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (50-2)

[0523] Compound Int 1 (100 mg, 0.19 mmol), 50-1 (71 mg, 0.29 mmol), xantphos (28 mg, 0.05 mmol), Pd(OAc)2 (43 mg, 0.19 mmol), and Cs2CO3 (125 mg, 0.38 mmol) were added to a 50 ml single-necked flask. Toluene (6 mL) was added for dissolution, and the mixture was reacted at 110°C overnight under nitrogen. After completion of the reaction, the mixture was washed with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (hex / EA = 2:1) to obtain 50 mg of a light yellow oil with a yield of 50.97%. [M-100+H] + :414.26.

[0524] Step 2: Synthesis of 1-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenyl)azetidin-2-one hydrochloride (III-50)

[0525] Compound 50-2 (50 mg, 0.10 mmol) was dissolved in dichloromethane (1 mL) at room temperature, followed by addition of 4M hydrochloric acid / 1,4-dioxane (3 mL) and stirring at room temperature for 3 h. The mixture was concentrated, a small amount of n-hexane was added, and the mixture was dried to afford 30 mg of a brown solid. Yield: 68.74% [M+H] + :414.25.

[0526] 1 H NMR (400MHz, CD3OD) δ7.77(d,J=2.0Hz,1H),7.55–7.52(m,1H),7.47(d,J=5.2Hz, 2H),7.20–7.14(m,2H),7.12–7.04(m,3H),6.40(d,J=2.0Hz,1H),4.11(s,2H),3.65(t,J=4.8Hz, 2H),3.16(t,J=4.8Hz,2H),2.71(s,3H).

[0527] Example 51

[0528] Synthesis of 1-(1-((3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-51)

[0529]

[0530] Step 1: Synthesis of tert-butyl ((1-((3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate (51-2)

[0531] At room temperature, compound Int 1 (200 mg, 0.38 mmol), compound 51-1 (61 mg, 0.42 mmol), Pd(OAc)2 (8.5 mg, 0.04 mmol), xantphos (26.4 mg, 0.05 mmol), and cesium carbonate (248 mg, 0.76 mmol) were added to toluene (5 mL). The atmosphere was purged with nitrogen three times, the temperature was raised to 100°C, and 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 = 10:1) to obtain 150 mg of the compound as an oil with a yield of 67.38% ([M+H] + : 529.19.

[0532] Step 2: Synthesis of 1-(1-((3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-51)

[0533] Compound 51-2 (150 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL) at room temperature, and trifluoroacetic acid (1.5 mL) was added. The mixture was stirred at room temperature for 2 h, and water (5 mL) was added. Aqueous potassium carbonate solution was added to adjust the pH to 8. The organic phase was separated and the aqueous phase was extracted once with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to obtain a filtrate. The filtrate was concentrated under reduced pressure at 45°C to obtain 100 mg of a yellow oil with a yield of 79.21%. [M+H] + :48 6.27.

[0534] 1 H NMR (400MHz, CD3OD) δ7.51 (s, 1H), 7.45 (t, J = 7.2Hz, 1H), 7.32-7.26 (m, 1H), 7.19 (d,J=8.4Hz,1H),7.16(d,J=7.4Hz,1H),7.13-7.06(m,2H),6.89(d,J=7.6Hz,1H),6.82(t, J=2.4Hz,1H),6.30(d,J=2.0Hz,1H),4.01(s,4H),3.68(s,2H),3.30-3.26(m,4H),2.43(s,3H),1.79-1.70(m,4H).

[0535] Example 52

[0536] Synthesis of 1-(1-((3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-52)

[0537]

[0538] Step 1: Synthesis of (3-bromophenylsulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (52-1)

[0539] In an ice bath, compound Int 1-1 (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 Int 3-6 (3.3 g, 12.69 mmol) was added to the reaction system 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 (30 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 1), 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.

[0540] Step 2: Synthesis of 1-((3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (52-3)

[0541] Compound 52-1 (300 mg, 0.74 mmol), 52-2 (235 mg, 0.88 mmol), K2CO3 (203 mg, 1.48 mmol), and Pd(dppf)Cl2 (27 mg, 0.04 mmol) were added to a 50 mL single-necked bottle, dissolved in 1,4-dioxane (15 mL) and water (3 mL), and heated and stirred at 85°C under nitrogen protection to react overnight. After the reaction, the mixture was cooled to room temperature, washed with water (20 mL), and extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. 322 mg of a light yellow oil was obtained by silica gel column chromatography (hex / EA = 2:1) with a yield of 93.71%. [M+H] + :46 8.20.

[0542] Step 3: Synthesis of 1-(1-((3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-52)

[0543] In a 50 mL single-necked flask, compound 52-3 (135 mg, 0.29 mmol) and methylamine (120 mg, 1.16 mmol, 30% wt) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 30 min. Sodium triacetoxyborohydride (245 mg, 1.16 mmol) was added under an ice bath, and the mixture was allowed to warm to room temperature under nitrogen protection overnight. After completion, the reaction was quenched with 10 mL of water and extracted with DCM (30 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. TLC analysis (DCM / MeOH = 8:1) yielded 88 mg of a pale purple solid. Yield: 63.10% [M+H] + :483.26.

[0544] 1 H NMR (400MHz, DMSO) δ7.75(d,J=8.0Hz,1H),7.60(s,1H),7.55-7.45(m,2H),7.40–7.35(m,1H),7.27(t,J=2.0Hz,1H),7.23–7.17(m,2H ),7.10-7.02(m,1H),6.40(s,1H),6.01(s,1H),3.94(s,4H),3.69(s,2H),2.45–2.41(m,2H),2.40–2.37(m,2H),2.33(s,3H),1.81(t, J=6.4Hz,2H).

[0545] Example 53

[0546] Synthesis of 1-(1-((3-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-53)

[0547]

[0548] Step 1: Synthesis of 1-((3-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (53-1)

[0549] Compound 52-3 (60 mg, 0.13 mmol) was dissolved in ethyl acetate (5 mL) in a 25 mL single-necked flask. Pd / C (15 mg, 10% wt) was added and stirred at room temperature under a hydrogen atmosphere overnight. After completion of the reaction, the mixture was filtered, the filter cake was washed with EA several times, and the organic phase was dried to give 60 mg of a light yellow oil. Yield: 99.18%, [M+H] + :470.26.

[0550] Step 2: Synthesis of 1-(1-((3-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine (III-53)

[0551] Compound 53-1 (60 mg, 0.13 mmol) and methylamine (53 mg, 0.52 mmol, 30% wt) were added to a 50 mL single-necked flask and dissolved in DCM (5 mL). The mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (109 mg, 0.52 mmol) and a drop of glacial acetic acid were added under ice-cooling conditions, and the mixture was allowed to warm to room temperature for 6 h. After the reaction, 10 mL of water was added to quench the reaction, and the mixture was extracted with DCM (20 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. TLC analysis (DCM / MeOH = 8:1) yielded 35 mg of an off-white solid with a yield of 56.45%. [M+H] + :485.23.

[0552] 1 H NMR(400MHz, DMSO-d6)δ7.56(d,J=7.6Hz,1H),7.51–7.44(m,3H),7.36(d,J=7.8 Hz,1H),7.23–7.18(m,2H),7.14(d,J=2.0Hz,1H),7.10-7.05(m,1H),6.33(d,J=2.0Hz,1H), 4.01-3.95(m,4H),3.53(s,2H),2.62-2.54(m,1H),2.24(s,3H),1.77–1.67(m,4H),1.63–1.51(m, 4H).

[0553] H + / K + -ATPase biological evaluation

[0554] The following in vitro screening test is used to determine the effects of the compounds of the present invention on H + / K + -Inhibition of ATPase activity.

[0555] Experimental materials and instruments:

[0556] ATP, malachite green, valinomycin, ammonium molybdate

[0557] No K + Buffer: 50 mM Tris-HCl pH 6.5, 5 mM magnesium chloride, 10 μM valinomycin

[0558] Contains K + Buffer: 50 mM Tris-HCl pH 6.5, 5 mM magnesium chloride, 10 μM valinomycin, 20 mM KCl

[0559] MLG color development solution: 0.1% w / v malachite green, 1.5% w / v ammonium molybdate, 0.2% v / v Tween-20 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 3M NaCl solution respectively, and then the surface moisture is removed with filter paper. Pre-cooled homogenization buffer (4ml / g tissue) is added and homogenized 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 and centrifuged at 20000g for 30min. Then the supernatant is transferred to a clean centrifuge tube and further centrifuged at 100000g for 90min to collect the precipitate; the precipitate is suspended with the homogenate and evenly dispersed. The protein concentration is measured by Bradford method and the concentration is adjusted to 10mg / ml; 7.5% Ficoll layering solution is added in equal proportions, and after centrifugation at 100000g for 60min, the middle layer (H + / K + Collect the ATPase-enriched gastric membranes in a clean centrifuge tube, dilute 4-5 times with the homogenate, and centrifuge at 100,000 g for 90 min to collect the precipitate. Resuspend the precipitate in the homogenate and homogenize evenly. Measure the protein concentration using the Bradford assay and adjust it to 22.5 mg / ml. Freeze at -80°C until ready for use.

[0560] Experimental process:

[0561] 45 μL buffer (containing K + 5 μL of gastric mucosal microsomes (H + / K + -ATPase), then add 5 μL of compound solution, and then add 5 μL of 5 mM ATP to start the reaction. Pre-reaction at 37°C for 30 minutes. Add 15 μL of malachite green solution to terminate the reaction, equilibrate at room temperature for 20 minutes, and read the absorbance at 620 nm.

[0562] At the same time, a reaction with the same volume but without potassium chloride was performed as background and subtracted when calculating enzyme activity.

[0563] Compound IC 50 The inhibition rate of the compound of the present invention on H + / K + -ATPase has obvious inhibitory activity, IC 50 The range is 20 to 100 nM, preferably 20 to 50 nM. Control group 1 is selected from Vonoprazan, the preparation method of which is based on patent CN101300229A; Control group 2 is selected from a compound having the following structural formula.

[0564]

[0565] IC of some compounds of the present invention 50 Value (H + / K + -ATPase) are shown in Table 1 below;

[0566] Table 1:

[0567]

[0568]

[0569] The compounds of the present invention are effective for H + / K + -ATPase has obvious inhibitory activity.

[0570] In vitro cytotoxicity assay

[0571] HepG2 cells, a human hepatocellular carcinoma cell line, were cultured and passaged in Dulbecco's Modified Eagle's Medium (DMEM; Invitrogen) at 5% CO₂ at 37°C. Cells in the logarithmic growth phase were harvested, counted, and resuspended in complete medium. The cell concentration was adjusted to the appropriate concentration (determined based on the results of a cell density optimization experiment) and seeded into a 96-well plate. 75 μL / well of the cell suspension was added according to the platemap below. Test compounds were diluted in culture medium to the desired concentration and added to the cells according to the platemap at 25 μL / well. Test compounds were diluted starting at 100 μM and serially diluted fourfold, for a total of nine concentrations, with two replicates. Cells were incubated for 24 hours in a 37°C, 100% relative humidity, 5% CO₂ incubator. Cells were then added at 50 μL / well of CellTiter Glo RT and incubated in the dark for 30 minutes. After gentle shaking, the cells were assayed using Envision, and the inhibition rate was calculated.

[0572] 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.

[0573] As: OA of sample (cells + CTG + test compound),

[0574] Ac: OA of normal growth cell control (cells+CTG+DMSO).

[0575] IC was calculated using the software Graphpad Prism 6 using 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.

[0576] Some compounds of the present invention have low toxicity to cell growth, as shown in Table 2 below;

[0577] Table 2:

[0578] Compound number <![CDATA[IC 50 ]]> III-5 +++ III-6 +++ III-9 +++ III-20 +++ III-41 +++ Control group 1 +++

[0579] Note: IC 50 >20μM is +++, 20μM>IC 50 >10μM is ++, 10μM>IC 50 is +.

[0580] Liver microparticle stability test

[0581] Prepare liver microsomes from the desired species (e.g., mouse, rat, dog, monkey, or human). Prepare 10 mM 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 an NADPH regeneration system composed 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.

[0582] The buffer used in this study was 100 mM potassium phosphate buffer. A mixture containing 0.2 mg / mL liver microsomal protein and 1 μM test article / positive control was incubated in 100 mM potassium phosphate buffer.

[0583] 80 μL of each incubation solution was added to 300 μL of quenching reagent to precipitate proteins, preparing a 0-minute sample. After vortexing, 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, and 0.6 U / mL glucose-6-phosphate dehydrogenase. The mixture was placed in a 37°C water bath and gently shaken. At 0, 5, 10, 30, and 60 minutes, 100 μL of the mixture was aliquoted onto a 96-well plate containing 300 μL of quenching reagent to precipitate proteins. The plate was centrifuged (5000 × g, 10 minutes). 80 μL of the supernatant was added to a 96-well assay plate pre-filled with 160 μL of ultrapure water and analyzed by LC-MS / MS. Data processing to obtain the elimination half-life (T 1 / 2 , T 1 / 2 =0.693 / K) and in vitro clearance (Cl int ).

[0584] The stability results of some compounds of the present invention in SD rat liver microsomes are shown in Table 3 below;

[0585] Table 3:

[0586]

[0587] The experiment found that the compound of the present invention has a T 1 / 2 (min)>80min, preferably T 1 / 2 (min)>100min, with good liver microparticle metabolic stability.

[0588] Pharmacokinetic experiments

[0589] 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) and blood is collected at fixed time points. Immediately after blood sample collection, the test tube is gently inverted at least 5 times to ensure sufficient mixing and then placed 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. High-concentration samples are diluted with blank plasma for measurement. 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 the pharmacokinetic parameters using a validated pharmacokinetic computer program. The experiment found that the compounds of the present invention have good pharmacokinetic properties.

[0590] After oral administration of the compounds listed in Table 4 (equimolar doses in each group, with the vehicle consisting of 5% DMSO + 10% Solutol (HS-15) + 85% saline, 3 rats per group), blood samples were collected at fixed time points for analysis. The pharmacokinetic parameters of the free molecules in rat plasma for some of the compounds of this invention are shown in Table 4.

[0591] Table 4:

[0592]

[0593] The experiment found that the AUC of the prototype free molecule of the compound of the present invention in rat plasma increased by more than 50% compared with the AUC of the prototype free molecule in the plasma of the control group, and the compound of the present invention has good pharmacokinetic properties.

[0594] Male beagle dogs were orally administered the compounds listed in Table 5 (each group was administered equimolar doses in a vehicle consisting of 5% DMSO + 10% Solutol (HS-15) + 85% saline, with 3 animals per group). Blood samples were collected at fixed time points for analysis. The pharmacokinetic parameters of some compounds of the present invention as free molecules in beagle dog plasma are shown in Table 5.

[0595] Table 5:

[0596]

[0597] The experiment found that the AUC of the prototype free molecule of the compound of the present invention in beagle dog plasma increased by more than 20% compared with the AUC of the prototype free molecule in the plasma of the control group, the half-life was significantly prolonged, and the compound had good pharmacokinetic properties.

[0598] Acute toxicity test

[0599] The compound was administered intravenously once (solvent 5% DMSO + 10% Solutol (HS-15) + 85% saline) to SD rats (4-6 dose groups were set for each compound, 10 rats per dose group, half of which were female). Clinical observation was performed after administration. Clinical observation was conducted twice on the first day and once a day starting from the second day for 14 consecutive days. The observation included behavioral observation, autonomic activity and neurological behavior, and death, etc., to obtain the maximum tolerated dose (MTD value) and median lethal dose (LD50) of the compound. 50 The experimental results are shown in Table 6 below;

[0600] Table 6:

[0601] serial number MTD value (mg / kg) <![CDATA[LD 50 Value (mg / kg)]]> Control group 1 3.75 21.88 III-20 27.31 44.23

[0602] The experiment found that the MTD value and LD value of the compound of the present invention in rats after single intravenous administration 50 The values ​​were significantly higher than those in the control group, the MTD value increased by 7 times, and the LD 50 The value is increased by 2 times, which has good security.

[0603] Study on the role of hERG potassium channels

[0604] Test system

[0605] Cells: Chinese hamster ovary (CHO) cell line, CHO-hERG cells were used in this experiment.

[0606] Cell culture medium and culture conditions: The complete culture medium is F12 medium supplemented with 10% fetal bovine serum, 1% Selective antibiotic (G418), 89 μg / mL hygromycin B (HB). Recovery medium consisted of F12 medium supplemented with 10% fetal bovine serum. CHO-hERG cells were grown in a 37°C (±2°C) incubator with 5% CO2 (4% to 8%) and high humidity. Cells were revived in recovery medium and passaged in complete medium. Cells used for patch-clamp experiments were replaced with recovery medium at the final passage.

[0607] Extracellular and intracellular fluid components:

[0608] Reagents External solution (mM) Internal fluid (mM) CaCl2 2 5.37 MgCl2 1 1.75 KCl 4 120 NaCl 145 - Glucose 10 - HEPES 10 10 EGTA - 5 Na2ATP - 4 pH 7.3-7.4 7.2-7.3

[0609] Test methods

[0610] (1) Collect CHO-hERG cells in the exponential growth phase and resuspend them in ECS for later use.

[0611] (2) Manual patch clamp test

[0612] hERG currents were recorded using the whole-cell patch-clamp technique at room temperature. The output signal from the patch-clamp amplifier was converted to digital-to-analog and low-pass filtered at 2.9 kHz. Data were acquired using Patchmaster Pro software.

[0613] Cells are seeded in a cell recording chamber and placed on the stage of an inverted microscope. One cell in the recording chamber is randomly selected for testing. The perfusion system is fixed to the stage of the inverted microscope and the cells are continuously perfused with ECS.

[0614] Manual patch-clamp recording microelectrodes were prepared using glass capillaries filled with intracellular solution. On the day of the patch-clamp experiment, electrodes were prepared using borosilicate glass tubes (BF150-117-10, SUTTER INSTRUMENT USA). After filling with ICS, the resistance of the electrodes was between 2 and 5 MΩ.

[0615] The clamping voltage is -80mV. The first step is to depolarize to +60mV and maintain it 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 returned to the clamping voltage (-80mV). During the experiment, this command voltage program is repeated every 15s. The command voltage program for manual patch clamp hERG current test is as follows Figure 1 shown.

[0616] At the beginning of the recording phase of perfusion of the vehicle control working solution, monitor the tail current peak until more than three 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 flushed with the vehicle control working solution until the hERG current returns to more than 80% of the size before the drug was added. The standard deviation of the inhibition rate of each recorded cell at the same concentration shall not exceed 15%.

[0617] The positive control, cisapride, was tested at a concentration of 0.1 μM in duplicate. According to scientific literature, 0.1 μM cisapride inhibits hERG currents by more than 50% (Milnes, JT, et al.).

[0618] (3) Acceptance criteria for manual patch clamp data

[0619] Sealing criteria: After whole-cell formation, applying a clamping voltage (-80mV) allows recording of cell membrane parameters (Cm, Rm, and Ra). A good whole-cell recording should meet the following criteria: path resistance (Rs) less than 10MΩ; membrane resistance (Rm) greater than 500MΩ; and membrane capacitance (Cm) less than 100pF.

[0620] Current magnitude: The peak current amplitude before the test article / positive control is between 400pA and 5000pA. Otherwise, the cell should be discarded.

[0621] Leakage Current: At a clamping 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.

[0622] Data Analysis

[0623] 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%.

[0624] For each concentration, all the cell inhibition percentages were recorded and averaged, and the IC 50 The values ​​were obtained from the concentration-effect curves by the Hill fitting method.

[0625] Test results

[0626] The results of the inhibition of hERG current by some compounds of the present invention are shown in Table 7 below;

[0627] Table 7:

[0628] serial number <![CDATA[hERGIC 50 ]]> III-5 +++ III-9 + III-14 + III-15 +++ III-20 ++ III-21 +++ III-22 ++ III-47 +++ Control group 1 +

[0629] Note: IC 50 >20μM is +++, 20μM>IC 50 >10μM is ++, 10μM>IC 50 >1μM is considered positive.

[0630] Experiments have found that the compounds of the present invention have a higher hERG IC 50 The value indicates that the compound of the present invention has a low risk of cardiotoxicity.

[0631] 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, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

[0632] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A pyrrolesulfonyl derivative, its tautomer 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, its tautomer and pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier and / or excipient.

3. The pyrrole sulfonyl derivatives, their tautomers and pharmaceutically acceptable salts according to claim 1 or the pharmaceutical composition according to claim 2 in the preparation of gastric acid secretion inhibitors, H + / K + - Use as an ATPase inhibitor or potassium ion competitive acid blocker.

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

5. Use of the pyrrole sulfonyl derivative, its tautomer and pharmaceutically acceptable salt thereof according to claim 1 or the pharmaceutical composition according to claim 2 in the preparation of a medicament for inhibiting upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress.

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